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Sample records for heterozygote

  1. Cystic fibrosis Delta F508 heterozygotes, smoking, and reproduction

    Dahl, Morten; Tybjaerg-Hansen, A; Wittrup, H H

    1998-01-01

    Cystic fibrosis is the most common fatal autosomal recessive disease affecting Caucasian populations. It remains a puzzle how this disease is maintained at such a remarkably high incidence, however, it could be due to a reproductive advantage in cystic fibrosis heterozygotes. We tested this hypot......Cystic fibrosis is the most common fatal autosomal recessive disease affecting Caucasian populations. It remains a puzzle how this disease is maintained at such a remarkably high incidence, however, it could be due to a reproductive advantage in cystic fibrosis heterozygotes. We tested.......001). In conclusion, overall these results do not support a reproductive advantage for cystic fibrosis DeltaF508 heterozygotes. However, the data cannot totally exclude the possibility that nonsmoking DeltaF508 heterozygotes experience a reproductive advantage while smoking DeltaF508 heterozygotes experience...... the opposite, a reproductive disadvantage. Accordingly, the data suggest a previously undocumented role of smoking on fecundity among cystic fibrosis heterozygotes....

  2. Cystic fibrosis heterozygotes do not have increased platelet activation

    Tarnow, Inge; Michelson, Alan D.; Frelinger III, Andrew L.

    2007-01-01

    Introduction: We have previously demonstrated platelet hyperreactivity in cystic fibrosis (CF) patients. Carriers of one CF m utation (heterozygotes) have been shown to have abnormalities related to the presence of only one-half the normal amount of CF transmembrane conductance regulator protein...

  3. Oxidative stress and antioxidant status in beta-thalassemia heterozygotes

    Luciana de Souza Ondei

    2013-01-01

    Full Text Available Background: Several studies have evaluated the oxidant and antioxidant status of thalassemia patients but most focused mainly on the severe and intermediate states of the disease. Moreover, the oxidative status has not been evaluated for the different beta-thalassemia mutations. Objective: To evaluate lipid peroxidation and Trolox equivalent antioxidant capacity in relation to serum iron and ferritin in beta thalassemia resulting from two different mutations (CD39 and IVS-I-110 compared to individuals without beta-thalassemia. Methods: One hundred and thirty subjects were studied, including 49 who were heterozygous for beta-thalassemia and 81 controls. Blood samples were subjected to screening tests for hemoglobin. Allele-specific polymerase chain reaction was used to confirm mutations for beta-thalassemia, an analysis of thiobarbituric acid reactive species was used to determine lipid peroxidation, and Trolox equivalent antioxidant capacity evaluations were performed. The heterozygous beta-thalassemia group was also evaluated for serum iron and ferritin status. Results: Thiobarbituric acid reactive species (486.24 ± 119.64 ng/mL and Trolox equivalent antioxidant capacity values (2.23 ± 0.11 mM/L were higher in beta-thalassemia heterozygotes compared to controls (260.86 ± 92.40 ng/mL and 2.12 ± 0.10 mM/L, respectively; p-value < 0.01. Increased thiobarbituric acid reactive species values were observed in subjects with the CD39 mutation compared with those with the IVS-I-110 mutation (529.94 ± 115.60 ng/mL and 453.39 ± 121.10 ng/mL, respectively; p-value = 0.04. However, average Trolox equivalent antioxidant capacity values were similar for both mutations (2.20 ± 0.08 mM/L and 2.23 ± 0.12 mM/L, respectively; p-value = 0.39. There was no influence of serum iron and ferritin levels on thiobarbituric acid reactive species and Trolox equivalent antioxidant capacity values. Conclusion: This study shows an increase of oxidative stress and

  4. Heterozygote Advantage in a Finite Population: Black Color in Wolves.

    Hedrick, Philip W; Stahler, Daniel R; Dekker, Dick

    2014-01-01

    There is a striking color polymorphism for wolves in the Yellowstone National Park where approximately half the wolves are black. The genetic basis for this polymorphism is known, and fitnesses of the genotypes are estimated. These estimates suggest that there is strong heterozygote advantage but substantial asymmetry in the fitness differences of the 2 homozygotes. Theoretically, such fitnesses in a finite population are thought to reduce genetic variation at least as fast as if there were no selection at all. Because the color polymorphism has remained at about the same frequency for 17 years, about 4 generations, we investigated whether this was consistent with the theoretical predictions. Counter to this general expectation of loss, given the initial frequency of black wolves, the theoretical expectation in this case was found to be that the frequency would only decline slowly over time. For example, if the effective population size is 20, then the expected black allele frequency after 4 generations would be 0.191, somewhat less than the observed value of 0.237. However, nearly 30% of the time the expected frequency is 0.25 or greater, consistent with the contemporary observed frequency. In other words and in contrast to general theoretical predictions, because of the short period of time in evolutionary terms and the relatively weak selection at low frequencies, the observed variation and the predicted theoretical variation are not inconsistent. © The American Genetic Association 2014. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  5. Breast cancer risk in ataxia telangiectasia (AT) heterozygotes: haplotype study in French AT families

    Janin, N; Andrieu, N; Ossian, K; Laugé, A; Croquette, M-F; Griscelli, C; Debré, M; Bressac-de-Paillerets, B; Aurias, A; Stoppa-Lyonnet, D

    1999-01-01

    Epidemiological studies in ataxia telangiectasia (AT) families have suggested that AT heterozygotes could have an increased cancer risk, especially breast cancer (BC) in women. It has also been suggested that an increased sensibility of AT heterozygotes to the effect of ionizing radiation could be responsible for the increased BC risk. BC relative risk (RR) estimation in AT heterozygotes within families ascertained through AT children is presented here. Family data collected included demographic characteristics, occurrence of cancers, past radiation exposures and blood samples. DNA samples were studied using seven ATM linked microsatellites markers allowing AT haplotypes reconstitution. The relative risk of BC was assessed using French estimated incidence rates. A significant increase risk of BC is found among obligate ATM heterozygotes with a point estimate of 3.32 (P = 0.002). BC relative risk calculated according to age is significantly increased among the obligate ATM heterozygotes female relatives with an age ≤ 44 years (RR = 4.55, P = 0.005). The BC relative risk is statistically borderline among the obligate ATM heterozygote female relatives with an age ≥ 45 years (RR = 2.48, P = 0.08). The estimated BC relative risk among ATM heterozygotes is consistent with previously published data. However, the increased risk is only a little higher than classical reproductive risk factors and similar to the risk associated with a first-degree relative affected by BC. © 1999 Cancer Research Campaign PMID:10362113

  6. Dwarfism and age-associated spinal degeneration of heterozygote cmd mice defective in aggrecan

    Watanabe, Hideto; Nakata, Ken; Kimata, Koji; Nakanishi, Isao; Yamada, Yoshihiko

    1997-01-01

    Mouse cartilage matrix deficiency (cmd) is an autosomal recessive disorder caused by a genetic defect of aggrecan, a large chondroitin sulfate proteoglycan in cartilage. The homozygotes (−/−) are characterized by cleft palate and short limbs, tail, and snout. They die just after birth because of respiratory failure, and the heterozygotes (+/−) appear normal at birth. Here we report that the heterozygotes show dwarfism and develop spinal misalignment with age. Within 19 months of age, they exhibit spastic gait caused by misalignment of the cervical spine and die because of starvation. Histological examination revealed a high incidence of herniation and degeneration of vertebral discs. Electron microscopy showed a degeneration of disc chondrocytes in the heterozygotes. These findings may facilitate the identification of mutations in humans predisposed to spinal degeneration. PMID:9192671

  7. Comparison of Parkinson risk in Ashkenazi Jewish Gaucher patients and GBA heterozygotes

    Alcalay, Roy N.; Dinur, Tama; Quinn, Timothy; Sakanaka, Karina; Levy, Oren; Waters, Cheryl; Fahn, Stanley; Dorovski, Tsvyatko; Chung, Wendy K; Pauciulo, Michael; Nichols, William; Rana, Huma Q.; Balwani, Manisha; Bier, Louise; Elstein, Deborah; Zimran, Ari

    2014-01-01

    Importance Information on age-specific risk for Parkinson disease (PD) in Gaucher disease (GD) patients and glucocerebrosidase (GBA) heterozygotes is important for understanding the pathophysiology of the genetic association and for counseling these populations. Objective To estimate the age-specific risk of PD in Ashkenazi Jewish (AJ) patients with Type-1 GD and in GBA heterozygotes. Setting Two tertiary Gaucher centers and a Parkinson’s tertiary center. Participants GD patients at Shaare Zedek, Jerusalem, Israel (n=332) and Mount Sinai School of Medicine, NY (n=95), and GBA non-carrier non-PD spouse controls at Columbia University, NY (n=77). All were AJ and most GD patients (98.1%) carried at least one N370S mutation. Main outcome measure Main outcome measure was a diagnosis of PD. Diagnosis was established in GD patients on examination. We used a validated family history interview that identifies PD with a sensitivity of 95.5% and specificity of 96.2% to identify PD in family members. Kaplan-Meier survival curves were used to estimate age-specific PD risk among GD patients (n=427), among their parents, who are obligate GBA mutation carriers (heterozygotes, n=694) and among non-carriers (parents of non-PD non-GD controls, n=154). The age-specific risk was compared among groups using the log-rank test. Results Among those who developed PD, patients with GD had a younger age-at-onset than GBA heterozygotes (54.2, versus 65.2, p=0.003). Estimated age-specific risk for PD at ages 60 and 80 was 4.7% and 9.1% among GD patients, 1.5% and 7.7% among heterozygotes, and 0.7% and 2.1% among non-carriers. PD risk was higher in GD patients than non-carriers (p=0.008, log-rank test) and in heterozygotes than non-carriers (p=0.026, log-rank test) but did not reach significance between GD patients and GBA heterozygotes (p=0.074, log-rank test). Conclusion GD patients and GBA heterozygotes have an increased age-specific risk for PD compared to controls, with a similar

  8. Heterologous Synapsis and Crossover Suppression in Heterozygotes for a Pericentric Inversion in the Zebra Finch.

    del Priore, Lucía; Pigozzi, María I

    2015-01-01

    In the zebra finch, 2 alternative morphs regarding centromere position were described for chromosome 6. This polymorphism was interpreted to be the result of a pericentric inversion, but other causes of the centromere repositioning were not ruled out. We used immunofluorescence localization to examine the distribution of MLH1 foci on synaptonemal complexes to test the prediction that pericentric inversions cause synaptic irregularities and/or crossover suppression in heterozygotes. We found complete suppression of crossing over in the region involved in the rearrangement in male and female heterozygotes. In contrast, the same region showed high levels of crossing over in homozygotes for the acrocentric form of this chromosome. No inversion loops or synaptic irregularities were detected along bivalent 6 in heterozygotes suggesting that heterologous pairing is achieved during zygotene or early pachytene. Altogether these findings strongly indicate that the polymorphic chromosome 6 originated by a pericentric inversion. Since inversions are common rearrangements in karyotypic evolution in birds, it seems likely that early heterologous pairing could help to fix these rearrangements, preventing crossing overs in heterozygotes and their deleterious effects on fertility. © 2015 S. Karger AG, Basel.

  9. Heterozygote advantage: the effect of artificial selection in livestock and pets.

    Hedrick, Philip W

    2015-01-01

    There are a number of mutants in livestock and pets that have a heterozygote advantage because of artificial selection for these mutants in heterozygotes and strong detrimental effects from natural selection in homozygotes. In livestock, these mutants include ones that influence milk yield in dairy cattle, fecundity in sheep, litter size in pigs, muscling in beef cattle, color in horses, lean meat content in pigs, and comb morphology in chickens. In pets, these mutants include ones that influence tail length in cats and hairlessness, muscling, color, or ridgeback hair in dogs. A large variety of mutants are responsible, including small or large deletions or insertions and single base-pair nonsynonymous changes. Many of the mutants cause loss of function for the genes involved, a change that results in the pleiotropic effects of a desired phenotype in heterozygotes and low fitness or an undesirable phenotype in mutant homozygotes. I examine how selection changes the frequency of these mutants and provide an approach to estimate the amount of artificial selection that is necessary to maintain these mutants at the high frequencies often observed. The amount of artificial selection ranges from low selection favoring heterozygotes for double muscling in whippet dogs to very strong selection favoring the "flash" (part white, part solid) heterozygote in boxer dogs and the rose comb in chickens. In several examples (rose comb in Wyandotte chickens and the hair ridge in Rhodesian ridgeback dogs), there is actually stronger selection for the mutant than against it, making the frequency of the mutant greater than 50%. © The American Genetic Association 2014. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  10. Heterozygote deficits in cyst plant-parasitic nematodes: possible causes and consequences.

    Montarry, Josselin; Jan, Pierre-Loup; Gracianne, Cecile; Overall, Andrew D J; Bardou-Valette, Sylvie; Olivier, Eric; Fournet, Sylvain; Grenier, Eric; Petit, Eric J

    2015-04-01

    Deviations of genotypic frequencies from Hardy-Weinberg equilibrium (HWE) expectations could reveal important aspects of the biology of populations. Deviations from HWE due to heterozygote deficits have been recorded for three plant-parasitic nematode species. However, it has never been determined whether the observed deficits were due (i) to the presence of null alleles, (ii) to a high level of consanguinity and/or (iii) to a Wahlund effect. The aim of the present work was, while taking into the possible confounding effect of null alleles, to disentangle consanguinity and Wahlund effect in natural populations of those three economically important cyst nematodes using microsatellite markers: Globodera pallida, G. tabacum and Heterodera schachtii, pests of potato, tobacco and sugar beet, respectively. The results show a consistent pattern of heterozygote deficiency in the three nematode species sampled at the spatial scale of the host plant. We demonstrate that the prevalence of null alleles is weak and that heterozygote deficits do not have a single origin. Our results suggested that it is restricted dispersal that leads to heterozygote deficits through both consanguinity and substructure, which effects can be linked to soil movement, cyst density, and the number of generations per year. We discuss potential implications for the durability of plant resistances that are used to protect crops against parasites in which mating between relatives occur. While consanguineous mating leads to homozygosity at all loci, including loci governing avirulence/virulence, which favours the expression of virulence when recessive, the Wahlund effect is expected to have no particular effect on the adaptation of nematodes to resistances. © 2015 John Wiley & Sons Ltd.

  11. Heterozygote loss of ACE2 is sufficient to increase the susceptibility to heart disease.

    Wang, Wang; Patel, Vaibhav B; Parajuli, Nirmal; Fan, Dong; Basu, Ratnadeep; Wang, Zuocheng; Ramprasath, Tharmarajan; Kassiri, Zamaneh; Penninger, Josef M; Oudit, Gavin Y

    2014-08-01

    Angiotensin-converting enzyme 2 (ACE2) metabolizes Ang II into Ang 1-7 thereby negatively regulating the renin-angiotensin system. However, heart disease in humans and in animal models is associated with only a partial loss of ACE2. ACE2 is an X-linked gene; and as such, we tested the clinical relevance of a partial loss of ACE2 by using female ACE2(+/+) (wildtype) and ACE2(+/-) (heterozygote) mice. Pressure overload in ACE2(+/-) mice resulted in greater LV dilation and worsening systolic and diastolic dysfunction. These changes were associated with increased myocardial fibrosis, hypertrophy, and upregulation of pathological gene expression. In response to Ang II infusion, there was increased NADPH oxidase activity and myocardial fibrosis resulting in the worsening of Ang II-induced diastolic dysfunction with a preserved systolic function. Ang II-mediated cellular effects in cultured adult ACE2(+/-) cardiomyocytes and cardiofibroblasts were exacerbated. Ang II-mediated pathological signaling worsened in ACE2(+/-) hearts characterized by an increase in the phosphorylation of ERK1/2 and JNK1/2 and STAT-3 pathways. The ACE2(+/-) mice showed an exacerbated pressor response with increased vascular fibrosis and stiffness. Vascular superoxide and nitrotyrosine levels were increased in ACE2(+/-) vessels consistent with increased vascular oxidative stress. These changes occurred with increased renal fibrosis and superoxide production. Partial heterozygote loss of ACE2 is sufficient to increase the susceptibility to heart disease secondary to pressure overload and Ang II infusion. Heart disease in humans with idiopathic dilated cardiomyopathy is associated with a partial loss of ACE2. Heterozygote female ACE2 mutant mice showed enhanced susceptibility to pressure overload-induced heart disease. Heterozygote female ACE2 mutant mice showed enhanced susceptibility to Ang II-induced heart and vascular diseases. Partial loss of ACE2 is sufficient to enhance the susceptibility to

  12. Heterozygote to homozygote related living donor liver transplantation in maple syrup urine disease: a case report.

    Patel, N; Loveland, J; Zuckerman, M; Moshesh, P; Britz, R; Botha, J

    2015-05-01

    Liver transplantation is an accepted treatment modality in the management of MSUD. To our knowledge, ours is only the second successful case to date of a patient with MSUD receiving an allograft from an RLD who is a heterozygous carrier for the disease. In view of the worldwide shortage of available organs for transplantation, heterozygote to homozygote transplantation in the setting of MSUD may provide a viable alternative for those awaiting transplantation. We report on the case of a two-yr-old infant with MSUD, who received a left lateral segment (segments II and III) liver transplant from his mother, a heterozygote carrier of one of the three abnormal genes implicated in MSUD. Post-operative BCAA levels normalized in our patient and remained so on an unrestricted protein diet and during times of physiological stress. To date, this is only the second case of a successful RLD liver transplant in a child with MSUD. Preliminary results indicate that RLD liver transplants are at least equivalent to deceased donor liver transplants in the treatment of MSUD, although longer term follow-up is required. Heterozygote to homozygote RLD transplant in patients with MSUD presents a new pool of potential liver donors. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity.

    Gurrin, Lyle C; Bertalli, Nadine A; Dalton, Gregory W; Osborne, Nicholas J; Constantine, Clare C; McLaren, Christine E; English, Dallas R; Gertig, Dorota M; Delatycki, Martin B; Nicoll, Amanda J; Southey, Melissa C; Hopper, John L; Giles, Graham G; Anderson, Gregory J; Olynyk, John K; Powell, Lawrie W; Allen, Katrina J

    2009-07-01

    The risk of hemochromatosis-related morbidity is unknown among HFE compound heterozygotes (C282Y/H63D). We used a prospective population-based cohort study to estimate the prevalence of elevated iron indices and hemochromatosis-related morbidity for compound heterozygotes. In all, 31,192 subjects of northern European descent were genotyped for HFE C282Y and H63D. An HFE-genotype stratified random sample of 1,438 subjects, followed for an average of 12 years to a mean age of 65 years, completed questionnaires and gave blood. Clinical examinations were blinded to HFE genotype. A total of 180 (84 males) clinically examined C282Y/H63D participants were compared with 330 (149 males) controls with neither HFE mutation; 132 (65 males) and 270 (122 males), respectively, had serum iron measures at both timepoints. Mean serum ferritin (SF) and transferrin saturation (TS) were significantly greater for male and female compound heterozygotes than for wild-types at baseline and follow-up (all P females who were premenopausal at baseline, where SF was similar in both genotype groups. For subjects with serum measures from both baseline and follow-up, mean SF and TS levels did not change significantly for men or for postmenopausal women, but for premenopausal women SF levels increased from 43 to 109 microg/L for compound heterozygotes and from 35 to 64 microg/L for wild-types (both P female compound heterozygotes had a similar prevalence of hemochromatosis-related morbidity to wild-types. One of 82 males and zero of 95 females had documented iron overload-related disease. For male compound heterozygotes, mean iron indices do not change during middle age but for female compound heterozygotes menopause results in increased mean SF. Although compound heterozygotes might maintain elevated iron indices during middle age, documented iron overload-related disease is rare.

  14. Radioimmunoassay and heat denaturation enzyme assay for the detection of Tay-Sachs heterozygotes during pregnancy

    Nguyen, C.; Gold, R.J.M.; Mahuran, D.; Lowden, J.A.

    1981-01-01

    Tay-Sachs disease results from a loss of activity of hexosaminidase A (HEX A) in body tissues and fluids. Heterozygotes for the disease are usually identified by their relatively low ratio of heat-labile HEX A to total hexosaminidase. During pregnancy an intermediate isoenzyme (HEX I) increases in activity in serum and obscures the heterozygote status. HEX I does not increase in leucocytes, tears and other body tissues but because of technical difficulties in these assays the authors examined the feasibility of using a radioimmunoassay for HEX A. By univariate analysis, the heat denaturation assay gave a lower cost of misclassification for non-pregnant normals while RIA did so for pregnant normals. A combination of both tests led to reduced cost of misclassification compared to either alone. Bayesian analysis of bivariate gaussian density functions for heat denaturation and for radioimmunoassays of HEX isoenzymes was employed to calculate misclassification frequencies. Among the parameters examined, HEX A measured by RIA and % HEX A by heat-denaturation assay were the two having the best discriminatory power. (Auth.)

  15. Identification of ataxia telangiectasia heterozygotes by flow cytometric analysis of X-ray damage

    Rudolph, N.S.

    1989-01-01

    Flow cytometry was used to identify heterozygotes for the autosomal recessive DNA-repair deficiency disease ataxia telangiectasia (AT). Confluent G 0 /G 1 fibroblasts from 4 homozygotes (at/at), 5 obligate heterozygates (at/+) and 7 presumed normal (+/+) were X-irradiated with 200 Rad and subcultured immediately in medium containing 5-bromodeoxyuridine (BrdU). Cells were harvested 72 h later and stained with fluoresceinated anti-BrdU antibody to identify cells that had entered S phase. They were counterstained with propidium iodide to measure total DNA content. On the basis of relative release from G 0 /G 1 , the at/+ strains as a group were distinguished from both the presumed +/+ strains and at/at strains, although the individual values for some strains did show overlap between genotypes. When 10 cell strains were coded and analyzed in 'blind' experiments, all 4 heterozygotes were correctly assigned. By a similar assay in which exponentially growing cultures were pulsed briefly with BrdU 8 h after irradiation with 400 Rad and then harvested immediately, presumed +/+ cells as a group could be distinguished from at/at cells but not from at/- cells. This combination of assays assists in the identification of all 3 AT genotypes. This should be of both basic and diagnostic use, particularly in families known to segregate AT. (author). 37 refs.; 3 figs.; 5 tabs

  16. Urinary excretion of radiocopper in presymptomatic and symptomatic Wilson's disease, heterozygotes and controls: its significance in diagnosis and management

    Gibbs, K; Hanka, R; Walshe, J M [Cambridge Univ. (UK). Clinical School

    1978-07-01

    Radiocopper (/sup 64/Cu, /sup 67/Cu), given intravenously, has been used to study the pattern of excretion of copper in patients with presymptomatic, symptomatic and treated Wilson's disease, together with heterozygotes for the Wilson's disease gene and a control group of patients with a variety of neurological lesions mimicking wilson's disease. The most important radiochemical findings were as follows. Heterozygotes excreted less of the injected copper than controls both under basal conditions and after penicillamine. Presymptomatic patients excreted less radiocopper than heterozygotes after penicillamine although the excretion during the basal 24 hour period was very much greater. Patients with symptomatic Wilson's disease had by far the highest excretion of radiocopper in all three time periods which fell after treatment, pro rata with time, as had been found for stable copper. These results were subjected to computer analysis. There was no overlap between the various groups with the exception of a single control subject who had combined pyramidal and extrapyramidal system degeneration of obscure aetiology. This patient was classified by the computer as 'heterozygote'. These findings lend further support to the hypothesis that the loss of a single gene for copper balance can be detected with a high degree of accuracy and also that presymptomatic patients can be selected from a sibship for prophylactic treatment without the risk of subjecting healthy heterozygotes to unnecessary and potentially hazardous longterm therapy.

  17. HFE C282Y/H63D Compound Heterozygotes Are at Low Risk of Hemochromatosis-Related Morbidity

    Gurrin, Lyle C.; Bertalli, Nadine A.; Dalton, Gregory W.; Osborne, Nicholas J.; Constantine, Clare C.; McLaren, Christine E.; English, Dallas R.; Gertig, Dorota M.; Delatycki, Martin B.; Nicoll, Amanda J.; Southey, Melissa C.; Hopper, John L.; Giles, Graham G.; Anderson, Gregory J.; Olynyk, John K.

    2009-01-01

    The risk of hemochromatosis-related morbidity is unknown among HFE compound heterozygotes (C282Y/H63D). We used a prospective population-based cohort study to estimate the prevalence of elevated iron indices and hemochromatosis-related morbidity for compound heterozygotes. In all, 31,192 subjects of northern European descent were genotyped for HFE C282Y and H63D. An HFE-genotype stratified random sample of 1,438 subjects, followed for an average of 12 years to a mean age of 65 years, complete...

  18. Two sibs who are double heterozygotes for achondroplasia and pseudoachondroplastic dysplasia.

    Woods, C G; Rogers, J G; Mayne, V

    1994-01-01

    We report a family in which two sibs have both achondroplasia and pseudoachondroplastic dysplasia. The mother has achondroplasia and the father has pseudoachondroplastic dysplasia, which he had inherited from his father. Both children appeared typical of achondroplasia at birth. By 1 1/2 years they had developed a fixed lumbar kyphosis with gibbus and had additional x ray changes unusual for just achondroplasia and suggestive of pseudoachondroplastic dysplasia. Subsequently both children have shown characteristic features of both conditions and have grown less well than expected for achondroplasia. Radiographs show the striking synergistic effects of the two conditions. MRI in both sibs confirmed brain stem compression at the foramen magnum. This may be an important complication and should be actively sought in any double heterozygote. Images PMID:7966194

  19. Stigmatization of carrier status: social implications of heterozygote genetic screening programs.

    Kenen, R H; Schmidt, R M

    1978-01-01

    Possible latent psychological and social consequences ensuing from genetic screening programs need to be investigated during the planning phase of national genetic screening programs. The relatively few studies which have been performed to determine psychological, social, and economic consequences resulting from a genetic screening program are reviewed. Stigmatization of carrier-status, having major psychosocial implications in heterozygote genetic screening programs, is discussed and related to Erving Goffman's work in the area of stigmatization. Questions are raised regarding the relationship between such variables as religiosity and sex of the individual and acceptance of the status of newly identified carrier of a mutant gene. Severity of the deleterious gene and visibility of the carrier status are two important factors to consider in an estimation of potential stigma. Specific implications are discussed for four genetic diseases: Tay-Sachs, Sickle-Cell Anemia, Huntington's disease and Hemophilia. PMID:152585

  20. Alterations in plasma lipoproteins and apolipoproteins before the age of 40 in heterozygotes for lipoprotein lipase deficiency

    Bijvoet, S.; Gagné, S. E.; Moorjani, S.; Gagné, C.; Henderson, H. E.; Fruchart, J. C.; Dallongeville, J.; Alaupovic, P.; Prins, M. [=Martin H.; Kastelein, J. J.; Hayden, M. R.

    1996-01-01

    We have assessed the expression of heterozygosity for lipoprotein lipase (LPL) deficiency by studying a single large French Canadian family comprising 92 persons including 21 carriers of the catalytically defective P207L mutation. Phenotypic changes distinguishing heterozygotes from controls were

  1. FISH-aimed karyotyping and characterization of Renner complexes in permanent heterozygote Rhoeo spathacea.

    Golczyk, Hieronim; Hasterok, Robert; Joachimiak, Andrzej J

    2005-02-01

    Fluorescence in situ hybridization (FISH) using 25S rDNA, 5S rDNA, and telomere sequences as probes was carried out in the complex permanent heterozygote Rhoeo spathacea. Telomere sites were exclusively terminal. All 10 25S rDNA loci were located distally and appeared transcriptionally active after silver staining. Six distal and 2 interstitial 5S rDNA sites were detected; 2 of the distal sites strictly colocalized with 25S rDNA loci. The 2 intercalary 5S rDNA loci occurred in short arms of 2 chromosomes that conjoined at meiosis. Chromosomes differed as to the amount of AT-rich centric heterochromatin, suggesting involvement of pericentromeric regions in translocations. The possibility of Robertsonian-like rearrangements was discussed. Double target FISH with ribosomal probes along with DAPI fluorescence gave the basis for full chromosome identification in mitosis. The 2 Renner complexes are structurally balanced, both having 5 25S and 4 5S rDNA sites. Centromere clustering, telomere association, a high number of NOR sites, and a strong tendency for formation of joint nucleoli contribute to the preservation of highly polarized Rabl arrangement at interphase. These findings were discussed in relation to meiotic catenation in Rhoeo.

  2. Ribosomal DNA, tri- and bi-partite pericentromeres in the permanent translocation heterozygote Rhoeo spathacea.

    Golczyk, Hieronim; Hasterok, Robert; Szklarczyk, Marek

    2010-12-01

    High- and low-stringency FISH and base-specific fluorescence were performed on the permanent translocation heterozygote Rhoeo spathacea (2n = 12). Our results indicate that 45S rDNA arrays, rDNA-related sequences and other GC-rich DNA fraction(s) are located within the pericentromeric regions of all twelve chromosomes, usually colocalizing with the chromomycin A(3)-positive bands. Homogenization of the pericentromeric regions appears to result from the concerted spread of GC-rich sequences, with differential amplification likely. We found new 5S rDNA patterns, which suggest a variability in the breakpoints and in the consequent chromosome reorganizations. It was found that the large 5S rDNA locus residing on each of the 8E and 9E arms consisted of two smaller loci. On each of the two chromosome arms 3b and 4b, in addition to the major subtelomeric 5S rDNA locus, a new minor locus was found interstitially about 40% along the arm length. The arrangement of cytotogenetic landmarks and chromosome arm measurements are discussed with regard to genome repatterning in Rhoeo.

  3. The risk of familial Mediterranean fever in MEFV heterozygotes: a statistical approach.

    Jéru, Isabelle; Hentgen, Véronique; Cochet, Emmanuelle; Duquesnoy, Philippe; Le Borgne, Gaëlle; Grimprel, Emmanuel; Stojanovic, Katia Stankovic; Karabina, Sonia; Grateau, Gilles; Amselem, Serge

    2013-01-01

    Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder due to MEFV mutations and one of the most frequent Mediterranean genetic diseases. The observation of many heterozygous patients in whom a second mutated allele was excluded led to the proposal that heterozygosity could be causal. However, heterozygosity might be coincidental in many patients due to the very high rate of mutations in Mediterranean populations. To better delineate the pathogenicity of heterozygosity in order to improve genetic counselling and disease management. Complementary statistical approaches were used: estimation of FMF prevalence at population levels, genotype comparison in siblings from 63 familial forms, and genotype study in 557 patients from four Mediterranean populations. At the population level, we did not observe any contribution of heterozygosity to disease prevalence. In affected siblings of patients carrying two MEFV mutations, 92% carry two mutated alleles, whereas 4% are heterozygous with typical FMF diagnosis. We demonstrated statistically that patients are more likely to be heterozygous than healthy individuals, as shown by the higher ratio heterozygous carriers/non carriers in patients (pclassical Mendelian FMF per se, but constitutes a susceptibility factor for clinically-similar multifactorial forms of the disease. We also provide a first estimate of the risk for heterozygotes to develop FMF.

  4. Prenatal detection of a probable heterozygote for ADA deficiency and severe combined immunodeficiency disease using a microradioassay

    Aitken, D.A.; Kleijer, W.J.; Niermeijer, M.F.; Galjaard, H.; Herbschleb-Voogt, E.

    1980-01-01

    A pregnancy at risk for adenosine deaminase deficiency and severe combined immunodeficiency disease has been investigated by assay of adenosine deaminase activity in cultured amniotic fluid cells using a microradioassay. A low-normal level of consistent with heterozygote status in the foetus was found and confirmed after birth by assay of red cell and fibroblast adenosine deaminase activities. It is suggested that the radioassay method offers significant advantages in sensitivity and specificity over the standard spectrophotometric procedure. (author)

  5. Iron overload in HFE C282Y heterozygotes at first genetic testing: a strategy for identifying rare HFE variants.

    Aguilar-Martinez, Patricia; Grandchamp, Bernard; Cunat, Séverine; Cadet, Estelle; Blanc, François; Nourrit, Marlène; Lassoued, Kaiss; Schved, Jean-François; Rochette, Jacques

    2011-04-01

    Heterozygotes for the p.Cys282Tyr (C282Y) mutation of the HFE gene do not usually express a hemochromatosis phenotype. Apart from the compound heterozygous state for C282Y and the widespread p.His63Asp (H63D) variant allele, other rare HFE mutations can be found in trans on chromosome 6. We performed molecular investigation of the genes implicated in hereditary hemochromatosis in six patients who presented with iron overload but were simple heterozygotes for the HFE C282Y mutation at first genetic testing. Functional impairment of new variants was deduced from computational methods including molecular modeling studies. We identified four rare HFE mutant alleles, three of which have not been previously described. One mutation is a 13-nucleotide deletion in exon 6 (c.1022_1034del13, p.His341_Ala345 > LeufsX119), which is predicted to lead to an elongated and unstable protein. The second one is a substitution of the last nucleotide of exon 2 (c.340G > A, p.Glu114Lys) which modifies the relative solvent accessibility in a loop interface. The third mutation, p.Arg67Cys, also lies in exon 2 and introduces a destabilization of the secondary structure within a loop of the α1 domain. We also found the previously reported c.548T > C (p.Leu183Pro) missense mutation in exon 3. No other known iron genes were mutated. We present an algorithm at the clinical and genetic levels for identifying patients deserving further investigation. Conclusions Our results suggest that additional mutations in HFE may have a clinical impact in C282Y carriers. In conjunction with results from previously described cases we conclude that an elevated transferrin saturation level and elevated hepatic iron index should indicate the utility of searching for further HFE mutations in C282Y heterozygotes prior to other iron gene studies.

  6. All paired up with no place to go: pairing, synapsis, and DSB formation in a balancer heterozygote.

    Wei J Gong

    2005-11-01

    Full Text Available The multiply inverted X chromosome balancer FM7 strongly suppresses, or eliminates, the occurrence of crossing over when heterozygous with a normal sequence homolog. We have utilized the LacI-GFP: lacO system to visualize the effects of FM7 on meiotic pairing, synapsis, and double-strand break formation in Drosophila oocytes. Surprisingly, the analysis of meiotic pairing and synapsis for three lacO reporter couplets in FM7/X heterozygotes revealed they are paired and synapsed during zygotene/pachytene in 70%-80% of oocytes. Moreover, the regions defined by these lacO couplets undergo double-strand break formation at normal frequency. Thus, even complex aberration heterozygotes usually allow high frequencies of meiotic pairing, synapsis, and double-strand break formation in Drosophila oocytes. However, the frequencies of failed pairing and synapsis were still 1.5- to 2-fold higher than were observed for corresponding regions in oocytes with two normal sequence X chromosomes, and this effect was greatest near a breakpoint. We propose that heterozygosity for breakpoints creates a local alteration in synaptonemal complex structure that is propagated across long regions of the bivalent in a fashion analogous to chiasma interference, which also acts to suppress crossing over.

  7. Quantitative Trait Loci Influencing Hb F Levels in Southern Thai Hb E (HBB: c.79G>A) Heterozygotes.

    Kesornsit, Aumpika; Jeenduang, Nutjaree; Horpet, Dararat; Plyduang, Thunyaluk; Nuinoon, Manit

    2018-01-01

    Variation of fetal hemoglobin (Hb F) expression in heterozygous Hb E (HBB: c.79G>A) individuals is associated with several genetic modifiers and not well understood. This study was undertaken in order to determine the effect of single nucleotide polymorphisms (SNPs), including XmnI G γ (rs7482144), rs766432 on the BCL11A gene and rs9376074 on the HBS1L gene, on Hb F levels in Southern Thai heterozygous Hb E individuals. A total of 97 Southern Thai subjects carrying heterozygous Hb E were selected for the hematological study. After excluding the samples with α-thalassemia (α-thal) interaction or moderate anemia, because both conditions can affect the hematological parameters, the remaining 74 samples were submitted to SNP analysis. Hematological parameters were measured using an automated hematology analyzer and high performance liquid chromatography (HPLC). The results show that rs766432 was strongly associated with increased Hb F levels and rs7482144 was associated with Hb F levels in each subgroup (genotype) of rs766432. This study suggested that the BCL11A locus has a major effect on Hb F levels compared with the XmnI polymorphism in Hb E heterozygotes. This association of Hb F levels with SNPs is useful for the interpretation of hemoglobin (Hb) typing in heterozygous Hb E samples with high Hb F levels. Future research will need to address the better understanding of the mechanisms of the SNPs that regulate Hb F production without stress erythropoiesis in Hb E heterozygotes.

  8. Male meiosis and gametogenesis in wild house mice (Mus musculus domesticus) from a chromosomal hybrid zone; a comparison between "simple" Robertsonian heterozygotes and homozygotes.

    Wallace, B M; Searle, J B; Everett, C A

    1992-01-01

    Wild male house mice Mus musculus domesticus were collected from the hybrid zone between the John o'Groats race (2n = 32) and the standard race (2n = 40) in northern Scotland. Meiosis in both homozygotes (2n = 32, 36, and 40) and single Robertsonian heterozygotes (2n = 33, 35, and 37) was found to be orderly. At prophase/metaphase I in heterozygotes, a trivalent was formed from the metacentric and two homologous acrocentrics. At pachytene, this trivalent usually had a single side arm at the position of the centromeres, as a result of nonhomologous pairing of the acrocentrics. This side arm persisted into diplotene. Generally only a single chiasma was formed between each acrocentric and the metacentric. Anaphase I nondisjunction frequencies were estimated as 1.5% for the homozygotes and 2.7% for the heterozygotes. The extent of germ cell death between the pachytene and round spermatid stages was 18% greater in heterozygotes than in homozygotes. Our results concur with previous studies which indicate that single Robertsonian heterozygotes in wild house mice have near-normal fertility.

  9. The use of heterozygote soybean chlorophyll-deficient mutant gene Y11 as a test-system for environmental monitoring after the Chernobyl accident

    Rashidov, N.; Grodzinski, D.

    1994-01-01

    A heterozygote soybean line contains a gene of chlorophyll-deficiency, y 11 gene. The gene Y 11 is only partially dominant over y 11 ; thus heterozygote Y 11 y 11 plant has leaves of light green colour. Mitotic crossing-over and somatic mosaicism on Y 11 y 11 leaves of heterozygote plants are observed by scheme Y 11 Y 11 - Y 11 y 11 - y 11 y 11 as double and/or single spots. Investigation has been carried out to evaluate the low level radioactivity effects on heterozygote soybean as test-system. Solution of 3 H 2 O and 90 SrCl 2 has been used as a beta-source. The seeds were soaked in 3 H 2 O (0.2 MBq/ml) for 96 h or in 90 SrCl 2 water solution (10 MBq/ml) during 3 days. The effects of beta-irradiation were compared with the data from experiments with acute gamma-irradiation. The dose used ranged from 1 to 30 Gy (dose rate 0.14 Gy/c). Some experimental plots were also selected in Kiev, Zaporozhe regions and in the 10-km zone around Chernobyl. In the field experiments the lowest frequency of somatic mutation was registered in Kiev and Zaporozhe region where the environmental conditions were comparatively clear. But for the low accumulated doses in the 10-km zone around Chernobyl and in the laboratory experiments with beta-irradiation (for 3 H and 90 Sr), the genetic effects were high enough. It is necessary to take into account that for acute gamma-irradiation a nearly linear relationship between the dose and frequency of the somatic mutation was estimated. This fact allows to determine RBE for environmental pollution with various radioactive isotopes. It is proposed to use the heterozygote soybean as a sensitive test-system for studying the genetic effects in radioactive contaminated areas of Chernobyl region. (author)

  10. Thyroid aplasia in male sibling of heterozygotic twins born to the hyperthyroid mother treated with propylthiouracil during pregnancy (case report).

    Almarzouki, A A

    2012-01-01

    A 30-year-old pregnant female was diagnosed to have thyrotoxicosis (TSH= 0.005 µU/ml) at 13th week of gestation. Propylthiouracil (PTU; 200 mg daily) was prescribed to her and four weekly follow ups by the endocrinologist and obstetrician were ensured. At each examination TSH, FT4 and FT3 levels were normal and she became symptom free. Repeated ultrasound examination throughout the pregnancy did not reveal any fetal abnormality. The lady normally delivered heterozygotic twins. Umbilical cord blood of the baby boy twin showed a high TSH (541 µU/ml; reference range 0.270 - 4.20 μU/ml). He was started on thyroxine therapy (50 µg once daily). Ultrasound reported the absence of the thyroid gland. One month later TSH was within normal range and thyroxine dose was adjusted to 25 µg once daily. Repeated ultrasound confirmed the absence of thyroid gland. TSH was repeatedly normal. The boy is currently doing well on thyroxine replacement therapy. The other non-identical twin was a healthy girl with normal thyroid function tests and always thereafter. This case report suggested that PTU could be a hazardous drug to the fetus, since the mother gave birth to a baby with thyroid aplasia. PTU, Thyroid aplasia, Thyrotoxicosis, TSH.

  11. Critical Newborn Screens in Double Heterozygotes of Inborn Errors of Metabolism—A Clinical Report and Recommendations

    Katherine G. Langley

    2016-11-01

    Full Text Available The practice of newborn screening has been in place in the USA since the 1960s, with individual states initially screening for different numbers of disorders. In the early 2000s many efforts were made to standardize the various disorders being screened. Currently, there are at least 34 disorders that each state is mandated to include on their screening panel. Of those 34 disorders, the majority are inborn errors of metabolism (IEM which include urea cycle disorders (UCD, citrullinemia (CIT and argininosuccinic aciduria (ASA, as well as a number of fatty acid oxidation disorders. We present here four cases of infants who had critical newborn screens (NBS in the Commonwealth of Virginia and underwent genetic testing because their clinical presentation and follow-up laboratory studies were not consistent with the disorder that was flagged by NBS. These newborns were found to be carriers for two different IEMs (in three cases or compound heterozygotes (in one case. Currently no guidelines exist with respect to the appropriate way to manage these children who may or may not be symptomatic in the newborn period. We propose some general recommendations for management based on our experience with these four probands, and discuss the necessity for further conversation and collaboration between physicians encountering these not-so-infrequent presentations.

  12. A guinea pig strain with recessive heredity of deafness, producing normal-hearing heterozygotes with resistance to noise trauma.

    Skjönsberg, Asa; Herrlin, Petra; Duan, Maoli; Johnson, Ann-Christin; Ulfendahl, Mats

    2005-01-01

    A new strain of waltzing guinea pigs arose spontaneously in a guinea pig breeding facility in Germany in 1996. In addition to obvious vestibular dysfunction, the waltzing animals appear deaf already at birth. Histological analysis revealed that the waltzers lack an open scala media due to the collapse of Reissner's membrane onto the surface of the hearing organ. Subsequent breeding has shown that this strain has a recessive mode of inheritance. The homozygotes are deaf and display a waltzing behaviour throughout their lives while the heterozygotes show no significant signs of inner ear injury despite being carriers of this specific mutated gene of hearing impairment. However, the heterozygous animals offer the opportunity to study how hereditary factors interact with auditory stress. In the present study, the susceptibility of the carriers to noise was investigated. Auditory brainstem responses were obtained prior to and after noise exposure (4 kHz, 110 dB, 6 h). The carriers were significantly less affected by the noise as compared to control animals. This difference was still significant at 4 weeks following noise exposure. It is suggested that the heterozygous animals have an endogenous resistance to auditory stress. Copyright (c) 2005 S. Karger AG, Basel.

  13. Increased Risk for Other Cancers in Addition to Breast Cancer for CHEK2*1100delC Heterozygotes Estimated From the Copenhagen General Population Study

    Näslund-Koch, Charlotte; Nordestgaard, Børge G; Bojesen, Stig E

    2016-01-01

    % CI, 1.01 to 1.85) for men (sex difference: P = .63). For CHEK2*1100delC heterozygotes compared with noncarriers, the age- and sex-adjusted hazard ratios were 5.76 (95% CI, 2.12 to 15.6) for stomach cancer, 3.61 (95% CI, 1.33 to 9.79) for kidney cancer, 3.45 (95% CI, 1.09 to 10.9) for sarcoma, and 1...

  14. Autosomal recessive polycystic kidney disorder due to two novel compound heterozygote mutations in PKHD1 gene: case report

    Mohammad Miryounesi

    2017-01-01

    Full Text Available Background: Autosomal recessive polycystic kidney disorder (ARPCKD is one of the most prevalent hereditary disorders in neonates and children. Its frequency is between 1/6000 to 1/55000 births. In the most severe cases, it can be diagnosed prenatally by the presence of enlarged, echogenic kidneys and oligohydramnios. However, in the milder forms, clinical manifestations are usually detected in neonatal and childhood period. PKHD1 gene located on chromosome 6 is linked with this disorder. About half of detected mutations in this gene are missense ones. The largest protein product of this gene is called the FPC/polyductin complex (FPC. It is a single-membrane spanning protein whose absence leads to abnormal ciliogenesis in the kidneys. Case presentation: Here we present a 5-year-old female patient affected with ARPCKD. She has been born to a non-consanguineous healthy Iranian parents. No similar disorder has been seen in the family. Prenatal history has been normal. In order to find the genetic background, DNA was extracted from patient's peripheral blood lymphocytes. PKHD1 gene exons and exon-intron boundaries were sequenced using next generation sequencing platform. Two novel variants have been detected in compound heterozygote state in the patient (c.6591C>A, c.8222C>A. Bioinformatics tools predicted these variants to be pathogenic. Conclusion: In the present study, we detected two novel variants in PKHD1 gene in a patient with ARPCKD. The relatively mild phenotype of this patient is in accordance with the missense mutations found. Molecular genetic tools can help in accurate risk assessment as well as precise genotype-phenotype correlation establishment in families affected with such disorder to decrease the birth of affected individuals through preimplantation genetic diagnosis or better management of disorder.

  15. DNA damage in leukocytes from fanconi anemia patients and heterozygotes induced by mitomycin C and ionizing radiation as assessed by the comet and comet - FISH assay

    Mohseni Meybodi, A.; Mozdarani, H.

    2009-01-01

    Lymphocytes of Fanconi anemia (FA) show an increased sensitivity to the alkylating agents such as mitomycin C (MMC), but their responses to gamma-irradiation is controversial. The extent of DNA damage in leukocytes of FA patients following irradiation and MMC treatment was studied at cellular and single chromosome level. Methods: DNA damage induced by gamma-rays and MMC was measured in leukocytes of FA patients and carriers at whole genome level using the comet assay. Also, at the DNA level of specific chromosome involved in this disease using a modified comet-FISH protocol with whole chromosome painting probes (chromosomes 16 and 13), DNA damage in leukocytes of FA patients and heterozygotes were compared to healthy individuals. Results: Baseline DNA damage in leukocytes of patients and heterozygotes was higher than in controls. Net induced DNA damage by gamma-rays in leukocytes of FA cases was not significantly different from that of healthy donors and heterozygotes. Net induced DNA damage by MMC was statistically higher and significantly different (P<0.05) in patients than other groups. Hybridization of chromosome 16 reveals more signals in the tail but the number of spots in the tail was not significantly higher than the hybridization spots for chromosome 13 in both gamma-irradiated and MMC treated samples. Conclusion: Results indicate that DNA damage induced by MMC could be a better index for diagnosis of FA patients compared to gamma-rays. Results of comet-FISH showed no difference between the sensitivity of chromosome 16 and 13 to MMC and radiation. It may indicate that, although the FA-A gene is located on chromosome 16, this chromosome might have a similar sensitivity as other chromosomes

  16. FTO Is Associated with Aortic Valve Stenosis in a Gender Specific Manner of Heterozygote Advantage: A Population-Based Case-Control Study.

    Cindy Thron

    Full Text Available Single nucleotide polymorphisms (SNPs within the Fat mass and obesity associated (FTO gene have been linked with increased body weight. However, the data on an association of FTO with cardiovascular diseases remains conflicting. Therefore, we ascertained whether FTO is associated with aortic valve stenosis (AVS, one of the most frequent cardiovascular diseases in the Western world.In this population-based case-control study the FTO SNP rs9939609 was analyzed in 300 German patients with AVS and 429 German controls of the KORA survey S4, representing a random population. Blood samples were collected prior to aortic valve replacement in AVS cases and FTO rs9939609 was genotyped via ARMS-PCR. Genotype frequencies differed significantly between AVS cases and KORA controls (p = 0.004. Separate gender-analyses uncovered an association of FTO with AVS exclusively in males; homozygote carriers for the risk-allele (A had a higher risk to develop AVS (p = 0.017, odds ratio (OR 1.727; 95% confidence interval (CI 1.087-2.747, recessive model, whereas heterozygote carriers for the risk-allele showed a lower risk (p = 0.002, OR 0.565, 95% CI 0.384-0.828, overdominant model. After adjustment for multiple co-variables, the odds ratios of heterozygotes remained significant for an association with AVS (p = 0.008, OR 0.565, 95% CI 0.369-0.861.This study revealed an association of FTO rs9939609 with AVS. Furthermore, this association was restricted to men, with heterozygotes having a significantly lower chance to develop AVS. Lastly, the association between FTO and AVS was independent of BMI and other variables such as diabetes mellitus.

  17. FTO Is Associated with Aortic Valve Stenosis in a Gender Specific Manner of Heterozygote Advantage: A Population-Based Case-Control Study.

    Thron, Cindy; Akhyari, Payam; Godehardt, Erhard; Lichtenberg, Artur; Rüther, Ulrich; Seehaus, Stefanie

    2015-01-01

    Single nucleotide polymorphisms (SNPs) within the Fat mass and obesity associated (FTO) gene have been linked with increased body weight. However, the data on an association of FTO with cardiovascular diseases remains conflicting. Therefore, we ascertained whether FTO is associated with aortic valve stenosis (AVS), one of the most frequent cardiovascular diseases in the Western world. In this population-based case-control study the FTO SNP rs9939609 was analyzed in 300 German patients with AVS and 429 German controls of the KORA survey S4, representing a random population. Blood samples were collected prior to aortic valve replacement in AVS cases and FTO rs9939609 was genotyped via ARMS-PCR. Genotype frequencies differed significantly between AVS cases and KORA controls (p = 0.004). Separate gender-analyses uncovered an association of FTO with AVS exclusively in males; homozygote carriers for the risk-allele (A) had a higher risk to develop AVS (p = 0.017, odds ratio (OR) 1.727; 95% confidence interval (CI) 1.087-2.747, recessive model), whereas heterozygote carriers for the risk-allele showed a lower risk (p = 0.002, OR 0.565, 95% CI 0.384-0.828, overdominant model). After adjustment for multiple co-variables, the odds ratios of heterozygotes remained significant for an association with AVS (p = 0.008, OR 0.565, 95% CI 0.369-0.861). This study revealed an association of FTO rs9939609 with AVS. Furthermore, this association was restricted to men, with heterozygotes having a significantly lower chance to develop AVS. Lastly, the association between FTO and AVS was independent of BMI and other variables such as diabetes mellitus.

  18. Familial study of ataxia telangiectasia. Heterozygotes identification on the basis of sensitivity of gamma-irradiated cultures to caffeine post-treatment

    Pawlak, A.L.; Kotecki, M. [Polska Akademia Nauk, Poznan (Poland). Zaklad Genetyki Czlowieka; Ignatowicz, R. [Centrum Zdrowia Dziecka, Warsaw (Poland)

    1994-12-31

    The effects of caffeine (CF), {gamma}-irradiation + CF post-treatment on chromosomal aberrations were studied in lymphocyte cultures from a patient with ataxia telangiectasia (AT), his parents and brother. In the studied family both the homozygotes and the obligatory heterozygotes of AT showed increased sensitivity to CF post-treatment. Individual differences in sensitivity to {gamma}-irradiation + CF post-treatment proved to be correlated with the sensitivity of non-irradiated cells to CF treatment, but not to {gamma}-irradiation. (author). 19 refs, 1 fig., 1 tab.

  19. Familial study of ataxia telangiectasia. Heterozygotes identification on the basis of sensitivity of gamma-irradiated cultures to caffeine post-treatment

    Pawlak, A.L.; Kotecki, M.

    1994-01-01

    The effects of caffeine (CF), γ-irradiation + CF post-treatment on chromosomal aberrations were studied in lymphocyte cultures from a patient with ataxia telangiectasia (AT), his parents and brother. In the studied family both the homozygotes and the obligatory heterozygotes of AT showed increased sensitivity to CF post-treatment. Individual differences in sensitivity to γ-irradiation + CF post-treatment proved to be correlated with the sensitivity of non-irradiated cells to CF treatment, but not to γ-irradiation. (author). 19 refs, 1 fig., 1 tab

  20. Assay of the β-glucosidase activity with natural labelled and artificial substrates in leukocytes from homozygotes and heterozygotes with the Norrbottnian type (Type 3) of Gaucher disease

    Svennerholm, L.; Haakansson, G.; Dreborg, S.

    1980-01-01

    Leukocytes were isolated from 14 patients (7 males and 7 females) with Gaucher disease of the Norrbottnian type (Type 3), 32 obligate heterozygotes (16 males and 16 females) for this disease and 20 controls (10 males and 10 females). After collection, the cells were transported in dry ice to the laboratory, where they were assayed. The assays were repeated after the cells had been stored for 12 months. β-Glucosidase activity was assayed with D-[glucose-U- 14 C]glucosylceramide at pH 5.8 with Cutscum-Na-cholate as a detergent and 4-methylumbelliferyl-β-glucoside at pH 4.1 with Triton-Na-taurocholate as a detergent. The activities of two marker enzymes, 4-methylumbelliferyl-β-galactosidase and N-acetyl-β-glucosaminidase, were assayed in aliquots of the same leukocyte samples. (Auth.)

  1. Short alleles revealed by PCR demonstrate no heterozygote deficiency at minisatellite loci D1S7, D7S21, and D12S11

    Alonso, S.; Castro, A.; Fernandez-Fernandez, I.; Pancorbo, M.M. de [Universidad del Pais Vasco, Vizcaya (Spain)

    1997-02-01

    Short VNTR alleles that go undetected after conventional Southern blot hybridization may constitute an alternative explanation for the heterozygosity deficiency observed at some minisatellite loci. To examine this hypothesis, we have employed a screening procedure based on PCR amplification of those individuals classified as homozygotes in our databases for the loci D1S7, D7S21, and D12S11. The results obtained indicate that the frequency of these short alleles is related to the heterozygosity deficiency observed. For the most polymorphic locus, D1S7, {approximately}60% of those individuals previously classified as homozygotes were in fact heterozygotes for a short allele. After the inclusion of these new alleles, the agreement between observed and expected heterozygosity, along with other statistical tests employed, provide additional evidence for lack of population substructuring. Comparisons of allele frequency distributions reveal greater differences between racial groups than between closely related populations. 45 refs., 3 figs., 6 tabs.

  2. Allelic hierarchy of CDH23 mutations causing non-syndromic deafness DFNB12 or Usher syndrome USH1D in compound heterozygotes.

    Schultz, Julie M; Bhatti, Rashid; Madeo, Anne C; Turriff, Amy; Muskett, Julie A; Zalewski, Christopher K; King, Kelly A; Ahmed, Zubair M; Riazuddin, Saima; Ahmad, Nazir; Hussain, Zawar; Qasim, Muhammad; Kahn, Shaheen N; Meltzer, Meira R; Liu, Xue Z; Munisamy, Murali; Ghosh, Manju; Rehm, Heidi L; Tsilou, Ekaterini T; Griffith, Andrew J; Zein, Wadih M; Brewer, Carmen C; Riazuddin, Sheikh; Friedman, Thomas B

    2011-11-01

    Recessive mutant alleles of MYO7A, USH1C, CDH23, and PCDH15 cause non-syndromic deafness or type 1 Usher syndrome (USH1) characterised by deafness, vestibular areflexia, and vision loss due to retinitis pigmentosa. For CDH23, encoding cadherin 23, non-syndromic DFNB12 deafness is associated primarily with missense mutations hypothesised to have residual function. In contrast, homozygous nonsense, frame shift, splice site, and some missense mutations of CDH23, all of which are presumably functional null alleles, cause USH1D. The phenotype of a CDH23 compound heterozygote for a DFNB12 allele in trans configuration to an USH1D allele is not known and cannot be predicted from current understanding of cadherin 23 function in the retina and vestibular labyrinth. To address this issue, this study sought CDH23 compound heterozygotes by sequencing this gene in USH1 probands, and families segregating USH1D or DFNB12. Five non-syndromic deaf individuals were identified with normal retinal and vestibular phenotypes that segregate compound heterozygous mutations of CDH23, where one mutation is a known or predicted USH1 allele. One DFNB12 allele in trans configuration to an USH1D allele of CDH23 preserves vision and balance in deaf individuals, indicating that the DFNB12 allele is phenotypically dominant to an USH1D allele. This finding has implications for genetic counselling and the development of therapies for retinitis pigmentosa in Usher syndrome. ACCESSION NUMBERS: The cDNA and protein Genbank accession numbers for CDH23 and cadherin 23 used in this paper are AY010111.2 and AAG27034.2, respectively.

  3. A Novel Occulta-Type Spina Bifida Mediated by Murine Double Heterozygotes EphA2 and EphA4 Receptor Tyrosine Kinases

    Nor Linda Abdullah

    2017-12-01

    Full Text Available Members of the Eph receptor tyrosine kinase have previously been implicated in cranial neural tube development. Failure of neural tube closure leads to the devastating conditions known as anencephaly and spina bifida. EphA2 and EphA4 are expressed at the tips of the closing spinal neural folds prior and during neural tube closure. We investigated the possible role of murine EphA2 and EphA4 during the last step of primary neural tube closure, which is adhesion and fusion. The individual mouse knockouts of EphA2 and EphA4 per se do not exhibit neural tube defects (NTDs. The embryos generated by the crossing of double heterozygotes Epha2tm1Jrui/+Epha4rb-2J/+ displayed NTDs with a wide degree of severity including close exencephaly and close spina bifida (spina bifida occulta. Interestingly, mutants displaying NTDs had skin covering the underlying lesion. The tissue sections revealed the elevated neural folds had not adhered and fused. The phenotypes seen in Epha2tm1Jrui/+Epha4rb-2J/+ double heterozygous embryos suggest both genes play a compensatory role with each other in the adhesion and fusion of the neural tube. In this study, there exists a >50% penetrance of NTDs in the mouse mutants, which genetically have a single allele each of EphA2 and EphA4 absent.

  4. Positive selection at codon 38 of the human KCNE1 (= minK gene and sporadic absence of 38Ser-coding mRNAs in Gly38Ser heterozygotes

    Pfeufer Arne

    2009-08-01

    Full Text Available Abstract Background KCNE1 represents the regulatory beta-subunit of the slowly activating delayed rectifier potassium channel (IKs. Variants of KCNE1 have repeatedly been linked to the long-QT syndrome (LQTS, a disorder which predisposes to deafness, ventricular tachyarrhythmia, syncope, and sudden cardiac death. Results We here analyze the evolution of the common Gly38Ser variant (rs1805127, using genomic DNAs, complementary DNAs, and HEK293-expressed variants of altogether 19 mammalian species. The between species comparison reveals that the human-specific Gly38Ser polymorphism evolved under strong positive Darwinian selection, probably in adaptation to specific challenges in the fine-tuning of IKs channels. The involved amino acid exchanges (Asp > Gly, Gly > Ser are moderately radical and do not induce apparent changes in posttranslational modification. According to population genetic analyses (HapMap phase II a heterozygote advantage accounts for the maintenance of the Gly38Ser polymorphism in humans. On the other hand, the expression of the 38Ser allele seems to be disadvantageous under certain conditions, as suggested by the sporadic deficiency of 38Ser-coding mRNAs in heterozygote Central Europeans and the depletion of homozygotes 38Ser in the Yoruban sample. Conclusion We speculate that individual differences in genomic imprinting or genomic recoding might have contributed to conflicting results of recent association studies between Gly38Ser polymorphism and QT phenotype. The findings thus highlight the relevance of mRNA data in future association studies of genotypes and clinical disorders. To the best of our knowledge, they moreover provide first time evidence for a unique pattern; i.e. coincidence of positive Darwinian selection and polymorphism with a sporadically suppressed expression of one allele.

  5. Expression of serum insulin-like growth factors, insulin-like growth factor-binding proteins, and the growth hormone-binding protein in heterozygote relatives of Ecuadorian growth hormone receptor deficient patients.

    Fielder, P J; Guevara-Aguirre, J; Rosenbloom, A L; Carlsson, L; Hintz, R L; Rosenfeld, R G

    1992-04-01

    Recently, an isolated population of apparent GH-receptor deficient (GHRD) patients has been identified in the Loja province of southern Ecuador. These individuals presented many of the physical and biochemical phenotypes characteristic of Laron-Syndrome and are believed to have a defect in the GH-receptor gene. In this study, we have compared the biochemical phenotypes between the affected individuals and their parents, considered to be obligate heterozygotes for the disorder. Serum GH, insulin-like growth factor I and II (IGF-I and IGF-II) levels were measured by RIA Insulin-like growth factor binding proteins. (IGFBPs) were measured by Western ligand blotting (WLB) of serum samples, following separation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and relative quantitation of serum IGFBPs was performed with a scanning laser densitometer. Serum GH-binding protein (GHBP) levels were measured with a ligand-mediated immunofunctional assay using a monoclonal antibody raised against the GHBP. These values were then compared to values obtained from normal, sex-matched adult Ecuadorian controls, to determine if the above parameters were abnormal in the heterozygotes. The serum IGF-I levels of the GHRD patients were less than 13% of control values for adults and 2% for children. However, the IGF-I levels of both the mothers and fathers were not significantly different from that of the control population. The serum IGF-II levels of the GHRD patients were approximately 20% of control values for adults and 12% for the children. The IGF-II levels of the mothers were reduced, but were not significantly different from that of the control population. However, IGF-II levels of the fathers were significantly lower than those of controls (64% of control male levels). WLB analysis of serum IGFBP levels of the affected subjects demonstrated increased IGFBP-2 and decreased IGFBP-3, suggesting an inverse relationship between these IGFBPs. The GHRD patients who had the

  6. Comparative human cellular radiosensitivity: I. The effect of SV40 transformation and immortalisation on the gamma-irradiation survival of skin derived fibroblasts from normal individuals and from ataxia-telangiectasia patients and heterozygotes.

    Arlett, C F; Green, M H; Priestley, A; Harcourt, S A; Mayne, L V

    1988-12-01

    We have compared cell killing following 60Co gamma irradiation in 22 primary human fibroblast strains, nine SV40-immortalized human fibroblast lines and seven SV40-transformed pre-crisis human fibroblast cultures. We have examined material from normal individuals, from ataxia-telangiectasia (A-T) patients and from A-T heterozygotes. We have confirmed the greater sensitivity of A-T derived cells to gamma radiation. The distinction between A-T and normal cells is maintained in cells immortalized by SV40 virus but the immortal cells are more gamma radiation resistant than the corresponding primary fibroblasts. Cells transformed by plasmids (pSV3gpt and pSV3neo) expressing SV40 T-antigen, both pre- and post-crisis, show this increased resistance, indicating that it is expression of SV40 T-antigen, rather than immortalization per se which is responsible for the change. We use D0, obtained from a straight line fit, and D, estimated from a multitarget curve, as parameters to compare radiosensitivity. We suggest that both have their advantages; D0 is perhaps more reproducible, but D is more realistic when comparing shouldered and non-shouldered data.

  7. Classic Phenylketonuria: Diagnosis Through Heterozygote Detection

    Griffin, Robert F.; Elsas, Louis J.

    1975-01-01

    In an attempt to improve the identification of the asymptomatic carrier of classic phenylketonuria (PKU) 59 male and female normal control Ss were differentiated from 18 males and females heterozgous for PKU. (DB)

  8. Risk for Sporadic Breast Cancer in Ataxia Telangiectasia Heterozygotes

    2001-08-01

    cervix , kidney and colon cancer ) and 1 large benign ovarian tumour (serous cystadenoma), DNp73 was specifically upregulated 3 to 78-fold in 10...solos, alliances and feuds among family members. This article is in press in Biochimica and Biophysica Acta Reviews on Cancer . Appendix: manuscript...role in carcinogenesis, no related genes were known for HPV -mediated cancers (23). However, the adenovirus E4orf6 20 years. In 1997, two novel family

  9. Ectopic expression of DLK1 protein in skeletal muscle of padumnal heterozygotes causes the callipyge phenotype

    Davis, Erica; Jensen, Charlotte Harken; Farnir, Frédéric

    2004-01-01

    profile causes the callipyge muscular hypertrophy has remained unclear. Herein, we demonstrate that the callipyge phenotype is perfectly correlated with ectopic expression of DLK1 protein in hypertrophied muscle of +(MAT)/CLPG(PAT) sheep. We demonstrate the causality of this association by inducing...... a generalized muscular hypertrophy in transgenic mice that express DLK1 in skeletal muscle. The absence of DLK1 protein in skeletal muscle of CLPG/CLPG animals, despite the presence of DLK1 mRNA, supports a trans inhibition mediated by noncoding RNAs expressed from the maternal allele.......The callipyge (CLPG) phenotype is an inherited skeletal muscle hypertrophy described in sheep. It is characterized by an unusual mode of inheritance ("polar overdominance") in which only heterozygous individuals having received the CLPG mutation from their father (+(MAT)/CLPG(PAT)) express...

  10. Reduced Plasmodium vivax erythrocyte infection in PNG Duffy-negative heterozygotes.

    Kasehagen, Laurin J; Mueller, Ivo; Kiniboro, Benson; Bockarie, Moses J; Reeder, John C; Kazura, James W; Kastens, Will; McNamara, David T; King, Charles H; Whalen, Christopher C; Zimmerman, Peter A

    2007-03-28

    Erythrocyte Duffy blood group negativity reaches fixation in African populations where Plasmodium vivax (Pv) is uncommon. While it is known that Duffy-negative individuals are highly resistant to Pv erythrocyte infection, little is known regarding Pv susceptibility among heterozygous carriers of a Duffy-negative allele (+/-). Our limited knowledge of the selective advantages or disadvantages associated with this genotype constrains our understanding of the effect that interventions against Pv may have on the health of people living in malaria-endemic regions. We conducted cross-sectional malaria prevalence surveys in Papua New Guinea (PNG), where we have previously identified a new Duffy-negative allele among individuals living in a region endemic for all four human malaria parasite species. We evaluated infection status by conventional blood smear light microscopy and semi-quantitative PCR-based strategies. Analysis of a longitudinal cohort constructed from our surveys showed that Duffy heterozygous (+/-) individuals were protected from Pv erythrocyte infection compared to those homozygous for wild-type alleles (+/+) (log-rank tests: LM, p = 0.049; PCR, p = 0.065). Evaluation of Pv parasitemia, determined by semi-quantitative PCR-based methods, was significantly lower in Duffy +/- vs. +/+ individuals (Mann-Whitney U: p = 0.023). Overall, we observed no association between susceptibility to P. falciparum erythrocyte infection and Duffy genotype. Our findings provide the first evidence that Duffy-negative heterozygosity reduces erythrocyte susceptibility to Pv infection. As this reduction was not associated with greater susceptibility to Pf malaria, our in vivo observations provide evidence that Pv-targeted control measures can be developed safely.

  11. Two sibs who are double heterozygotes for achondroplasia and pseudoachondroplastic dysplasia.

    Woods, C G; Rogers, J G; Mayne, V

    1994-01-01

    We report a family in which two sibs have both achondroplasia and pseudoachondroplastic dysplasia. The mother has achondroplasia and the father has pseudoachondroplastic dysplasia, which he had inherited from his father. Both children appeared typical of achondroplasia at birth. By 1 1/2 years they had developed a fixed lumbar kyphosis with gibbus and had additional x ray changes unusual for just achondroplasia and suggestive of pseudoachondroplastic dysplasia. Subsequently both children have...

  12. The cystic fibrosis gene: Medical and social implications for heterozygote detection

    Wilfond, B.S.; Fost, N. (Univ. of Wisconsin School of Medicine, Madison (USA))

    1990-05-23

    The primary goal of mass screening programs for cystic fibrosis carriers should be to allow people to make more informed reproductive decisions. However, previous experience with genetic screening programs, including those for phenylketonuria and sickle cell disease, have revealed complex problems including error, confusion, and stigmatization. These problems could be greater with cystic fibrosis, since more than 8 million Americans may be carriers and entrepreneurial interests can be expected to promote screening in what could become a billion-dollar industry. The present frequency of the detectable mutation ({Delta}F{sub 508}), 75%, will complicate the counseling process. The sensitivity of the test to detect at-risk couples would be 56%. The cost of screening could be as much as $2.2 million for each cystic fibrosis birth avoided. Regardless of improvements in the detection rate, implementation of population screening should be delayed until pilot studies that demonstrate its safety and effectiveness are completed. While studies are in progress, preconception testing should be offered to adult relatives of cystic fibrosis patients as part of a comprehensive program following institutional review board approval for compassionate use.

  13. Biochemical and cytochemical evaluation of heterozygote individuals with glucose-6-phosphate dehydrogenase deficiency

    Gurbuz, Nilgun; Aksu, Tevfik Aslan; van Noorden, Cornelis J. F.

    2005-01-01

    The aim of this study was to diagnose heterozygous glucose-6-phosphate dehydrogenase (G6PD) deficient females by an inexpensive cytochemical G6PD staining method that is easy to perform, allowing diagnosis of G6PD deficiency without cumbersome genetic analysis. Three subject groups were included in

  14. Heterozygote FANCD2 mutations associated with childhood T Cell ALL and testicular seminoma.

    Smetsers, Stephanie; Muter, Joanne; Bristow, Claire; Patel, Leena; Chandler, Kate; Bonney, Denise; Wynn, Robert F; Whetton, Anthony D; Will, Andrew M; Rockx, Davy; Joenje, Hans; Strathdee, Gordon; Shanks, Jonathan; Klopocki, Eva; Gille, Johan J P; Dorsman, Josephine; Meyer, Stefan

    2012-12-01

    Fanconi anaemia (FA) is an inherited disease with congenital and developmental abnormalities characterised by cellular cross linker hypersensitivity. FA is caused by mutations in any of so far 15 identified FANC genes, which encode proteins that interact in a common DNA damage response (DDR) pathway. Individuals with FA have a high risk of developing acute myeloid leukaemia (AML) and squamous cell carcinoma. An increased cancer risk has been firmly established for carriers of mutations in FANCD1/BRCA2, FANCJ/BRIP1, FANCN/PALB2, RAD51C/FANCO and link the FA pathway to inherited breast and ovarian cancer. We describe a pedigree with FANCD2 mutations c.458T > C (p.Leu153Ser) and c.2715 + 1G > A (p.Glu906LeufsX4) with mild phenotype FA in the index case, T cell ALL in the Leu153Ser heterozygous brother and testicular seminoma in the p.Glu906LeufsX4 heterozygous father. Both FANCD2 alleles were present in the T Cell ALL and the seminoma. This links specific FANCD2 mutations to T cell ALL and seminoma without evidence of allelic loss in the tumour tissue.

  15. Functional and structural nerve fiber findings in heterozygote patients with Fabry disease

    Torvin, Moller A.; Winther, Bach F.; Feldt-Rasmussen, U.

    2009-01-01

    recently disease manifestations in female carriers of Fabry disease have been questioned. To explore the frequency of symptoms and the functional and structural involvement of the nervous system in female patients we examined the presence of pain, manifestations of peripheral neuropathy and nerve density......Fabry disease is an X-linked inherited lysosomal disorder with dysfunction of the lysosomal enzyme alpha-galactosidase A causing accumulation of glycolipids in multiple organs including the nervous system. Pain and somatosensory disturbances are prominent manifestations of this disease. Until...

  16. Iron metabolism in heterozygotes for hemoglobin E (HbE), alpha-thalassemia1, or beta-thalassemia and in compound heterozygotes for HbE/ beta-thalassemia

    Zimmermann, M.B.; Fucharoen, S.; Winichagoon, P.; Sirankapracha, P.; Zeder, C.; Gowachirapant, S.; Judprasong, K.; Tanno, T.; Miller, J.L.; Hurrell, R.F.

    2008-01-01

    BACKGROUND: Despite large populations carrying traits for thalassemia in countries implementing universal iron fortification, there are few data on the absorption and utilization of iron in these persons. OBJECTIVE: We aimed to determine whether iron absorption or utilization (or both) in women

  17. SERPINA1 PiZ and PiS heterozygotes and lung function decline in the SAPALDIA cohort.

    Gian-Andri Thun

    Full Text Available BACKGROUND: Severe alpha1-antitrypsin (AAT deficiency is a strong risk factor for COPD. But the impact of gene variants resulting in mild or intermediate AAT deficiency on the longitudinal course of respiratory health remains controversial. There is indication from experimental studies that pro-inflammatory agents like cigarette smoke can interact with these variants and thus increase the risk of adverse respiratory health effects. Therefore, we tested the effect of the presence of a protease inhibitor (Pi S or Z allele (PiMS and PiMZ on the change in lung function in different inflammation-exposed subgroups of a large, population-based cohort study. METHODOLOGY AND PRINCIPAL FINDINGS: The SAPALDIA population includes over 4600 subjects from whom SERPINA1 genotypes for S and Z alleles, spirometry and respiratory symptoms at baseline and after 11 years follow-up, as well as proxies for inflammatory conditions, such as detailed smoking history, obesity and high sensitivity C-reactive protein (hs-CRP, were available. All analyses were performed by applying multivariate regression models. There was no overall unfavourable effect of PiMS or PiMZ genotype on lung function change. We found indication that PiZ heterozygosity interacted with inflammatory stimuli leading to an accelerated decline in measures in use as indices for assessing mild airway obstruction. Obese individuals with genotype PiMM had an average annual decline in the forced mid expiratory flow (ΔFEF25-75% of 58.4 ml whereas in obese individuals with PiMZ it amounted to 92.2 ml (p = 0.03. Corresponding numbers for persistent smokers differed even more strongly (66.8 ml (PiMM vs. 108.2 ml (PiMZ, p = 0.005. Equivalent, but less strong associations were observed for the change in the FEV1/FVC ratio. CONCLUSIONS: We suggest that, in addition to the well established impact of the rare PiZZ genotype, one Z allele may be sufficient to accelerate lung function decline in population subgroups characterized by elevated levels of low grade inflammation.

  18. Identification of a breast cancer family double heterozygote for RAD51C and BRCA2 gene mutations

    Ahlborn, Lise B; Steffensen, Ane Y; Jønson, Lars

    2015-01-01

    for mutations in the RAD51C and BRCA2 genes. The RAD51C missense mutation p.Arg258His has previously been identified in a homozygous state in a patient with Fanconi anemia. This mutation is known to affect the DNA repair function of the RAD51C protein. The BRCA2 p.Leu3216Leu synonymous mutation has not been...

  19. Health risks for ataxia-telangiectasia mutated heterozygotes : a systematic review, meta-analysis and evidence-based guideline

    van Os, N J H; Roeleveld, N; Weemaes, C M R; Jongmans, M C J; Janssens, G O; Taylor, A M R; Hoogerbrugge, N; Willemsen, Michel A A P

    Ataxia-telangiectasia (AT) is an autosomal recessive neurodegenerative disorder with immunodeficiency and an increased risk of developing cancer, caused by mutations in the ataxia-telangiectasia mutated (ATM) gene. Logically, blood relatives may also carry a pathogenic ATM mutation. Female carriers

  20. Phenotypic presentation of thrombophilia in double heterozygote for factor v leiden and prothrombin 20210 G>A mutations: Case report

    Nagorni-Obradović Ljudmila

    2014-01-01

    Full Text Available Physicians usually do not suspect pulmonary thromboembolism in younger patients except in those who have thrombophilia. In those latter patients some special conditions such as trauma or surgery may provoke the disease. In some adult persons, thrombophilia may still remain unrecognized, until appearance of additional conditions influence development of thrombosis. A 55-year-old Caucasian female, non-smoker, experienced sudden chest pain and hemoptysis without chest trauma. History taking revealed type 2 diabetes mellitus and hypothyroidism. She was overweight with body mass index 29.0. The review of the family history revealed that her father and mother died of brain infarction, while her 22-year-old son and 24-year-old daughter were healthy. Due to suspicion for thrombosis, multi-slice computerized tomography thorax scan was done and pulmonary embolism was diagnosed. Although without clear risk factor for thrombosis in our patient, we performed laboratory investigation for congenital thrombophilia. Genetic analysis showed double heterozygous for factor V Leiden and prothrombin 20210 G>A mutations. Congenital thrombophilia was risk factor for thrombosis in our patient but haemostatic imbalance was not previously clinically recognized. She had two pregnancies without complications. Appearance of other associative factors such as endocrine disorders - hypothyroidism and metabolic syndrome with diabetes type 2, and overweigh were additional potential triggers for clinical manifestation of pulmonary thromboembolism in her adult age. Her children underwent genetic analysis, too. The son was also double heterozygous for factor V Leiden and prothrombin 20210 G>A mutations, while daughter was heterozygous for factor V Leiden, and none had clinical signs of thrombosis. [Projekat Ministarstva nauke Republike Srbije, br. ON175081 i br. ON 175091

  1. Change in lung function and morbidity from chronic obstructive pulmonary disease in alpha1-antitrypsin MZ heterozygotes

    Dahl, Morten; Tybjaerg-Hansen, Anne; Lange, Peter

    2002-01-01

    A deteriorating effect of severe alpha(1)-antitrypsin deficiency (ZZ genotype) on lung function is well known, whereas the role of intermediate deficiency (MZ genotype) remains uncertain.......A deteriorating effect of severe alpha(1)-antitrypsin deficiency (ZZ genotype) on lung function is well known, whereas the role of intermediate deficiency (MZ genotype) remains uncertain....

  2. Lipoprotein profiles in human heterozygote carriers of a functional mutation P297S in scavenger receptor class B1

    Ljunggren, Stefan A.; Levels, Johannes H. M.; Hovingh, Kees; Holleboom, Adriaan G.; Vergeer, Menno; Argyri, Letta; Gkolfinopoulou, Christina; Chroni, Angeliki; Sierts, Jeroen A.; Kastelein, John J.; Kuivenhoven, Jan Albert; Lindahl, Mats; Karlsson, Helen

    2015-01-01

    The scavenger receptor class B type 1 (SR-B1) is an important HDL receptor involved in cholesterol uptake and efflux, but its physiological role in human lipoprotein metabolism is not fully understood. Heterozygous carriers of the SR-B1(P297S) mutation are characterized by increased HDL cholesterol

  3. The effect of hydroxyurea on compound heterozygotes for sickle cell-hemoglobin D-Punjab--a single centre experience in eastern India.

    Patel, Siris; Purohit, Prasanta; Mashon, Ranjeet Singh; Dehury, Snehadhini; Meher, Satyabrata; Sahoo, Sulia; Dash, Subhransu Sekhar; Das, Kishalaya; Das, Padmalaya; Patel, Dilip Kumar

    2014-08-01

    Although hydroxyurea is the only effective agent for the treatment of sickle cell disease, published experience with this drug is limited to treatment of homozygous sickle cell anemia and HbS/β thalassemia. The role of hydroxyurea in the treatment of patients with HbSD-Punjab, a rare hemoglobinopathy with phenotypic expression similar to that of sickle cell anemia is unknown. Over a period of 10 years, we followed 42 patients with HbSD-Punjab, of which 20 presented with severe clinical manifestations (≥3 episodes of VOC and/or ≥2 units of blood transfusion in the previous 12 months). These 20 patients were enrolled for treatment with hydroxyurea at a dose of 10 mg/kg/day and followed prospectively for a period of 24 months. The frequency of VOC decreased significantly and none of them required blood transfusion while receiving hydroxyurea. The HbF, total hemoglobin, MCV, MCH, and MCHC levels increased significantly, whereas HbS, WBC, platelet count, total serum bilirubin, and LDH levels decreased significantly in all the patients. No short-term drug toxicity was observed. This study describes the use of hydroxyurea therapy in patients with HbSD-Punjab. Low dose hydroxyurea (10 mg/kg/day) was found to be effective in reducing the clinical severity in patients with HbSD-Punjab without any short-term toxicity. In view of easy affordability amongst poor patients, widespread acceptability by patients and doctors, the need of infrequent monitoring and its potential effectiveness, low dose hydroxyurea is suitable for treatment of patients with HbSD-Punjab. © 2014 Wiley Periodicals, Inc.

  4. Heterozygote Hemoglobin G-Coushatta as the Cause of a Falsely Decreased Hemoglobin A1C in an Ion-Exchange HPLC Method

    Kurtoğlu Ayşegül Uğur

    2017-09-01

    Full Text Available Glycated hemoglobin (HbA1c is used for the assessment of glycemic control in patients with diabetes. The presence of genetic variants of hemoglobin can profoundly affect the accuracy of HbA1c measurement. Here, we report two cases of Hemoglobin G-Coushatta (HBB:c.68A>C variant that interferes in the measurement of HbA1c by a cation-exchange HPLC (CE-HPLC method. HbA1c was measured by a CE-HPLC method in a Tosoh HLC-723 G7 instrument. The HbA1c levels were 2.9% and 4%. These results alerted us to a possible presence of hemoglobinopathy. In the hemoglobin variant analysis, HbA2 levels were detected as 78.3% and 40.7% by HPLC using the short program for the Biorad Variant II. HbA1c levels were measured by an immunoturbidimetric assay in a Siemens Dimension instrument. HbA1c levels were reported as 5.5% and 5.3%. DNA mutation analysis was performed to detect the abnormal hemoglobin variant. Presence of Hemoglobin G-Coushatta variant was detected in the patients. The Hb G-Coushatta variants have an impact on the determination of glycated hemoglobin levels using CEHPLC resulting in a false low value. Therefore, it is necessary to use another measurement method.

  5. Digenic inheritance in autosomal recessive non-syndromic hearing loss cases carrying GJB2 heterozygote mutations: assessment of GJB4, GJA1, and GJC3.

    Kooshavar, Daniz; Tabatabaiefar, Mohammad Amin; Farrokhi, Effat; Abolhasani, Marziye; Noori-Daloii, Mohammad-Reza; Hashemzadeh-Chaleshtori, Morteza

    2013-02-01

    Autosomal recessive non-syndromic hearing loss (ARNSHL) can be caused by many genes. However, mutations in the GJB2 gene, which encodes the gap-junction (GJ) protein connexin (Cx) 26, constitute a considerable proportion differing among population. Between 10 and 42 percent of patients with recessive GJB2 mutations carry only one mutant allele. Mutations in GJB4, GJA1, and GJC3 encoding Cx30.3, Cx43, and Cx29, respectively, can lead to HL. Combination of different connexins in heteromeric and heterotypic GJ assemblies is possible. This study aims to determine whether variations in any of the genes GJB4, GJA1 or GJC3 can be the second mutant allele causing the disease in the digenic mode of inheritance in the studied GJB2 heterozygous cases. We examined 34 unrelated GJB2 heterozygous ARNSHL subjects from different geographic and ethnic areas in Iran, using polymerase chain reaction (PCR) followed by direct DNA sequencing to identify any sequence variations in these genes. Restriction fragment length polymorphism (RFLP) assays were performed on 400 normal hearing individuals. Sequence analysis of GJB4 showed five heterozygous variations including c.451C>A, c.219C>T, c.507C>G, c.155_158delTCTG and c.542C>T, with only the latter variation not being detected in any of control samples. There were three heterozygous variations including c.758C>T, c.717G>A and c.3*dupA in GJA1 in four cases. We found no variations in GJC3 gene sequence. Our data suggest that GJB4 c.542C>T variant and less likely some variations of GJB4 and GJA1, but not possibly GJC3, can be assigned to ARNSHL in GJB2 heterozygous mutation carriers providing clues of the digenic pattern. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  6. Host-cell reactivation of UV-irradiated and chemically-treated herpes simplex virus-1 by xeroderma pigmentosum, xp heterozygotes and normal skin fibroblasts

    Selsky, C.A.

    1978-01-01

    The host-cell reactivation of UV-irradiated and N-acetoxy-2-acetylamino-fluorene-treated herpes simplex virus type 1 strain MP was studied in normal and xeroderma pigmentosum human skin fibroblasts. Virus treated with either agent demonstrated lower survival in XP cells from complementation groups A, B, C and D than in normal fibroblasts. The relative reactivation ability of XP cells from the different genetic complementation groups was found to be the same for both irradiated and chemically treated virus. In addition, the inactivation kinetics for virus treated with either agent in the XP variant were comparable to that seen in normal skin fibroblasts. The addition of 2 or 4 mmoles caffeine to the post-infection assay medium had no effect on the inactivation kinetics of virus treated by either agent in the XP variant or in XP cells from the different genetic complementation groups. Treatment of the virus with nitrogen mustard resulted in equivalent survival in normal and XP genetic complementation group D cells. No apparent defect was observed in the ability of XP heterozygous skin fibroblasts to repair virus damaged with up to 100 μg N-acetoxy-2-acetylaminofluorene per ml. These findings indicate that the repair of UV-irradiated and N-acetoxy-2-acetylaminofluorene-treated virus is accomplished by the same pathway or different pathways sharing a common intermediate step and that the excision defect of XP cells plays little if any role in the reactivation of nitrogen mustard treated virus. (Auth.)

  7. Internal jugular vein thrombosis due to heterozygote methylene tetrahydrofolate reductase (MTHFR) 1298C and Factor V G1691A mutations after a minor trauma

    Gumussoy, Murat; Arslan, Ilker B.; Cukurova, Ibrahim; Uluyol, Sinan

    2014-01-01

    Internal jugular vein thrombosis usually appears in central venous catheterization, distant malignancies, hypercoagulation, infections, or secondary to ovarian hyperstimulation syndrome. A 44-year-old female patient presented to us with sore throat, and pain and swelling on the right side of her neck. She had a history of simple neck trauma 10 days ago. Ultrasonography and computed tomography showed bilateral multiple lymphadenopathies and right internal jugular vein thrombosis. Patient was p...

  8. Identification of a common single nucleotide polymorphism at the primer binding site of D2S1360 that causes heterozygote peak imbalance when using the Investigator HDplex Kit.

    Inokuchi, Shota; Yamashita, Yasuhiro; Nishimura, Kazuma; Nakanishi, Hiroaki; Saito, Kazuyuki

    2017-11-01

    Phenomena known as null alleles and peak imbalance can occur because of mutations in the primer binding sites used for DNA typing. In these cases, an accurate statistical evaluation of DNA typing is difficult. The estimated likelihood ratio is incorrectly calculated because of the null allele and allele dropout caused by mutation-induced peak imbalance. Although a number of studies have attempted to uncover examples of these phenomena, few reports are available on the human identification kit manufactured by Qiagen. In this study, 196 Japanese individuals who were heterozygous at D2S1360 were genotyped using an Investigator HDplex Kit with optimal amounts of DNA. A peak imbalance was frequently observed at the D2S1360 locus. We performed a sequencing analysis of the area surrounding the D2S1360 repeat motif to identify the cause for peak imbalance. A point mutation (G>A transition) 136 nucleotides upstream from the D2S1360 repeat motif was discovered in a number of samples. The allele frequency of the mutation was 0.0566 in the Japanese population. Therefore, human identification or kinship testing using the Investigator HDplex Kit requires caution because of the higher frequency of single nucleotide polymorphisms at the primer binding site of D2S1360 locus in the Japanese population.

  9. [Identification of a novel WART-like chromosome rearrangement in complex heterozygotes in an interracial hybrid zone of the common shrew Sorex araneus L].

    Pavlova, S V; Bulatova, N Sh

    2010-09-01

    Karyotypes uncharacteristic of pure races or hybrids were identified in the interracial hybrid zones of the common shrew Sorex araneus L. that were recently discovered in the European part of Russia. This suggests the actual existence in natural populations of WART-like rearrangements (whole-arm reciprocal translocations) along with Robertsonian fusions of acrocentrics. Demonstration of new and still rare chromosome variants is the aim of this communication.

  10. CYP2D6 and CYP2C19 in Papua New Guinea: High frequency of previously uncharacterized CYP2D6 alleles and heterozygote excess.

    von Ahsen, Nicolas; Tzvetkov, Mladen; Karunajeewa, Harin A; Gomorrai, Servina; Ura, Alice; Brockmöller, Jürgen; Davis, Timothy M E; Mueller, Ivo; Ilett, Kenneth F; Oellerich, Michael

    2010-08-18

    A high frequency of previously unknown CYP2D6 alleles have been reported in Oceania populations. Genetic and functional properties of these alleles remain unknown. We performed analyses of the genetic variability of CYP2D6 and CYP2C19 genes using AmpliChip genotyping in cohorts from two distinct Papua New Guinea (PNG) populations (Kunjingini, n=88; Alexishafen, n=84) focussing on the genetic characterisation of PNG-specific alleles by re-sequencing. Previously unknown CYP2D6 alleles have population frequencies of 24% (Kunjingini) and 12% (Alexishafen). An allele similar to CYP2D6*1, but carrying the 1661G>C substitution, was the second most frequent CYP2D6 allele (20% Kunjingini and 10% Alexishafen population frequency). Sequencing suggests the CYP2D6* 1661G>C allele originated from a cross-over between CYP2D6*1 and *2 and thus is predicted to confer fully active CYP2D6 enzyme. Two additional predicted full activity alleles [1661G>C;4180G>C] and 31G>A were found in the Kunjingini cohort (frequencies 3 c/c and 1%, respectively) and a novel predicted reduced activity allele [100C>T;1039C>T] was found in the Alexishafen cohort (frequency 2%). A high frequency of ultra-rapid (15%) and notably low frequencies of intermediate and poor CYP2D6 metabolizers (exogamy and recent introduction of alleles by migration that are yet to reach HWE in relatively isolated populations. The CYP2D6*1661 allele common in Oceania may be regarded as functionally equivalent to the full activity CYP2D6*1 allele.

  11. Enhanced radiosensitivity of cultured fibroblasts from ataxia telangiectasia heterozygotes manifested by defective colony-forming ability and reduced DNA repair replication after hypoxic γ-irradiation

    Paterson, M.C.; Anderson, A.K.; Smith, B.P.; Smith, P.J.

    1979-01-01

    We have measured the sensitivity to γ-ray inactivation of diploid skin fibroblasts cultured from 10 persons in four families with ataxia telangiectasia (AT). Persons heterozygous for AT, including parents of afflicted patients, are not as yet detectable by any specific clinical or laboratory marker but are believed to constitute a substantial portion of the middle-aged cancer population. In one AT family, fibroblast strains from both parents exhibited a colony-forming ability after hypoxic irradiation which was intermediate between that displayed by five control strains from normal children and that from the affected child. In the remaining three families, cultures from only one parent were available; one parental strain displayed an intermediate survival capacity as above, whereas the other two responded normally. The homozygous recessive strains from the five afflicted children in the four families were all equally hypersensitive to hypoxic γ-ray inactivation. The three presumed AT heterozygous strains that displayed intermediate rayiosensitivity also carried out γ-rad-induced DNA repair replication to an extent intermediate between those in normals and AT homozygotes. These findings suggest that a numerically significant, cancer-prone subpopulation of humans carrying one normal and one abnormal AT gene may also be moderately sensitive to lethal effects of hypoxic γ-rays due to a defect in the enzymatic repair of DNA

  12. Characterisation of adiponectin multimers and the IGF axis in humans with a heterozygote mutation in the tyrosine kinase domain of the insulin receptor gene

    Højlund, Kurt; Beck-Nielsen, Henning; Flyvbjerg, Allan

    2012-01-01

    Objective: Low levels of adiponectin, IGF-binding protein (IGFBP)-1, and IGFBP-2, and high levels of leptin correlate with several indices of insulin resistance and risk of type 2 diabetes. However, in insulin receptoropathies plasma adiponectin is paradoxically increased despite severe insulin...... resistance, whereas the IGF-axis is sparsely described. Here, we aimed to characterize the multimeric distribution of adiponectin and the IGF-axis in humans with a heterozygous INSR mutation (Arg1174Gln).Methods: Blood samples obtained in six Arg1174Gln-carriers and 10 lean, healthy controls before and after...... an euglycemic-hyperinsulinemic clamp were examined for plasma adiponectin multimers, leptin, total IGF-I, IGF-II, free IGF-I, IGFBP-1 and IGFBP-2.Results: Despite 10-fold elevated fasting insulin and marked insulin resistance in Arg1174Gln-carriers, the levels of total adiponectin, leptin, IGFBP-1 and IGFBP-2...

  13. Fabry Disease: prevalence of affected males and heterozygotes with pathogenic GLA mutations identified by screening renal, cardiac and stroke clinics, 1995-2017.

    Doheny, Dana; Srinivasan, Ram; Pagant, Silvere; Chen, Brenden; Yasuda, Makiko; Desnick, Robert J

    2018-04-01

    Fabry Disease (FD), an X linked lysosomal storage disease due to pathogenic α-galactosidase A ( GLA ) mutations, results in two major subtypes, the early-onset Type 1 'Classic' and the Type 2 'Later-Onset' phenotypes. To identify previously unrecognised patients, investigators screened cardiac, renal and stroke clinics by enzyme assays. However, some screening studies did not perform confirmatory GLA mutation analyses, and many included recently recognised 'benign/likely-benign' variants, thereby inflating prevalence estimates. Online databases were searched for all FD screening studies in high-risk clinics (1995-2017). Studies reporting GLA mutations were re-analysed for pathogenic mutations, sex and phenotype. Phenotype-specific and sex-specific prevalence rates were determined. Of 67 studies, 63 that screened 51363patients (33943M and 17420F) and provided GLA mutations were reanalysed for disease-causing mutations. Of reported GLA mutations, benign variants occurred in 47.9% of males and 74.1% of females. The following were the revised prevalence estimates: among 36820 (23954M and 12866F) haemodialysis screenees, 0.21% males and 0.15% females; among 3074 (2031M and 1043F) renal transplant screenees, 0.25% males and no females; among 5491 (4054M and 1437F) cardiac screenees, 0.94% males and 0.90% females; and among 5978 (3904M and 2074F) stroke screenees, 0.13% males and 0.14% females. Among male and female screenees with pathogenic mutations, the type 1 Classic phenotype was predominant (~60%), except more male cardiac patients (75%) had type 2 Later-Onset phenotype. Compared with previous findings, reanalysis of 63 studies increased the screenee numbers (~3.4-fold), eliminated 20 benign/likely benign variants, and provided more accurate sex-specific and phenotype-specific prevalence estimates, ranging from ~0.13% of stroke to ~0.9% of cardiac male or female screenees. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  14. Hexavalents in spermatocytes of Robertsonian heterozygotes between Mus m. domesticus 2n=26 from the Vulcano and Lipari Islands (Aeolian Archipelago, Italy).

    Berríos, Soledad; Fernández-Donoso, Raúl; Page, Jesús; Ayarza, Eliana; Capanna, Ernesto; Solano, Emanuela; Castiglia, Riccardo

    2018-02-20

    The size and shape of the chromosomes, as well as the chromosomal domains that compose them, are determinants in the distribution and interaction between the bivalents within the nucleus of spermatocytes in prophase I of meiosis. Thus the nuclear architecture characteristic of the karyotype of a species can be modified by chromosomal changes such as Rb chromosomes. In this study we analysed the meiotic prophase nuclear organization of the heterozygous spermatocytes from Mus musculus domesticus 2n=26, and the synaptic configuration of the hexavalent formed by the dependent Rb chromosomes Rbs 6.16, 16.10, 10.15, 15.17 and the telocentric chromosomes 6 and 17. Spreads of 88 pachytene spermatocytes from two males were studied and in all of them five metacentric bivalents, four telocentric bivalents, one hexavalent and the XY bivalent were observed. About 48% of the hexavalents formed a chain or a ring of synapsed chromosomes, the latter closed by synapsis between the short arms of telocentric chromosomes 6 and 17.  About 52% of hexavalents formed an open chain of 10 synapsed chromosomal arms belonging to 6 chromosomes.  In about half of the unsynapsed hexavalents one of the telocentric chromosome short arms appears associated with the X chromosome single axis, which was otherwise normally paired with the Y chromosome.  The cluster of pericentromeric heterochromatin mostly determines the hexavalent's nuclear configuration, dragging the centromeric regions and all the chromosomes towards the nuclear envelope similar to an association of five telocentric bivalents. These reiterated encounters between these chromosomes restrict the interactions with other chromosomal domains and might favour eventual rearrangements within the metacentric, telocentric or hexavalent chromosome subsets. The unsynapsed short arms of telocentric chromosomes frequently bound to the single axis of the X chromosome could further complicate the already complex segregation of hexavalent chromosomes.

  15. Hexavalents in spermatocytes of Robertsonian heterozygotes between Mus m. domesticus 2n 26 from the Vulcano and Lipari Islands (Aeolian Archipelago, Italy)

    Berríos, Soledad; Fernández-Donoso, Raúl; Page, Jesús; Ayarza, Eliana; Capanna, Ernesto; Solano, Emanuela; Castiglia, Riccardo

    2018-01-01

    The size and shape of the chromosomes, as well as the chromosomal domains that compose them, are determinants in the distribution and interaction between the bivalents within the nucleus of spermatocytes in prophase I of meiosis. Thus the nuclear architecture characteristic of the karyotype of a species can be modified by chromosomal changes such as Robertsonian (RB) chromosomes. In this study we analysed the meiotic prophase nuclear organization of the heterozygous spermatocytes from Mus musculus domesticus 2n=26, and the synaptic configuration of the hexavalent formed by the dependent Rb chromosomes Rbs 6.16, 16.10, 10.15, 15.17 and the telocentric chromosomes 6 and 17. Spreads of 88 pachytene spermatocytes from two males were studied and in all of them five metacentric bivalents, four telocentric bivalents, one hexavalent and the XY bivalent were observed. About 48% of the hexavalents formed a chain or a ring of synapsed chromosomes, the latter closed by synapsis between the short arms of telocentric chromosomes 6 and 17. About 52% of hexavalents formed an open chain of 10 synapsed chromosomal arms belonging to 6 chromosomes. In about half of the unsynapsed hexavalents one of the telocentric chromosome short arms appears associated with the X chromosome single axis, which was otherwise normally paired with the Y chromosome. The cluster of pericentromeric heterochromatin mostly determines the hexavalent’s nuclear configuration, dragging the centromeric regions and all the chromosomes towards the nuclear envelope similar to an association of five telocentric bivalents. These reiterated encounters between these chromosomes restrict the interactions with other chromosomal domains and might favour eventual rearrangements within the metacentric, telocentric or hexavalent chromosome subsets. The unsynapsed short arms of telocentric chromosomes frequently bound to the single axis of the X chromosome could further complicate the already complex segregation of hexavalent chromosomes. PMID:29569877

  16. Hexavalents in spermatocytes of Robertsonian heterozygotes between Mus m. domesticus 2n=26 from the Vulcano and Lipari Islands (Aeolian Archipelago, Italy

    Soledad Berríos

    2018-02-01

    Full Text Available The size and shape of the chromosomes, as well as the chromosomal domains that compose them, are determinants in the distribution and interaction between the bivalents within the nucleus of spermatocytes in prophase I of meiosis. Thus the nuclear architecture characteristic of the karyotype of a species can be modified by chromosomal changes such as Rb chromosomes. In this study we analysed the meiotic prophase nuclear organization of the heterozygous spermatocytes from Mus musculus domesticus 2n=26, and the synaptic configuration of the hexavalent formed by the dependent Rb chromosomes Rbs 6.16, 16.10, 10.15, 15.17 and the telocentric chromosomes 6 and 17. Spreads of 88 pachytene spermatocytes from two males were studied and in all of them five metacentric bivalents, four telocentric bivalents, one hexavalent and the XY bivalent were observed. About 48% of the hexavalents formed a chain or a ring of synapsed chromosomes, the latter closed by synapsis between the short arms of telocentric chromosomes 6 and 17.  About 52% of hexavalents formed an open chain of 10 synapsed chromosomal arms belonging to 6 chromosomes.  In about half of the unsynapsed hexavalents one of the telocentric chromosome short arms appears associated with the X chromosome single axis, which was otherwise normally paired with the Y chromosome.  The cluster of pericentromeric heterochromatin mostly determines the hexavalent’s nuclear configuration, dragging the centromeric regions and all the chromosomes towards the nuclear envelope similar to an association of five telocentric bivalents. These reiterated encounters between these chromosomes restrict the interactions with other chromosomal domains and might favour eventual rearrangements within the metacentric, telocentric or hexavalent chromosome subsets. The unsynapsed short arms of telocentric chromosomes frequently bound to the single axis of the X chromosome could further complicate the already complex segregation of hexavalent chromosomes.

  17. Detection of Hb Constant Spring (HBA2: c.427T>C) Heterozygotes in Combination with β-Thalassemia or Hb E Trait by Capillary Electrophoresis.

    Pornprasert, Sakorn; Saoboontan, Supansa; Punyamung, Manoo

    2015-01-01

    Hb Constant Spring (Hb CS; HBA2: c.427T>C) is often missed by routine laboratory testing as its mRNA as well as gene product are unstable and presented at a low level in peripheral blood. This study aimed to analyze the efficacy of capillary electrophoresis (CE) for detecting and quantifying of Hb CS in β-thalassemia (β-thal) trait or Hb E (HBB: c.79G>A) trait samples with reduced β-globin chain expression. Thalassemia diagnostic data were reviewed in 2524 blood samples that were submitted to the laboratory of the Associated Medical Sciences Clinical Service Center, Chiang Mai, Thailand for hemoglobinopathy and thalassemia diagnosis. DNA analysis for Hb CS was performed in 322 β-thal trait and 397 Hb E trait samples using the amplification refractory mutation system (ARMS). The CE electropherogram of Hb CS at zone 2 was observed in all five samples with β-thal trait and nine samples with Hb E trait with levels varying from 0.1-2.8 and 0.1-2.3%, respectively. Thus, the CE method proved useful for screening of Hb CS in samples with β-thal trait or Hb E trait, which is essential for providing accurate diagnosis, genetic counseling, prevention and control programs of Hb H-CS disease.

  18. Meiosis and speciation

    Meiotic analysis shows normal overall progression of meiosis in the heterozygotes, which is consistent with their normal gametogenesis. Nevertheless, both the inversion and fusion heterozygotes had undergone some alterations in the regular process of homologous synapsis, and it appeared that certain features of the ...

  19. Pathogen burden, co-infection and major histocompatibility complex variability in the European badger (Meles meles)

    Sin, Yung Wa; Annavi, Geetha; Dugdale, Hannah L.; Newman, Chris; Burke, Terry; MacDonald, David W.

    2014-01-01

    Pathogen-mediated selection is thought to maintain the extreme diversity in the major histocompatibility complex (MHC) genes, operating through the heterozygote advantage, rare-allele advantage and fluctuating selection mechanisms. Heterozygote advantage (i.e. recognizing and binding a wider range

  20. Canalization of Gene Action in the Gossypium Leaf Shape System

    The important, .... Canalization of gene action is important from two aspects. In the first .... indices for the heterozygotes also agree with Silow's actual figures, and it may be inferred .... demic outbreaks which often annihilate the whole stock.

  1. NOD2/CARD15 genotype and common gastrointestinal diseases in 43 600 individuals

    Yazdanyar, S.; Nordestgaard, B.G.

    2010-01-01

    heterozygotes. Cumulative incidences differed by genotype for appendicitis (log-rank P = 0.02), anal fissure, fistula and abscess (P = 0.003) and gastrointestinal cancer (P = 0.004), but not for any of the other endpoints. Compared with non-carriers, age and sex adjusted hazard ratios were 2.7 (95% CI 1...... appendicitis, 646 irritable bowel syndrome, 1301 infectious diseases of the gastrointestinal tract, 681 anal fissure, fistula and abscess, 826 gastrointestinal cancer and 161 developed cancer in liver and pancreas. Results. Some 89% were non-carriers, 11% heterozygotes, 0.15% homozygotes and 0.23% compound.......4-5.5) for appendicitis amongst compound heterozygotes, 3.2 (1.3-7.8) for anal fissure, fistula and abscess amongst compound heterozygotes, and 3.8 (1.6-9.2) for gastrointestinal cancer amongst homozygotes, whilst other genotypes did not have increased risk. The increased risk of gastrointestinal cancer amongst...

  2. The association of XRCC3 Thr241Met genetic variant with risk of ...

    genetic variant could be potentially associated with the risk of prostate cancer. However ... Results: Overall, significant associations were detected in the heterozygote comparison genetic model. (CT versus (vs.) ..... Quantifying hetero- geneity in ...

  3. Elevated globotriaosylsphingosine is a hallmark of Fabry disease

    Aerts, Johannes M.; Groener, Johanna E.; Kuiper, Sijmen; Donker-Koopman, Wilma E.; Strijland, Anneke; Ottenhoff, Roelof; van Roomen, Cindy; Mirzaian, Mina; Wijburg, Frits A.; Linthorst, Gabor E.; Vedder, Anouk C.; Rombach, Saskia M.; Cox-Brinkman, Josanne; Somerharju, Pentti; Boot, Rolf G.; Hollak, Carla E.; Brady, Roscoe O.; Poorthuis, Ben J.

    2008-01-01

    Fabry disease is an X-linked lysosomal storage disease caused by deficiency of alpha-galactosidase A that affects males and shows disease expression in heterozygotes. The characteristic progressive renal insufficiency, cardiac involvement, and neuropathology usually are ascribed to

  4. Genotype Data (Phase II) - D-HaploDB | LSDB Archive [Life Science Database Archive metadata

    Full Text Available ed heterozygote. These typings were judged to be errors because the materials were presumed to be homozygote...ginal Affymetrix data contained a small fraction (< 1%) of SNPs that were genotyp

  5. NOD2/CARD15 genotype, cardiovascular disease and cancer in 43 600 individuals from the general population

    Yazdanyar, S.; Nordestgaard, B.G.

    2010-01-01

    from two large Danish general population cohorts followed for 31 years: the Copenhagen City Heart Study (n = 10 597) and the Copenhagen General Population Study (n = 32 999). We examined the risk of cardiovascular disease (2743 and 3890, respectively, in the two studies) and cancer (2144 and 3241......, respectively) by NOD2/CARD15 genotype using Cox and logistic regressions in both studies. To maximize statistical power, the three NOD2/CARD15 genetic variants were analysed together as follows: noncarriers for all three variants, heterozygotes for one of the three variants and homozygotes for one of the three...... variants pooled with compound heterozygotes for two variants. Results. Multifactorially adjusted hazard ratios for cardiovascular disease and cancer in NOD2/CARD15 heterozygotes or homozygotes/compound heterozygotes versus noncarries did not differ from 1.0 in the Copenhagen City Heart Study...

  6. NOD2/CARD15 genotype and common gastrointestinal diseases in 43 600 individuals

    Yazdanyar, S.; Nordestgaard, B.G.

    2010-01-01

    appendicitis, 646 irritable bowel syndrome, 1301 infectious diseases of the gastrointestinal tract, 681 anal fissure, fistula and abscess, 826 gastrointestinal cancer and 161 developed cancer in liver and pancreas. Results. Some 89% were non-carriers, 11% heterozygotes, 0.15% homozygotes and 0.23% compound...... heterozygotes. Cumulative incidences differed by genotype for appendicitis (log-rank P = 0.02), anal fissure, fistula and abscess (P = 0.003) and gastrointestinal cancer (P = 0.004), but not for any of the other endpoints. Compared with non-carriers, age and sex adjusted hazard ratios were 2.7 (95% CI 1.......4-5.5) for appendicitis amongst compound heterozygotes, 3.2 (1.3-7.8) for anal fissure, fistula and abscess amongst compound heterozygotes, and 3.8 (1.6-9.2) for gastrointestinal cancer amongst homozygotes, whilst other genotypes did not have increased risk. The increased risk of gastrointestinal cancer amongst...

  7. Biochemical and clinical studies in Libyan Jewish cystinuria patients and their relatives.

    Pras, E; Kochba, I; Lubetzky, A; Pras, M; Sidi, Y; Kastner, D L

    1998-11-02

    Cystinuria is a hereditary disorder manifested by the development of kidney stones. Three subtypes of the disease have been described, based on urinary excretion of cystine and the dibasic amino acids in heterozygotes, and oral loading tests in homozygotes. Cystinuria is very common among Libyan Jews living in Israel. Recently, we mapped the disease-causing gene in Libyan Jews to 19q, and have shown a very strong founder effect. In this report we present the results of biochemical and clinical studies performed on Libyan Jewish cystinuria patients and members of their families. High levels of cystine and the dibasic amino acids in heterozygotes support previous data that cystinuria in Libyan Jews is a non-type I disease. Oral loading tests performed with lysine showed some degree of intestinal absorption, but less than in normal controls. Previous criteria for determining the disease type, based solely on urinary amino acid levels, proved useless due to a very wide range of cystine and the dibasic amino acids excreted by the heterozygotes. Urinary cystine levels were useful in distinguishing between unaffected relatives and heterozygotes, but were unhelpful in differentiating between heterozygotes and homozygotes. Urinary levels of ornithine or arginine, and the sum of urinary cystine and the dibasic amino acids, could distinguish between the last two groups. Among stone formers, 90% were homozygotes and 10% were heterozygotes; 15% of the homozygotes were asymptomatic.

  8. Failure to detect variant (CRM+) plasma thromboplastin antecedent (factor XI) molecules in hereditary plasma thromboplastin antecedent deficiency: a study of 125 patients of several ethnic backgrounds.

    Saito, H; Ratnoff, O D; Bouma, B N; Seligsohn, U

    1985-12-01

    Plasma samples of 125 patients from 80 kindreds with hereditary plasma thromboplastin antecedent (PTA, factor XI) deficiency were tested by factor XI radioimmunoassay (RIA) and electroimmunoassay (EIA) in an attempt to detect variant molecules. Ninety-six patients (70 kindreds) were Jewish, and 29 (10 kindreds) were of other ethnic backgrounds, namely, Japanese, black American, Korean, Arab, Indian, and English. Seventy-eight patients were homozygotes, and 47 were heterozygotes. Both non-Jewish homozygotes and heterozygotes had lower factor XI activity than respective Jewish subjects. Twenty-eight homozygotes whose factor XI clotting activities (XI:C) were 1.5% to 13% had factor XI-related antigen (XI:RAG) levels less than 10% by EIA. In 72 homozygotes, including 22 patients who were also tested with EIA, XI:C was 2.9% +/- 3.0% (mean +/- SD) and XI:RAG tested by RIA, 2.9% +/- 3.0%. In 47 heterozygotes, XI:C and XI:RAG tested by RIA were 51.9% +/- 16.6% and 51.0% +/- 16.2%, respectively. Similar results were obtained when only unrelated patients (62 homozygotes and 27 heterozygotes) were analyzed. There was a highly significant correlation between XI:C and XI:RAG (RIA) in 38 homozygotes and 47 heterozygotes (r = 0.94, n = 85, P less than 0.001). Thus, we failed to identify functionally abnormal factor XI molecules (CRM+ variant) in these patients with hereditary factor XI deficiency.

  9. Reduced noise susceptibility in littermate offspring from heterozygous animals of the German waltzing guinea pig.

    Skjönsberg, Åsa; Mannström, Paula

    2015-07-08

    The German waltzing guinea pig is a spontaneously mutated strain with severe auditory and vestibular impairment caused by a so far unknown genetic mutation. The animals are born deaf and show a circling behavior. The heterozygote animals of this guinea pig strain have functionally normal hearing and balance. However, these animals have, in earlier studies, shown an increased resistance to noise compared with normal wild-type guinea pigs. In the present study, we explored the functional hearing with auditory brainstem response thresholds before and at different time points after noise exposure. Symptom-free littermates from heterozygote couples of the German waltzing guinea pigs were exclusively used for the study, which, after the hearing test, were sent back for breeding to confirm their genotype (i.e. heterozygote or normal). The aim of this paper was to ascertain that the previously shown reduced susceptibility to noise trauma in the heterozygote animals of the German waltzing guinea pig was also evident when littermates were used as control animals. The findings are important for further analysis of the heterozygote animals of this strain and for future investigations of the underlying mechanisms behind the diverse susceptibility to exposures of loud sound.

  10. Conserved role of unc-79 in ethanol responses in lightweight mutant mice.

    David J Speca

    2010-08-01

    Full Text Available The mechanisms by which ethanol and inhaled anesthetics influence the nervous system are poorly understood. Here we describe the positional cloning and characterization of a new mouse mutation isolated in an N-ethyl-N-nitrosourea (ENU forward mutagenesis screen for animals with enhanced locomotor activity. This allele, Lightweight (Lwt, disrupts the homolog of the Caenorhabditis elegans (C. elegans unc-79 gene. While Lwt/Lwt homozygotes are perinatal lethal, Lightweight heterozygotes are dramatically hypersensitive to acute ethanol exposure. Experiments in C. elegans demonstrate a conserved hypersensitivity to ethanol in unc-79 mutants and extend this observation to the related unc-80 mutant and nca-1;nca-2 double mutants. Lightweight heterozygotes also exhibit an altered response to the anesthetic isoflurane, reminiscent of unc-79 invertebrate mutant phenotypes. Consistent with our initial mapping results, Lightweight heterozygotes are mildly hyperactive when exposed to a novel environment and are smaller than wild-type animals. In addition, Lightweight heterozygotes exhibit increased food consumption yet have a leaner body composition. Interestingly, Lightweight heterozygotes voluntarily consume more ethanol than wild-type littermates. The acute hypersensitivity to and increased voluntary consumption of ethanol observed in Lightweight heterozygous mice in combination with the observed hypersensitivity to ethanol in C. elegans unc-79, unc-80, and nca-1;nca-2 double mutants suggests a novel conserved pathway that might influence alcohol-related behaviors in humans.

  11. MR imaging of adrenoleukodystrophy

    Uchiyama, M.; Hata, Y.; Tada, S.

    1991-01-01

    We performed MRI in 7 cases with adrenoleukodystrophy (ALD), including 3 cases with childhood ALD, 3 cases with adrenomyeloneuropathy (AMN) and one symptomatic heterozygote. The symptomatic heterozygote was the mother of the patient with AMN. High-field-strength (2.0T) MRI was used in two cases with childhood ALD. In all 3 cases of childhood ALD, MR showed widespread lesions in both cerebral hemispheres. Areas of low intensity in the diencephalon or striatum on heavily T2-weighted images at 2.0T were seen in 2 cases with childhood ALD. Cerebral lesions confined to the internal capsule, cerebral peduncle and optic radiation in the adult onset ALD including AMN and symptomatic heterozygote, have not been reported and this confinement may indicate an early stage of the disease. (orig.)

  12. HFE mutations and hemochromatosis in Danish patients admitted for HFE genotyping

    Koefoed, P; Dalhoff, K; Dissing, J

    2002-01-01

    Analysis of the common C282Y and H63D mutations in the HFE gene is widely used to diagnose hereditary hemochromatosis (HH). The aim of this study was to evaluate the efficiency with which different hospitals and general practitioners select patients for HH genotype and to determine the distribution...... of HFE mutations in such patients. Nine hundred unrelated patients from Danish hospitals and general practitioners (group A) and 69 consecutive patients from a specialized liver unit (group B) were examined for HFE substitutions using multiplex real-time polymerase chain reaction. In group A we found 13...... in the H63D homozygotes or S65C heterozygotes. Moreover, 7 wild-type patients, 2 C282Y heterozygote patients and one H63D heterozygote patient fulfilled the criteria for HH. The significant enrichment of HH among associated genotype samples submitted for HFE testing indicates that the clinical selection...

  13. An in vitro method for screening for the presence of thepat-2 gene in tomatoes (Lycopersicon esculentum Mill.).

    Young, T E; Juvik, J A; Sullivan, J G; Skirvin, R M

    1990-01-01

    Under field conditions,pat-2, the gene which conditions parthenocarpy in tomatoes, is recessive. A simple method has been devised for distinguishing the heterozygote from the two homozygotes using tissue culture. Ovaries of plants segregating for thepat-2 gene were excised and cultured on a medium containing 100 ppm gibberellic acid. After three weeks in culture, three distinct ovary sizes could be seen. It was shown, using F 3 progeny tests, that the largest ovaries corresponded to those plants homozygous for thepat-2 gene, the smallest ovaries corresponded to those plants homozygous for the wild type allele, and the intermediate sized ovaries were the heterozygotes. The ability to identify the heterozygote would greatly simplify a backcross breeding program aimed at incorporating thepat-2 gene into commercial cultivars by eliminating the need for an F 3 progeny test to determine the genotype of a plant.

  14. Transcranial sonography and functional imaging in glucocerebrosidase mutation Parkinson disease.

    Barrett, M J; Hagenah, J; Dhawan, V; Peng, S; Stanley, K; Raymond, D; Deik, A; Gross, S J; Schreiber-Agus, N; Mirelman, A; Marder, K; Ozelius, L J; Eidelberg, D; Bressman, S B; Saunders-Pullman, R

    2013-02-01

    Heterozygous glucocerebrosidase (GBA) mutations are the leading genetic risk factor for Parkinson disease, yet imaging correlates, particularly transcranial sonography, have not been extensively described. To determine whether GBA mutation heterozygotes with Parkinson disease demonstrate hyperechogenicity of the substantia nigra, transcranial sonography was performed in Ashkenazi Jewish Parkinson disease subjects, tested for the eight most common Gaucher disease mutations and the LRRK2 G2019S mutation, and in controls. [(18)F]-fluorodeoxyglucose or [(18)F]-fluorodopa positron emission tomography is also reported from a subset of Parkinson disease subjects with heterozygous GBA mutations. Parkinson disease subjects with heterozygous GBA mutations (n = 23) had a greater median maximal area of substantia nigral echogenicity compared to controls (n = 34, aSNmax = 0.30 vs. 0.18, p = 0.007). There was no difference in median maximal area of nigral echogenicity between Parkinson disease groups defined by GBA and LRRK2 genotype: GBA heterozygotes; GBA homozygotes/compound heterozygotes (n = 4, aSNmax = 0.27); subjects without LRRK2 or GBA mutations (n = 32, aSNmax = 0.27); LRRK2 heterozygotes/homozygotes without GBA mutations (n = 27, aSNmax = 0.28); and GBA heterozygotes/LRRK2 heterozygotes (n = 4, aSNmax = 0.32, overall p = 0.63). In secondary analyses among Parkinson disease subjects with GBA mutations, maximal area of nigral echogenicity did not differ based on GBA mutation severity or mutation number. [(18)F]-fluorodeoxyglucose (n = 3) and [(18)F]-fluorodopa (n = 2) positron emission tomography in Parkinson disease subjects with heterozygous GBA mutations was consistent with findings in idiopathic Parkinson disease. Both transcranial sonography and positron emission tomography are abnormal in GBA mutation associated Parkinson disease, similar to other Parkinson disease subjects. Copyright © 2012 Elsevier Ltd. All rights reserved.

  15. The dosage of the neuroD2 transcription factor regulates amygdala development and emotional learning

    Lin, Chin-Hsing; Hansen, Stacey; Wang, Zhenshan; Storm, Daniel R.; Tapscott, Stephen J.; Olson, James M.

    2005-01-01

    The amygdala is centrally involved in formation of emotional memory and response to fear or risk. We have demonstrated that the lateral and basolateral amygdala nuclei fail to form in neuroD2 null mice and neuroD2 heterozygotes have fewer neurons in this region. NeuroD2 heterozygous mice show profound deficits in emotional learning as assessed by fear conditioning. Unconditioned fear was also diminished in neuroD2 heterozygotes compared to wild-type controls. Several key molecular regulators ...

  16. Quantitative immunoassays for diagnosis and carrier detection in cystic fibrosis

    Bullock, S.; Hayward, C.; Manson, J.; Brock, D.J.H.; Raeburn, J.A.

    1982-01-01

    Quantitative immunoprecipitation and immunoradiometric assays have been developed for a protein present in the serum of cystic fibrosis homozygotes, and to a lesser extent in the serum of heterozygotes. When tested on a panel of sera from 14 cystic fibrosis patients, 29 heterozygotes and 23 controls, the immunoprecipitation assay allowed correct assignments to be made on 94% of occasions with one batch of antiserum and 95% with another. With the same panel of sera, the immunoradiometric assay allowed 94% correct assignments. It is suggested that such accuracy is the maximum that can be expected in the present state of knowledge of cystic fibrosis. (author)

  17. Novel compound heterozygous mutations in the GPR98 (USH2C) gene identified by whole exome sequencing in a Moroccan deaf family.

    Bousfiha, Amale; Bakhchane, Amina; Charoute, Hicham; Detsouli, Mustapha; Rouba, Hassan; Charif, Majida; Lenaers, Guy; Barakat, Abdelhamid

    2017-10-01

    In the present work, we identified two novel compound heterozygote mutations in the GPR98 (G protein-coupled receptor 98) gene causing Usher syndrome. Whole-exome sequencing was performed to study the genetic causes of Usher syndrome in a Moroccan family with three affected siblings. We identify two novel compound heterozygote mutations (c.1054C > A, c.16544delT) in the GPR98 gene in the three affected siblings carrying post-linguale bilateral moderate hearing loss with normal vestibular functions and before installing visual disturbances. This is the first time that mutations in the GPR98 gene are described in the Moroccan deaf patients.

  18. Induced mutations for quantitative traits in rice

    Chakrabarti, B.N.

    1974-01-01

    The characteristics and frequency of micro-mutations induced in quantitative traits by radiation treatment and the extent of heterozygotic effects of different recessive chlorophyll-mutant-genes on quantitative trait has been presented. Mutagenic treatments increased the variance for quantitative traits in all cases although the magnitude of increase varied depending on the treatment and the selection procedure adopted. The overall superiority of the chlorophyll-mutant heterozygotes over the corresponding wild homozygotes, as noted in consecutive two seasons, was not observed when these were grown at a high level of nitrogen fertiliser. (author)

  19. Diagnostic dilemma: a young woman with Fabry disease symptoms, no family history, and a "sequencing cryptic" α-galactosidase a large deletion

    Feldt-Rasmussen, Ulla; Dobrovolny, Robert; Nazarenko, Irina

    2011-01-01

    Fabry disease, an X-linked lysosomal storage disorder, results from the deficient activity of a-galactosidase A (a-Gal A). In affected males, the clinical diagnosis is confirmed by the markedly decreased a-Gal A activity. However, in female heterozygotes, the a-Gal A activity can range from low t...... on enzyme replacement therapy. Thus, gene dosage analyses can detect large deletions (>50bp) in suspect heterozygotes for X-linked and autosomal dominant diseases that are "sequencing cryptic," resolving molecular diagnostic dilemmas....

  20. Implications of compound heterozygous insulin receptor mutations in congenital muscle fibre type disproportion myopathy for the receptor kinase activation

    Klein, H H; Müller, R; Vestergaard, H

    1999-01-01

    We studied insulin receptor kinase activation in two brothers with congenital muscle fibre type disproportion myopathy and compound heterozygous mutations of the insulin receptor gene, their parents, and their unaffected brother. In the father who has a heterozygote Arg1174-->Gln mutation, in sit...

  1. Detection of new single nucleotide polymorphisms by means of real ...

    Unknown

    amplified millions to billions of times by means of a PCR before the PCR product ... Keywords. Single nucleotide polymorphism; real time PCR; DNA melting curve analysis. ... VAL158MET SNP and alcoholism and to test for interac- tions between the .... indicate a heterozygote sample (VAL/MET genotype). The curve with ...

  2. Sequence Classification: 893673 [

    Full Text Available n of unknown function; deletion heterozygote is sensitive to compounds that target ergosterol biosynthesis, ...Non-TMB Non-TMH Non-TMB Non-TMB Non-TMB Non-TMB >gi|6325092|ref|NP_015160.1| Protei

  3. Locus specificity in the mutability of mouse lymphoma strain LY-S

    Evans, H.H.; Mencl, J.; Horng, M.F.

    1985-01-01

    Mouse lymphoma L5178Y strains, LY-R and LY-S, are closely related but differ in their sensitivity to the lethal effects of radiation and various chemicals. Strain LY-S was originally isolated in 1961 following a spontaneous change in the sensitivity of cultured LY-R cells to ionizing radiation. The authors previously reported that, although strain LY-S is more sensitive to the lethal effects of ionizing radiation and alkylating agents than strain LY-R, it is markedly less mutable than strain LY-R at the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus. The isolated sublines of strains LY-R and LY-S which are heterozygous at the thymidine kinase (TK) locus. The LY-S TK+/- heterozygote, like its TK+/+ parent, is more sensitive to the lethal effects of ionizing radiation and alkylating agents and less mutable at the HGPRT locus by these agents than the LY-R TK+/- heterozygote. However, the LY-S heterozygote is 100 times more mutable by these agents at the TK locus than at the HGRT locus. In contrast to LY-R, the majority of the spontaneous and induced LY-S TK-/- mutants form small colonies in the presence of trifluorothymidine, indicating that in the LY-S heterozygote, the inactivation of the TK gene is accompanied by damage to, or rearrangement of neighboring genes

  4. Post-irradiation DNA synthesis inhibition and G2 phase delay in radiosensitive body cells from non-Hodgkin's lymphoma patients: An indication of cell cycle defects

    Hannan, Mohammed A.; Kunhi, Mohammed; Einspenner, Michael; Khan, Bashir A.; Al-Sedairy, Sultan

    1994-01-01

    In the present study, both post-irradiation DNA synthesis and G 2 phase accumulation were analyzed in lymphoblastoid cell lines (LCLs) and fibroblast cell strains derived from (Saudi) patients with non-Hodgkin's lymphoma (NHL), ataxia telangiectasia (AT), AT heterozygotes and normal subjects. A comparison of the percent DNA synthesis inhibition (assayed by 3 H-thymidine uptake 30 min after irradiation), and a 24 h post-irradiation G 2 phase accumulation determined by flow cytometry placed the AT heterozygotes and the NHL patients in an intermediate position between the normal subjects (with maximum DNA synthesis inhibition and minimum G 2 phase accumulation) and the AT homozygotes (with minimum DNA synthesis inhibition and maximum G 2 accumulation). The similarity between AT heterozygotes and the NHL patients with respect to the two parameters studied after irradiation was statistically significant. The data indicating a moderate abnormality in the control of cell cycle progression after irradiation in the LCLs and fibroblasts from NHL patients may explain the enhanced cellular and chromosomal radiosensitivity in these patients reported by us earlier. In addition to demonstrating a link between cell cycle abnormality and radiosensitivity as a possible basis for cancer susceptibility, particularly in the NHL patients, the present studies emphasized the usefulness of the assay for 24 h post-irradiation G 2 phase accumulation developed elsewhere in characterizing AT heterozygote-like cell cycle anomaly in cancer patients irrespective of whether they carried the AT gene or any other affecting the cell cycle

  5. Impact of MCT1 Haploinsufficiency on the Mouse Retina

    Peachey, Neal S.

    2018-05-02

    The monocarboxylate transporter 1 (MCT1) is highly expressed in the outer retina, suggesting that it plays a critical role in photoreceptors. We examined MCT1+/− heterozygotes, which express half of the normal complement of MCT1. The MCT1+/− retina developed normally and retained normal function, indicating that MCT1 is expressed at sufficient levels to support outer retinal metabolism.

  6. Polymorphic microsatellite markers in Taxus chinensis var. mairei ...

    in 1995 and is one of the first-grade state protection plants. (The State Council of ... marker system in population genetics analysis (Walter and. Epperson 2001) .... heterozygote deficiency may be due to the presence of null alleles at the three ...

  7. Pathogen-mediated selection for MHC variability in wild zebrafish

    Smith, C.; Ondračková, Markéta; Spence, R.; Adams, S.; Betts, D. S.; Mallon, E.

    2011-01-01

    Roč. 13, č. 6 (2011), s. 589-605 ISSN 1522-0613 Institutional support: RVO:68081766 Keywords : digenean * frequency-dependent selection * heterozygote advantage * major histocompatibility complex * metazoan parasite * pathogen-driven selection Subject RIV: EG - Zoology Impact factor: 1.029, year: 2011

  8. Impact of MCT1 Haploinsufficiency on the Mouse Retina

    Peachey, Neal S.; Yu, Minzhong; Han, John Y. S.; Lengacher, Sylvain; Magistretti, Pierre J.; Pellerin, Luc; Philp, Nancy J.

    2018-01-01

    The monocarboxylate transporter 1 (MCT1) is highly expressed in the outer retina, suggesting that it plays a critical role in photoreceptors. We examined MCT1+/− heterozygotes, which express half of the normal complement of MCT1. The MCT1+/− retina developed normally and retained normal function, indicating that MCT1 is expressed at sufficient levels to support outer retinal metabolism.

  9. A novel phenotype of a hepatocyte nuclear factor homeobox A (HNF1A) gene mutation, presenting with neonatal cholestasis

    de Vries, Aleida G. M.; Bakker-van Waarde, Willie M.; Dassel, Anne C. M.; Losekoot, Monique; Duiker, Evelien W.; Gouw, Annette S. H.; Bodewes, Frank A. J. A.

    We report a novel phenotype of a hepatocyte nuclear factor homeobox A (HNF1A) mutation (heterozygote c.130dup, p.Leu44fs) presenting with transient neonatal cholestasis, subsequently followed by persistent elevation of transaminases, maturity-onset diabetes of the young (MODY) type 3 and

  10. 40 CFR 798.5460 - Rodent heritable translocation assays.

    2010-07-01

    ... fertile animals for cytological confirmation as translocation heterozygotes. (3) Animal selection—(i... administration include oral, inhalation, admixture with food or water, and IP or IV injection. (e) Test.... Criteria for determining normal and semisterile males are usually established for each new strain because...

  11. Clinical relevance and cost-effectiveness of HLA genotyping in children with Type 1 diabetes mellitus in screening for coeliac disease in the Netherlands.

    Elias, J; Hoorweg-Nijman, J J G; Balemans, W A

    2015-06-01

    To investigate the clinical relevance and cost-effectiveness of human leukocyte antigen (HLA)-genotyping in the Netherlands as a screening tool for the development of coeliac disease in children with Type 1 diabetes mellitus. A retrospective analysis was performed in 110 children with Type 1 diabetes mellitus diagnosed between January 1996 and January 2013. All children were screened for coeliac disease using coeliac disease-specific antibodies and HLA genotyping was performed in all children. One hundred and ten children were screened for coeliac disease, and coeliac disease could be confirmed in seven. Eighty-six per cent of the children with Type 1 diabetes mellitus had one of the variants of HLA-DQ2.5 and DQ8. HLA genotypes observed in children with Type 1 diabetes mellitus children and coeliac disease were heterozygote DQ2.5, homozygote DQ2.5 and heterozygote DQ2.5/DQ8. HLA genotyping in coeliac disease screening in children with Type 1 diabetes mellitus is more expensive than screening for coeliac disease with antibodies alone (€326 vs. €182 per child). The risk of coeliac disease development in children with Type 1 diabetes mellitus is increased when they are heterozygote DQ2.5/DQ8, homozygote or heterozygote DQ2.5. The implementation of HLA genotyping as a first-line screening tool has to be reconsidered because it is not distinctive or cost-effective. © 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.

  12. A comprehensive screening program for β-thalassemia and other hemoglobinopathies in the Hooghly District of West Bengal, India, dealing with 21 137 cases.

    Bhattacharyya, Kallol Kumar; Chatterjee, Tridip; Mondal, Ujjalendu Bikash

    2016-11-01

    We here present a report of population screening programs (January 2012-December 2015) conducted by the Thalassemia Control Unit, Imambara Sadar Hospital, Chinsurah, Hooghly in the Hooghly District of West Bengal, India for prevention of thalassemia. We screened β-thalassemia (β-thal) heterozygotes and homozygotes, and Hb E (HBB: c.79G > A)-β-thal compound heterozygotes. Among 21 137 cases, we found 1968 heterozygotes and 192 homozygotes or compound heterozygotes. Results were evaluated with standard hematological analyses including red cell indices, hemoglobin (Hb) typing and quantification. The participants of the screening program were divided into six groups (children, pre-marriage cases, post-marital cases, family members of affected individuals, family members of carriers and pregnant women). While considering the average frequency of carriers, many reports recorded both related individuals (family members of trait and affected individuals) as well as unrelated individuals such as school children and pregnant women. These would have to be considered separately and only the unrelated individuals taken to estimate carrier frequencies in this article that would give more realistic data on carrier frequency of unrelated individuals.

  13. Occurrence of differential meiotic associations and additional ...

    A small population of complex translocation heterozygote plants of Allium roylei from the Bani region of Jammu Province was studied for meiosis in the female track. This study resulted in identification of two variants, having embryo-sac mother cells (EMCs) with more than 16 chromosomes. EMCs of the remaining plants ...

  14. Assay for mutagenesis in heterozygous diploid human lymphoblasts

    Skopek, Thomas R.; Liber, Howard L.; Penman, Bruce W.; Thilly, William G.; Hoppe, IV, Henry

    1981-01-01

    An assay is disclosed for determining mutagenic damage caused by the administration of a known or suspected mutagen to diploid human lymphoblastoid cell lines. The gene locus employed for this assay is the gene for thymidine kinase, uridine kinase, or cytidine deaminase. Since human lymphoblastoid cells contain two genes for these enzymes, heterozygotes of human lymphoblastoid cells are used in this assay.

  15. A DUF-246 family glycosyltransferase-like gene affects male fertility and the biosynthesis of pectic arabinogalactans

    Stonebloom, Solomon; Ebert, Berit; Xiong, Guangyan

    2016-01-01

    rates of pollen tube formation in pollen from pagr heterozygotes. To characterize a loss-of-function phenotype for PAGR, the Nicotiana benthamiana orthologs, NbPAGR-A and B, were transiently silenced using Virus Induced Gene Silencing. NbPAGR-silenced plants exhibited reduced internode and petiole...

  16. Metabolic rate changes proportionally to circadian frequency in tau mutant Syrian hamsters

    Oklejewicz, M; Hut, RA; Daan, S; Loudon, ASI; Stirland, AJ; Loudon, Andrew S.I.; Stirland, Anne J.

    1997-01-01

    The tau mutation in Syrian hamsters (Mesocricetus auratus) is phenotypically expressed in a period of the circadian rhythm of about 20 h in homozygotes (SS) and about 22 h in heterozygotes (S+). The authors investigate whether this well-defined model for variation in circadian period exhibits

  17. Synthetic review on the different anthropological aspects of ...

    Hemoglobinopathies are a group of hereditary hemolytic anemia characterized by qualitative (sickle cell disease) or quantitative (thalassemia) defects in the alpha or beta-globin chain synthesis. Homozygotes or compound heterozygotes for the mutated alpha or beta-globin genes can cause severe anemia at an early age.

  18. Single locus complementary sex determination in Hymenoptera : an "unintelligent" design?

    Wilgenburg, Ellen van; Driessen, Gerard; Beukeboom, Leo W.

    2006-01-01

    The haplodiploid sex determining mechanism in Hymenoptera (males are haploid, females are diploid) has played an important role in the evolution of this insect order. In Hymenoptera sex is usually determined by a single locus, heterozygotes are female and hemizygotes are male. Under inbreeding,

  19. Single locus complementary sex determination in Hymenoptera: an "unintelligent" design?

    van Wilgenburg, E.; Driessen, G.J.J.; Beukeboom, L.W.

    2006-01-01

    The haplodiploid sex determining mechanism in Hymenoptera (males are haploid, females are diploid) has played an important role in the evolution of this insect order. In Hymenoptera sex is usually determined by a single locus, heterozygotes are female and hemizygotes are male. Under inbreeding,

  20. Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease

    Frikke-Schmidt, R.; Nordestgaard, B.G.; Stene, M.C.A.

    2008-01-01

    increased risk of ischemic heart disease ( IHD). Design, Setting, and Participants Three studies of white individuals from Copenhagen, Denmark, were used: the Copenhagen City Heart Study ( CCHS), a 31-year prospective general population study ( n= 9022; 28 heterozygotes); the Copenhagen General Population...

  1. Slow inbred lines of Drosophila melanogaster express as much inbreeding depression as fast inbred lines under semi-natural conditions

    Kristensen, Torsten Nygård; Knudsen, Morten Ravn; Loeschcke, Volker

    2011-01-01

    Selection may reduce the deleterious consequences of inbreeding. This may be due to purging of recessive deleterious alleles or balancing selection favouring heterozygote offspring. Such selection is expected to be more efficient at slower compared to at faster rates of inbreeding. In this study ...

  2. Comparison of the optimized conditions for genotyping of ACE ID ...

    STORAGESEVER

    2009-10-19

    Oct 19, 2009 ... variants (Koyama et al., 2008). This method removed the chances of mistyping and gave 100% accuracy in the confirmation of ID heterozygotes but expenses of chromatography did not prove it to be cost effective. Normally, genomic DNA is used as template DNA for. PCR based studies. It is very difficult to ...

  3. A meiotic study of two translocations and a tertiary trisomic in the mouse (Mus musculus)

    Boer, de P.

    1975-01-01

    In this section, the order of the articles has not been closely followed. Each point ends with the number(s) of the article(s) (as given in the contents), where the conclusion is based on.

    1) Cytological meiotic studies of T(2;8)26H and T(1;13)70H heterozygotes and Ts(1

  4. Red Queen Processes Drive Positive Selection on Major Histocompatibility Complex (MHC Genes.

    Maciej Jan Ejsmond

    2015-11-01

    Full Text Available Major Histocompatibility Complex (MHC genes code for proteins involved in the incitation of the adaptive immune response in vertebrates, which is achieved through binding oligopeptides (antigens of pathogenic origin. Across vertebrate species, substitutions of amino acids at sites responsible for the specificity of antigen binding (ABS are positively selected. This is attributed to pathogen-driven balancing selection, which is also thought to maintain the high polymorphism of MHC genes, and to cause the sharing of allelic lineages between species. However, the nature of this selection remains controversial. We used individual-based computer simulations to investigate the roles of two phenomena capable of maintaining MHC polymorphism: heterozygote advantage and host-pathogen arms race (Red Queen process. Our simulations revealed that levels of MHC polymorphism were high and driven mostly by the Red Queen process at a high pathogen mutation rate, but were low and driven mostly by heterozygote advantage when the pathogen mutation rate was low. We found that novel mutations at ABSs are strongly favored by the Red Queen process, but not by heterozygote advantage, regardless of the pathogen mutation rate. However, while the strong advantage of novel alleles increased the allele turnover rate, under a high pathogen mutation rate, allelic lineages persisted for a comparable length of time under Red Queen and under heterozygote advantage. Thus, when pathogens evolve quickly, the Red Queen is capable of explaining both positive selection and long coalescence times, but the tension between the novel allele advantage and persistence of alleles deserves further investigation.

  5. AlleleCoder: a PERL script for coding codominant polymorphism data for PCA analysis

    A useful biological interpretation of diploid heterozygotes is in terms of the dose of the common allele (0, 1 or 2 copies). We have developed a PERL script that converts FASTA files into coded spreadsheets suitable for Principal Component Analysis (PCA). In combination with R and R Commander, two- ...

  6. Variations of Human DNA Polymerase Genes as Biomarkers of Prostate Cancer Progression

    2011-07-01

    Pesche S, Latil A, Muzeau F, Cussenot O, Fournier G, Longy M, Eng C, Lidereau R. 1998. PTEN/MMAC1/TEP1 involvement in primary prostate cancers. Oncogene 16...skin fibroblasts from heterozygotes for the Lesch-Nyhan syndrome : a sensitive marker for carrier detection. Hum Hered 29:64–68. 48 HUMAN MUTATION, Vol

  7. FADS single-nucleotide polymorphisms are associated with behavioral outcomes in children, and the effect varies between sexes and is dependent on PPAR genetype

    Nielsen, Maria Søgaard; AR Jensen, Heidi; BS Harsløf, Laurine

    2014-01-01

    of breastfeeding as well as by gender-specific analysis if indicated by interactions.Results: SNP-gender interactions were found for both communication and problem solving (p=0.008-0.025). Relative to wild type individuals female rs174448 heterozygotes had better communication (=4.895%CI: 0.7;9.0) and problem...

  8. Excision repair of bulky lesions in the DNA of mammalian cells

    Setlow, R.B.; Grist, E.

    1980-01-01

    The report examines the process of excision repair of pyrimidine dimers from uv-irradiated and chemically challenged human cells. It is shown by means of a sensitive endonuclease assay that the amount of excision observed depends upon the isotope used to label cells, and that XP heterozygotes are between normals and XPs

  9. Resolving the Conflict Between Associative Overdominance and Background Selection

    Zhao, Lei; Charlesworth, Brian

    2016-01-01

    In small populations, genetic linkage between a polymorphic neutral locus and loci subject to selection, either against partially recessive mutations or in favor of heterozygotes, may result in an apparent selective advantage to heterozygotes at the neutral locus (associative overdominance) and a retardation of the rate of loss of variability by genetic drift at this locus. In large populations, selection against deleterious mutations has previously been shown to reduce variability at linked neutral loci (background selection). We describe analytical, numerical, and simulation studies that shed light on the conditions under which retardation vs. acceleration of loss of variability occurs at a neutral locus linked to a locus under selection. We consider a finite, randomly mating population initiated from an infinite population in equilibrium at a locus under selection. With mutation and selection, retardation occurs only when S, the product of twice the effective population size and the selection coefficient, is of order 1. With S >> 1, background selection always causes an acceleration of loss of variability. Apparent heterozygote advantage at the neutral locus is, however, always observed when mutations are partially recessive, even if there is an accelerated rate of loss of variability. With heterozygote advantage at the selected locus, loss of variability is nearly always retarded. The results shed light on experiments on the loss of variability at marker loci in laboratory populations and on the results of computer simulations of the effects of multiple selected loci on neutral variability. PMID:27182952

  10. Population Genetics and Genetic Variability ofBulinus globosus (Gastropoda: Planorbidae) From the Two Main River Systems in Zimbabwe

    Mukaratirwa, S.; Siegismund, Hans Redlef; Kristensen, Thomas K.

    1996-01-01

    screened eight loci were resolved, and six of them were polymorphic in at least one of the populations sampled. Genotypic distributions showed deviations from Hardy-Weinberg proportions due to deficiency of heterozygotes and this was attributed to selfing. The Save River drainage system, which falls under...

  11. HLA-G polymorphisms in couples with recurrent spontaneous abortions

    Hviid, T V; Hylenius, S; Hoegh, A M

    2002-01-01

    % of the RSA women carried the HLA-G*0106 allele compared to 2% of the control women. The 14 bp deletion polymorphism in exon 8 was investigated separately. There were a greater number of heterozygotes for the 14 bp polymorphism in the group of fertile control women than expected, according to Hardy-Weinberg...

  12. HLA-DPB1 typing with polymerase chain reaction and restriction fragment length polymorphism technique in Danes

    Hviid, T V; Madsen, H O; Morling, N

    1992-01-01

    endonucleases: RsaI, FokI, ApaI, SacI, BstUI, EcoNI, and DdeI, and the DNA fragments were separated by electrophoresis in agarose gels. Altogether, 71 individuals were investigated and 16 different HLA-DPB1 types were observed in 26 different heterozygotic combinations, as well as five possible homozygotes...

  13. Two novel mutations in surfactant protein-C, lung function and obstructive lung disease

    Baekvad-Hansen, Marie; Nordestgaard, Børge G; Tybjaerg-Hansen, Anne

    2010-01-01

    ,604) and the Copenhagen General Population Study(n=37,337) to assess the clinical relevance of these mutations. Genotyping identified 36 individuals heterozygous for A53T and 3 individuals heterozygous for Y106X. A53T heterozygotes and Y106X heterozygotes did not differ from non-carriers in FEV(1)% predicted, FVC...... or disease in the general population. We resequenced the SFTPC gene in 760 individuals and identified 18 genetic variants, of which 5 were novel. Of the five novel mutations, two were situated in highly conserved areas of the SFTPC gene: A53T and Y106X. We genotyped the Copenhagen City Heart Study(n=10......% predicted or FEV(1)/FVC. A53T heterozygotes had a two-fold increased risk for asthma in the Copenhagen City Heart Study and Copenhagen General Population Study combined (adjusted odds ratio 2.2(1.0-4.9)). A53T heterozygotes did not differ consistently from non-carriers in risk of chronic obstructive...

  14. Superoxide Dismutase 3 Polymorphism Associated with Reduced Lung Function in Two Large Populations

    Dahl, Morten; Bowler, Russell P; Juul, Klaus

    2008-01-01

    . Measurements and Main Results: Genotyping the Copenhagen City Heart Study identified 35 E1/I1 homozygotes, 1,050 heterozygotes, and 8,008 noncarriers (Hardy-Weinberg equilibrium: P = 0.93). Using quadruple lung function measurements, we found that E1/I1 homozygotes had 7% lower FVC % predicted (P = 0...

  15. Population estimators or progeny tests: what is the best method to assess null allele frequencies at SSR loci?

    Oddou-Muratorio, S.; Vendramin, G.G.; Buiteveld, J.; Fady, B.

    2009-01-01

    Nuclear SSRs are notorious for having relatively high frequencies of null alleles, i.e. alleles that fail to amplify and are thus recessive and undetected in heterozygotes. In this paper, we compare two kinds of approaches for estimating null allele frequencies at seven nuclear microsatellite

  16. Defective immuno- and thymoproteasome assembly causes severe immunodeficiency

    Treise, Irina; Huber, Eva M.; Klein-Rodewald, Tanja

    2018-01-01

    By N-ethyl-N-nitrosourea (ENU) mutagenesis, we generated the mutant mouse line TUB6 that is characterised by severe combined immunodeficiency (SCID) and systemic sterile autoinflammation in homozygotes, and a selective T cell defect in heterozygotes. The causative missense point mutation results...

  17. The Analysis Mutation Of The CARD 15 Gene Variants In Chronic Periodontis

    Bahruddin Thalib, Dr.drg. M.Kes,Sp.Pros.

    2014-01-01

    As Conclusion, CARD 15 gene mutation with chronic periodontitis was found to have heterozygote mutation and homozygote mutation variants, and also found genetics variation that changed the composition of C??? T nucleotide at codon 802 in exon 4 amino acid changed from alanine to valine. Purpose of This study was to determine the variant of card 15 gene mutation with periodontitis chronic.

  18. ISO 17025 validation of a next-generation sequencing assay for relationship testing

    Buchard, Anders; Kampmann, Marie-Louise; Poulsen, Lena

    2016-01-01

    17025 accredited laboratory in 2015. Here, the essential parts of the validation report submitted to the Danish Accreditation Fund are presented. A total of 100 unrelated Danes were typed in duplicates and the locus balance, heterozygote balance (Hb) and noise levels were analysed in detail. Two loci...

  19. Genetic characterization of Zanskari breed of horse

    known for their ability to survive on scarce food in the win- ter snow-bound months and yet ... liability, are the markers of choice for evaluation of genetic diversity of a ... cant heterozygotic excess in both infinite allele model (IAM) and sequential ...

  20. The Frequency of Factor V Leiden, Prothrombin G20210A and Methylenetetrahydrofolate Reductase C677T Mutations in Migraine Patients

    Ruhsen Öcal

    2010-12-01

    Full Text Available OBJECTIVE: Migraine is an independent risk factor for ischemic stroke, but its pathophysiology is still unclear. Genetic factors that predispose patients to thrombosis have been studied in patients with migraine to highlight the pathogenesis, but the results remain controversial. In this study, the frequencies of factor V Leiden (FVL, prothrombin (Pt G20210A and methylenetetrahydrofolate reductase (MTHFR C677T mutations were investigated. METHODS: One hundred and sixty patients aged of 15 to 55 years with no history of systemic disease and who had been diagnosed as migraine according to the International Headache Society (IHS diagnostic criteria at Baskent University Hospital Neurology Outpatient Clinics were investigated for FVL, Pt G20210A and MTHFR C677T mutations from their genomic DNA, and the results were compared with those of healthy controls. RESULTS: One hundred and fifty five (96.9% of 160 migraine patients were homozygote normal, 5 (3.1% were heterozygote and none of them were homozygote mutant for FVL. The control group had 9.8% heterozygote individuals but the difference between the percentages was not statistically significant (p> 0.05. There were no homozygote mutant individuals in the Turkish population study in normal subjects like our study. Thirty nine (24.4% of 160 migraine patients were heterozygote and 8 (5% were homozygote mutant for MTHFR C677T. The control group had 37 (34.9% heterozygote and 6 (5.6% homozygote mutant individuals. The difference between the percentages was not statistically significant (p= 0.15. Three (1.9% of 160 migraine patients were heterozygote and 5 (2.9% of the control group were heterozygote mutant for Pt G20210A mutation. The control group had 37 (34.9% heterozygote and 6 (5.6% homozygote mutant individuals. The difference between the percentages was not statistically significant (p= 0.420. CONCLUSION: Our study indicates that FVL, Pt G20210A and MTHFR C677T gene mutations, which are considered

  1. The Frequency of Factor V Leiden, Prothrombin G20210A and Methylenetetrahydrofolate Reductase C677T Mutations in Migraine Patients

    Ruhsen Öcal

    2010-12-01

    Full Text Available OBJECTIVE: Migraine is an independent risk factor for ischemic stroke, but its pathophysiology is still unclear. Genetic factors that predispose patients to thrombosis have been studied in patients with migraine to highlight the pathogenesis, but the results remain controversial. In this study, the frequencies of factor V Leiden (FVL, prothrombin (Pt G20210A and methylenetetrahydrofolate reductase (MTHFR C677T mutations were investigated. METHODS: One hundred and sixty patients aged of 15 to 55 years with no history of systemic disease and who had been diagnosed as migraine according to the International Headache Society (IHS diagnostic criteria at Baskent University Hospital Neurology Outpatient Clinics were investigated for FVL, Pt G20210A and MTHFR C677T mutations from their genomic DNA, and the results were compared with those of healthy controls. RESULTS: One hundred and fifty five (96.9% of 160 migraine patients were homozygote normal, 5 (3.1% were heterozygote and none of them were homozygote mutant for FVL. The control group had 9.8% heterozygote individuals but the difference between the percentages was not statistically significant (p> 0.05. There were no homozygote mutant individuals in the Turkish population study in normal subjects like our study. Thirty nine (24.4% of 160 migraine patients were heterozygote and 8 (5% were homozygote mutant for MTHFR C677T. The control group had 37 (34.9% heterozygote and 6 (5.6% homozygote mutant individuals. The difference between the percentages was not statistically significant (p= 0.15. Three (1.9% of 160 migraine patients were heterozygote and 5 (2.9% of the control group were heterozygote mutant for Pt G20210A mutation. The control group had 37 (34.9% heterozygote and 6 (5.6% homozygote mutant individuals. The difference between the percentages was not statistically significant (p= 0.420. CONCLUSION: Our study indicates that FVL, Pt G20210A and MTHFR C677T gene mutations, which are considered

  2. Laboratory studies bearing on pigment pattern polymorphisms in wild populations of Rana pipiens.

    Merrell, D J

    1972-01-01

    Data are presented for 2,393 progeny from a number of crosses related to a study in ecological genetics of the Burnsi and Kandiyohi polymorphisms in natural populations of the leopard frog, Rana pipiens. No significant differences in viability were found between wild-type homozygotes (+/+) and Burnsi heterozygotes (B/+) or homozygotes (B/B). Similarly, no difference in viability was found between wild-type (+/+) and Kandiyohi heterozygotes (K/+) and homozygotes (K/K). However, there appears to be slight reduction in viability of the double dominant heterozygote (B/+; K/+) in comparison with (+/+), (B/+), and (K/+) progeny from the same cross.-The Kandiyohi heterozygotes (K/+) appeared to have a more rapid rate of development from fertilization through metamorphosis than wild-type (+/+) or Burnsi (B+/) or Burnsi-Kandiyohi heterozygotes (B+K/+). Since Kandiyohi is associated primarily with the prairie habitat (Merrell 1965), this finding suggests that the adaptive advantage of Kandiyohi lies in the more rapid rate of development of frogs carrying this gene, enabling them to complete metamorphosis before the prairie breeding ponds dry up.-Data are presented from crosses involving dorsal spot number. The results suggest that heredity plays a role in the determination of dorsal spot number but that non-genetic influences are also of considerable importance.-The results of these crosses are discussed with respect to their bearing on the formation of pigment patterns in Rana pipiens. From the available data it is clear that the pigment pattern in Rana pipiens is a complex trait influenced by major gene loci, by modifying genes, and by environmental effects. The relative importance of these factors varies depending on the particular combination of genetic and environmental conditions.

  3. Mutation spectrum of β-globin gene in thalassemia patients at Hasan Sadikin Hospital - West Java Indonesia.

    Maskoen, Ani Melani; Rahayu, Nurul S; Reniarti, Lelani; Susanah, Susi; Laksono, Bremmy; Fauziah, Prima Nanda; Zada, Almira; Hidayat, Dadang S

    2017-12-30

    Thalassemia is the most common hereditary haemolytic anemia in Southeast Asia, in which Indonesia is among countries that are at a high risk for thalassemia. It has been reported that mutation in the beta-globin gene is responsible in severe Thalassemia. However, the spectrum of beta-globin gene mutations in Indonesian population varies in different regions . Thus, this study aimed to identify the most prevalent mutation of Thalassemia patients from the Hasan Sadikin Hospital, Bandung, using this as a reference hospital for Thalassemia in West Java. The three most prevalent mutations of beta globin (IVS1nt5, Cd26 (HbE), and IVS1nt1), were conducted in the beginning of this study. Mutations of 291 samples were detected by PCR-RFLP in the Molecular Genetic Laboratory, Faculty of Medicine Universitas Padjadjaran, Bandung. The prevalence of the beta globin gene mutation types were 47.4% IVS1nt5 homozygote, 9.9% compound heterozygote IVS1nt5/HbE, 5.4% compound heterozygote IVS1nt5/IVS1nt1, 1.4% compound heterozygote HbE/IVS1nt1, 1% HbE homozygote, 14.4% Compound heterzygote IVS1nt5/… (no paired mutation), 2.06% compound heterozygote HbE/… (no paired mutation), 1.3% compound heterozygote IVS1nt1/… (no paired mutation), and 7 samples were unidentified. The thalassemia mutation IVS1nt5 homozygote is the most common mutation found in Thalassemia patients at Hasan Sadikin Hospital, Bandung. The samples with unidentified results might carry mutations other than the three that are observed in the present study.

  4. Cooperative function of Pdx1 and Oc1 in multipotent pancreatic progenitors impacts postnatal islet maturation and adaptability.

    Kropp, Peter A; Dunn, Jennifer C; Carboneau, Bethany A; Stoffers, Doris A; Gannon, Maureen

    2018-04-01

    The transcription factors pancreatic and duodenal homeobox 1 (Pdx1) and onecut1 (Oc1) are coexpressed in multipotent pancreatic progenitors (MPCs), but their expression patterns diverge in hormone-expressing cells, with Oc1 expression being extinguished in the endocrine lineage and Pdx1 being maintained at high levels in β-cells. We previously demonstrated that cooperative function of these two factors in MPCs is necessary for proper specification and differentiation of pancreatic endocrine cells. In those studies, we observed a persistent decrease in expression of the β-cell maturity factor MafA. We therefore hypothesized that Pdx1 and Oc1 cooperativity in MPCs impacts postnatal β-cell maturation and function. Here our model of Pdx1-Oc1 double heterozygosity was used to investigate the impact of haploinsufficiency for both of these factors on postnatal β-cell maturation, function, and adaptability. Examining mice at postnatal day (P) 14, we observed alterations in pancreatic insulin content in both Pdx1 heterozygotes and double heterozygotes. Gene expression analysis at this age revealed significantly decreased expression of many genes important for glucose-stimulated insulin secretion (e.g., Glut2, Pcsk1/2, Abcc8) exclusively in double heterozygotes. Analysis of P14 islets revealed an increase in the number of mixed islets in double heterozygotes. We predicted that double-heterozygous β-cells would have an impaired ability to respond to stress. Indeed, we observed that β-cell proliferation fails to increase in double heterozygotes in response to either high-fat diet or placental lactogen. We thus report here the importance of cooperation between regulatory factors early in development for postnatal islet maturation and adaptability.

  5. The effect of multiple simple Robertsonian heterozygosity on chromosome pairing and fertility of wild-stock house mice (Mus musculus domesticus).

    Wallace, B M N; Searle, J B; Everett, C A

    2002-01-01

    The influence of Robertsonian (Rb) heterozygosity on fertility has been the subject of much study in the house mouse. However, these studies have been largely directed at single simple heterozygotes (heterozygous for a single Rb metacentric) or complex heterozygotes (heterozygous for several to many metacentrics which share common chromosome arms). In this paper we describe studies on male multiple simple heterozygotes, specifically the F(1) products of crosses between wild-stock mice homozygous for four or seven metacentrics and wild-stock mice with a standard all-acrocentric karyotype; these F(1) products were characterized by four and seven trivalents at meiosis I, respectively. Mice with the same karyotype, but two different genetic backgrounds were examined. Although a range of meiotic and fertility studies were conducted, particular emphasis was paid to analysis of chromosome pairing, previously not well-described in multiple simple heterozygous mice. The progression of spermatocytes through prophase I was followed by electron microscopy of surface spread material. As previously shown for single simple Rb heterozygotes, the trivalents that characterize multiple simple heterozygotes initially showed delayed pairing of the centromeric region and later showed side arm formation, resulting from non-homologous pairing by the centromeric ends of the acrocentric chromosomes. In the four trivalent groups of mice, 15 and 32% of trivalents showed unpairing in the centromeric region at mid pachytene; equivalent values were 29 and 39% for the seven trivalent groups. Pairing abnormalities (largely attachments and interlocks between trivalents and between a trivalent and the XY configuration) were observed in 18 and 23% of mid pachytene cells in the four trivalent groups and 36 and 49% of cells in the seven trivalent groups. The greater level of pachytene irregularity (unpairing and pairing abnormalities) in seven versus four trivalent heterozygotes was mirrored in terms

  6. Hybrid recreation by reverse breeding in Arabidopsis thaliana.

    Wijnker, Erik; Deurhof, Laurens; van de Belt, Jose; de Snoo, C Bastiaan; Blankestijn, Hetty; Becker, Frank; Ravi, Maruthachalam; Chan, Simon W L; van Dun, Kees; Lelivelt, Cilia L C; de Jong, Hans; Dirks, Rob; Keurentjes, Joost J B

    2014-04-01

    Hybrid crop varieties are traditionally produced by selecting and crossing parental lines to evaluate hybrid performance. Reverse breeding allows doing the opposite: selecting uncharacterized heterozygotes and generating parental lines from them. With these, the selected heterozygotes can be recreated as F1 hybrids, greatly increasing the number of hybrids that can be screened in breeding programs. Key to reverse breeding is the suppression of meiotic crossovers in a hybrid plant to ensure the transmission of nonrecombinant chromosomes to haploid gametes. These gametes are subsequently regenerated as doubled-haploid (DH) offspring. Each DH carries combinations of its parental chromosomes, and complementing pairs can be crossed to reconstitute the initial hybrid. Achiasmatic meiosis and haploid generation result in uncommon phenotypes among offspring owing to chromosome number variation. We describe how these features can be dealt with during a reverse-breeding experiment, which can be completed in six generations (∼1 year).

  7. HLA-DPB1 typing with polymerase chain reaction and restriction fragment length polymorphism technique in Danes

    Hviid, Thomas Vauvert F.; Madsen, Hans O; Morling, Niels

    1992-01-01

    We have used the polymerase chain reaction (PCR) in combination with the restriction fragment length polymorphism (RFLP) technique for HLA-DBP1 typing. After PCR amplification of the polymorphic second exon of the HLA-DPB1 locus, the PCR product was digested with seven allele-specific restriction...... endonucleases: RsaI, FokI, ApaI, SacI, BstUI, EcoNI, and DdeI, and the DNA fragments were separated by electrophoresis in agarose gels. Altogether, 71 individuals were investigated and 16 different HLA-DPB1 types were observed in 26 different heterozygotic combinations, as well as five possible homozygotes....... Four heterozygotes could not be unequivocally typed with the PCR-RFLP method. The HLA-DPB1 typing results obtained with the PCR-RFLP method were compared with the typing results obtained with PCR allele-specific oligonucleotides (PCR-ASO) in 50 individuals. The results obtained with the two methods...

  8. Cell and Molecular Biology of Ataxia Telangiectasia Heterozygous Human Mammary Epithelial Cells Irradiated in Culture

    Richmond, Robert C.

    2001-01-01

    Autologous isolates of cell types from obligate heterozygotes with the autosomal disorder ataxia-telangiectasia (A-T)were used to begin a tissue culture model for assessing pathways of radiation-induced cancer formation in this target tissue. This was done by establishing cultures of stromal fibroblasts and long-term growth human mammary epithelial cells (HMEC) in standard 2-dimensional tissue culture in order to establish expression of markers detailing early steps of carcinogenesis. The presumptive breast cancer susceptibility of A-T heterozygotes as a sequel to damage caused by ionizing radiation provided reason to study expression of markers in irradiated HMEC. Findings from our study with HMEC have included determination of differences in specific protein expression amongst growth phase (e.g., log vs stationary) and growth progression (e.g., pass 7 vs pass 9), as well as differences in morphologic markers within populations of irradiated HMEC (e.g., development of multinucleated cells).

  9. A pragmatic randomized controlled trial of thiopurine methyltransferase genotyping prior to azathioprine treatment: the TARGET study.

    Newman, William G; Payne, Katherine; Tricker, Karen; Roberts, Stephen A; Fargher, Emily; Pushpakom, Sudeep; Alder, Jane E; Sidgwick, Gary P; Payne, Debbie; Elliott, Rachel A; Heise, Marco; Elles, Robert; Ramsden, Simon C; Andrews, Julie; Houston, J Brian; Qasim, Faeiza; Shaffer, Jon; Griffiths, Christopher E M; Ray, David W; Bruce, Ian; Ollier, William E R

    2011-06-01

    To conduct a pragmatic, randomized controlled trial to assess whether thiopurine methyltransferase (TPMT) genotyping prior to azathioprine reduces adverse drug reactions (ADRs). A total of 333 participants were randomized 1:1 to undergo TPMT genotyping prior to azathioprine or to commence treatment without genotyping. There was no difference in the primary outcome of stopping azathioprine due to an adverse reaction (ADR, p = 0.59) between the two study arms. ADRs were more common in older patients (p = 0.01). There was no increase in stopping azathioprine due to ADRs in TPMT heterozygotes compared with wild-type individuals. The single individual with TPMT variant homozygosity experienced severe neutropenia. Our work supports the strong evidence that individuals with TPMT variant homozygosity are at high risk of severe neutropenia, whereas TPMT heterozygotes are not at increased risk of ADRs at standard doses of azathioprine.

  10. Identification of genetic defects in primary immunodeficiencies by whole exome sequencing

    Christiansen, Mette; Jensen, Jens Magnus Bernth; Veirum, Jens Erik

    2014-01-01

    to hypogammaglobulinaemia, and increased risk of both infections as well as cancer. We employed whole exome sequencing (WES) to identify mutations associated with primary immunodeficiency in severely affected children. We present WES data on 2 patients with severe immunodeficiency. WES was performed using TruSeq exome kit...... and severe infections including sepsis. Second, we identified compound heterozygote stopgain mutations in RAD52 and a heterozygote mutation in LRRC8A in a 7 year-old girl with T-cell deficiency, reduced T-cell mediated B-cell activity, hypogammaglobulinaemia, prolonged splenomegali and benign adenopathy. RAD......52 has not previously been linked to immunodeficiency and we are currently investigating the functional consequences. Knowledge of the mechanisms underlying immunodeficiencies is a prerequisite for understanding disease pathogenesis. WES allows the demonstration of immune defects that may result from...

  11. Estudo da anomalia de Pelger-Huët em núcleo familiar Pelger-Huët anomaly study in a family

    Patrícia H. O. Calderan

    2008-02-01

    Full Text Available The Pelger-Huët anomaly is a dominant autosomal disease, characterized by the incomplete segmentation of the granulocytes nucleus without lost of the cellular function. The heterozygotes form of this anomaly is assintomatic and it did not possess physic meant, while the homozygote form is rare and can be lethal, being therefore, important differentiates of other infectious alterations. The pseudo-anomaly can occasionally be observed in cases of granulocitic leukemia, mieloproliferatives Diseases, some infections and after exposition the determined drugs. We evaluate eleven members of a familiar nucleus and, after the blood cells analysis, six of then had presented neutrophils and eosinophils with nuclei characteristic of the heterozygotes form of the Pelger-Huët anomaly. The recognition of this leukocyte anomaly, mainly in patients without infection and presenting great number of not segmented neutrophils, can prevent wrong interpretations of the blood cells count and unnecessary clinical and therapeutically behaviors.

  12. Response to Lefebvre et al.

    Takeda, K; Kou, I; Kawakami, N; Yasuhiko, Y; Ogura, Y; Imagawa, E; Miyake, N; Matsumoto, N; Sudo, H; Kotani, T; Nakamura, M; Matsumoto, M; Watanabe, K; Ikegawa, S

    2017-11-01

    Congenital scoliosis (CS) is a common vertebral malformation with incidence of up to 1 of 1000 births worldwide. Recently, TBX6 has been reported as the first disease gene for CS: about 10% of CS patients are compound heterozygotes of rare null mutations and a common haplotype composed by 3 SNPs in TBX6. Lefebvre et al in this journal reported that 2 patients with spondylocostal dysostosis (SCD), a rare skeletal dysplasia affecting spine and ribs also have TBX6 mutations: 1 carried the microdeletion and a rare missense variant, and another 2 rare missense variants. We investigated the pathogenicity of the 3 missense variants in SCD by a luciferase assay. The results were negative for the proposal of Lefebvre et al. We consider these 2 SCD patients are more probably compound heterozygotes of null mutations and a common risk haplotype just as CS patients with TBX6 mutations. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Cathecol-O-methyl transferase Val158Met genotype is not a risk factor for conversion disorder.

    Armagan, E; Almacıoglu, M L; Yakut, T; Köse, A; Karkucak, M; Köksal, O; Görükmez, O

    2013-03-19

    Alterations in catechol-O-methyltransferase (COMT) activity are involved in various types of neurological disorders. We examined a possible association between the COMT Val158Met polymorphism and conversion disorder in a study of 48 patients with conversion disorder and 48 control patients. In the conversion disorder group, 31 patients were Val/Met heterozygotes, 15 patients were Val/Val homozygotes and 2 patients were Met/Met homozygotes. In the control group, 32 patients were Val/Met heterozygotes and 16 patients were Val/Val homozygotes. There was no significant difference between the groups. We conclude that the COMT Val158Met genotype is quite common in Turkey and that it is not a risk factor for conversion disorder in the Turkish population.

  14. A false single nucleotide polymorphism generated by gene duplication compromises meat traceability.

    Sanz, Arianne; Ordovás, Laura; Zaragoza, Pilar; Sanz, Albina; de Blas, Ignacio; Rodellar, Clementina

    2012-07-01

    Controlling meat traceability using SNPs is an effective method of ensuring food safety. We have analyzed several SNPs to create a panel for bovine genetic identification and traceability studies. One of these was the transversion g.329C>T (Genbank accession no. AJ496781) on the cytochrome P450 17A1 gene, which has been included in previously published panels. Using minisequencing reactions, we have tested 701 samples belonging to eight Spanish cattle breeds. Surprisingly, an excess of heterozygotes was detected, implying an extreme departure from Hardy-Weinberg equilibrium (PT SNP is a false positive polymorphism, which allows us to explain the inflated heterozygotic value. We recommend that this ambiguous SNP, as well as other polymorphisms located in this region, should not be used in identification, traceability or disease association studies. Annotation of these false SNPs should improve association studies and avoid misinterpretations. Copyright © 2012 Elsevier Ltd. All rights reserved.

  15. Mutagenic effect of radionuclides incorporated into DNA of Drosophila melanogaster. Technical progress report, December 15, 1985-July 15, 1986

    Lee, W.R.

    1986-01-01

    This project compares the mutagenic effect of ionizing radiation from tritium to that of x-ray. Mutants are described at the molecular level after having been characterized by classical genetic techniques in Drosophila melanogaster, therefore tying together the molecular studies with previous work in mutagenesis. The objectives of this project are to analyze x-ray and tritium induced mutants by ''walking down'' the chromosomes and studying the frequency of breaks that are not associated with the gene used in screening for the mutants, to study the molecular effect of these mutants in heterozygotes with the aim of developing methods of detecting mutants in heterozygotes that may be applicable to human populations, and to induce mutants from tritium beta radiation and analyze them at the molecular level. 9 refs., 4 figs

  16. Properties of acatalasic cells growing in vitro

    Krooth, R S; Howell, R R; Hamilton, H B

    1961-07-19

    Acatalasia, a disease due to homozygosity for a Mendelian gene, is characterized by the absence of the enzyme catalase from the tissues of the human body. Red cells from heterozygotes have enzyme activities about one-half normal. In this report, the development of cell lines from skin biopsies of an affected homozygote, a heterozygote and eight control patients is described. The cell type is the euploid fibroblast. It was found that acatalasic cells lacked the enzyme, even after growing for many months in a medium rich in catalase. The control lines all had mean catalase activity double or more that of the heterozygous line. Selection experiments, measuring growth of cells exposed for 20 minutes to varying concentrations of hydrogen peroxide, did not provide a system for preferentially eliminating acatalastic cells. Certain other experiments were performed bearing on the enzymatic defect in this disease. 23 references, 7 figures, 6 tables.

  17. Genetic analysis of Aspergillus niger

    Debets, F.

    1990-01-01

    Dit proefschrift handelt over genetische analyse van de voor de biotechnologie belangrijke schimmel Aspergillusniger . A.niger is een imperfecte schimmel, met andere woorden A.niger heeft geen geslachtelijk stadium, en mist daardoor meiotische recombinatie. Toch is genetisch onderzoek aan imperfecte schimmels mogelijk en wel op basis van af en toe optredende mitotische recombinatie in heterozygote diploiden. Twee typen recombinanten zijn hierbij van belang. Ten eerste kunnen door opeenvolgend...

  18. Carcinogen-Induced Microenvironment in Breast Cancer

    2000-04-01

    occurs in other tissues like liver from TGF-3-null both estrous and pregnancy [531]. Furthermore, trans- mutant heterozygotes [1 21. plant ...of COMMA-D outgrowths. COMMA-D cells were trans- period of 10 weeks was 39% of transplanted CUPs examined. Tumor planted into CFPs at 10 weeks of age...receptor and transforming growth factor P, levels during melysin- 1. Sem. Cancer Biol. 6:159-163. monoterpene -induced regresssion of mammary tumors. Cancer

  19. RHOEO SPATHACEA: A CYTOGENETICAL REVIEW

    Datta Animesh K.; Mandal Aninda; Bhattacharya Arnab; Saha Aditi; Paul Rita

    2012-01-01

    A cytogenetical review is conducted on Rhoeo spathacea (Swartz) Stearn (monotypic genus of the family Commelinaceae) including conventional heterozygote (var. bicolor) form (2n=12) and a rare bivalent forming clone of var. concolor (2n=12) with an objective to provide cytological configurations explaining some of the important cytogenetical aspects, which is rather difficult in sexually propagated plant species due to sterility barriers. Cytological configurations documented may generate inte...

  20. Increased glucocerebrosidase (GBA) 2 activity in GBA1 deficient mice brains and in Gaucher leucocytes.

    Burke, Derek G; Rahim, Ahad A; Waddington, Simon N; Karlsson, Stefan; Enquist, Ida; Bhatia, Kailash; Mehta, Atul; Vellodi, Ashok; Heales, Simon

    2013-09-01

    Lysosomal glucocerebrosidase (GBA1) deficiency is causative for Gaucher disease. Not all individuals with GBA1 mutations develop neurological involvement raising the possibility that other factors may provide compensatory protection. One factor may be the activity of the non-lysosomal β-glucosidase (GBA2) which exhibits catalytic activity towards glucosylceramide and is reported to be highly expressed in brain tissue. Here, we assessed brain GBA2 enzymatic activity in wild type, heterozygote and GBA1 deficient mice. Additionally, we determined activity in leucocytes obtained from 13 patients with Gaucher disease, 10 patients with enzymology consistent with heterozygote status and 19 controls. For wild type animals, GBA2 accounted for over 85 % of total brain GBA activity and was significantly elevated in GBA1 deficient mice when compared to heterozygote and wild types (GBA1 deficient; 92.4 ± 5.6, heterozygote; 71.5 ± 2.4, wild type 76.8 ± 5.1 nmol/h/mg protein). For the patient samples, five Gaucher patients had GBA2 leucocyte activities markedly greater than controls. No difference in GBA2 activity was apparent between the control and carrier groups. Undetectable GBA2 activity was identified in four leucocyte preparations; one in the control group, two in the carrier group and one from the Gaucher disease group. Work is now required to ascertain whether GBA2 activity is a disease modifying factor in Gaucher disease and to identify the mechanism(s) responsible for triggering increased GBA2 activity in GBA1 deficiency states.

  1. A Drosophila model of dominant inclusion body myopathy type 3 shows diminished myosin kinetics that reduce muscle power and yield myofibrillar defects.

    Suggs, Jennifer A; Melkani, Girish C; Glasheen, Bernadette M; Detor, Mia M; Melkani, Anju; Marsan, Nathan P; Swank, Douglas M; Bernstein, Sanford I

    2017-06-01

    Individuals with inclusion body myopathy type 3 (IBM3) display congenital joint contractures with early-onset muscle weakness that becomes more severe in adulthood. The disease arises from an autosomal dominant point mutation causing an E706K substitution in myosin heavy chain type IIa. We have previously expressed the corresponding myosin mutation (E701K) in homozygous Drosophila indirect flight muscles and recapitulated the myofibrillar degeneration and inclusion bodies observed in the human disease. We have also found that purified E701K myosin has dramatically reduced actin-sliding velocity and ATPase levels. Since IBM3 is a dominant condition, we now examine the disease state in heterozygote Drosophila in order to gain a mechanistic understanding of E701K pathogenicity. Myosin ATPase activities in heterozygotes suggest that approximately equimolar levels of myosin accumulate from each allele. In vitro actin sliding velocity rates for myosin isolated from the heterozygotes were lower than the control, but higher than for the pure mutant isoform. Although sarcomeric ultrastructure was nearly wild type in young adults, mechanical analysis of skinned indirect flight muscle fibers revealed a 59% decrease in maximum oscillatory power generation and an approximately 20% reduction in the frequency at which maximum power was produced. Rate constant analyses suggest a decrease in the rate of myosin attachment to actin, with myosin spending decreased time in the strongly bound state. These mechanical alterations result in a one-third decrease in wing beat frequency and marginal flight ability. With aging, muscle ultrastructure and function progressively declined. Aged myofibrils showed Z-line streaming, consistent with the human heterozygote phenotype. Based upon the mechanical studies, we hypothesize that the mutation decreases the probability of the power stroke occurring and/or alters the degree of movement of the myosin lever arm, resulting in decreased in vitro

  2. Deficiency in monocarboxylate transporter 1 (MCT1) in mice delays regeneration of peripheral nerves following sciatic nerve crush

    Morrison, Brett M.; Tsingalia, Akivaga; Vidensky, Svetlana; Lee, Youngjin; Jin, Lin; Farah, Mohamed H.; Lengacher, Sylvain; Magistretti, Pierre J.; Pellerin, Luc; Rothsteinb, Jeffrey D.

    2015-01-01

    Peripheral nerve regeneration following injury occurs spontaneously, but many of the processes require metabolic energy. The mechanism of energy supply to axons has not previously been determined. In the central nervous system, monocarboxylate transporter 1 (MCT1), expressed in oligodendroglia, is critical for supplying lactate or other energy metabolites to axons. In the current study, MCT1 is shown to localize within the peripheral nervous system to perineurial cells, dorsal root ganglion neurons, and Schwann cells by MCT1 immunofluorescence in wild-type mice and tdTomato fluorescence in MCT1 BAC reporter mice. To investigate whether MCT1 is necessary for peripheral nerve regeneration, sciatic nerves of MCT1 heterozygous mice are crushed and peripheral nerve regeneration was quantified electrophysiologically and anatomically. Compound muscle action potential (CMAP) recovery is delayed from a median of 21. days in wild-type mice to greater than 38. days in MCT1 heterozygote mice. In fact, half of the MCT1 heterozygote mice have no recovery of CMAP at 42. days, while all of the wild-type mice recovered. In addition, muscle fibers remain 40% more atrophic and neuromuscular junctions 40% more denervated at 42. days post-crush in the MCT1 heterozygote mice than wild-type mice. The delay in nerve regeneration is not only in motor axons, as the number of regenerated axons in the sural sensory nerve of MCT1 heterozygote mice at 4. weeks and tibial mixed sensory and motor nerve at 3. weeks is also significantly reduced compared to wild-type mice. This delay in regeneration may be partly due to failed Schwann cell function, as there is reduced early phagocytosis of myelin debris and remyelination of axon segments. These data for the first time demonstrate that MCT1 is critical for regeneration of both sensory and motor axons in mice following sciatic nerve crush.

  3. Novel PMS2 Pseudogenes Can Conceal Recessive Mutations Causing a Distinctive Childhood Cancer Syndrome

    De Vos, Michel; Hayward, Bruce E.; Picton, Susan; Sheridan, Eamonn; Bonthron, David T.

    2004-01-01

    We investigated a family with an autosomal recessive syndrome of café-au-lait patches and childhood malignancy, notably supratentorial primitive neuroectodermal tumor. There was no cancer predisposition in heterozygotes; nor was there bowel cancer in any individual. However, autozygosity mapping indicated linkage to a region of 7p22 surrounding the PMS2 mismatch-repair gene. Sequencing of genomic PCR products initially failed to identify a PMS2 mutation. Genome searches then revealed a previo...

  4. The prevalence of primary hereditary hemochromatosis in central Anatolia.

    Karaca, Halit; Güven, Kadri; Önal, Müge; Gürsoy, Şebnem; Başkol, Mevlüt; Özkul, Yusuf

    2013-01-01

    Hereditary hemochromatosis is an autosomal recessive disorder associated with the HFE genes. Early identification and diagnosis is important as end stage organ damage may occur if treatment is delayed.. This study aimed to identify the prevalence of hereditary hemochromatosis in Kayseri and surroundings known as Central Anatolia. 2304 participants (1220 males, 1084 females) who were older then the age of 17 were included in the study conducted between December 2005 and December 2006 in Kayseri, Turkey. Transferin saturation was measured from overnight fasting blood samples. Serum iron, total iron binding capacity, and transferin saturation were measured. Serum ferritin levels and hereditary hemochromatosis genetic analysis were also performed after an overnight fasting blood samples from participants whose transferin saturation results were more than 50% in man and more than 45% in women. The homozygote C282Y mutation and heterozygote C282Y mutation prevalences were found as 0.08% (1/1220) and 0.08% (1/1220) in male participants, respectively. The heterozygote H63D mutation prevalence was found in 0.09% (1/1084) of female participants. Calculated prevalences in general population are as follows; The homozygote C282Y mutation prevalence is 0.043% (1/2304), the heterozygote C282Y mutation prevalence is 0.043% (1/2304) and the heterozygote H63D mutation prevalence is 0.043% (1/2304). The prevalence of hereditary hemochromatosis in Central Anatolia is 0.043% (1/2304). Because of the relatively low frequency, population screening studies are not cost-effective.

  5. A Drosophila model of dominant inclusion body myopathy type 3 shows diminished myosin kinetics that reduce muscle power and yield myofibrillar defects

    Jennifer A. Suggs

    2017-06-01

    Full Text Available Individuals with inclusion body myopathy type 3 (IBM3 display congenital joint contractures with early-onset muscle weakness that becomes more severe in adulthood. The disease arises from an autosomal dominant point mutation causing an E706K substitution in myosin heavy chain type IIa. We have previously expressed the corresponding myosin mutation (E701K in homozygous Drosophila indirect flight muscles and recapitulated the myofibrillar degeneration and inclusion bodies observed in the human disease. We have also found that purified E701K myosin has dramatically reduced actin-sliding velocity and ATPase levels. Since IBM3 is a dominant condition, we now examine the disease state in heterozygote Drosophila in order to gain a mechanistic understanding of E701K pathogenicity. Myosin ATPase activities in heterozygotes suggest that approximately equimolar levels of myosin accumulate from each allele. In vitro actin sliding velocity rates for myosin isolated from the heterozygotes were lower than the control, but higher than for the pure mutant isoform. Although sarcomeric ultrastructure was nearly wild type in young adults, mechanical analysis of skinned indirect flight muscle fibers revealed a 59% decrease in maximum oscillatory power generation and an approximately 20% reduction in the frequency at which maximum power was produced. Rate constant analyses suggest a decrease in the rate of myosin attachment to actin, with myosin spending decreased time in the strongly bound state. These mechanical alterations result in a one-third decrease in wing beat frequency and marginal flight ability. With aging, muscle ultrastructure and function progressively declined. Aged myofibrils showed Z-line streaming, consistent with the human heterozygote phenotype. Based upon the mechanical studies, we hypothesize that the mutation decreases the probability of the power stroke occurring and/or alters the degree of movement of the myosin lever arm, resulting in

  6. Wild-Type Male Offspring of fmr-1+/− Mothers Exhibit Characteristics of the Fragile X Phenotype

    Zupan, Bojana; Toth, Miklos

    2008-01-01

    Fragile X syndrome is an X-linked disorder caused by the inactivation of the FMR-1 gene with symptoms ranging from impaired cognitive functions to seizures, anxiety, sensory abnormalities, and hyperactivity. Males are more severely affected than heterozygote (H) females, who, as carriers, have a 50% chance of transmitting the mutated allele in each pregnancy. fmr-1 knockout (KO) mice reproduce fragile X symptoms, including hyperactivity, seizures, and abnormal sensory processing. In contrast ...

  7. Reciprocal translocations in mice taken from the thirty-kilometer zone around the crippled reactor of Chernobyl

    Pomerantseva, M.D.; Ramajya, L.K.; Testov, B.V.; Chekhovich, A.V.; Shevchenko, V.A.; Shaks, A.I.; Lobaneva, N.V.

    1990-01-01

    A study was made of the incidence of genetic damages to germ cells of male mice taken from or exposed within the thirty-kilometer Zone of Chernobyl, the contaminated no-man's-land around the reactor that failed. At all contamination levels mouse spermatocytes exhibited reciprocal translocations, a relatively low frequency of which increased with increasing dose rate. Heterozygotes, with respect to reciprocal translocations (5%), were found among males exposed to enhanced radiation background as early embryons

  8. Hypersensitivities for Acetaldehyde and Other Agents among Cancer Cells Null for Clinically Relevant Fanconi Anemia Genes

    Ghosh, Soma; Sur, Surojit; Yerram, Sashidhar R.; Rago, Carlo; Bhunia, Anil K.; Hossain, M. Zulfiquer; Paun, Bogdan C.; Ren, Yunzhao R.; Iacobuzio-Donahue, Christine A.; Azad, Nilofer A.; Kern, Scott E.

    2014-01-01

    Large-magnitude numerical distinctions (>10-fold) among drug responses of genetically contrasting cancers were crucial for guiding the development of some targeted therapies. Similar strategies brought epidemiological clues and prevention goals for genetic diseases. Such numerical guides, however, were incomplete or low magnitude for Fanconi anemia pathway (FANC) gene mutations relevant to cancer in FANC-mutation carriers (heterozygotes). We generated a four-gene FANC-null cancer panel, inclu...

  9. [Clinical analysis of three cases with beta-thalassemia].

    Li, X Y; Liu, M J; Xu, L H; Xu, H G; Chen, H L; Fang, J P

    2018-04-02

    Objective: To study the diagnostic strategy of β-thalassemia through retrospective analysis of 3 cases of β-thalassemia. Methods: Three patients were admitted to the Department of Pediatrics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University from January 2014 to June 2015. The clinical manifestations, hemoglobin electrophoresis and gene detection of these patients and their parents were analyzed, diagnostic ideas and key points were discussed when beta thalassemia gene detection did not explain clinical manifestations or hemoglobin electrophoresis. Results: Case 1, boy, 5 years old, was diagnosed as compound heterozygotes of β41-42 and IVS-Ⅱ-654 with hereditary persistence of fetal hemoglobin(HPFH) according to the clinical manifestations of mild anemia, normal size of liver and spleen, 92.8% fetal hemoglobin (HbF) and gene analysis. Case 2, girl, 3 years old, was confirmed the diagnosis of thalassemia intermedia with β41-42 heterozygote compound and ααα anti3.7 heterozygote in accordance with the manifestations of severe anemia, hepatosplenomegaly, 8.6% HbF, 4.1% hemoglobin A 2 (HbA 2 ) and gene analysis. Case 3, girl, 3 years old, with severe anemia, hepatosplenomegaly, 51.2% HbF and 3.7% HbA 2 , was diagnosed as thalassemia major with compound heterozygotes of PolyA (T→C) and β17 by DNA sequencing. Conclusion: The diagnosis of β-thalassemia should be confirmed by clinical manifestations of hemolytic anemia, hemoglobin electrophoresis, gene diagnosis and family survey.

  10. Prevalence of Co-Inheritance of Alpha-Thalassemia with Beta-Thalassemia and Beta-Hemoglobinopathy in Ahvaz City

    Najmaddin Saki; Akbar Dorgalaleh; Zahra Kashani Khatib; Shaban Alizadeh; Fakher Rahim; Hamid Galehdari; Bijan Kaikhaei; Mohammad Pedram; Ali Dehghani Fard

    2013-01-01

    Background: Co-inheritance of hemoglobin gene defects is a rare important status that can lead to double heterozygote or homozygote with significant clinical manifestations. Such conditions can be observed in co-inheritance of alpha-thalassemia with beta-thalassemia or hemoglobinopathy. The aim of this study was to evaluate the prevalence of alpha-thalassemia with beta-thalassemia and hemoglobinopathy co-inheritance in a considerable number of Iranian.   Methods: This descriptive study was pe...

  11. Chromosome orientation and sterility in gamma-ray induced interchanges in chili pepper (Capsicum annuum L.)

    Kumar, O.A.; Panda, R.C.; Rao, K.G.R.

    1986-01-01

    After gamma irradiation (30 Kr) of seeds of Capsicum annuum cultivar cerasiformis (2 n = 24) two plants were recorded each carrying two interchanges. The nucleolus organiser chromosome appeared not to be involved. The interchange heterozygotes were weak and meiosis was irregular. At least one multivalent association per PMC was recorded. At metaphase I the predominant orientation was adjacent. The probable reasons for anaphase I and other meiotic irregularities and the incidence of high pollen sterility are discussed. (author)

  12. Haematological and genetic features of delta beta-thalassaemia in Pakistan

    Ahmad, S.; Anwar, M.

    2006-01-01

    Objective: To describe the hematological and genetic features of delta beta-thalassaemia in Pakistani patients. Design: Descriptive case series. Place and Duration of Study: Department of Pathology, PNS Shifa, Karachi and Department of Hematology, Armed Forces Institute of Pathology, Rawalpindi, from January 1994 to April 2004. Patients and Methods: Thirteen individuals from six unrelated Pakistani families with a hematological diagnosis of delta beta-thalassaemia were studied. A brief clinical history, and the results of blood counts, absolute values, Hb-F, Hb-A/sub 2/, and hemoglobin electrophoresis were recorded. The DNA from each subject was first screened for the delta beta-thalassaemia mutations found in the Pakistani population. The samples were then screened for the Invl Del sup G/gamma(sup A/gamma delta beta). Results: The subjects included six heterozygote, six homozygotes and one compound heterozygote of delta beta and delta beta-thalassaemia. All heterozygote and 4/6 homozygotes were asymptomatic. One homo zygote had thalassaemia intermedia while another had transfusion dependent anemia. The mean Hb, TRBC, MCV, MCH, Hb-F and Hb-A/sub 2/ in delta beta-thalassaemia heterozygote were 11.6 g/dl, 5.37 x 1012/L, 70.9 fl, and 21.7 pg, 14% and 2.6% respectively. The same values in the four un transfused homo zygote were 10.6 g/dl, 5.34x1012/L, 69.211, and 20.8pg, 100% and 0% respectively. The mutation analysis revealed that all 13 individuals had the same Invl Del sup G/gamma(sup A/gamma delta beta). Conclusion: delta beta-thalassaemia is a rare disorder in Pakistan. Although the clinical picture is very mild its combination with delta beta-thalassaemia trait can produce a sever transfusion dependent thalassaemia. The DNA based diagnosis is possible in the prenatal as well as the postnatal period. (author)

  13. p.H1069Q mutation in ATP7B and biochemical parameters of copper metabolism and clinical manifestation of Wilson's disease.

    Gromadzka, Graznya; Schmidt, Harmut H J; Genschel, Janine; Bochow, Bettina; Rodo, M; Tarnacka, Beatek; Litwin, Thomas; Chabik, Grzegorz; Członkowska, Anna

    2006-02-01

    We compared the effect of the p.H1069Q mutation and other non-p.H1069Q mutations in ATP7B on the phenotypic expression of Wilson's disease (WD), and assessed whether the clinical phenotype of WD in compound heterozygotes depends on the type of mutation coexisting with the p.H1069Q. One hundred forty-two patients with clinically, biochemically, and genetically diagnosed WD were studied. The mutational analysis of ATP7B was performed by direct sequencing. A total number of 26 mutations in ATP7B were identified. The p.His1069Gln was the most common mutation (allelic frequency: 72%). Seventy-three patients were homozygous for this mutation. Of compound heterozygotes, 37 had frameshift/nonsense mutation, and 20 had other missense mutation on one of their ATP7B alleles. Twelve patients had two non-p.H1069Q mutations. Patients homozygous for the p.H1069Q mutation had the less severe disturbances of copper metabolism and the latest presentation of first WD symptoms. The most severely disturbed copper metabolism and the earliest age at initial disease manifestation was noticed in non-p.H1069Q patients. In compound heterozygotes, the type of mutation coexisting with the p.H1069Q to a small extent influenced WD phenotype. The phenotype of WD varied considerably among patients with the same genotype. The p.H1069Q mutation is associated with late WD manifestation and with a mild disruption of copper metabolism. In compound heterozygotes, the phenotype of WD to a small extent depends on the type of mutation coexisting with the p.H1069Q. Besides genotype, additional modifying factors seem to determine WD manifestations. Copyright (c) 2005 Movement Disorder Society.

  14. Maximizing the effect of an α7 nicotinic receptor PAM in a mouse model of schizophrenia-like sensory inhibition deficits.

    Stevens, Karen E; Zheng, Lijun; Floyd, Kirsten L; Stitzel, Jerry A

    2015-06-22

    Positive allosteric modulators (PAMs) for the α7 nicotinic receptor hold promise for the treatment of sensory inhibition deficits observed in schizophrenia patients. Studies of these compounds in the DBA/2 mouse, which models the schizophrenia-related deficit in sensory inhibition, have shown PAMs to be effective in improving the deficit. However, the first published clinical trial of a PAM for both sensory inhibition deficits and related cognitive difficulties failed, casting a shadow on this therapeutic approach. The present study used both DBA/2 mice, and C3H Chrna7 heterozygote mice to assess the ability of the α7 PAM, PNU-120596, to improve sensory inhibition. Both of these strains of mice have reduced hippocampal α7 nicotinic receptor numbers and deficient sensory inhibition similar to schizophrenia patients. Low doses of PNU-120596 (1 or 3.33mg/kg) were effective in the DBA/2 mouse but not the C3H Chrna7 heterozygote mouse. Moderate doses of the selective α7 nicotinic receptor agonist, choline chloride (10 or 33mg/kg), were also ineffective in improving sensory inhibition in the C3H Chrna7 heterozygote mouse. However, combining the lowest doses of both PNU-120596 and choline chloride in this mouse model did improve sensory inhibition. We propose here that the difference in efficacy of PNU-120596 between the 2 mouse strains is driven by differences in hippocampal α7 nicotinic receptor numbers, such that C3H Chrna7 heterozygote mice require additional direct stimulation of the α7 receptors. These data may have implications for further clinical testing of putative α7 nicotinic receptor PAMs. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Selenoproteinrelateret muskeldystrofi

    Hansen, Lars Kjærsgaard; Schrøder, Henrik; Ousager, Lilian Bomme

    2011-01-01

    A nine year-old girl with selenoprotein-related muscular dystrophy was diagnosed. The primary symptom was weak neck muscles. During childhood she developed a rigid spine and over a period of a few years a severe scoliosis. She was compound heterozygote for a mutation in the SEPN1 gene. Experimental...... treatment with N-acetylcystein for a period of two years was initiated....

  16. Diagnostic and clinical characteristics of early-manifesting females with Duchenne or Becker muscular dystrophy.

    Imbornoni, Lauren; Price, Elinora T; Andrews, Jennifer; Meaney, F John; Ciafaloni, Emma; Cunniff, Christopher

    2014-11-01

    Manifestations of Duchenne and Becker muscular dystrophy (DBMD) are present in up to 40% of heterozygous females, but there are few reports of females who exhibit skeletal muscle symptoms in childhood. From the Muscular Dystrophy Surveillance Tracking and Research Network, a multi-site population-based surveillance network for dystrophinopathy, nine symptomatic female heterozygotes with onset of symptoms prior to age 9 years were identified. The median age at diagnosis was 8.3 years, and the median interval from first symptoms to diagnosis was 1.35 years. Of the nine female heterozygotes, four had a positive family history, seven had intellectual disability and five had at least one mental health disorder. Mental health concerns included attention deficit hyperactivity disorder (ADHD), autism spectrum features, bipolar disorder, and depression. The frequency of intellectual and mental health problems in this group is higher than previously reported for affected males and for symptomatic females. These findings may have implications for diagnosis of early manifesting heterozygotes and for their health supervision. © 2014 Wiley Periodicals, Inc.

  17. Surfactant Protein-B 121ins2 Heterozygosity, Reduced Pulmonary Function and COPD in Smokers

    Bækvad-Hansen, Marie; Dahl, Morten; Tybjærg-Hansen, Anne

    2010-01-01

    .2-4.8) for spirometry defined COPD and of 2.2(1.0-5.1) for hospitalization due to COPD. Among never smokers, 121ins2 heterozygotes did not differ from wildtypes in lung function or risk of COPD. CONCLUSIONS: Surfactant protein-B 121ins2 heterozygosity is associated with reduced lung function and increased risk for COPD......2 mutation have reduced lung function and increased risk for chronic obstructive pulmonary disease (COPD) among smokers. METHODS: We genotyped 47,600 individuals from the adult Danish general population and recorded smoking habits, spirometry and hospital admissions due to COPD. The study...... that the effect of genotype differ by smoking status. Among smokers, 121ins2 heterozygotes had 9% reduced FEV1%predicted(p=0.0008), 6% reduced FVC%predicted(p=0.01) and 6% reduced FEV1/FVC(p=0.00007), compared with wildtypes. Also among smokers, 121ins2 heterozygotes had odds ratios of 2.4(95%CI 1...

  18. Clinical, biochemical, and neuropsychiatric evaluation of a patient with a contiguous gene syndrome due to a microdeletion Xp11.3 including the Norrie disease locus and monoamine oxidase (MAOA and MAOB) genes.

    Collins, F A; Murphy, D L; Reiss, A L; Sims, K B; Lewis, J G; Freund, L; Karoum, F; Zhu, D; Maumenee, I H; Antonarakis, S E

    1992-01-01

    Norrie disease is a rare X-linked recessive disorder characterized by blindness from infancy. The gene for Norrie disease has been localized to Xp11.3. More recently, the genes for monoamine oxidase (MAOA, MAOB) have been mapped to the same region. This study evaluates the clinical, biochemical, and neuropsychiatric data in an affected male and 2 obligate heterozygote females from a single family with a submicroscopic deletion involving Norrie disease and MAO genes. The propositus was a profoundly retarded, blind male; he also had neurologic abnormalities including myoclonus and stereotopy-habit disorder. Both obligate carrier females had a normal IQ. The propositus' mother met diagnostic criteria for "chronic hypomania and schizotypal features." The propositus' MAO activity was undetectable and the female heterozygotes had reduced levels comparable to patients receiving MAO inhibiting antidepressants. MAO substrate and metabolite abnormalities were found in the propositus' plasma and CSF. This study indicates that subtle biochemical and possibly neuropsychiatric abnormalities may be detected in some heterozygotes with the microdeletion in Xp11.3 due to loss of the gene product for the MAO genes; this deletion can also explain some of the complex phenotype of this contiguous gene syndrome in the propositus.

  19. Aebp2 as an epigenetic regulator for neural crest cells.

    Hana Kim

    Full Text Available Aebp2 is a potential targeting protein for the mammalian Polycomb Repression Complex 2 (PRC2. We generated a mutant mouse line disrupting the transcription of Aebp2 to investigate its in vivo roles. Aebp2-mutant homozygotes were embryonic lethal while heterozygotes survived to adulthood with fertility. In developing mouse embryos, Aebp2 is expressed mainly within cells of neural crest origin. In addition, many heterozygotes display a set of phenotypes, enlarged colon and hypopigmentation, similar to those observed in human patients with Hirschsprung's disease and Waardenburg syndrome. These phenotypes are usually caused by the absence of the neural crest-derived ganglia in hindguts and melanocytes. ChIP analyses demonstrated that the majority of the genes involved in the migration and development process of neural crest cells are downstream target genes of AEBP2 and PRC2. Furthermore, expression analyses confirmed that some of these genes are indeed affected in the Aebp2 heterozygotes. Taken together, these results suggest that Aebp2 may regulate the migration and development of the neural crest cells through the PRC2-mediated epigenetic mechanism.

  20. Time of Anderson-Fabry Disease Detection and Cardiovascular Presentation

    K. Selthofer-Relatic

    2018-01-01

    Full Text Available Background. Anderson-Fabry disease is an X-linked inherited disease, which manifests in a different manner depending on gender and genotype. Making a working diagnosis of Anderson-Fabry disease is difficult because of several reasons: (a that it is a multiorgan disease with wide variety of phenotypes, (b different timelines of presentation, (c gender differences, and (d possible coexistence with other comorbidities. Late-onset/cardiac type of presentation with minimal involvement of other organs can additionally make diagnosis difficult. Aim. To describe different cardiac manifestations at different time points in the course of the disease: (1 72-year-old female (echocardiography detection, heterozygote, significant left and mild right ventricular hypertrophy; (2 62-year-old male (echocardiography detection, hemizygote, left ventricular hypertrophy, implanted cardiac pacemaker, a performed percutaneous coronary intervention after myocardial infarction, degenerative medium degree aortic valve stenosis; (3 45-year-old female (asymptomatic/family screening, heterozygote, thickened mitral papillary muscle, mild left ventricular hypertrophy, first degree diastolic dysfunction; and (4 75-year-old female (symptomatic/family screening, heterozygote, cardiomyopathy with reduced left ventricular ejection fraction after heart surgery (mitral valve annuloplasty and plastic repair of the tricuspid valve. Conclusion. All patients have Anderson-Fabry disease but with different clinical presentations depending on the gender, the type of mutation, and the time of detection. All these features can make the patients’ profiles unique and delay the time of detection.

  1. Familial hypofibrinogenaemia associated with heterozygous substitution of a conserved arginine residue; Bbeta255 Arg-->His (Fibrinogen Merivale).

    Maghzal, Ghassan J; Brennan, Stephen O; Fellowes, Andrew P; Spearing, Ruth; George, Peter M

    2003-02-21

    Sequencing of all three fibrinogen genes from an individual with hypofibrinogenaemia led to the identification of two new point mutations in the Bbeta gene. Family studies showed the mutations Bbeta255 Arg-->His (Fibrinogen Merivale) and Bbeta148 Lys-->Asn (Fibrinogen Merivale II) were on different alleles and that only the Bbeta255 Arg-->His mutation segregated with hypofibrinogenaemia. Three simple heterozygotes for this mutation had mean fibrinogen concentrations of 1.4 mg/ml, while heterozygotes for the Bbeta148 Lys-->Asn mutation had normal fibrinogen concentrations. ESI MS analysis of endoproteinase Asp-N digests of Bbeta chains showed that the Bbeta255 Arg-->His substitution was not expressed in plasma, confirming it as the cause of the hypofibrinogenaemia. The Bbeta148 Lys-->Asn chains, on the other hand, were equally expressed with wild-type Bbeta chains in simple heterozygotes. Genotype analysis failed to detect either substitution in 182 healthy controls. Arg(255) is located in the first strand of the five-stranded sheet that forms the main feature of the betaD domain and appears to form an essential H bond with Gly(414). Both the Arg and Gly are absolutely conserved, not only in all known Bbeta chains, but also in all homologous alphaE and gamma chains and in all fibrinogen-related proteins. Protein instability from loss of this contact could easily explain the association of this mutation with hypofibrinogenaemia.

  2. [Hemoglobin variants in Colombian patients referred to discard hemoglobinopathies].

    Romero-Sánchez, Consuelo; Gómez Gutiérrez, Alberto; Duarte, Yurani; Amazo, Constanza; Manosalva, Clara; Chila M, Lorena; Casas-Gómez, María Consuelo; Briceño Balcázar, Ignacio

    2015-10-01

    Oxygen transport is altered in hemoglobinopathies. To study the distribution of hemoglobinopathies in Andean subjects without African ancestry. We analyzed blood samples of 1,407 subjects aged 18 to 59 years (58% females), living in the central Andean region of Colombia, referred to discard hemoglobinopathies. The frequency and type of hemoglobinopathy was established by capillary and agarose gel electrophoresis. The frequency of hemoglobinopathies was 34.5% and higher among females. The structural variants found were: AS-heterozygous hemoglobin (8.1%), homozygous SS (3.7%), heterozygous SC (2.2%), AC heterozygotes (0.5%) and heterozygous AE (0.3%). Quantitative variants found were Hb A-Beta thalassemia (13.91%) and Hb H (0.06%), Beta-thalassemia heterozygotes C (0.88%), S-Beta thalassemia heterozygotes (6.07%) and compound heterozygous SC/Beta thalassemia (0.25%), with a persistence of fetal hemoglobin 0. Composite thalassemia was also found in 31%. All techniques showed good correlation and capillary electrophoresis demonstrated a greater detection of hemoglobin variants. The frequency of hemoglobin variants in the analyzed population was high, which is an important public health indicator. The most common hemoglobin variant was HbA/Increased structural Hb A2 and the mos frequent structural hemoglobinopathy was sickle cell trait. Capillary electrophoresis can discern any Hb variants present in the population.

  3. Evidence that the ancestral haplotype in Australian hemochromatosis patients may be associated with a common mutation in the gene

    Crawford, D.H.G.; Powell, L.W.; Leggett, B.A. [Univ. of Queensland (Australia)] [and others

    1995-08-01

    Hemochromatosis (HC) is a common inherited disorder of iron metabolism for which neither the gene nor biochemical defect have yet been identified. The aim of this study was to look for clinical evidence that the predominant ancestral haplotype in Australian patients is associated with a common mutation in the gene. We compared indices of iron metabolism and storage in three groups of HC patients categorized according to the presence of the ancestral haplotype (i.e., patients with two copies, one copy, and no copies of the ancestral haplotype). We also examined iron indices in two groups of HC heterozygotes (those with the ancestral haplotype and those without) and in age-matched controls. These analyses indicate that (i) HC patients with two copies of the ancestral haplotype show significantly more severe expression of the disorder than those with one copy or those without, (ii) HC heterozygotes have partial clinical expression, which may be influenced by the presence of the ancestral haplotype in females but not in males, and (iii) the high population frequency of the HC gene may be the result of the selective advantage conferred by protecting heterozygotes against iron deficiency. 18 refs., 3 tabs.

  4. Prothrombin G20210A mutation, hypogonadotropic hypogonadism, and generalized vitiligo-related ischemic stroke in a young adult.

    Varoglu, Asuman Orhan; Kocatürk, Idris; Tatar, Abdulgani

    2010-06-01

    Cerebral infarction is a rare neurological situation in young adults, usually caused by genetic factors. We report here a case of multiple cerebral infarctions with prothrombin G20210A mutation, hypogonadotropic hypogonadism, and generalized vitiligo as a first case report. A 17-year-old female adolescent was admitted to our clinic due to a change in mental status. The patient's neurological examination revealed loss of consciousness and the presence of tetraparesia. Generalized vitiligo was also detected. Magnetic resonance imaging (MRI) and diffusion-weighted investigations (DWIs) showed acute ischemic stroke in the bilateral cerebellum, pons and left occipital regions. Heterozygote prothrombin G20210A mutation was found upon genetic examination. She had never had a menstrual cycle. Laboratory data revealed that the level of luteinizing hormone (LH) was 0.5 mIU/mL (1.1-11.6) and follicle-stimulating hormone (FSH) was 1.7 mIU/mL (2.8-11.3). Therefore, she was diagnosed with hypogonadotropic hypogonadism. The causes of ischemic stroke are heterozygote prothrombin G20210A mutation, generalized vitiligo, and hypogonadotropic hypogonadism. After treatment, the patient's neurological deficit partially improved and she was discharged. In order to identify the etiology of ischemic stroke, we suggest physicians take into account heterozygote prothrombin G20210A mutation and endocrine abnormalities, especially hypogonadotropic hypogonadism and generalized vitiligo.

  5. Alpha 1,3-Galactosyltransferase Deficiency in Pigs Increases Sialyltransferase Activities That Potentially Raise Non-Gal Xenoantigenicity

    Jong-Yi Park

    2011-01-01

    Full Text Available We examined whether deficiency of the GGTA1 gene in pigs altered the expression of several glycosyltransferase genes. Real-time RT-PCR and glycosyltransferase activity showed that 2 sialyltransferases [α2,3-sialyltransferase (α2,3ST and α2,6-sialyltransferase (α2,6ST] in the heterozygote GalT KO liver have higher expression levels and activities compared to controls. Enzyme-linked lectin assays indicated that there were also more sialic acid-containing glycoconjugate epitopes in GalT KO livers than in controls. The elevated level of sialic-acid-containing glycoconjugate epitopes was due to the low level of α-Gal in heterozygote GalT KO livers. Furthermore, proteomics analysis showed that heterozygote GalT KO pigs had a higher expression of NAD+-isocitrate dehydrogenase (IDH, which is related to the CMP-N-acetylneuraminic acid hydroxylase (CMAH enzyme reaction. These findings suggest the deficiency of GGTA1 gene in pigs results in increased production of N-glycolylneuraminic acid (Neu5Gc due to an increase of α2,6-sialyltransferase and a CMAH cofactor, NAD+-IDH. This indicates that Neu5Gc may be a critical xenoantigen. The deletion of the CMAH gene in the GalT KO background is expected to further prolong xenograft survival.

  6. The Plasminogen Activator Inhibitor 1 4G/5G Polymorphism and the Risk of Alzheimer's Disease.

    Fekih-Mrissa, Najiba; Mansour, Malek; Sayeh, Aicha; Bedoui, Ines; Mrad, Meriem; Riahi, Anis; Mrissa, Ridha; Nsiri, Brahim

    2017-09-01

    The aim of this study was to determine whether plasminogen activator inhibitor 1 (PAI-1) is associated with the risk of Alzheimer's disease (AD) in Tunisian patients. We analyzed the genotype and allele frequency distribution of the PAI-1 polymorphism in 60 Tunisian patients with AD and 120 healthy controls. The results show a significantly increased risk of AD in carriers of the 4G/4G and 4G/5G genotypes versus the wild-type 5G/5G genotype (4G/4G: 28.33% in patients vs 10.0% in controls; P 5G: 55.0% in patients vs 38.33% in controls; OR = 4.45; P < 10 -3 ). The 4G allele was also more frequently found in patients compared with controls; P < 10 -3 ; OR = 3.07. For all participants and by gender, homozygotic carriers (4G/4G) were at an increased risk of AD over heterozygotes and women were at an increased risk over their male genotype counterparts. The odds ratio for AD among 4G/4G carriers for any group was approximately twice that of heterozygotes in the same group. Women homozygotes ranked highest for AD risk (OR = 20.8) and, in fact, women heterozygotes (OR = 9.03) ranked higher for risk than male homozygotes (OR = 6.12). These preliminary exploratory results should be confirmed in a larger study.

  7. Radiographic evaluation and unusual bone formations in different genetic patterns in synpolydactyly

    Yucel, Aylin; Acar, Murat; Kuru, Ilhami; Bozan, M. Eray; Solak, Mustafa

    2005-01-01

    To compare the radiological findings of heterozygous and homozygous subjects with synpolydactyly (SPD) and to discuss their unusual bone formations. Families with hand and foot SPD were examined. Genetic analysis was performed with blood samples and the pedigree was constructed. The affected individuals, especially those with distinctive phenotypic features, were invited to our orthopaedics clinic for further diagnostic studies. All participants underwent detailed clinical and X-ray examinations. Of the invited patients, 16 (five female and 11 male; age range 4-37 years, mean age 10.75 years) were included in our study, and hand and foot radiographs were obtained. All subjects had bilateral hand radiographs (32 hands), and 14 had bilateral foot radiographs (28 feet). Genetic analysis revealed 12 heterozygote (75%) and four (25%) homozygote phenotypes. Among patients enrolled into the study nine (three homozygotes, six heterozygotes) had SPD of both hands and feet bilaterally (tetrasynpolydactyly). Six unusual bone formations were observed in the hands and feet: delta phalanx, delta metacarpal/metatarsal, kissing delta phalanx, true double epiphysis, pseudoepiphysis and cone-shaped epiphysis. There were major differences in radiological and clinical manifestations of homozygote and heterozygote phenotypes. The homozygous SPD presented with very distinctive unusual bone formations. The existence and variety of unusual bones may indicate the severity of penetrance and expressivity of SPD. (orig.)

  8. HFE Gene Mutations and Iron Status in 100 Healthy Polish Children.

    Kaczorowska-Hac, Barbara; Luszczyk, Marcin; Antosiewicz, Jedrzej; Ziolkowski, Wieslaw; Adamkiewicz-Drozynska, Elzbieta; Mysliwiec, Malgorzata; Milosz, Ewa; Kaczor, Jan J

    2017-07-01

    Iron participates in oxygen transport, energetic, metabolic, and immunologic processes. There are 2 main causes of iron overload: hereditary hemochromatosis which is a primary cause, is a metabolic disorder caused by mutations of genes that control iron metabolism and secondary hemochromatosis caused by multitransfusions, chronic hemolysis, and intake of iron rich food. The most common type of hereditary hemochromatosis is caused by HFE gene mutation. In this study, we analyzed iron metabolism in 100 healthy Polish children in relation to their HFE gene status. The wild-type HFE gene was predominant being observed in 60 children (60%). Twenty-five children (25%), presented with heterozygotic H63D mutation, and 15 children (15%), presented with other mutations (heterozygotic C282Y and S65C mutation, compound heterozygotes C282Y/S65C, C282Y/H63D, H63D homozygote). The mean concentration of iron, the level of ferritin, and transferrin saturation were statistically higher in the group of HFE variants compared with the wild-type group. H63D carriers presented with higher mean concentration of iron, ferritin levels, and transferrin saturation compared with the wild-type group. Male HFE carriers presented with higher iron concentration, transferrin saturation, and ferritin levels than females. This preliminary investigation demonstrates allelic impact on potential disease progression from childhood.

  9. The induction by X-rays of chromosome aberrations in male guinea-pigs, golden hamsters and rabbits

    Cox, B.D.; Lyon, M.F.

    1975-01-01

    Translocations induced by X-rays in post-meiotic germ cells of male guinea-pigs, golden hamsters and rabbits were studied cytologically in the F 1 sons of the irradiated males. The percentage of spermatocytes displaying multivalent configurations varied with the translocation, but the average percentage appeared to depend on the species: fewer quadrivalents were observed in hamster than in guinea-pig heterozygotes and most were recorded for rabbit heterozygotes. Chain quadrivalents were more abundant than ring quadrivalents at meiosis for the guinea-pig and hamster in contrast to the mouse. Too few translocation heterozygotes were examined to determine which meiotic configuration was the more prevalent in the rabbit. In all three species, as in the mouse, translocations were found which caused male sterility, due to partial or complete failure of spermatogenesis, although most translocations caused semi-sterility. For these semi-sterile males both the frequency and time of embryonic death in the progeny appeared to be the same as in the mouse. It is concluded that similar types of chromosome aberrations are induced by X-rays in post-meiotic germ cells of male guinea-pigs, rabbits, golden hamsters and mice

  10. Effects of X-irradiation on cell-cycle progression, induction of chromosomal aberrations and cell killing in ataxia telangiectasia (AT) fibroblasts

    Nagasawa, H.; Little, J.B.; Latt, S.A.; Lalande, M.E.

    1985-01-01

    Survival, cumulative labeling indices, chromosomal aberrations and cell-cycle distribution by flow microfluorometry (FMF) were studied in fibroblasts from normal and three ataxia telangiectasia (AT) families after X-irradiation during density-inhibition of growth and immediate release by subculture to low density. Homozygotic AT (proband) fibroblasts were very hypersensitive to cell killing by X-irradiation. Fibroblasts from AT heterozygotes (parents) were minimally hypersensitive, with D 0 's slightly lower than those for normal fibroblasts. There were three different response groups for a G 1 phase block induced by 400 rad of X-rays: (1) minimal or no G 1 block was observed in AT homozygote cell strains; (2) 10-20% of the cells were blocked in G 1 in normal cell strains; and (3) 50% or more of the cells were blocked in AT heterozygote strains. FMF profiles and cumulative labeling indices showed that homozygotic AT cells irradiated in plateau phase moved into the S-phase following subculture with no additional delay over non-irradiated controls. Homozygotic AT cells showed not only a 4-5 times higher frequency of X-ray-induced chromosomal aberrations than normal strains, but approximately 30% of these were of the chromatid-type. There were no differences in the frequency or type of X-ray-induced chromosomal aberrations between normal and heterozygotic AT cells. (orig.)

  11. IkappaBalpha polymorphism at promoter region (rs2233408) influences the susceptibility of gastric cancer in Chinese.

    Wang, Shiyan; Tian, Linwei; Zeng, Zhirong; Zhang, Mingdong; Wu, Kaichun; Chen, Minhu; Fan, Daiming; Hu, Pinjin; Sung, Joseph J Y; Yu, Jun

    2010-02-05

    Nuclear factor of kappa B inhibitor alpha (I kappaB alpha) protein is implicated in regulating a variety of cellular process from inflammation to tumorigenesis. The objective of this study was to investigate the susceptibility of rs2233408 T/C genotype in the promoter region of I kappaB alpha to gastric cancer and the association of this polymorphism with clinicopathologic variables in gastric cancer patients. A population-based case-control study was conducted between 1999 and 2006 in Guangdong Province, China. A total of 564 gastric cancer patients and 566 healthy controls were enrolled in this study. rs2233408 genotypes in I kappaB alpha were analyzed by TaqMan SNP genotyping assay. Both rs2233408 T homozygote (TT) and T heterozygotes (TC and TT) had significantly reduced gastric cancer risk (TT: OR = 0.250, 95% CI = 0.069-0.909, P = 0.035; TC and TT: OR = 0.721, 95% CI = 0.530-0.981, P = 0.037), compared with rs2233408 C homozygote (CC). rs2233408 T heterozygotes were significantly associated with reduced risk of intestinal-type gastric cancer with ORs of 0.648 (95% CI = 0.459-0.916, P = 0.014), but not with the diffuse or mix type of gastric cancer. The association between rs2233408 T heterozygotes and gastric cancer appeared more apparent in the older patients (age>40) (OR = 0.674, 95% CI = 0.484-0.939, P = 0.02). rs2233408 T heterozygotes was associated with non-cardiac gastric cancer (OR = 0.594, 95% CI = 0.411-0.859, P = 0.006), but not with cardiac gastric cancer. However, rs2233408 polymorphism was not associated with the prognosis of gastric cancer patients. I kappaB alpha rs2233408 T heterozygotes were associated with reduced risk of gastric cancer, especially for the development of certain subtypes of gastric cancer in Chinese population.

  12. IκBα polymorphism at promoter region (rs2233408 influences the susceptibility of gastric cancer in Chinese

    Sung Joseph JY

    2010-02-01

    Full Text Available Abstract Background Nuclear factor of kappa B inhibitor alpha (IκBα protein is implicated in regulating a variety of cellular process from inflammation to tumorigenesis. The objective of this study was to investigate the susceptibility of rs2233408 T/C genotype in the promoter region of IκBα to gastric cancer and the association of this polymorphism with clinicopathologic variables in gastric cancer patients. Methods A population-based case-control study was conducted between 1999 and 2006 in Guangdong Province, China. A total of 564 gastric cancer patients and 566 healthy controls were enrolled in this study. rs2233408 genotypes in IκBα were analyzed by TaqMan SNP genotyping assay. Results Both rs2233408 T homozygote (TT and T heterozygotes (TC and TT had significantly reduced gastric cancer risk (TT: OR = 0.250, 95% CI = 0.069-0.909, P = 0.035; TC and TT: OR = 0.721, 95% CI = 0.530-0.981, P = 0.037, compared with rs2233408 C homozygote (CC. rs2233408 T heterozygotes were significantly associated with reduced risk of intestinal-type gastric cancer with ORs of 0.648 (95% CI = 0.459-0.916, P = 0.014, but not with the diffuse or mix type of gastric cancer. The association between rs2233408 T heterozygotes and gastric cancer appeared more apparent in the older patients (age>40 (OR = 0.674, 95% CI = 0.484-0.939, P = 0.02. rs2233408 T heterozygotes was associated with non-cardiac gastric cancer (OR = 0.594, 95% CI = 0.411-0.859, P = 0.006, but not with cardiac gastric cancer. However, rs2233408 polymorphism was not associated with the prognosis of gastric cancer patients. Conclusions IκBα rs2233408 T heterozygotes were associated with reduced risk of gastric cancer, especially for the development of certain subtypes of gastric cancer in Chinese population.

  13. BDNF Val66Met Genotype Interacts With a History of Simulated Stress Exposure to Regulate Sensorimotor Gating and Startle Reactivity.

    Notaras, Michael J; Hill, Rachel A; Gogos, Joseph A; van den Buuse, Maarten

    2017-05-01

    Reduced expression of Brain-Derived Neurotrophic Factor (BDNF) has been implicated in the pathophysiology of schizophrenia. The BDNF Val66Met polymorphism, which results in deficient activity-dependent secretion of BDNF, is associated with clinical features of schizophrenia. We investigated the effect of this polymorphism on Prepulse Inhibition (PPI), a translational model of sensorimotor gating which is disrupted in schizophrenia. We utilized humanized BDNFVal66Met (hBDNFVal66Met) mice which have been modified to carry the Val66Met polymorphism, as well as express humanized BDNF in vivo. We also studied the long-term effect of chronic corticosterone (CORT) exposure in these animals as a model of history of stress. PPI was assessed at 30ms and 100ms interstimulus intervals (ISI). Analysis of PPI at the commonly used 100ms ISI identified that, irrespective of CORT treatment, the hBDNFVal/Met genotype was associated with significantly reduced PPI. In contrast, PPI was not different between hBDNFMet/Met and hBDNFVal/Val genotype mice. At the 30ms ISI, CORT treatment selectively disrupted sensorimotor gating of hBDNFVal/Met heterozygote mice but not hBDNFVal/Val or hBDNFMet/Met mice. Analysis of startle reactivity revealed that chronic CORT reduced startle reactivity of hBDNFVal/Val male mice by 51%. However, this was independent of the effect of CORT on PPI. In summary, we provide evidence of a distinct BDNFVal66Met heterozygote-specific phenotype using the sensorimotor gating endophenotype of schizophrenia. These data have important implications for clinical studies where, if possible, the BDNFVal/Met heterozygote genotype should be distinguished from the BDNFMet/Met genotype. © The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  14. [Molecular genetic analysis and clinical aspects of patients with hereditary hemochromatosis].

    Lange, U; Teichmann, J; Dischereit, G

    2014-08-01

    The purpose of the study was to perform a molecular genetic analysis and to document clinical aspects in patients with hereditary hemochromatosis. The study included 33 outpatients (23 males average age 50.6 years and 10 females average age 60.6 years) with a disorder of iron metabolism (transferrin saturation > 75 %) as confirmation of hemochromatosis who were subjected to molecular genetic and clinical analyses. A homozygous mutation of the hemochromatosis (HFE) gene (C282YY) was detected in 63.6 %, a compound heterozygous mutation (C282Y/H63D) in 30.3% and no mutation of the HFE gene was detected in 6.1 %. The following organ manifestations could be objectified: arthralgia (78.8 %), liver disease (39.9 %), skin hyperpigmentation (30.3 %), osteoporosis (24.2 %), diabetes mellitus (24.2 %) and cardiomyopathy (12.1 %). Comparison between patients with heterozygous and homozygous hemochromatosis revealed the following differences: compound heterozygote patients presented less frequently with osteoarthritis of the metacarpophalangeal (MCP) joints and hands (85.7 %/71.4 % homozygotes vs. 60 %/60 % heterozygotes). Osteoarthritis of the shoulder joints and osteoporosis as well as hypothyroidism were more frequent in compound heterozygote patients, whereas osteoarthritis of the knee and hip joints as well as liver disease were more common in homozygote patients. No differences between both groups were seen with respect to the clinical manifestations of cardiomyopathy and diabetes mellitus. Prevalent causes of death in hereditary hemochromatosis are heart failure, liver disease (cirrhosis and hepatocellular carcinoma) and portal hypertension. Therefore, an early diagnosis, adequate therapy and genetic screening of family members are of great importance. Medicinal treatment will only effectively prevent deleterious organ involvement and subsequent complications if initiated at an early stage. Furthermore, an overview of the current data is given.

  15. Red mangrove (Rhizophora mangle) reproduction and seedling colonization after Hurricane Charley: Comparisons of Charlotte Harbor and Tampa Bay

    Proffitt, C.E.; Milbrandt, E.C.; Travis, S.E.

    2006-01-01

    Reproductive aspects of life history are known to be important in recovery following disturbance in many plant species although this has not been well studied in mangroves. Hurricane Charley devastated large areas of mangroves in Charlotte Harbor, Florida, in August 2004. We surveyed 6 forests in Charlotte Harbor (2002, 2003, and 2005) and 16 in Tampa Bay, Florida (2001, 2002, 2003, and 2005) for total numbers of reproducing trees and trees heterozygotic for albinism that produce both normal and albino propagules. Tree size (estimated height and diameter at breast height) was also recorded for sentinel heterozygotic trees. Total number of reproducing trees km-1 was used as an index of reproductive output of the population, and deviation from the 3:1 (normal:albino propagules) ratio on heterozygotic trees expected with 100% selfing was used to estimate outcrossing. Numbers of Rhizophora mangle reproducing trees km-1 of shoreline in Charlotte Harbor were reduced by an order of magnitude following Hurricane Charley, while numbers of reproducing trees in Tampa Bay were similar to those of previous years. Reduced reproduction in Charlotte Harbor was accompanied by fewer new recruits in plots on Sanibel and Captiva Islands. Numbers of new recruits after the storm also tended to be fewer in plots where canopy loss was greater. More new recruits occurred in sites that had higher densities of pre-storm Rhizophora seedlings and greater relative dominance by Rhizophora. Outcrossing of sentinel trees was 2.5 times greater in Charlotte Harbor (mean site-1 = 33.6 ?? 6.7%; with 17% of forest sites completely selfing) than in Tampa Bay (mean site-1 = 13.4 ?? 4.7%; with 40% of sites completely selfing), although the implications for seedling recruitment of this difference are not known. ?? 2006 Estuarine Research Federation.

  16. Care for Haemoglobinopathy Patients in Slovakia.

    Fábryová, Viera; Božek, Peter; Drakulová, Monika; Kollárová, Andrea; Striežencová, Zuzana Laluhová; Macichová, Michaela; Sakalová, Adriena

    2017-03-01

    The paper presents the results od 22-year study of screening and follow-up of haemoglobinopathies in Slovakia, an overview of genetic mutations, the coincidence with hereditary haemochromatosis mutations, and the procedure in genetic councelling. Between 1993-2015, in three centres in Bratislava and in one centre in Kosice, carriers of beta-thalassaemic genes or other haemoglobinopathies were searched for. Diagnosis was performed by haematologists, whereby the family history was evaluated, together with the overall clinical condition, blood count and blood smear, iron and haemolysis parameters, mutations of hereditary haemochromatosis, and haemoglobin electrophoresis testing. In the last years the haemoglobin division also examined by high performance liquid chromatography (HPLC). A clinical suspicion of the heterozygous form of beta-thalassaemia or other haemoglobinopathies was documented in 554 patients. Of them 32 (5.8%) were foreigners. 213 (38.45%) patients were genetically examined. In 190 (33.93%) of them heterozygote beta-thalassaemia was confirmed. The most frequent mutations were IVS 1.110 (33.15%), IVS 2.1 (33.15%), and IVS 1.6 (14.7%). Evidence of haemoglobin S (heterozygote sickle cell anaemia) was also notable in two non-relative children, whose fathers were of African origin, and one patient from Ghana. One female patient was followed up for haemoglobin Santa Ana (non-stabile haemoglobin previously diagnosed as mutation de novo). In our group, we took care of pregnant patients with haemoglobinopathies. The study showed that there is a higher number of heterozygotes for beta-thalassaemia and rarely haemoglobinopathies in Slovakia. Over the past years, we have recorded an increase number of foreigners coming to our country. It is necessary to continue in search of pathological gene carriers to avoid serious forms of haemoglobinopathies. Copyright© by the National Institute of Public Health, Prague 2017

  17. Fabry Disease in Families With Hypertrophic Cardiomyopathy: Clinical Manifestations in the Classic and Later-Onset Phenotypes.

    Adalsteinsdottir, Berglind; Palsson, Runolfur; Desnick, Robert J; Gardarsdottir, Marianna; Teekakirikul, Polakit; Maron, Martin; Appelbaum, Evan; Neisius, Ulf; Maron, Barry J; Burke, Michael A; Chen, Brenden; Pagant, Silvere; Madsen, Christoffer V; Danielsen, Ragnar; Arngrimsson, Reynir; Feldt-Rasmussen, Ulla; Seidman, Jonathan G; Seidman, Christine E; Gunnarsson, Gunnar Th

    2017-08-01

    The screening of Icelandic patients clinically diagnosed with hypertrophic cardiomyopathy resulted in identification of 8 individuals from 2 families with X-linked Fabry disease (FD) caused by GLA (α-galactosidase A gene) mutations encoding p.D322E (family A) or p.I232T (family B). Familial screening of at-risk relatives identified mutations in 16 family A members (8 men and 8 heterozygotes) and 25 family B members (10 men and 15 heterozygotes). Clinical assessments, α-galactosidase A (α-GalA) activities, glycosphingolipid substrate levels, and in vitro mutation expression were used to categorize p.D322E as a classic FD mutation and p.I232T as a later-onset FD mutation. In vitro expression revealed that p.D322E and p.I232T had α-GalA activities of 1.4% and 14.9% of the mean wild-type activity, respectively. Family A men had markedly decreased α-GalA activity and childhood-onset classic manifestations, except for angiokeratoma and cornea verticillata. Family B men had residual α-GalA activity and developed FD manifestations in adulthood. Despite these differences, all family A and family B men >30 years of age had left ventricular hypertrophy, which was mainly asymmetrical, and had similar late gadolinium enhancement patterns. Ischemic stroke and severe white matter lesions were more frequent among family A men, but neither family A nor family B men had overt renal disease. Family A and family B heterozygotes had less severe or no clinical manifestations. Men with classic or later-onset FD caused by GLA missense mutations developed prominent and similar cardiovascular disease at similar ages, despite markedly different α-GalA activities. © 2017 American Heart Association, Inc.

  18. Genetic structure along a gaseous organic pollution gradient: a case study with Poa annua L

    Chen Xiaoyong; Li Ning; Shen Lang; Li Yuanyuan

    2003-01-01

    Genetic composition of Poa annua populations showed clinal change along an organic pollution gradient. - The population genetic composition of Poa annua L. was studied by starch electrophoresis along a transect running NE from an organic reagents factory at Shanghai, China. Five enzyme systems were stained. We have reached the following preliminary conclusions: (1) Organic pollution has dramatically changed genotypic frequencies at some loci of Poa annua populations. At polluted sites, significant deviations from Hardy-Weinberg equilibrium were observed on loci Sod-1 and Me due to the excess of heterozygote. Especially in the two nearest sites to pollution source, all the individuals were heterozygous at locus Sod-1. The data suggests that heterozygotes were more tolerant to organic pollution than homozygotes, indicating the fitness superiority of heterozygotes. (2) A tendency towards clinal changes of allele frequencies was found at some polymorphic loci. Frequencies of the common alleles at loci Sod-1, Me and Fe-1 increased as the distance to the pollution source increased. (3) The effective number of alleles per locus, and the observed and expected heterozygosity were much higher in the pollution series than in the clear control site (Botanic Park population), but genetic multiplicity (number of alleles per locus) was lower than for the control. (4) Most genetic variability was found within populations, and only 2.56% were among populations of the polluted series. However, 9.48% of the total genetic variation occurred among populations when including the Botanic Park population. The genetic identity between populations of the pollution series (0.9869-1.0000, mean 0.9941) was higher than those between the pollution series and the Botanic Park population. UPGMA divided the five populations into two groups. One contained the four polluted populations, and the other only contained the Botanic Park population

  19. Genetic structure along a gaseous organic pollution gradient: a case study with Poa annua L

    Xiaoyong, Chen; Ning, Li; Lang, Shen; Yuanyuan, Li

    2003-08-01

    Genetic composition of Poa annua populations showed clinal change along an organic pollution gradient. - The population genetic composition of Poa annua L. was studied by starch electrophoresis along a transect running NE from an organic reagents factory at Shanghai, China. Five enzyme systems were stained. We have reached the following preliminary conclusions: (1) Organic pollution has dramatically changed genotypic frequencies at some loci of Poa annua populations. At polluted sites, significant deviations from Hardy-Weinberg equilibrium were observed on loci Sod-1 and Me due to the excess of heterozygote. Especially in the two nearest sites to pollution source, all the individuals were heterozygous at locus Sod-1. The data suggests that heterozygotes were more tolerant to organic pollution than homozygotes, indicating the fitness superiority of heterozygotes. (2) A tendency towards clinal changes of allele frequencies was found at some polymorphic loci. Frequencies of the common alleles at loci Sod-1, Me and Fe-1 increased as the distance to the pollution source increased. (3) The effective number of alleles per locus, and the observed and expected heterozygosity were much higher in the pollution series than in the clear control site (Botanic Park population), but genetic multiplicity (number of alleles per locus) was lower than for the control. (4) Most genetic variability was found within populations, and only 2.56% were among populations of the polluted series. However, 9.48% of the total genetic variation occurred among populations when including the Botanic Park population. The genetic identity between populations of the pollution series (0.9869-1.0000, mean 0.9941) was higher than those between the pollution series and the Botanic Park population. UPGMA divided the five populations into two groups. One contained the four polluted populations, and the other only contained the Botanic Park population.

  20. Recent Trends in WRN Gene Mutation Patterns in Individuals with Werner Syndrome.

    Yamaga, Masaya; Takemoto, Minoru; Takada-Watanabe, Aki; Koizumi, Naoko; Kitamoto, Takumi; Sakamoto, Kenichi; Ishikawa, Takahiro; Koshizaka, Masaya; Maezawa, Yoshiro; Yokote, Koutaro

    2017-08-01

    To determine recent trends in mutation patterns in the WRN gene, which cause Werner syndrome (WS), a rare, inheritable progeroid syndrome in Japan. Retrospective cohort. Longitudinal survey of WS and literature search for case reports. Individuals whose genetic testing their facilities had requested between 2009 and October 2016 (N = 67). A nationwide epidemiological study was conducted from 2009 to 2011 to improve understanding of the pathology of WS and develop therapeutic guidelines. Since 2009, Chiba University Hospital consecutively evaluated the WRN gene in 67 individuals throughout Japan who had requested genetic testing. A literature search was also conducted for case reports on Japanese WS reported since 1997. A definitive diagnosis of WS was confirmed genetically in 50 of 67 participants. Through the literature search, 16 individuals diagnosed genetically with WS were identified. Of these 66 individuals with WS, 42 were homozygous for a WRN mutation, and 21 were compound heterozygotes. One novel mutant allele was identified in an individual with the compound heterozygous genotype. The proportion of compound heterozygotes (31.8%) was significantly greater than reported previously (14.2%), indicating that the incidence of consanguineous marriage of parents has decreased. The increased frequency of individuals with WS with the compound heterozygous genotype is a recent trend in Japan. A long-term follow-up study on WRN homozygotes and compound heterozygotes will allow the relationship between WRN genotype and clinical severity of WS to be evaluated in the future. © 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.

  1. Q Sepharose micro-column chromatography: A simple screening method for identifying beta thalassemia traits and hemoglobin E carriers.

    Wong, Peerapon; Sritippayawan, Suchila; Suwannakhon, Narutchala; Tapprom, Akamon; Deoisares, Rawisut; Sanguansermsri, Torpong

    2016-11-01

    For beta thalassemia control program in pregnancy, mass screening of the carrier state by determination of the hemoglobin (Hb) A 2 and Hb E proportions and mutation analysis is a preferred method for making prenatal diagnoses. Q Sepharose micro-column chromatography, developed for the determination of Hb A 2 and Hb E for screening purposes, was compared with high performance liquid chromatography (HPLC) to ascertain its relative accuracy and reliability. Results using Q Sepharose micro-column chromatography in 350 blood specimens, including 50 samples genetically proven to be beta thalassemia heterozygotes, were compared to HPLC for validation. An additional study was conducted to test a clinical application on a large-scale survey for beta thalassemia in 1581 pregnant women and their spouses. The mean (±SD) Hb A 2 proportions in the normal and genetically proven beta thalassemia heterozygotes were 2.70±0.40% and 6.30±1.23%, respectively, as determined by Q-Sepharose micro-column chromatography, and 2.65±0.31% and 5.37±0.96%, respectively, as determined by HPLC. The mean Hb E proportions in the Hb E heterozygotes were 23.25±4.13% and 24.72±3.5% as determined by Q Sepharose micro-column chromatography and HPLC, respectively. In the large-scale survey for beta thalassemia, 23 at risk couples were detected. Seven affected fetuses were identified by prenatal diagnosis. Q Sepharose micro-column chromatography was found to be reliable, reproducible and well-suited for large-scale surveys. Additionally, by being reusable and convenient, this simple and economical chromatography method may be an alternative means to screen for beta thalassemia and Hb E carriers in the mass population. Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  2. SCREENING FOR GENETIC CHANGES AND CODON 129 POLYMORPHISM IN PRNP GENE IN HEALTHY SLOVENIAN POPULATION AND SPORADIC CASES OF CREUTZFELDT-JAKOB DISEASE

    Sava Smerkolj

    2004-11-01

    Full Text Available Background. Prion protein has an important role in development of prion diseases, fatal neurodegenerative disorders. As the codon 129 genotype of the prion protein gene (PRNP is a known susceptibility factor for the diseases, we wanted to determine its distribution in healthy Slovenian population and also in cases of sporadic Creutzfeldt-Jakob disease (sCJD. Furthermore, we wanted to screen the whole gene in order to establish the presence of genetic changes.Methods. We screened 350 DNA samples of healthy blood donors and 12 DNA samples of patients deceased of sCJD. After the amplification and conformation analysis had been done, the gene was sequenced using an automatic sequencer.Results. Methionine homozygotes comprised 46.8% of healthy population, valine homozygotes 12.1% and heterozygotes 41.1%; out of 12 sCJD patients 10 were methionine homozygotes (83.3%, 1 was valine homozygote (8.3% and 1 was heterozygote (8.3%.Found SNPs were combination of codon 76 change (228C > T and codon 84 change (252T > C in a single sample of healthy population, combination of codon 68 change (204T > C and codon 76 change (228C > T in two samples of healthy population and codon 117 change (351A > G in a healthy population sample and in a valine homozygote patient.Conclusions. In comparison to the pooled Caucasian population is genotype M/M frequency slightly increased on account of decreased genotype M/V frequency in healthy Slovenian population, suggesting a little higher risk for acquiring a new variant of CJD (vCJD, because up to date all confirmed vCJD cases except one heterozygote were methionine homozygotes. Codon 129 genotype distribution in sCJD can be described as disease-specific. The absence of pathogenic mutations in sCJD patients confirms the non-familial, sporadic disease form.

  3. Drosophila Longevity Assurance Conferred by Reduced Insulin Receptor Substrate Chico Partially Requires d4eBP.

    Hua Bai

    Full Text Available Mutations of the insulin/IGF signaling (IIS pathway extend Drosophila lifespan. Based on genetic epistasis analyses, this longevity assurance is attributed to downstream effects of the FOXO transcription factor. However, as reported FOXO accounts for only a portion of the observed longevity benefit, suggesting there are additional outputs of IIS to mediate aging. One candidate is target of rapamycin complex 1 (TORC1. Reduced TORC1 activity is reported to slow aging, whereas reduced IIS is reported to repress TORC1 activity. The eukaryotic translation initiation factor 4E binding protein (4E-BP is repressed by TORC1, and activated 4E-BP is reported to increase Drosophila lifespan. Here we use genetic epistasis analyses to test whether longevity assurance mutants of chico, the Drosophila insulin receptor substrate homolog, require Drosophila d4eBP to slow aging. In chico heterozygotes, which are robustly long-lived, d4eBP is required but not sufficient to slow aging. Remarkably, d4eBP is not required or sufficient for chico homozygotes to extend longevity. Likewise, chico heterozygote females partially require d4eBP to preserve age-dependent locomotion, and both chico genotypes require d4eBP to improve stress-resistance. Reproduction and most measures of growth affected by either chico genotype are always independent of d4eBP. In females, chico heterozygotes paradoxically produce more rather than less phosphorylated 4E-BP (p4E-BP. Altered IRS function within the IIS pathway of Drosophila appears to have partial, conditional capacity to regulate aging through an unconventional interaction with 4E-BP.

  4. Diagnosis and molecular characterization of non-classic forms of Tay-Sachs disease in Brazil.

    Rozenberg, R; Kok, F; Burin, M G; Sá Miranda, M C; Vasques, C; Henriques-Souza, A M M; Giugliani, R; Vainzof, Mariz; Pereira, L V

    2006-06-01

    Molecular analysis of five Brazilian families, including eight patients presenting with nonclassic Tay-Sachs disease, was performed to identify frequent causative mutations and their correlation with clinical course. Three patients were affected by the B1 subacute variant and were shown to carry the R178H mutation (the DN allele), which is also common among Portuguese patients. Two of them were compound heterozygotes, whereas the third presented with the mutation in both alleles. Since Brazil was a Portuguese colony for over two centuries, common ancestry might be the probable explanation. The fourth patient presented with a juvenile phenotype and carries the R499H mutation, which has been reported only once worldwide and is associated with residual enzyme activity, responsible for a slower clinical course. The fifth family, of an Ashkenazi Jewish background, showed an extensive intrafamilial clinical variability among three affected sibs presenting with muscle atrophy, ataxia, and psychiatric symptoms. They were first diagnosed as having atypical spinal muscular atrophy and, subsequently, spinocerebellar ataxia, but, recently, the diagnosis of late-onset Tay-Sachs disease was confirmed based on reduced plasma hexosaminidase A activity and the G269S/InsTATC1278 genotype. It is therefore highly recommended to test patients with a similar clinical history for Tay-Sachs disease. In the same family, one first cousin committed suicide at the age of 24 years, presenting with a clinical phenotype that suggested an undiagnosed case and highlighting the effect of the intrafamilial clinical variability in delaying a prompt diagnosis. It is now recognized that his parents are, in fact, a carrier couple. Additionally, another relative had been previously identified as a heterozygote in a Tay-Sachs disease screening program, but the information was not shared among the family. Since this information might anticipate diagnosis and genetic counseling, it is advisable that

  5. Long-term improvements in sensory inhibition with gestational choline supplementation linked to α7 nicotinic receptors through studies in Chrna7 null mutation mice.

    Stevens, Karen E; Choo, Kevin S; Stitzel, Jerry A; Marks, Michael J; Adams, Catherine E

    2014-03-13

    Perinatal choline supplementation has produced several benefits in rodent models, from improved learning and memory to protection from the behavioral effects of fetal alcohol exposure. We have shown that supplemented choline through gestation and lactation produces long-term improvement in deficient sensory inhibition in DBA/2 mice which models a similar deficit in schizophrenia patients. The present study extends that research by feeding normal or supplemented choline diets to DBA/2 mice carrying the null mutation for the α7 nicotinic receptor gene (Chrna7). DBA/2 mice heterozygotic for Chrna7 were bred together. Dams were placed on supplemented (5 gm/kg diet) or normal (1.1 gm/kg diet) choline at mating and remained on the specific diet until offspring weaning. Thereafter, offspring were fed standard rodent chow. Adult offspring were assessed for sensory inhibition. Brains were obtained to ascertain hippocampal α7 nicotinic receptor levels. Choline-supplemented mice heterozygotic or null-mutant for Chrna7 failed to show improvement in sensory inhibition. Only wildtype choline-supplemented mice showed improvement with the effect solely through a decrease in test amplitude. This supports the hypothesis that gestational-choline supplementation is acting through the α7 nicotinic receptor to improve sensory inhibition. Although there was a significant gene-dose-related change in hippocampal α7 receptor numbers, binding studies did not reveal any choline-dose-related change in binding in any hippocampal region, the interaction being driven by a significant genotype main effect (wildtype>heterozygote>null mutant). These data parallel a human study wherein the offspring of pregnant women receiving choline supplementation during gestation, showed better sensory inhibition than offspring of women on placebo. Published by Elsevier B.V.

  6. Isolation of 21 polymorphic microsatellite markers for the Virginia opossum (Didelphis virginiana).

    Fike, Jennifer A; Beasley, James C; Rhodes, Olin E

    2009-07-01

    Twenty-one polymorphic microsatellite markers were developed for the Virginia opossum (Didelphis virginiana). The number of alleles ranged from two to 13 and observed heterozygosities ranged from 0.464 to 0.964. Significant heterozygote deficiencies were observed at three loci and null alleles were detected at five loci. Evidence for gametic disequilibrium was observed between three sets of paired loci after a sequential Bonferroni correction was applied. These markers will enable us to investigate the mating tactics, movement behaviour and social structure of Virginia opossum populations inhabiting fragmented agricultural landscapes. © 2009 Blackwell Publishing Ltd.

  7. Xeroderma Pigmentosum-Trichothiodystrophy overlap patient with novel XPD/ERCC2 mutation

    Kralund, Henrik H; Ousager, Lilian; Jaspers, Nicolaas G

    2013-01-01

    outcome from many of these mutations. We demonstrate a patient, believed to represent an overlap between XP and TTD/CS. In addition to other organ dysfunctions, the young man presented with Photosensitivity, Ichthyosis, Brittle hair, Impaired physical and mental development, Decreased fertility and Short...... appearance also suggested XP, but fibroblast cultures only demonstrated x2 UV-sensitivity with expected NER and TFIIH-activity decrease. Genetic sequencing of the XPD/ERCC2 gene established the patient as heterozygote compound with a novel, N-terminal Y18H mutation and a known C-terminal (TTD) mutation, A725...

  8. DNA-repair synthesis in ataxia telangiectasia lymphoblastoid cells

    Ford, M.D.; Houldsworth, J.; Lavin, M.F. (Queensland Univ., Brisbane (Australia). Dept. of Biochemistry)

    1981-12-01

    The ability of a number of Epstein-Barr virus-transformed lymphoblastoid cells from ataxia telangiectasia (AT) patients to repair ..gamma..-radiation damage to DNA was determined. All of these AT cells were previously shown to be hypersensitive to ..gamma..-radiation. Two methods were used to determine DNA-repair synthesis: isopycnic gradient analysis and a method employing hydroxyurea to inhibit semiconservative DNA synthesis. Control, AT heterozygote and AT homozygote cells were demonstrated to have similar capacities for repair of radiation damage to DNA. In addition at high radiation doses (10-40 krad) the extent of inhibition of DNA synthesis was similar in the different cell types.

  9. Autosomal recessive anhidrotic ectodermal dysplasia: A rare entity

    Sangita Ghosh

    2014-01-01

    Full Text Available We describe a case of anhidrotic ectodermal dysplasia (AED with an autosomal recessive mode of inheritance, a very rare entity, in a 2-year-old female child of two asymptomatic, consanguineous parents. Their previous child also had a similar condition. Autosomal recessive AED (AR-AED can have its full expression both in males and females and it is clinically indistinguishable from the x-linked recessive AED (XL-AED, which is the most common type of ectodermal dysplasia. Unlike the partially symptomatic carriers of XL-AED, the heterozygotes of AR-AED are phenotypically asymptomatic.

  10. Recombinant Chromosome 4 from a Familial Pericentric Inversion: Prenatal and Adulthood Wolf-Hirschhorn Phenotypes

    Francesca Malvestiti

    2013-01-01

    Full Text Available Pericentric inversion of chromosome 4 can give rise to recombinant chromosomes by duplication or deletion of 4p. We report on a familial case of Wolf-Hirschhorn Syndrome characterized by GTG-banding karyotypes, FISH, and array CGH analysis, caused by a recombinant chromosome 4 with terminal 4p16.3 deletion and terminal 4q35.2 duplication. This is an aneusomy due to a recombination which occurred during the meiosis of heterozygote carrier of cryptic pericentric inversion. We also describe the adulthood and prenatal phenotypes associated with the recombinant chromosome 4.

  11. Aag-initiated base excision repair drives alkylation-induced retinal degeneration in mice.

    Meira, Lisiane B; Moroski-Erkul, Catherine A; Green, Stephanie L; Calvo, Jennifer A; Bronson, Roderick T; Shah, Dharini; Samson, Leona D

    2009-01-20

    Vision loss affects >3 million Americans and many more people worldwide. Although predisposing genes have been identified their link to known environmental factors is unclear. In wild-type animals DNA alkylating agents induce photoreceptor apoptosis and severe retinal degeneration. Alkylation-induced retinal degeneration is totally suppressed in the absence of the DNA repair protein alkyladenine DNA glycosylase (Aag) in both differentiating and postmitotic retinas. Moreover, transgenic expression of Aag activity restores the alkylation sensitivity of photoreceptors in Aag null animals. Aag heterozygotes display an intermediate level of retinal degeneration, demonstrating haploinsufficiency and underscoring that Aag expression confers a dominant retinal degeneration phenotype.

  12. Petroleum pollution and mutation in mangroves

    Klekowski, E.J. Jr.; Corredor, J.E.; Morell, J.M.; Del Castillo, C.A.

    1994-01-01

    Chlorophyll-deficiency has often been used as a sensitive genetic end-point in plant mutation research. The frequency of trees heterozygous for nuclear chlorophyll-deficient mutations was determined for mangrove populations growing along the southwest coast of Puerto Rico. The frequency of heterozygotes was strongly correlated with the concentration of polycyclic aromatic hydrocarbons in the underlying sediment and with both acute and chronic petroleum pollution. Although epidemiological studies can seldom prove causation, a strong correlation is certainly compatible with a cause-effect relationship. Our results suggest that the biota of oil-polluted habitats may be experiencing increased mutation. (Author)

  13. Radiation-induced intestinal neoplasia in a genetically-predisposed mouse (Min)

    Ellender, M.; Larder, S.M.; Harrison, J.D.; Cox, R.; Silver, A.R.J.

    1997-01-01

    A mouse lineage with inherited predisposition to multiple intestinal neoplasia (min) has been proposed as a model to study human colorectal cancer. Min mice are heterozygous for the adenomatous polyposis coli (Apc) gene implicated in human familial adenomatous polyposis (FAP). There is an increased risk of intestinal cancer in humans following radiation exposure and the min mouse model may be used to further our understanding of the molecular mechanisms involved. The present study showed a 2 Gy dose of x-rays doubles the tumour numbers in the murine gastrointestinal tract of F1 min heterozygotes. The distribution of tumours through the gut was also recorded. (authors)

  14. Homocystinuria due to cystathionine beta-synthase (CBS deficiency in Russia: Molecular and clinical characterization

    Elena Voskoboeva

    2018-03-01

    Full Text Available We present the results of the 45-year clinical observation of 27 Russian homocystinuria patients. We made a mutation analysis of the CBS gene for thirteen patients from eleven unrelated genealogies. All patients except for the two were compound heterozygotes for the mutations detected. The most frequent mutation in the cohort investigated was splice mutation IVS11-2a->c. We detected one new nonsense mutation, one new missense-mutation and three novel small deletions. We also report the clinical case of the B6-responsive patient genotyped as Ile278Thr/Cys109Arg.

  15. Compound heterozygosity with a novel S222N GALT mutation leads to atypical galactosemia with loss of GALT activity in erythrocytes but little evidence of clinical disease

    Benjamin Cocanougher

    2015-03-01

    Full Text Available Galactosemia is an inborn error of galactose metabolism caused by mutations in the GALT gene. Though early detection and galactose restriction prevent severe liver disease, affected individuals have persistently elevated biomarkers and often neuro-developmental symptoms. We present a teenage compound heterozygote for a known pathogenic mutation (H132Q and a novel variant of unknown significance (S222N, with nearly absent erythrocyte GALT enzyme activity but normal biomarkers and only mild anxiety despite diet non-adherence. This case is similar to a previously reported S135L mutation. In this report we investigate the novel S222N variant and critically evaluate a clinically puzzling case.

  16. CYP3A4*18: it is not rare allele in Japanese population.

    Yamamoto, Takehito; Nagafuchi, Nobue; Ozeki, Takeshi; Kubota, Takahiro; Ishikawa, Hiroshi; Ogawa, Seishi; Yamada, Yasuhiko; Hirai, Hisamaru; Iga, Tatsuji

    2003-01-01

    We sequenced all 13 exons of the CYP3A4 gene derived from 48 Japanese subjects. One subject possess the 20070 T>C mutation in the exon 10 (result in leu293Pro substitution, namely CYP3A4(*)18), as heterozygote. Thus, we investigated the frequency of CYP3A4(*)18 in 118 Japanese population using polymerase chain reaction-restriction fragment length polymorphism with Msp I and determined that the frequency of the CYP3A4(*)18 allele was 1.3%.

  17. Molecular characterization and multidisciplinary management of Gerbich hemolytic disease of the newborn.

    Levitt, Rebecca N; Gourri, Elise; Gassner, Christoph; Banez-Sese, Grace; Salam, Abdus; Denomme, Gregory A; Yang, Elizabeth

    2018-06-01

    Gerbich (Ge) antigens are high frequency red cell antigens expressed on glycophorin C (GYPC) and glycophorin D. Hemolytic disease of the fetus and newborn (HDFN) due to Gerbich antibody is rare and presents a clinical challenge, as Gerbich negative blood is scarce. We report a case of HDFN due to maternal Ge3 negative phenotype and anti-Ge3 alloimmunization, successfully managed by transfusion of maternal blood. Molecular testing revealed that the mother has homozygous deletion of exon 3 of GYPC, the father is homozygous wildtype for GYPC, and the infant is obligate heterozygote expressing Ge3. © 2018 Wiley Periodicals, Inc.

  18. Progressive dysphagia in limb-girdle muscular dystrophy type 2B.

    Walsh, Richard

    2012-02-01

    Dysphagia has not been reported in genetically confirmed limb-girdle muscular dystrophy type 2B (LGMD2B). A 40-year-old woman reported exercise-induced calf pain at age 34, followed by progressive lower and upper limb weakness. At age 38, progressive dysphagia for solids, and subsequently liquids, ensued. Endoscopic and videofluoroscopic-radiological findings indicated a myopathic swallowing disorder. Molecular genetic analysis confirmed two dysferlin gene mutations consistent with a compound heterozygote state. Progressive dysphagia should be considered as part of the expanding dysferlinopathy phenotype.

  19. Impaired cholesterol esterification in primary brain cultures of the lysosomal cholesterol storage disorder (LCSD) mouse mutant

    Patel, S.C.; Suresh, S.; Weintroub, H.; Brady, R.O.; Pentchev, P.G.

    1987-01-01

    Esterification of cholesterol was investigated in primary neuroglial cultures obtained from newborn lysosomal cholesterol storage disorder (LCSD) mouse mutants. An impairment in 3 H-oleic acid incorporation into cholesteryl esters was demonstrated in cultures of homozygous LCSD brain. Primary cultures derived from other phenotypically normal pups of the carrier breeders esterified cholesterol at normal levels or at levels which were intermediary between normal and deficient indicating a phenotypic expression of the LCSD heterozygote genotype. These observations on LCSD mutant brain cells indicate that the defect in cholesterol esterification is closely related to the primary genetic defect and is expressed in neuroglial cells in culture

  20. X-ray induced pericentric inversions in Anopheles albimanus

    Rabbani, M.G.; Seawright, J.A.; Kitzmiller, J.B.

    1977-01-01

    Sixteen different pericentric inversions, ten on chromosome 2 and six on chromosome 3, have been isolated and characterized. The partial sterility in the inversion heterozygotes ranged from about 28 to 50%. Contrary to theoretical considerations, a curvilinear relationship exists between inversion length and partial sterility, whereby a reduction in sterility was noted for progressively longer inversions. The break-points are distributed randomly over the autosomes, but are observed more frequently in the areas of the salivary gland chromosomes where diffuse and broken bands of variable stainability are located. (author)

  1. Fabry Disease in Families With Hypertrophic Cardiomyopathy

    Adalsteinsdottir, Berglind; Palsson, Runolfur; Desnick, Robert J

    2017-01-01

    BACKGROUND: The screening of Icelandic patients clinically diagnosed with hypertrophic cardiomyopathy resulted in identification of 8 individuals from 2 families with X-linked Fabry disease (FD) caused by GLA(α-galactosidase A gene) mutations encoding p.D322E (family A) or p.I232T (family B...... asymmetrical, and had similar late gadolinium enhancement patterns. Ischemic stroke and severe white matter lesions were more frequent among family A men, but neither family A nor family B men had overt renal disease. Family A and family B heterozygotes had less severe or no clinical manifestations...

  2. Classical phenotype of Laron syndrome in a girl with a heterozygous mutation and heterozygous polymorphism of the growth hormone receptor gene.

    Shevah, Orit; Galli-Tsinopoulou, Assimina; Rubinstein, Menachem; Nousia-Arvanitakis, Sanda; Laron, Zvi

    2004-03-01

    We describe here a 19 month-old girl with classical Laron syndrome (LS). Molecular analysis of the GH receptor gene in the patient and her parents was performed. The patient was found to be heterozygous for a mutation in exon 4 (R43X) and heterozygous for a polymorphism in exon 6 (Gly168Gly). Her mother was also heterozygous for R43X but homozygous for the polymorphism. In the father, a heterozygous polymorphism was found. Contrary to previous assumptions that only homozygous patients express the typical phenotype, this patient shows all the classical features of LS, despite being a heterozygote for a pathological defect.

  3. The genetic basis of long QT and short QT syndromes: a mutation update

    Hedley, Paula L; Jørgensen, Poul; Schlamowitz, Sarah

    2009-01-01

    Long QT and short QT syndromes (LQTS and SQTS) are cardiac repolarization abnormalities that are characterized by length perturbations of the QT interval as measured on electrocardiogram (ECG). Prolonged QT interval and a propensity for ventricular tachycardia of the torsades de pointes (TdP) type......-Nielsen syndrome (JLNS), Andersen syndrome (AS), and Timothy syndrome (TS). The genetics are further complicated by the occurrence of double and triple heterozygotes in LQTS and a considerable number of nonpathogenic rare polymorphisms in the involved genes. SQTS is a very rare condition, caused by mutations...

  4. Microsatellite marker isolation and development for the giant Pacific Octopus (Enteroctopus dofleini)

    Toussaint, Rebecca K.; Sage, G. Kevin; Talbot, Sandra L.; Scheel, David

    2012-01-01

    We isolated and developed 18 novel microsatellite markers for the giant Pacific octopus (Enteroctopus dofleini) and examined them for 31 individuals from Prince William Sound (PWS), Alaska. These loci displayed moderate levels of allelic diversity (averaging 11 alleles per locus) and heterozygosity (averaging 65%). Seven loci deviated from Hardy–Weinberg Equilibrium (HWE) due to heterozygote deficiency for the PWS population, although deviations were not observed for all these loci in other populations, suggesting the PWS population is not in mutation-drift equilibrium. These novel microsatellite loci yielded sufficient genetic diversity for potential use in population genetics, individual identification, and parentage studies.

  5. Hypoparathyroidism, sensorineural deafness, and renal dysgenesis syndrome with a mutation

    Yong Suk Shim

    2015-03-01

    Full Text Available Hypoparathyroidism, sensorineural deafness, and renal dysgenesis syndrome is an autosomal dominant disease caused by mutations in the GATA3 gene on chromosome 10p15. We identified a patient diagnosed with hypoparathyroidism who also had a family history of hypoparathyroidism and sensorineural deafness, present in the father. The patient was subsequently diagnosed and found to be a heterozygote for an insertion mutation c.255_256ins4 (GTGC in exon 2 of GATA3. His father was also confirmed to have the same mutation in GATA3.

  6. HLA class I-mediated control of HIV-1 in the Japanese population, in which the protective HLA-B*57 and HLA-B*27 alleles are absent.

    Naruto, Takuya; Gatanaga, Hiroyuki; Nelson, George; Sakai, Keiko; Carrington, Mary; Oka, Shinichi; Takiguchi, Masafumi

    2012-10-01

    We investigated the effect of HLA class I alleles on clinical parameters for HIV-1 disease progression in the Japanese population, where two strongly protective alleles, HLA-B*57 and HLA-B*27, are virtually nonexistent. HLA-B alleles showed a dominant role, primarily through HLA-B*67:01 and the HLA-B*52:01-C*12:02 haplotype. Neither a rare-allele nor a heterozygote advantage was found, suggesting that the effect of HLA alleles in the Japanese population is either different from those observed in Africans and Caucasians or undetectable due to limited power.

  7. Fanconi Anemia: A Rarely Considered Cause of Macrocytosis During Childhood.

    Aslan, Deniz

    2017-10-01

    We describe a Turkish boy newly diagnosed with Fanconi anemia with mutation in the FANCA gene. The patient, with normal clinical phenotype and negative chromosomal breakage test result, presented with macrocytosis. No clinical or laboratory changes were observed in a follow-up period of 4 years. The diagnosis was confirmed molecularly after a prolonged and exhaustive investigation. He was found to be a compound heterozygote for 2 mutations in the FANCA gene (1 of which is novel, c.4261-2A>C). We present this experience to alert physicians that Fanconi anemia should be considered in the differential diagnosis of otherwise unexplained macrocytosis during childhood.

  8. Use of induced chlorophyll deficient mutants to identify 'heterotic blocks' in pearl millet chromosomes

    Burton, G.W.

    1989-01-01

    Full text: Chlorophyll deficient mutant stocks induced in 'Tift 23' of pearl millet (Pennisetum americanum L. Leeke) were crossed with 'Tift 23' and 5 other normal inbreds to study the effect of these deleterious recessive genes on yield. The difference between near-isogenic S 1 (F 2 ) populations homozygous or heterozygous for the chlorophyll deficiency was not significant. However among 69 S 1 progenies from crosses with other inbreds the heterozygotes were higher yielding than the homozygotes in 53 cases, 15 of which were significant. A mutant like 'M5' identified a high yield 'heterotic block' in 'Inbred 104' and a very low yield 'heterotic block' in 'Inbred 186'. (author)

  9. Genetic mapping in mice identifies DMBT1 as a candidate modifier of mammary tumors and breast cancer risk

    Blackburn, Anneke C; Hill, Linda Z; Roberts, Amy L

    2007-01-01

    Low-penetrance breast cancer susceptibility alleles seem to play a significant role in breast cancer risk but are difficult to identify in human cohorts. A genetic screen of 176 N2 backcross progeny of two Trp53(+/-) strains, BALB/c and C57BL/6, which differ in their susceptibility to mammary...... tumors, identified a modifier of mammary tumor susceptibility in an approximately 25-Mb interval on mouse chromosome 7 (designated SuprMam1). Relative to heterozygotes, homozygosity for BALB/c alleles of SuprMam1 significantly decreased mammary tumor latency from 70.7 to 61.1 weeks and increased risk...

  10. HLA-G polymorphisms in couples with recurrent spontaneous abortions

    Hviid, T V; Hylenius, S; Hoegh, A M

    2002-01-01

    % of the RSA women carried the HLA-G*0106 allele compared to 2% of the control women. The 14 bp deletion polymorphism in exon 8 was investigated separately. There were a greater number of heterozygotes for the 14 bp polymorphism in the group of fertile control women than expected, according to Hardy-Weinberg...... equilibrium. Furthermore, the HLA-G alleles without the 14 bp sequence were prominent in the RSA males in contrast to the RSA women in whom alleles including the 14 bp sequence were frequently observed, especially as homozygotes. These results are discussed in relation to two hypotheses concerning HLA...

  11. The motor and cognitive features of Parkinson's disease in patients with concurrent Gaucher disease over 2 years: a case series.

    Collins, Lucy M; Williams-Gray, Caroline H; Morris, Elizabeth; Deegan, Patrick; Cox, Timothy M; Barker, Roger A

    2018-05-29

    We report the cognitive features and progression of Parkinson's disease (PD) in five patients with concurrent Gaucher disease. The patients presented at an earlier age than patients with sporadic PD, as previously noted by others; but in contrast to many previous reports, our patients followed a variable clinical course. While two patients developed early cognitive deficits and dementia, three others remained cognitively intact over the follow-up period. Thus, in this small case series, PD in the context of GD more closely resembles idiopathic PD in terms of its clinical heterogeneity in contrast to PD associated with GBA heterozygote mutations.

  12. Thirteen nuclear microsatellite loci for butternut (Juglans cinerea L.).

    Hoban, Sean; Anderson, Robert; McCleary, Tim; Schlarbaum, Scott; Romero-Severson, Jeanne

    2008-05-01

    Butternut (Juglans cinerea L.) is an eastern North American forest tree severely threatened by an exotic fungal pathogen, Sirococcus clavigignenti-juglandacearum. We report here 13 nuclear microsatellites for genetic evaluation of the remaining natural populations. Summary statistics are reported for individuals from a population of butternuts in central Kentucky (N = 63). All markers were polymorphic, with an average of 13.7 alleles per locus observed. Four loci exhibited significantly fewer heterozygotes than expected under Hardy-Weinberg equilibrium (P < 0.05). © 2007 The Authors.

  13. A highly prevalent equine glycogen storage disease is explained by constitutive activation of a mutant glycogen synthase

    Maile, C A; Hingst, Janne Rasmuss; Mahalingan, K K

    2017-01-01

    BACKGROUND: Equine type 1 polysaccharide storage myopathy (PSSM1) is associated with a missense mutation (R309H) in the glycogen synthase (GYS1) gene, enhanced glycogen synthase (GS) activity and excessive glycogen and amylopectate inclusions in muscle. METHODS: Equine muscle biochemical...... had significantly higher glycogen content than control horse muscle despite no difference in GS expression. GS activity was significantly higher in muscle from homozygous mutants than from heterozygote and control horses, in the absence and presence of the allosteric regulator, glucose 6 phosphate (G6...

  14. Sources of contradictions in the evaluation of population genetic consequences after the chernobyl disaster.

    Glazko, V I; Glazko, T T

    2013-01-01

    The review covers the analysis of our own and published data pertaining to population and genetic consequences in various mammalian species under conditions of high levels of ionizing radiation as a result of the Chernobyl accident. The findings indicate that these conditions have promoted the reproduction of heterozygotes in polyloci spectra of molecular genetic markers and animals with a relatively increased stability of the chromosomal apparatus. The prospects of using the reproductive "success" of the carriers of these characteristics as an integral indicator of the selective influence of environmental stress factors are discussed.

  15. Absence of genotoxic activity from milk and water boiled in microwave oven in somatic cells from Drosophila melanogaster; Ausencia da atividade genotoxica do leite e agua, fervidos com microondas, em celulas somaticas de Drosophila melanogaster

    Dias, Cristina das Dores. E-mail: crisddias@yahoo.com.br

    2003-07-01

    This paper reports an experiment for evaluation of the possible genotoxic effects of food prepared in a microwave oven, through the mutation test and somatic recombination, in wings of Drosophila melanogaster. Two crossing have been performed: a standard cross-ST and a high bioactivation cross - HB resulting in marked trans -heterozygote descendents (MH) and balanced heterozygotes (BH). The 72 hours larvas were fed with water and milk boiled both in the microwave oven and in the traditional way. The MH individual wings were analyzed, where the spots can be induced either by mutation or mitotic recombination. The experiment presented negative results related to the genotoxic effects of the water and milk boiled using the microwave oven, in MH descendents of both crossing. Therefore, under these experimental conditions, genotoxic activity were not presented by milk and water boiled in the microwave oven. However, an extensive study using different techniques is necessary to investigate the action of the food prepared in the microwave oven on the genetic material.

  16. Interleukin-1 Receptor Antagonist Gene Polymorphism in Patients with Coronary Artery Diseases

    Abdel Aziz, A.F.; El Said, A.M.; El Maghraby, T.K.; Hassan, M.M.

    2012-01-01

    Cytokine gene variations are contributory factors in inflammatory pathology. Allele frequencies of Interleukin-1 receptor antagonist (IL-1Ra) gene intron 2 VNTR were measured in healthy blood donors (healthy control subjects) and patients with angina, myocardial infarction (MI) and acute coronary syndrome(ACS). Patients were classified into three groups: thirty one MI patients, twenty two angina patients and thirteen ACS patients. A1/A2 genotype showed significant resistant factor for angina and myocardial infarction and angina (70.97% vs. 29.03%; p=0.0001, 70.97% vs. 31.82%; p0.0004, respectively). A1/A1 homo zygote was a risk factor in MI and angina (p=0.012; p= 0.0001), Moreover, A1/A3 and A2/A3 heterozygotes were found in MI only (p= 0.025; p= 0.0047, respectively). All genotypes didn't show any effect on ACS patients. In conclusion, the data reflected that A1/A1 homo zygote was considered as a significantly risk factor associated with patients with angina as well as MI patients. But, A1/A2 heterozygote was considered a resistance factor against both diseases.

  17. Forensic genetic SNP typing of low-template DNA and highly degraded DNA from crime case samples

    Børsting, Claus; Mogensen, Helle Smidt; Morling, Niels

    2013-01-01

    the heterozygote balance. Allele drop-ins were only observed in experiments with 25 pg of DNA and not in experiments with 50 and 100 pg of DNA. The allele drop-in rate in the 25 pg experiments was 0.06% or 100 times lower than what was previously reported for STR typing of LtDNA. A composite model and two......Heterozygote imbalances leading to allele drop-outs and disproportionally large stutters leading to allele drop-ins are known stochastic phenomena related to STR typing of low-template DNA (LtDNA). The large stutters and the many drop-ins in typical STR stutter positions are artifacts from the PCR...... amplification of tandem repeats. These artifacts may be avoided by typing bi-allelic markers instead of STRs. In this work, the SNPforID multiplex assay was used to type LtDNA. A sensitized SNP typing protocol was introduced, that increased signal strengths without increasing noise and without affecting...

  18. Selective interactions among Rh, ABO, and sex ratio of newborns.

    Valenzuela, C Y; Walton, R

    1985-01-01

    The hypothesis that the Rh and ABO blood systems behave like the HLA system in relation to mother-conception tolerance-rejection mechanisms was tested in 25,501 mother-infant pairs. According to this hypothesis, heterozygotes carrying a paternal gene that is not present in their mothers should be better tolerated than homozygotes. Significantly more BO infants born to AO mothers. AO infants born to BO mothers, Rh(+) heterozygotes born to Rh(-) mothers, and less significantly AO infants born to OO mothers confirm the hypothesis. Fewer homozygotes occurred in Rh(-) infants born to Rh(+) mothers and in O infants born to non-O mothers. Deviations from the Hardy-Weinberg equilibrium found in the ABO system were modified by the Rh and sex of the infant. These data strongly support the hypothesis that at least two feto-maternal systems influence the destiny of pregnancies: the classical known incompatibility system which operates late in pregnancy and a new one which is based on the induction of maternal tolerance early in pregnancy: maternal tolerance seems to be better elicited by heterozygous eggs or embryos carrying a gene not present in the mother. The data also support the hypothesis that the sex ratio is influenced by feto-maternal tolerance-rejection mechanisms associated with the ABO and Rh systems.

  19. [Novel CHST6 compound heterozygous mutations cause macular corneal dystrophy in a Chinese family].

    Qi, Yan-hua; Dang, Xiu-hong; Su, Hong; Zhou, Nan; Liang, Ting; Wang, Zheng; Huang, Shang-zhi

    2010-02-01

    The aim of this study was to identify mutations of CHST6 gene in a Chinese family with macular corneal dystrophy (MCD) and to investigate the histopathological changes of MCD. Corneal button of the proband was obtained from penetrating keratoplasty for the treatment of severe corneal dystrophy. The sections and ultrathin sections of this specimen were examined under light microscope and transmission electron microscope (TEM). Genomic DNA was extracted from leukocytes in peripheral blood from the family members. The coding region of CHST6 was amplified by polymerase chain reaction (PCR). The PCR products were analyzed by direct sequencing and restriction enzyme digestion. Histochemical study revealed positive results of colloidal iron stain. TEM revealed enlargement of smooth endoplasmic reticulum and the presence of intracytoplasmic vacuoles. Two mutations, Q298X Y358H, were identified in exon 3 of CHST6. Three patients were compound heterozygotes of these two mutations. The C892T transversion occurred at codon 298 turned the codon of glutamine to a stop codon; the T1072C transversion occurred at codon 358 caused a missense mutation, tyrosine to histidine. All six unaffected family members were heterozygotes. These two mutations were not detected in any of the 100 control subjects. The novel compound heterozygous mutation results in loss of CHST6 function and causes the occurrence of MCD. This is the first report of this gene mutation.

  20. Influence of APOE Genotype on Hippocampal Atrophy over Time - An N=1925 Surface-Based ADNI Study.

    Bolun Li

    Full Text Available The apolipoprotein E (APOE e4 genotype is a powerful risk factor for late-onset Alzheimer's disease (AD. In the Alzheimer's Disease Neuroimaging Initiative (ADNI cohort, we previously reported significant baseline structural differences in APOE e4 carriers relative to non-carriers, involving the left hippocampus more than the right--a difference more pronounced in e4 homozygotes than heterozygotes. We now examine the longitudinal effects of APOE genotype on hippocampal morphometry at 6-, 12- and 24-months, in the ADNI cohort. We employed a new automated surface registration system based on conformal geometry and tensor-based morphometry. Among different hippocampal surfaces, we computed high-order correspondences, using a novel inverse-consistent surface-based fluid registration method and multivariate statistics consisting of multivariate tensor-based morphometry (mTBM and radial distance. At each time point, using Hotelling's T(2 test, we found significant morphological deformation in APOE e4 carriers relative to non-carriers in the full cohort as well as in the non-demented (pooled MCI and control subjects at each follow-up interval. In the complete ADNI cohort, we found greater atrophy of the left hippocampus than the right, and this asymmetry was more pronounced in e4 homozygotes than heterozygotes. These findings, combined with our earlier investigations, demonstrate an e4 dose effect on accelerated hippocampal atrophy, and support the enrichment of prevention trial cohorts with e4 carriers.

  1. Early detection of cystic fibrosis in newborns using radioimmunoanalysis of trypsin in drops of blood absorbed on filter paper. Final report for the period 1 July 1996 - 30 June 1997

    Menises, M.M.

    1998-03-01

    The objective was to establish the cut-off value for blood immunoreactive trypsin radioimmunoassay used in the screening program for cystic fibrosis. Ten thousand capillary blood samples were collected from newborns 48 hours after birth on Schleider and Schnell No.903 filter paper and screened for immunoreactive trypsin (IRT) using polyethylene glycol assisted double antibody radioimmunoassay. Samples with IRT values greater then 800 ng/ml were subjected to further molecular biological diagnosis by amplification of exons 10 and 11 of CFTR gene. The products were analysed for ΔF508 and G542X mutations by hybridization with specific allele probe and G551D and R553X mutations by restriction enzyme digestion and Southern Blot. One hundred and forty one patients showed IRT values of greater then 800 ng/ml. Five of them were homozygotes for mutation at and ΔF508 and one was heterozygote the disease (one allele was positive for ΔF508 and the other allele for G542X). Only one of them presented with meconium ileus and the rest were asymptomatic. None of them has value less than 1200ng/ml in the first week of life. Five heterozygote for mutation at ΔF508 was also detected using 800ng/ml as cut-off. Based on the above findings, the cut-off value is established at 1200ng/ml. This gives specificity and sensitivity of 100%. (author)

  2. PMS2 mutations in childhood cancer.

    De Vos, Michel; Hayward, Bruce E; Charlton, Ruth; Taylor, Graham R; Glaser, Adam W; Picton, Susan; Cole, Trevor R; Maher, Eamonn R; McKeown, Carole M E; Mann, Jill R; Yates, John R; Baralle, Diana; Rankin, Julia; Bonthron, David T; Sheridan, Eamonn

    2006-03-01

    Until recently, the PMS2 DNA mismatch repair gene has only rarely been implicated as a cancer susceptibility locus. New studies have shown, however, that earlier analyses of this gene have had technical limitations and also that the genetic behavior of mutant PMS2 alleles is unusual, in that, unlike MLH1 or MSH2 mutations, PMS2 mutations show low heterozygote penetrance. As a result, a dominantly inherited cancer predisposition has not been a feature reported in families with PMS2 mutations. Such families have instead been ascertained through childhood-onset cancers in homozygotes or through apparently sporadic colorectal cancer in heterozygotes. We present further information on the phenotype associated with homozygous PMS2 deficiency in 13 patients from six families of Pakistani origin living in the United Kingdom. This syndrome is characterized by café-au-lait skin pigmentation and a characteristic tumor spectrum, including leukemias, lymphomas, cerebral malignancies (such as supratentorial primitive neuroectodermal tumors, astrocytomas, and glioblastomas), and colorectal neoplasia with an onset in early adult life. We present evidence for a founder effect in five families, all of which carried the same R802-->X mutation (i.e., arginine-802 to stop) in PMS2. This cancer syndrome can be mistaken for neurofibromatosis type 1, with important management implications including the risk of the disorder occurring in siblings and the likelihood of tumor development in affected individuals.

  3. DNA Repair Gene Polymorphism and the Risk of Mitral Chordae Tendineae Rupture

    Aysel Kalayci Yigin

    2015-01-01

    Full Text Available Polymorphisms in Lys939Gln XPC gene may diminish DNA repair capacity, eventually increasing the risk of carcinogenesis. The aim of the present study was to evaluate the significance of polymorphism Lys939Gln in XPC gene in patients with mitral chordae tendinea rupture (MCTR. Twenty-one patients with MCTR and thirty-seven age and sex matched controls were enrolled in the study. Genotyping of XPC gene Lys939Gln polymorphism was carried out using polymerase chain reaction- (PCR- restriction fragment length polymorphism (RFLP. The frequencies of the heterozygote genotype (Lys/Gln-AC and homozygote genotype (Gln/Gln-CC were significantly different in MCTR as compared to control group, respectively (52.4% versus 43.2%, p=0.049; 38.15% versus 16.2%, p=0.018. Homozygote variant (Gln/Gln genotype was significantly associated with increased risk of MCTR (OR = 2.059; 95% CI: 1.097–3.863; p=0.018. Heterozygote variant (Lys/Gln genotype was also highly significantly associated with increased risk of MCTR (OR = 1.489; 95% CI: 1.041–2.129; p=0.049. The variant allele C was found to be significantly associated with MCTR (OR = 1.481; 95% CI: 1.101–1.992; p=0.011. This study has demonstrated the association of XPC gene Lys939Gln polymorphism with MCTR, which is significantly associated with increased risk of MCTR.

  4. Maize ROP2 GTPase provides a competitive advantage to the male gametophyte.

    Arthur, K M; Vejlupkova, Z; Meeley, R B; Fowler, J E

    2003-12-01

    Rop GTPases have been implicated in the regulation of plant signal transduction and cell morphogenesis. To explore ROP2 function in maize, we isolated five Mutator transposon insertions (rop2::Mu alleles). Transmission frequency through the male gametophyte, but not the female, was lower than expected in three of the rop2::Mu mutants. These three alleles formed an allelic series on the basis of the relative transmission rate of each when crossed as trans-heterozygotes. A dramatic reduction in the level of ROP2-mRNA in pollen was associated with the three alleles causing a transmission defect, whereas a rop2::Mu allele that did not result in a defect had wild-type transcript levels, thus confirming that mutation of rop2 causes the mutant phenotype. These data strongly support a role for rop2 in male gametophyte function, perhaps surprisingly, given the expression in pollen of the nearly identical duplicate gene rop9. However, the transmission defect was apparent only when a rop2::Mu heterozygote was used as the pollen donor or when a mixture of wild-type and homozygous mutant pollen was used. Thus, mutant pollen is at a competitive disadvantage compared to wild-type pollen, although mutant pollen grains lacked an obvious cellular defect. Our data demonstrate the importance in vivo of a specific Rop, rop2, in the male gametophyte.

  5. A novel mutation in the thyroglobulin gene that causes goiter and dwarfism in Wistar Hannover GALAS rats.

    Sato, Akira; Abe, Kuniya; Yuzuriha, Misako; Fujii, Sakiko; Takahashi, Naofumi; Hojo, Hitoshi; Teramoto, Shoji; Aoyama, Hiroaki

    2014-04-01

    Outbred stocks of rats have been used extensively in biomedical, pharmaceutical and/or toxicological studies as a model of genetically heterogeneous human populations. One of such stocks is the Wistar Hannover GALAS rat. However, the colony of Wistar Hannover GALAS rat has been suspected of keeping a problematic mutation that manifests two distinct spontaneous abnormalities, goiter and dwarfism, which often confuses study results. We have successfully identified the responsible mutation, a guanine to thymine transversion at the acceptor site (3' end) of intron 6 in the thyroglobulin (Tg) gene (Tgc.749-1G>T), that induces a complete missing of exon 7 from the whole Tg transcript by mating experiments and subsequent molecular analyses. The following observations confirmed that Tgc.749-1G>T/Tgc.749-1G>T homozygotes manifested both dwarfism and goiter, while Tgc.749-1G>T/+ heterozygotes had only a goiter with normal appearance, suggesting that the mutant phenotypes inherit as an autosomal semi-dominant trait. The mutant phenotypes, goiter and dwarfism, mimicked those caused by typical endocrine disrupters attacking the thyroid. Hence a simple and reliable diagnostic methodology has been developed for genomic DNA-based genotyping of animals. The diagnostic methodology reported here would allow users of Wistar Hannover GALAS rats to evaluate their study results precisely by carefully interpreting the data obtained from Tgc.749-1G>T/+ heterozygotes having externally undetectable thyroidal lesions. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. Enterovirus Exposure Uniquely Discriminates Type 1 Diabetes Patients with a Homozygous from a Heterozygous Melanoma Differentiation-Associated Protein 5/Interferon Induced with Helicase C Domain 1 A946T Genotype.

    Schulte, Barbara M; Gielen, Paul R; Kers-Rebel, Esther D; Prosser, Amy C; Lind, Katharina; Flodström-Tullberg, Malin; Tack, Cees J; Elving, Lammy D; Adema, Gosse J

    2016-09-01

    In children at risk for type 1 diabetes, innate immune activity is detected before seroconversion. Enterovirus infections have been linked to diabetes development, and a polymorphism (A946T) in the innate immune sensor recognizing enterovirus RNA, interferon-induced with helicase C domain 1/melanoma differentiation-associated protein 5, predisposes to disease. We hypothesized that the strength of innate antienteroviral responses is affected in autoimmune type 1 diabetes patients and linked to the A946T polymorphism. We compared induction of interferon-stimulated genes (ISGs) in peripheral blood mononuclear cells (PBMCs) and dendritic cells (DCs) in healthy individuals and diabetes patients upon stimulation with enterovirus, enterovirus-antibody complexes, or ligands mimicking infection in relation to the A946T polymorphism. Overall, PBMCs of diabetes patients and healthy donors showed comparable ISG induction upon stimulation. No differences were observed in DCs. Interestingly, the data imply that the magnitude of responses to enterovirus and enterovirus-antibody complexes in PBMCs is critically influenced by the A946T polymorphism and elevated in heterozygotes compared to TT homozygous individuals in autoimmune diabetes patients, but not healthy controls. These data imply an intrinsic difference in the responses to enterovirus and enterovirus-antibody complexes in diabetes patients carrying a TT risk genotype compared to heterozygotes that may influence control of enterovirus clearance.

  7. Re-evaluation of in vitro radiosensitivity of human fibroblasts of different genetic origins

    Deschavanne, P.J.; Debieu, D.; Malaise, E.P.; Fertil, B.

    1986-08-01

    Statistical analysis of the radiosensitivity of 204 survival curves of non-transformed human fibroblast cell strains of different genetic origins was made using the multi-target one-hit model (characterized by parameters eta and D/sub 0/), the surviving fraction for a 2 Gy dose (S/sub 2/) and the mean inactivation dose (D-bar). D-bar is found to be the parameter for characterization of anomalous radiosensitivity linked to a genetic disorder and discrimination between groups of cell strains of differing radiosensitivity. It allows the description of a range of 'normal' radiosensitivity for control fibroblasts and classification of genetic disorders as a function of their mean radiosensitivity expressed in terms of D-bar. Nine groups of cell strains appear to exhibit radiosensitivity differing significantly from the controls: seven groups are hypersensitive (ataxia-telengiectasia homozygotes and heterozygotes, Cockayne's syndrome, Gardner's syndrome, 5-oxoprolinuria homozygotes and heterozygotes, Fanconi's anaemia) and two groups are more radioresistant (fibroblasts from retinoblastoma patients and individuals with chromosome 13 anomalies). Since the coupled parameter eta and D/sub 0/ failed to discriminate between the radiosensitivity of the different genetic groups, the use of D-bar to make an intercomparison of intrinsic radiosensitivity of non-transformed human fibroblasts is recommended. (U.K.).

  8. Effects of polymorphic variations in tumor necrosis factor alpha and occupational exposure to grain dust on longitudinal decline in pulmonary function.

    Pahwa, Punam; Nakagawa, Kazuko; Koehncke, Niels; McDuffie, Helen H

    2009-01-01

    Longitudinal declines in pulmonary function are associated with individuals experiencing occupational exposure to organic dusts in combination with lifestyle factors such as cigarette smoking and with genetic factors, and interactions between these factors. To investigate the relationship between polymorphism of genes encoding Tumor Necrosis Factor Alpha (TNF-alpha) and longitudinal lung function decline in grain workers exposed to grain dust. Male grain handlers who participated in the Saskatchewan Grain Workers Surveillance Program from 2002 through 2005 provided demographic, occupational, lifestyle, and respiratory symptoms information as well as pulmonary function measurements and DNA for genotyping. Marginal models using the generalized estimating equations approach were fitted by using a SAS PROC GENMOD to predict the annual decline in Forced Expired Volume in one second (FEV(1)) and Forced Vital Capacity (FVC). Smoking intensity contributed to the decline in FEV(1.)Among *1/*1 homozygotes and *1/*2 heterozygotes, grain workers with grain industry had significantly lower FEV(1)declines compared to those of the other two exposure groups (>10 and 20 years in the grain industry). The annual declines in FEV(1)for grain workers who were either *1/*1 homozygote or *1/*2 heterozygote and had been in the grain industry for grain workers who were *2/*2 genotype and had been in the industry for grain industry is an effect modifier between TNF-alpha 308 genotype and longitudinal decline in FEV(1)in male subjects exposed to grain dust.

  9. A new mouse model for marfan syndrome presents phenotypic variability associated with the genetic background and overall levels of Fbn1 expression.

    Bruno L Lima

    2010-11-01

    Full Text Available Marfan syndrome is an autosomal dominant disease of connective tissue caused by mutations in the fibrillin-1 encoding gene FBN1. Patients present cardiovascular, ocular and skeletal manifestations, and although being fully penetrant, MFS is characterized by a wide clinical variability both within and between families. Here we describe a new mouse model of MFS that recapitulates the clinical heterogeneity of the syndrome in humans. Heterozygotes for the mutant Fbn1 allele mgΔloxPneo, carrying the same internal deletion of exons 19-24 as the mgΔ mouse model, present defective microfibrillar deposition, emphysema, deterioration of aortic wall and kyphosis. However, the onset of a clinical phenotypes is earlier in the 129/Sv than in C57BL/6 background, indicating the existence of genetic modifiers of MFS between these two mouse strains. In addition, we characterized a wide clinical variability within the 129/Sv congenic heterozygotes, suggesting involvement of epigenetic factors in disease severity. Finally, we show a strong negative correlation between overall levels of Fbn1 expression and the severity of the phenotypes, corroborating the suggested protective role of normal fibrillin-1 in MFS pathogenesis, and supporting the development of therapies based on increasing Fbn1 expression.

  10. Hereditary thrombophilia: identification of nonsense and missense mutations in the protein C gene

    Romeo, G.; Hassan, H.J.; Staempfli, S.

    1987-01-01

    The structure of the gene for protein C, an anticoagulant serine protease, was analyzed in 29 unrelated patients with hereditary thrombophilia and protein C deficiency. Gene deletion(s) or gross rearrangement(s) was not demonstrable by Southern blot hybridization to cDNA probes. However, two unrelated patients showed a variant restriction pattern after Pvu II or BamHi digestion, due to mutations in the last exon: analysis of their pedigrees, including three or seven heterozygotes, respectively, with ∼50% reduction of both enzymatic and antigen level, showed the abnormal restriction pattern in all heterozygous individuals, but not in normal relatives. Cloning of protein C gene and sequencing of the last exon allowed the authors to identify a nonsense and a missense mutation, respectively. In the first case, codon 306 (CGA, arginine) is mutated to an inframe stop codon, thus generating a new Pvu II recognition site. In the second case, a missense mutation in the BamHI palindrome (GGATCC → GCATCC) leads to substitution of a key amino acid (a tryptophan to cysteine substitution at position 402), invariantly conserved in eukaryotic serine proteases. These point mutations may explain the protein C-deficiency phenotype of heterozygotes in the two pedigrees

  11. A novel lipoprotein lipase gene missense mutation in Chinese patients with severe hypertriglyceridemia and pancreatitis

    2014-01-01

    Background Alterations or mutations in the lipoprotein lipase (LPL) gene contribute to severe hypertriglyceridemia (HTG). This study reported on two patients in a Chinese family with LPL gene mutations and severe HTG and acute pancreatitis. Methods Two patients with other five family members were included in this study for DNA-sequences of hyperlipidemia-related genes (such as LPL, APOC2, APOA5, LMF1, and GPIHBP1) and 43 healthy individuals and 70 HTG subjects were included for the screening of LPL gene mutations. Results Both patients were found to have a compound heterozygote for a novel LPL gene mutation (L279V) and a known mutation (A98T). Furthermore, one HTG subject out of 70 was found to carry this novel LPL L279V mutation. Conclusions The data from this study showed that compound heterozygote mutations of A98T and L279V inactivate lipoprotein lipase enzymatic activity and contribute to severe HTG and acute pancreatitis in two Chinese patients. Further study will investigate how these LPL gene mutations genetically inactivate the LPL enzyme. PMID:24646025

  12. Diagnostic dilemma

    Feldt-Rasmussen, Ulla; Dobrovolny, Robert; Nazarenko, Irina

    2011-01-01

    Fabry disease, an X-linked lysosomal storage disorder, results from the deficient activity of a-galactosidase A (a-Gal A). In affected males, the clinical diagnosis is confirmed by the markedly decreased a-Gal A activity. However, in female heterozygotes, the a-Gal A activity can range from low t...... on enzyme replacement therapy. Thus, gene dosage analyses can detect large deletions (>50bp) in suspect heterozygotes for X-linked and autosomal dominant diseases that are "sequencing cryptic," resolving molecular diagnostic dilemmas....... to normal due to random X-chromosomal inactivation, and diagnostic confirmation requires identification of the family's a-Gal A gene mutation. In a young female who had occasional acroparesthesias, corneal opacities, and 15 to 50% of the lower limit of normal leukocyte a-Gal A activity, a-Gal A sequencing...... in two expert laboratories did not identify a confirmatory mutation, presenting a diagnostic dilemma. A renal biopsy proved diagnostic and renewed efforts to detect an a-Gal A mutation. Subsequent gene dosage analyses identified a large a-Gal A deletion confirming her heterozygosity, and she was started...

  13. Chronic irradiation as an ecological factor affecting genetic population structure

    Kal'chenko, V.A.; Kalabushkin, B.A.; Rubanovich, A.V.

    1991-01-01

    Genetic structure of two Centaurea scabiosa L. populations was studied by frequency distribution of leucine aminopeptidase (LAP) locus genotypes. The experimental population has been growing under conditions of chronic irradiation, with the dose per generation amounting to 1.2 to 25.5 Gy. In it, mutational variants are observed with a frequency of 5.4.10(-3)-4.5.10(-2) per generation (as compared to control population frequency at 5.4.10(-4)). Indexes for heterozygosity, mean number of genotypes, and effective number of alleles were higher in the experimental population. Segregation analysis revealed no differences in viability in the control population, and all genotypic combinations were found to be nearly neutral. In the experimental population, however, significant differences in relative viability of the genotypes were disclosed. The relative viability of heterozygotes for mutant allele C' was nearly maximum, while heterozygotes for other mutant alleles showed minimum viability. We reach the conclusion that the differences in genetic structure of the populations under investigation can be explained by the chronic irradiation factor that brought out differences in adaptability of both normal and mutant genotypes. The suggestion is that intra-locus interactions of the C' allele with normal alleles determine plant resistance to a wide range of unfavorable environmental conditions

  14. Re-evaluation of in vitro radiosensitivity of human fibroblasts of different genetic origins

    Deschavanne, P.J.; Debieu, D.; Malaise, E.P.; Fertil, B.

    1986-01-01

    Statistical analysis of the radiosensitivity of 204 survival curves of non-transformed human fibroblast cell strains of different genetic origins was made using the multi-target one-hit model (characterized by parameters eta and D 0 ), the surviving fraction for a 2 Gy dose (S 2 ) and the mean inactivation dose (D-bar). D-bar is found to be the parameter for characterization of anomalous radiosensitivity linked to a genetic disorder and discrimination between groups of cell strains of differing radiosensitivity. It allows the description of a range of 'normal' radiosensitivity for control fibroblasts and classification of genetic disorders as a function of their mean radiosensitivity expressed in terms of D-bar. Nine groups of cell strains appear to exhibit radiosensitivity differing significantly from the controls: seven groups are hypersensitive (ataxia-telengiectasia homozygotes and heterozygotes, Cockayne's syndrome, Gardner's syndrome, 5-oxoprolinuria homozygotes and heterozygotes, Fanconi's anaemia) and two groups are more radioresistant (fibroblasts from retinoblastoma patients and individuals with chromosome 13 anomalies). Since the coupled parameter eta and D 0 failed to discriminate between the radiosensitivity of the different genetic groups, the use of D-bar to make an intercomparison of intrinsic radiosensitivity of non-transformed human fibroblasts is recommended. (U.K.)

  15. Genetic Polymorphism of Secretoglobin SCGB1A1 and Development of Lung Pathology in Children

    N.K. Malaya

    2014-02-01

    Full Text Available The purpose of investigation — to study of A(38G genetic polymorphism of the first exon of secretoglobin SCGB1A1 in Crimean children and to identify the possible correlation between the degree of polymorphism and development of lung pathology (bronchial asthma and recurrent bronchitis. There were investigated DNA samples from children with bronchial asthma (75 persons, recurrent bronchitis (19 persons and healthy children (20 persons aged from 6 to 16 years. The genetic polymorphism was determined by polymerase chain reaction with method of allele discrimination with registration the results by electrophoresis. Frequency of allele combinations of genetic variants of studied polymorphism was different in patients with bronchial asthma, recurrent bronchitis and in control group. Thus, among patients with bronchial asthma the frequency of homozygous allele AA carriers is lower, and among patients with recurrent bronchitis it is higher then in control group. Contrary, the frequency of AG heterozygotes was higher among patients with bronchial asthma then in patients with recurrent bronchitis and in control group. Also the frequency of AG heterozygotes in patients with recurrent bronchitis is much lower than homozygotes. The obtained results can be used for prognostic purpose to evaluate the prospects of the obstructive syndrome development.

  16. Cerebral Vein Thrombosis:Screening of Acquired and Hereditary Thrombophilic Risk Factors

    Sarraf Payam

    2009-10-01

    Full Text Available Cerebral vein thrombosis (CVT is an infrequent condition with a large variety of causes that can lead to serious disabilities. However, in 20% to 35% of cases, no cause is found. In this study we evaluated the hereditary (P & C Proteins, antithrombin, mutation of prothrombin G20210A and factor V Leiden, other risk factors (hyperhomocycteinemia, factor VIII, ACL-ab, APL-ab, and OCP and clinical manifestations among a population of Iranian patients with CVT. 18 women and 10 men aged 16 to 50 years with CVT were screened for inherited and acquired coagulation risk factors. No one had an abnormal ACL-ab, APL-ab or antithrombin III deficiency. One had prothrombin G20210A mutation (heterozygot (3.6%. Hyperhomocycteinemia was observed in 5 patients (17.9%. APC-R was decreased in 3 (10.7%. 2 had positive factor V Leiden mutation (heterozygot (7.1%. 17 had an increased of factor VIII (60.7. PS and PC deficiencies were each detected in two cases (7.1%. Conclusion: Our study suggests that screening for inherited thrombophilia may be an integral part in the diagnostic workup and duration of treatment in patients with CVT.

  17. Prevalence of and markers for the attenuated form of congenital adrenal hyperplasia and hyperprolactinemia masquerading as polycystic ovarian disease.

    Benjamin, F; Deutsch, S; Saperstein, H; Seltzer, V L

    1986-08-01

    To determine the prevalence of the attenuated form of congenital adrenal hyperplasia (CAH) and hyperprolactinemia (HPPN) relative to polycystic ovarian disease (PCOD), 100 consecutive women presenting with the classic clinical features of PCOD were evaluated by basal hormonal profiles and subsequent adrenocorticotropic hormone (ACTH) stimulation tests. The study also sought biochemical markers for CAH other than ACTH stimulation. The prevalences were found to be as follows: PCOD, 65%; PCOD with HPPN, 9%; HPPN, 3%, end-organ hypersensitivity (EOH), 4%; homozygotic CAH, 4%; and heterozygotic CAH, 15%. Other than the differential response to ACTH, the only other biochemical markers observed for homozygotic CAH were significantly higher basal levels of testosterone (T) and 17 alpha-hydroxyprogesterone (17-OHP). Luteinizing hormone/follicle-stimulating hormone ratio, androstenedione, and dehydroepiandrosterone sulfate all showed no significant differences between homozygotic CAH, heterozygotic CAH, HPPN, PCOD, and EOH. This study establishes the relative prevalences of the syndromes commonly mimicking PCOD. We also conclude that the observed low incidence of CAH does not justify routine ACTH testing on all patients presenting with features of PCOD--however, our data suggest that patients with basal serum levels of T and 17-OHP greater than 50% above the upper limit of normal should undergo this dynamic test, especially if there are also certain clinical features suggestive of CAH.

  18. Cognitive assessment of mice strains heterozygous for cell-adhesion genes reveals strain-specific alterations in timing.

    Gallistel, C R; Tucci, Valter; Nolan, Patrick M; Schachner, Melitta; Jakovcevski, Igor; Kheifets, Aaron; Barboza, Luendro

    2014-03-05

    We used a fully automated system for the behavioural measurement of physiologically meaningful properties of basic mechanisms of cognition to test two strains of heterozygous mutant mice, Bfc (batface) and L1, and their wild-type littermate controls. Both of the target genes are involved in the establishment and maintenance of synapses. We find that the Bfc heterozygotes show reduced precision in their representation of interval duration, whereas the L1 heterozygotes show increased precision. These effects are functionally specific, because many other measures made on the same mice are unaffected, namely: the accuracy of matching temporal investment ratios to income ratios in a matching protocol, the rate of instrumental and classical conditioning, the latency to initiate a cued instrumental response, the trials on task and the impulsivity in a switch paradigm, the accuracy with which mice adjust timed switches to changes in the temporal constraints, the days to acquisition, and mean onset time and onset variability in the circadian anticipation of food availability.

  19. Risk of cancer by ATM missense mutations in the general population

    Dombernowsky, Sarah Louise; Weischer, Maren; Allin, Kristine Højgaard

    2008-01-01

    PURPOSE: Truncating and missense mutations in the ATM gene, which cause insufficient DNA damage surveillance, allow damaged cells to proceed into mitosis, which eventually results in increased cancer susceptibility. We tested the hypotheses that ATM Ser49Cys and ATM Ser707Pro heterozygosity......: Multifactorially adjusted hazard ratios for ATM Ser49Cys heterozygotes versus noncarriers were 1.2 (95% CI, 0.9 to 1.5) for cancer overall, 0.8 (95% CI, 0.3 to 2.0) for breast cancer, 4.8 (95% CI, 2.2 to 11) for melanoma, 2.3 (95% CI, 1.1 to 5.0) for prostate cancer, and 3.4 (95% CI, 1.1 to 11) for cancer...... of the oral cavity/pharynx. Multifactorially adjusted hazard ratios for ATM Ser707Pro heterozygotes versus noncarriers were 0.8 (95% CI, 0.6 to 1.2) for cancer overall, 0.6 (95% CI, 0.2 to 1.6) for breast cancer, 10 (95% CI, 1.1 to 93) for thyroid/other endocrine tumors, and 2.7 (95% CI, 1.0 to 7...

  20. beta-Thalassemia present in cis to a new beta-chain structural variant, Hb Vicksburg [beta 75 (E19)Leu leads to 0].

    Adams, J G; Steinberg, M H; Newman, M V; Morrison, W T; Benz, E J; Iyer, R

    1981-01-01

    Hemoglobin Vicksburg was discovered in a 6-year-old Black boy who had been anemic since infancy. Examination of his hemolysate revealed 87.5% Hb F, 2.4% Hb A2, and 7.6% Hb Vicksburg, which had the electrophoretic and chromatographic properties of Hb A. Structural analysis of Hb Vicksburg demonstrated a deletion of leucine at beta 75(E19), a new variant. Hb Vicksburg was neither unstable nor subject to posttranslational degradation. The alpha/non-alpha biosynthetic ratio was 2.6. Because the proband appeared to be a mixed heterozygote for Hb Vicksburg and beta 0-thalassemia, Hb Vicksburg should have comprised the major portion of the hemolysate. Thus, Hb Vicksburg was synthesized at a rate considerably lower than would be expected on the basis of gene dosage. There was no reason to suspect abnormal translation of beta Vicksburg mRNA; in individuals with Hb St. Antoine (beta 74 and beta 75 deleted), the abnormal hemoglobin comprised 25% of the hemolysate in the simple heterozygote yet was unstable. Deletion of beta 75, therefore, would not in itself appear to lead to diminished synthesis. There was a profound deficit of beta Vicksburg mRNA when measured by liquid hybridization analysis with beta cDNA. The most plausible explanation for the low output of Hb Vicksburg is that a mutation for beta +-thalassemia is present in cis to the structural mutation.

  1. Chromosomal heterozygosity and fertility in house mice (Mus musculus domesticus) from Northern Italy.

    Hauffe, H C; Searle, J B

    1998-11-01

    Following the discovery of over 40 Robertsonian (Rb) races of Mus musculus domesticus in Europe and North Africa, the house mouse has been studied extensively as an ideal model to determine the chromosomal changes that may cause or accompany speciation. Current models of chromosomal speciation are based on the assumption that heterozygous individuals have a particularly low fertility, although recent studies indicate otherwise. Despite their importance, fertility estimates for the house mouse are incomplete because traditional measurements, such as anaphase I nondisjunction and germ cell death, are rarely estimated in conjunction with litter size. In an attempt to bridge this gap, we have taken advantage of the house mouse hybrid zone in Upper Valtellina (Lombardy, Italy) in which five Rb races interbreed. We present data on the fertility of naturally occurring ("wild-caught") hybrids and of offspring from laboratory crosses of wild-caught mice ("laboratory-reared"), using various measurements. Wild-caught mice heterozygous for one fusion were more infertile than predicted from past studies, possibly due to genic hybridity; laboratory-reared heterozygotes carrying seven or eight trivalents at meiosis I and heterozygotes carrying one pentavalent also had low fertilities. These low fertilities are especially significant given the probable occurrence of a reinforcement event in Upper Valtellina.

  2. XY pair associates with the synaptonemal complex of autosomal male-sterile translocations in pachytene spermatocytes of the mouse (Mus musculus).

    Forejt, J; Gregorová, S; Goetz, P

    1981-01-01

    Analysis of the chromosome behaviour at pachytene has been performed by means of the silver staining technique visualizing the synaptonemal complexes (SCs) in male mice heterozygous for the male-sterile translocations T(5;12)31Hm T(16;17)43H and T(7;19)145H, respectively. the T(9;17)138Ca male heterozygotes and T43H/T43H homozygous males were used as fertile controls. The sterile mice displayed a high frequency (about 60%) of pachytene spermatocytes with autosomal translocation configuration located in close vicinity of the XY pair. The dense round body (XAB), normally located near the X-chromosome axis in fertile males, exhibited abnormal affinity to translocation configuration in the sterile translocation heterozygotes. The incomplete synapsis of autosomes involved in translocation configuration was observed in more than 70% of the pachytene spermatocytes with the male-sterile translocations but less than 20% of the cells from T138Ca fertile male.s. A hypothesis relating the spermatogenic arrest of carriers of male-sterile rearrangements to the presumed interference with X chromosome inactivation in male meiosis is discussed.

  3. Effects of a radiation-induced α-thalassemia on the production of multiple forms of hemoglobins in fetal mice

    Popp, R.A.; Bradshaw, B.S.; Hirsch, G.P.

    1978-01-01

    Embryonic hemoglobins in α-thalassemic heterozygotes and normal fetuses were compared to study the effects of the deficient α chain on the synthesis of hemoglobins in the nucleated embryonic erythrocytes derived from the fetal yolk sac. Acrylamide gel electrophoresis showed that less hemoglobin Ell (α 2 y 2 ) was formed in α-thalassemic heterozygotes between 12 1 / 2 and 14 1 / 2 days of gestation. Quantitation of in vitro synthesis between 11 1 / 2 and 13 1 / 2 days of gestation also showed that Ell was synthesized less rapidly in α-thalassemic fetuses. In contrast, the synthesis of Elll (α 2 z 2 ) was higher in α-thalassemic than in normal fetuses at 12 1 / 2 and 13 1 / 2 days of gestation. Measurements of the synthesis of individual chains in El (x 2 y 2 ) and Ell showed that x chain synthesis was normal and that α chain synthesis was deficient in α-thalassemic fetuses at 11 1 / 2 and 12 1 / 2 days of gestation. Thus, there is still no proof for close linkage of x- and α-chain genes in chromosome 11. Differences in the electrophoretic patterns of embryonic hemoglobins of α-thalassemic and normal fetuses can be explained by normal synthesis of x chains, deficient synthesis of α chains, and a higher affinity of z than y for the reduced amount of α chain present in the nucleated embryonic erythrocytes of α-thalassemic mice

  4. Novel USH2A mutations in Israeli patients with retinitis pigmentosa and Usher syndrome type 2.

    Kaiserman, Nadia; Obolensky, Alexey; Banin, Eyal; Sharon, Dror

    2007-02-01

    To identify USH2A mutations in Israeli patients with autosomal-recessive Usher syndrome type 2 (USH2) and retinitis pigmentosa (RP). Patients from 95 families with RP and 4 with USH2 were clinically evaluated. USH2A exons 2-72 were scanned for mutations using single-strand conformation and sequencing analyses. The frequency of novel missense changes was determined in patients and controls using restriction endonucleases. The analysis revealed 3 USH2A mutations, 2 of which are novel, in 2 families with USH2 and a large family (MOL0051) with both USH2 and RP. Compound heterozygotes for 2 null mutations (Thr80fs and Arg737stop) in MOL0051 suffered from USH2 while compound heterozygotes for 1 of the null mutations and a novel missense mutation (Gly4674Arg) had nonsyndromic RP. Our results support the involvement of USH2A in nonsyndromic RP and we report here of a second, novel, missense mutation in this gene causing autosomal-recessive RP. Possible involvement of USH2A should be considered in the molecular genetic evaluation of patients with autosomal-recessive RP. Understanding the mechanism by which different USH2A mutations cause either USH2 or RP may assist in the development of novel therapeutic approaches.

  5. Gibberellins Promote Brassinosteroids Action and Both Increase Heterosis for Plant Height in Maize (Zea mays L.

    Songlin Hu

    2017-06-01

    Full Text Available Brassinosteroids (BRs and Gibberellins (GAs are two classes of plant hormones affecting plant height (PHT. Thus, manipulation of BR and GA levels or signaling enables optimization of crop grain and biomass yields. We established backcross (BC families, selected for increased PHT, in two elite maize inbred backgrounds. Various exotic accessions used in the germplasm enhancement in maize project served as donors. BC1-derived doubled haploid lines in the same two elite maize inbred backgrounds established without selection for plant height were included for comparison. We conducted genome-wide association studies to explore the genetic control of PHT by BR and GA. In addition, we used BR and GA inhibitors to compare the relationship between PHT, BR, and GA in inbred lines and heterozygotes from a physiological and biological perspective. A total of 73 genomic loci were discovered to be associated with PHT, with seven co-localized with GA, and two co-localized with BR candidate genes. PHT determined in field trials was significantly correlated with seedling stage BR and GA inhibitor responses. However, this observation was only true for maize heterozygotes, not for inbred lines. Path analysis results suggest that heterozygosity increases GA levels, which in turn promote BR levels. Thus, at least part of heterosis for PHT in maize can be explained by increased GA and BR levels, and seedling stage hormone inhibitor response is promising to predict heterosis for PHT.

  6. Effect of polymorphisms at the ghrelin gene locus on carcass, microstructure and physicochemical properties of longissimus lumborum muscle of Polish Landrace pigs.

    Wojtysiak, Dorota; Kaczor, Urszula

    2011-12-01

    The influence of RFLP-BsrI polymorphisms at the ghrelin gene locus on carcass, meat quality parameters and muscle fiber characteristics of longissimus lumborum was studied in 168 barrows of the Polish Landrace breed. Analysis revealed a high frequency of the 1 allele (0.60) with the frequencies of the 11, 12 and 22 genotypes being 0.45, 0.30 and 0.25, respectively. The most favorable parameters of meat traits were characteristic of pigs with the 22 genotype, together with a higher carcass and loin weight and lower thermal loss compared to 12 heterozygotes. The highest fat content was found in pigs with the 11 genotype, which had the highest abdominal fat weight and mean backfat thickness. Meanwhile, the 12 heterozygotes were characterized by the largest loin eye areas, highest lightness (L*) and yellowness (b*) values, and lowest redness (a*) values, as well as the greatest hardness and chewiness and largest diameter of type IIB muscle fibers compared to the other genotypes. Copyright © 2011 Elsevier Ltd. All rights reserved.

  7. Analysis of Suppressor of Cytokine Signaling 2 Gene (SOCS2 Polymorphism in Different Dog Breeds

    Martina Miluchová

    2011-05-01

    Full Text Available SOCS2 is a negative regulator of growth hormone signaling. The deletion of SOCS2 in mice results in a 30-50% increase in post-natal growth. The aim of the paper was to identify of suppressor of cytokine signaling 2 gene (SOCS2 polymorphism in different dog breeds. The material involved 77 dogs from 14 different breeds. Canine genomic DNA was isolated from saliva by modified method with using DNAzol® (Molecular Research Center and linear polyacrylamide (LPA carrier and from blood by using NucleospinBlood (Macherey-Nagel and used in order to estimate SOCS2 genotypes by PCR-RFLP method. The PCR products were digested with TaqI restriction enzyme. The T allele was distributed among large dog breeds (Czech pointer, Golden retriever, Rottweiler with an allele frequency ranging from 0.2857 to 1.00. In the population of Czech pointer we detected all genotypes. There were detected homozygote genotype GG with frequency 0.5476, heterozygote genotype GT with frequency 0.3333 and homozygote genotype TT with frequency 0.1191. Results point out that frequency of G allele was high and was represented 0.7143. Frequency of T allele was 0.2857. In Rottweiler was detected homozygote genotype TT. Genotypes GG and GT has not been observed. In Golden retriever we detected only heterozygote genotype GT.

  8. Analysis of Single Nucleotide Polymorphism (SNP rs22114085 Associated with Canine Atopic Dermatitis by PCR-RFLP Method

    Martina Miluchová

    2012-05-01

    Full Text Available Canine atopic dermatitis (cAD is a common inflammatory skin disease that is considered to be a naturally occurring, spontaneous model of human atopic dermatitis (eczema. The aim of the paper was to identify of the SNP rs22114085 in different dog breeds. The material involved 52 dogs from 5 different breeds. Canine genomic DNA was isolated from saliva by modified method with using DNAzol® and linear polyacrylamide (LPA carrier and from blood by using commercial kit NucleospinBlood and used in order to estimate rs22114085 SNP genotypes by PCR-RFLP method. The PCR products were digested with DdeI restriction enzyme. The C allele was distributed in Czech Pointer, Chihuahua, German Wirehaired Pointer with an allele frequency ranging from 0.4545 to 1.00. In the population of Czech Pointer we detected all genotypes CC, CT and TT with frequency in male 0.25, 0.5833 and 0.1667, and in female 0.2728, 0.3636 and 0.3636, subsequently. In German Wirehaired Pointer was detected homozygote genotype CC in male and heterozygote genotype CT in female with frequency 1 and 1. In Chihuahua was observed homozygote genotype CC and heterozygote genotype CT with frequency 0.3333 and 0.6667, subsequently. In Golden retriever and Pincher we detected genotype TT with frequency 1.

  9. Cellular radiosensitivity in human severe-combined-immunodeficiency (SCID) syndromes

    Sproston, Anthony R.M.; West, Catharine M.L.; Hendry, Jolyon H.

    1997-01-01

    Purpose: The aim of the work was to establish to what extent a variety of human severe-combined-immunodeficiency (SCID) disorders are associated with in vitro cellular hypersensitivity to ionizing radiation. Materials and methods: A study was made of fibroblast strains established from individuals with adenosine deaminase deficiency, T(-)B(-) SCID, Omenn's syndrome and a SCID heterozygote. For comparison, an assessment was also made of the radiosensitivity of a series of fibroblast strains derived from: normal donors, a patient with ataxia-telangiectasia (A-T) and an A-T heterozygote. Radiosensitivity was determined using a clonogenic assay following both high (HDR) and low (LDR) dose-rate irradiation. Results: Following HDR irradiation, the fibroblast strains derived from the different human SCID disorders displayed a wide range of radiosensitivity: the adenosine deaminase deficiency cells were similar in radiosensitivity to normal fibroblasts, T(-)B(-) cells were as hypersensitive to radiation as A-T cells and the Omenn's syndrome cells showed intermediate radiosensitivity. However, whereas all four normal cell strains studied showed significant LDR sparing, none of the SCID fibroblasts did. Conclusions: These data indicate that human SCID is variable in terms of radiosensitivity depending on the particular defect. In addition, the lack of LDR sparing of radiation-induced damage suggests the involvement of some form(s) of DNA repair defect in all the human SCID syndromes

  10. CHEK2*1100delC and risk of malignant melanoma

    Weischer, Maren; Heerfordt, Ida M; Bojesen, Stig E

    2012-01-01

    with increased risk of malignant melanoma. First, we performed case-control studies of 1,152 Danish and 752 German individuals with malignant melanoma compared with 9,142 Danish and 3,718 German controls. Second, we performed a meta-analysis of CHEK2*1100delC and malignant melanoma, involving 2,619 cases and 17......,481 controls. Third, we examined the risk of malignant melanoma associated with CHEK2*1100delC heterozygosity in an analysis stratified for sun exposure, as well as for subtype and location on the body. The odds ratios for malignant melanoma for CHEK2(*)1100del heterozygotes compared with those for noncarriers...... were 2.01 (95% confidence interval (CI), 1.03-3.91) in Danes, 1.42 (95% CI, 0.46-4.31) in Germans, and 1.79 (95% CI, 1.02-3.17) in Danes and Germans combined. In a meta-analysis, the odds ratio of malignant melanoma for CHEK2*1100delC heterozygotes compared with that for noncarriers was 1.81 (95% CI, 1...

  11. A part of patients with autism spectrum disorder has haploidy of HPC-1/syntaxin1A gene that possibly causes behavioral disturbance as in experimentally gene ablated mice.

    Kofuji, Takefumi; Hayashi, Yuko; Fujiwara, Tomonori; Sanada, Masumi; Tamaru, Masao; Akagawa, Kimio

    2017-03-22

    Autism spectrum disorder (ASD) is highly heritable and encompasses a various set of neuropsychiatric disorders with a wide-ranging presentation. HPC-1/syntaxin1A (STX1A) encodes a neuronal plasma membrane protein that regulates the secretion of neurotransmitters and neuromodulators. STX1A gene ablated mice (null and heterozygote mutant) exhibit abnormal behavioral profiles similar to human autistic symptoms, accompanied by reduction of monoamine secretion. To determine whether copy number variation of STX1A gene and the change of its expression correlate with ASD as in STX1A gene ablated mice, we performed copy number assay and real-time quantitative RT-PCR using blood or saliva samples from ASD patients. We found that some ASD patients were haploid for the STX1A gene similar to STX1A heterozygote mutant mice. However, copy number of STX1A gene was normal in the parents and siblings of ASD patients with STX1A gene haploidy. In ASD patients with gene haploidy, STX1A mRNA expression was reduced to about half of their parents. Thus, a part of ASD patients had haploidy of STX1A gene and lower STX1A gene expression. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Red cell 2,3-diphosphoglycerate levels in children with hereditary haemolytic anaemias.

    Haidas, S; Zannos-Mariolea, L; Matsaniotis, N

    1975-12-01

    The role of red cell 2,3-diphosphoglycerate (2,3-DPG) in increasing the availability of haemoglobin oxygen in neonatal jaundice and hereditary haemolytic anaemias was investigated. Measurements of 2,3-DPG were carried out on 58 normal children and six normal adults, 18 full-term newborns with neonatal jaundice and 57 cases (51 children and six adults) with hereditary haemolytic anaemias. In normal children and adults, with a mean haemoglobin of 12.69 g/dl, mean 2,3-DPG was 14.90 mumol/g Hb. In jaundiced newborns with a mean haemoglobin of 16.04 g/dl mean 2,3-DPG levels were 14.51 mumol/g Hb, i.e. normal. 2,3-DPG levels were increased in patients with beta-thalassaemia major, alpha-thalassaemia, sickle-cell disease, favism, hereditary spherocytosis and in heterozygotes for beta-thalassaemia with increased haemoglobin F. In heterozygotes for beta-thalassaemia with increased haemoglobin A2 only and in sickle cell trait 2,3-DPG levels were normal.

  13. The Candida albicans Ddr48 protein is essential for filamentation, stress response, and confers partial antifungal drug resistance.

    Dib, Leila; Hayek, Peter; Sadek, Helen; Beyrouthy, Berna; Khalaf, Roy A

    2008-06-01

    Candida albicans is a dimorphic pathogenic fungus that causes mucosal and systemic infections. C. albicans pathogenicity is attributed to its ability to exist in different morphologic states and to respond to stress by up regulating several key genes. DDR48 is a stress-associated gene involved in DNA repair and in response to antifungal drug exposure. One allele of DDR48 was knocked out by homologous recombination that inserted a marker cassette in its position. Furthermore, reintroducing DDR48 on a plasmid created a revertant strain. Strains were grown on filamentation inducing and noninducing media, subjected to an oxidative stress challenge, injected into mice to assess virulence, and assayed for antifungal susceptibility by the E-test method. DDR48 was found to be haploid insufficient and possibly essential, since only a heterozygote, but not a homozygous, null mutant was generated. The mutant was filamentation defective on all hyphal media tested including serum and corn meal agar. Discrepancies in drug resistance profiles also were present: compared with the parental strain, DDR48/ddr48 heterozygote strain was susceptible in a dose-dependent manner to itraconazole and fluconazole and susceptible to ketoconazole. The mutant also appeared to be hypersensitive to a potentially lethal hydrogen peroxide challenge. However, no reduction in virulence of the mutant was observed. The present findings provide evidence that DDR48 is essential for filamentation, stress response, and possibly viability of C. albicans, making it a prime target for antifungal drug design.

  14. The impact of H63D HFE gene carriage on hemoglobin and iron status in children.

    Barbara, Kaczorowska-Hac; Marcin, Luszczyk; Jedrzej, Antosiewicz; Wieslaw, Ziolkowski; Elzbieta, Adamkiewicz-Drozynska; Malgorzata, Mysliwiec; Ewa, Milosz; Jacek, Kaczor Jan

    2016-12-01

    The molecular mechanism that regulates iron homeostasis is based on a network of signals, which reflect on the iron requirements of the body. Hereditary hemochromatosis is a heterogenic metabolic syndrome which is due to unchecked transfer of iron into the bloodstream and its toxic effects on parenchymatous organs. It is caused by the mutation of genes that encode proteins that help hepcidin to monitor serum iron. These proteins include the human hemochromatosis protein -HFE, transferrin-receptor 2, hemojuvelin in rare instances, and ferroportin. HFE-related hemochromatosis is the most frequent form of the disease. Interestingly, the low penetrance of polymorphic HFE genes results in rare clinical presentation of the disease, predominantly in middle-aged males. Taking into account the wide dispersion of HFE mutation in our population and also its unknown role in heterozygotes, we analyzed the impact of H63D HFE carriage in the developmental age, with respect to gender, on the iron status and hemoglobin concentration of carriers in comparison to those of wild-type HFE gene (12.7 ± 3.07 years, 42 boys and 41 girls). H63D carriers presented higher blood iron, transferrin saturation, and ferritin concentration than wild-type probands (p HFE heterozygotes.

  15. Composition of nasal airway surface liquid in cystic fibrosis and other airway diseases determined by X-ray microanalysis.

    Vanthanouvong, V; Kozlova, I; Johannesson, M; Nääs, E; Nordvall, S L; Dragomir, A; Roomans, G M

    2006-04-01

    The ionic composition of the airway surface liquid (ASL) in healthy individuals and in patients with cystic fibrosis (CF) has been debated. Ion transport properties of the upper airway epithelium are similar to those of the lower airways and it is easier to collect nasal ASL from the nose. ASL was collected with ion exchange beads, and the elemental composition of nasal fluid was determined by X-ray microanalysis in healthy subjects, CF patients, CF heterozygotes, patients with rhinitis, and with primary ciliary dyskinesia (PCD). In healthy subjects, the ionic concentrations were approximately isotonic. In CF patients, CF heterozygotes, rhinitis, and PCD patients, [Na] and [Cl] were significantly higher compared when compared with those in controls. [K] was significantly higher in CF and PCD patients compared with that in controls. Severely affected CF patients had higher ionic concentrations in their nasal ASL than in patients with mild or moderate symptoms. Female CF patients had higher levels of Na, Cl, and K than male patients. As higher salt concentrations in the ASL are also found in other patients with airway diseases involving chronic inflammation, it appears likely that inflammation-induced epithelial damage is important in determining the ionic composition of the ASL. Copyright (c) 2006 Wiley-Liss, Inc.

  16. Variability in DNA repair capacity in the human population and its relationship to carcinogenic risk

    Nuzzo, F.; Stefanini, M.; Giulotto, E.; Falaschi, A.

    1980-01-01

    Several inherited diseases, all characterized by a high incidence of tumours in the homozygous patients, show pronounced defects in DNA repair mechanisms, thus confirming the relationship between the repair process and mutation induction, and indicating clearly that a fraction of the population is certainly much more exposed to cancer that the bulk of the human population. The basic molecular defects in such diseases are summarized. The estimated heterozygote frequency in tumour predisposing syndromes is considered and possible identification of heterozygotes discussed. A procedure to reveal DNA repair capacity at the cellular level would perhaps identify the cancer-prone fraction of the population. A simple assay for measuring repair synthesis is outlined which can be used to determine whether a given substance or treatment elicits repair synthesis and is hence harmful to DNA and potentially mutagenic and/or carcinogenic. It can also be used to assess the capacity of an individual to respond to a known DNA damaging agent. (Auth./C.F.)

  17. Immune mediated disorders in women with a fragile X expansion and FXTAS.

    Jalnapurkar, Isha; Rafika, Nuva; Tassone, Flora; Hagerman, Randi

    2015-01-01

    Premutation alleles in fragile X mental retardation 1 (FMR1) can cause the late-onset neurodegenerative disorder, fragile X-associated tremor ataxia syndrome (FXTAS) and/or the fragile X-associated primary ovarian insufficiency in approximately 20% of heterozygotes. Heterozygotes of the FMR1 premutation have a higher incidence of immune mediated disorders such as autoimmune thyroid disorder, especially when accompanied by FXTAS motor signs. We describe the time course of symptoms of immune mediated disorders and the subsequent development of FXTAS in four women with an FMR1 CGG expansion, including three with the premutation and one with a gray zone expansion. These patients developed an immune mediated disorder followed by neurological symptoms that become consistent with FXTAS. In all patients we observed a pattern involving an initial appearance of disease symptoms-often after a period of heightened stress (depression, anxiety, divorce, general surgery) followed by the onset of tremor and/or ataxia. Immune mediated diseases are associated with the manifestations of FXTAS temporally, although further studies are needed to clarify this association. If a cause and effect relationship can be established, treatment of pre-existing immune mediated disorders may benefit patients with pathogenic FMR1 mutations. © 2014 Wiley Periodicals, Inc.

  18. Herpes virus production as a marker of repair in ultra-violet irradiated human skin cells of different origin

    Coppey, J; Nocentini, S; Menezes, S [Institut du Radium, 75 - Paris (France). Lab. Curie; Moreno, G

    1979-07-01

    Human skin fibroblast cultures were irradiated with ultraviolet light 0 to 48 hours before infection with herpes simplex virus type 1 (HSV). Different viral yields were obtained according to the origin of the host cells. Cells from normal donors showed a dose-dependent recovery of HSV production during the 36-40 hours following U.V. exposure. The recovery was maximal for a dose at which a plateau level of unscheduled DNA synthesis (UDS) was reached (24Jm/sup -2/). In a xeroderma pigmentosum (XP) heterozygote line from a mother of XP children, the level of UDS after irradiation up to 48 Jm/sup -2/ was normal whereas the extent of recovery of HSV production capacity was lower than normal. In strains from XP children, with a normal UDS (XP variants), the recovery process was slower and its extent was lower than in normal or XP heterozygote cells. Excision-deficient XP strains from XP children presented little or no recovery, the extent of which was in good agreement with the corresponding level of UDS. Measurement of this recovery seems to be a very sensitive assay for detecting differences in the repair abilities of U.V.-irradiated human skin cells of various origins.

  19. Reducing Bias of Allele Frequency Estimates by Modeling SNP Genotype Data with Informative Missingness

    Wan-Yu eLin

    2012-06-01

    Full Text Available The presence of missing single-nucleotide polymorphism (SNP genotypes is common in genetic data. For studies with low-density SNPs, the most commonly used approach to deal with genotype missingness is to simply remove the observations with missing genotypes from the analyses. This naïve method is straightforward but is appropriate only when the missingness is random. However, a given assay often has a different capability in genotyping heterozygotes and homozygotes, causing the phenomenon of ‘differential dropout’ in the sense that the missing rates of heterozygotes and homozygotes are different. In practice, differential dropout among genotypes exists in even carefully designed studies, such as the data from the HapMap project and the Wellcome Trust Case Control Consortium. In this study, we propose a statistical method to model the differential dropout among different genotypes. Compared with the naïve method, our method provides more accurate allele frequency estimates when the differential dropout is present. To demonstrate its practical use, we further apply our method to the HapMap data and a scleroderma data set.

  20. Nonhomologous Synapsis and Reduced Crossing over in a Heterozygous Paracentric Inversion in Saccharomyces Cerevisiae

    Dresser, M. E.; Ewing, D. J.; Harwell, S. N.; Coody, D.; Conrad, M. N.

    1994-01-01

    Homologous chromosome synapsis (``homosynapsis'') and crossing over are well-conserved aspects of meiotic chromosome behavior. The long-standing assumption that these two processes are causally related has been challenged recently by observations in Saccharomyces cerevisiae of significant levels of crossing over (1) between small sequences at nonhomologous locations and (2) in mutants where synapsis is abnormal or absent. In order to avoid problems of local sequence effects and of mutation pleiotropy, we have perturbed synapsis by making a set of isogenic strains that are heterozygous and homozygous for a large chromosomal paracentric inversion covering a well marked genetic interval and then measured recombination. We find that reciprocal recombination in the marked interval in heterozygotes is reduced variably across the interval, on average to ~55% of that in the homozygotes, and that positive interference still modulates crossing over. Cytologically, stable synapsis across the interval is apparently heterologous rather than homologous, consistent with the interpretation that stable homosynapsis is required to initiate or consummate a large fraction of the crossing over observed in wild-type strains. When crossing over does occur in heterozygotes, dicentric and acentric chromosomes are formed and can be visualized and quantitated on blots though not demonstrated in viable spores. We find that there is no loss of dicentric chromosomes during the two meiotic divisions and that the acentric chromosome is recovered at only 1/3 to 1/2 of the expected level. PMID:7851761

  1. Differential bitterness in capsaicin, piperine, and ethanol associates with polymorphisms in multiple bitter taste receptor genes.

    Nolden, Alissa A; McGeary, John E; Hayes, John E

    2016-03-15

    To date, the majority of research exploring associations with genetic variability in bitter taste receptors has understandably focused on compounds and foods that are predominantly or solely perceived as bitter. However, other chemosensory stimuli are also known to elicit bitterness as a secondary sensation. Here we investigated whether TAS2R variation explains individual differences in bitterness elicited by chemesthetic stimuli, including capsaicin, piperine and ethanol. We confirmed that capsaicin, piperine and ethanol elicit bitterness in addition to burning/stinging sensations. Variability in perceived bitterness of capsaicin and ethanol were significantly associated with TAS2R38 and TAS2R3/4/5 diplotypes. For TAS2R38, PAV homozygotes perceived greater bitterness from capsaicin and ethanol presented on circumvallate papillae, compared to heterozygotes and AVI homozygotes. For TAS2R3/4/5, CCCAGT homozygotes rated the greatest bitterness, compared to heterozygotes and TTGGAG homozygotes, for both ethanol and capsaicin when presented on circumvallate papillae. Additional work is needed to determine how these and other chemesthetic stimuli differ in bitterness perception across concentrations and presentation methods. Furthermore, it would be beneficial to determine which TAS2R receptors are activated in vitro by chemesthetic compounds. Copyright © 2016. Published by Elsevier Inc.

  2. Absence of genotoxic activity from milk and water boiled in microwave oven in somatic cells from Drosophila melanogaster

    Dias, Cristina das Dores.

    2003-01-01

    This paper reports an experiment for evaluation of the possible genotoxic effects of food prepared in a microwave oven, through the mutation test and somatic recombination, in wings of Drosophila melanogaster. Two crossing have been performed: a standard cross-ST and a high bioactivation cross - HB resulting in marked trans -heterozygote descendents (MH) and balanced heterozygotes (BH). The 72 hours larvas were fed with water and milk boiled both in the microwave oven and in the traditional way. The MH individual wings were analyzed, where the spots can be induced either by mutation or mitotic recombination. The experiment presented negative results related to the genotoxic effects of the water and milk boiled using the microwave oven, in MH descendents of both crossing. Therefore, under these experimental conditions, genotoxic activity were not presented by milk and water boiled in the microwave oven. However, an extensive study using different techniques is necessary to investigate the action of the food prepared in the microwave oven on the genetic material

  3. Deficient Sleep in Mouse Models of Fragile X Syndrome

    R. Michelle Saré

    2017-09-01

    Full Text Available In patients with fragile X syndrome (FXS, sleep problems are commonly observed but are not well characterized. In animal models of FXS (dfmr1 and Fmr1 knockout (KO/Fxr2 heterozygote circadian rhythmicity is affected, but sleep per se has not been examined. We used a home-cage monitoring system to assess total sleep time in both light and dark phases in Fmr1 KO mice at different developmental stages. Fmr1 KOs at P21 do not differ from controls, but genotype × phase interactions in both adult (P70 and P180 groups are statistically significant indicating that sleep in Fmr1 KOs is reduced selectively in the light phase compared to controls. Our results show the emergence of abnormal sleep in Fmr1 KOs during the later stages of brain maturation. Treatment of adult Fmr1 KO mice with a GABAB agonist, R-baclofen, did not restore sleep duration in the light phase. In adult (P70 Fmr1 KO/Fxr2 heterozygote animals, total sleep time was further reduced, once again in the light phase. Our data highlight the importance of the fragile X genes (Fmr1 and Fxr2 in sleep physiology and confirm the utility of these mouse models in enhancing our understanding of sleep disorders in FXS.

  4. Congenital cataracts in two siblings with Wolfram syndrome.

    Mets, Rebecca B; Emery, Sarah B; Lesperance, Marci M; Mets, Marilyn B

    2010-12-01

    Wolfram syndrome is characterized by optic atrophy, insulin dependent diabetes mellitus, diabetes insipidus and deafness. There are several other associated conditions reported in the literature, but congenital or early childhood cataracts are not among them. Observational case series with confirmatory genetic analysis. A pair of siblings, followed over 17 years, who manifest congenital or early childhood cataracts, diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. They are both compound heterozygotes for mutations (V415 deletion and A684V substitution) in the WFS1 gene. Their father has congenital sensorineural hearing loss and developed optic atrophy. He is heterozygous for A684V in WFS1. Wolfram syndrome should be in the differential diagnosis of genetic syndromes associated with congenital and early childhood cataracts. Here, we report on a mother who is a phenotypically normal carrier of an autosomal recessive Wolfram syndrome gene, and a father who has some of the findings of the syndrome and carries a single mutation that appears to be responsible for his hearing loss and optic atrophy. Their 2 children are compound heterozygotes and manifest the full Wolfram syndrome, in addition to cataracts.

  5. Cataract as a phenotypic marker for a mutation in WFS1, the Wolfram syndrome gene.

    Titah, Salah Mohamed Cherif; Meunier, Isabelle; Blanchet, Catherine; Lopez, Severine; Rondouin, Gerard; Lenaers, Guy; Amati-Bonneau, Patrizia; Reynier, Pascal; Paquis-Flucklinger, Veronique; Hamel, Christian P

    2012-01-01

    Wolfram syndrome (WS) or diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD) (OMIM 222300) is an inherited neurodegenerative disease characterized by diabetes mellitus and optic atrophy as the 2 major criteria, followed later in life by deafness, diabetes insipidus, and various signs of neurologic impairment. The presence of a cataract has been variably mentioned in WS. Two members of a family had thorough ophthalmic examination and their DNA was screened for mutations in mitochondrial DNA, WFS1, OPA1, and OPA3 genes. We report a patient who first had surgery for bilateral cataract at age 5 and who subsequently presented typical signs of WS, i.e., diabetes mellitus, optic atrophy with reduced visual acuity at 20/400 on both eyes at age 22, and mild deafness. The patient was found to be a compound heterozygote for 2 truncating mutations in WFS1, the major WS gene. She carried the previously reported c.1231_1233 delCT and a novel c.2431_2465dup35 mutation. She also was heterozygote for a novel OPA1 sequence variant, c.929A>G in exon 9, whose pathogenicity remains uncertain. The patient's mother was a heterozygous carrier of the c.2431_2465dup35 mutation. She did not have diabetes mellitus or optic atrophy but had bilateral polar cataract. She did not carry the OPA1 sequence variant. Cataract could be a marker for the WFS1 heterozygosity in this family, namely the c.2431_2465dup35 mutation.

  6. The protease inhibitor PI*S allele and COPD

    Hersh, C P; Ly, N P; Berkey, C S

    2005-01-01

    In many countries, the protease inhibitor (SERPINA1) PI*S allele is more common than PI*Z, the allele responsible for most cases of chronic obstructive pulmonary disease (COPD) due to severe alpha 1-antitrypsin deficiency. However, the risk of COPD due to the PI*S allele is not clear. The current...... authors located studies that addressed the risk of COPD or measured lung function in individuals with the PI SZ, PI MS and PI SS genotypes. A separate meta-analysis for each genotype was performed. Aggregating data from six studies, the odds ratio (OR) for COPD in PI SZ compound heterozygotes compared...... with PI MM (normal) individuals was significantly increased at 3.26 (95% confidence intervals (CI): 1.24-8.57). In 17 cross-sectional and case-control studies, the OR for COPD in PI MS heterozygotes was 1.19 (95%CI: 1.02-1.38). However, PI MS genotype was not associated with COPD risk after correcting...

  7. Abnormal XPD-induced nuclear receptor transactivation in DNA repair disorders: trichothiodystrophy and xeroderma pigmentosum.

    Zhou, Xiaolong; Khan, Sikandar G; Tamura, Deborah; Ueda, Takahiro; Boyle, Jennifer; Compe, Emmanuel; Egly, Jean-Marc; DiGiovanna, John J; Kraemer, Kenneth H

    2013-08-01

    XPD (ERCC2) is a DNA helicase involved in nucleotide excision repair and in transcription as a structural bridge tying the transcription factor IIH (TFIIH) core with the cdk-activating kinase complex, which phosphorylates nuclear receptors. Mutations in XPD are associated with several different phenotypes, including trichothiodystrophy (TTD), with sulfur-deficient brittle hair, bone defects, and developmental abnormalities without skin cancer, xeroderma pigmentosum (XP), with pigmentary abnormalities and increased skin cancer, or XP/TTD with combined features, including skin cancer. We describe the varied clinical features and mutations in nine patients examined at the National Institutes of Health who were compound heterozygotes for XPD mutations but had different clinical phenotypes: four TTD, three XP, and two combined XP/TTD. We studied TFIIH-dependent transactivation by nuclear receptor for vitamin D (VDR) and thyroid in cells from these patients. The vitamin D stimulation ratio of CYP24 and osteopontin was associated with specific pairs of mutations (reduced in 5, elevated in 1) but not correlated with distinct clinical phenotypes. Thyroid receptor stimulation ratio for KLF9 was not significantly different from normal. XPD mutations frequently were associated with abnormal VDR stimulation in compound heterozygote patients with TTD, XP, or XP/TTD.

  8. Hybrid male sterility in rice is due to epistatic interactions with a pollen killer locus.

    Kubo, Takahiko; Yoshimura, Atsushi; Kurata, Nori

    2011-11-01

    In intraspecific crosses between cultivated rice (Oryza sativa) subspecies indica and japonica, the hybrid male sterility gene S24 causes the selective abortion of male gametes carrying the japonica allele (S24-j) via an allelic interaction in the heterozygous hybrids. In this study, we first examined whether male sterility is due solely to the single locus S24. An analysis of near-isogenic lines (NIL-F(1)) showed different phenotypes for S24 in different genetic backgrounds. The S24 heterozygote with the japonica genetic background showed male semisterility, but no sterility was found in heterozygotes with the indica background. This result indicates that S24 is regulated epistatically. A QTL analysis of a BC(2)F(1) population revealed a novel sterility locus that interacts with S24 and is found on rice chromosome 2. The locus was named Epistatic Factor for S24 (EFS). Further genetic analyses revealed that S24 causes male sterility when in combination with the homozygous japonica EFS allele (efs-j). The results suggest that efs-j is a recessive sporophytic allele, while the indica allele (EFS-i) can dominantly counteract the pollen sterility caused by S24 heterozygosity. In summary, our results demonstrate that an additional epistatic locus is an essential element in the hybrid sterility caused by allelic interaction at a single locus in rice. This finding provides a significant contribution to our understanding of the complex molecular mechanisms underlying hybrid sterility and microsporogenesis.

  9. Characterization of Hb Lepore variants in the UK population.

    Guo, Lina; Kausar, Anika; Old, John M; Henderson, Shirley J; Gallienne, Alice E

    2015-01-01

    A molecular study of Hb Lepore heterozygotes identified by the UK population screening program has revealed four out of the five known Lepore variants. The region of homologous δ- and β-globin gene sequence was determined in 58 unrelated Hb Lepore heterozygotes referred for confirmation of their carrier status by DNA analysis through the national thalassemia and sickle cell screening program over a period of 10 years. The most common variant found was Hb Lepore-Boston-Washington (Hb LBW, HBD: c.265 C > c.315 + 7 C) observed in 46 carriers (79.0%). Hb Lepore-Hollandia (HBD: c.69 A > c.92 + 16 A) was found in nine cases (16.0%); Hb Lepore-Baltimore (HBD: c.208 G > c.254 C) in two cases (4.0%) and Hb Lepore-ARUP (HBD: c.97 C > c.150 C) in one carrier (2.0%). Analysis of the hematological findings showed no significant differences between the four groups. The wide range of Hb Lepore variants observed in this study confirms the very diverse range of α- and β-globin gene mutations observed in the UK population by previous studies.

  10. 7 Tesla proton magnetic resonance spectroscopic imaging in adult X-linked adrenoleukodystrophy

    Ratai, Eva; Kok, Trina; Wiggins, Christopher; Wiggins, Graham; Grant, Ellen; Gagoski, Borjan; O'Neill, Gilmore; Adalsteinsson, Elfar; Eichler, Florian

    2010-01-01

    Background Adult patients with X-linked adrenoleukodystrophy (X-ALD) remain at risk for progressive neurological deterioration. Phenotypes vary in their pathology, ranging from axonal degeneration to inflammatory demyelination. The severity of symptoms is poorly explained by conventional imaging. Objective To test the hypothesis that neurochemistry in normal appearing brain differs among adult phenotypes of X-ALD, and that neurochemical changes correlate with the severity of symptoms. Patients and Methods Using a 7 Tesla scanner we performed structural and proton MRSI in 13 adult patients with X-ALD, including 4 patients with adult cerebral ALD (ACALD), 5 with adrenomyeloneuropathy (AMN) and 4 female heterozygotes. Studies were also performed in nine healthy controls. Results Among adult X-ALD phenotypes, MI/Cr was 46% higher and Cho/Cr 21% higher in normal appearing white matter of ACALD compared to AMN (p Tesla proton MRSI reveals differences in the neurochemistry of ACALD but is unable to distinguish AMN from female heterozygotes. MI/Cr correlates with the severity of the symptoms and may be a meaningful biomarker in adult X-ALD. PMID:19001168

  11. Caffeine and 3-km cycling performance: Effects of mouth rinsing, genotype, and time of day.

    Pataky, M W; Womack, C J; Saunders, M J; Goffe, J L; D'Lugos, A C; El-Sohemy, A; Luden, N D

    2016-06-01

    We assessed the efficacy of caffeine mouth rinsing on 3-km cycling performance and determined whether caffeine mouth rinsing affects performance gains influenced by the CYP1A2 polymorphism. Thirty-eight recreational cyclists completed four simulated 3-km time trials (TT). Subjects ingested either 6 mg/kg BW of caffeine or placebo 1 h prior to each TT. Additionally, 25 mL of 1.14% caffeine or placebo solution were mouth rinsed before each TT. The treatments were Placebo, caffeine Ingestion, caffeine Rinse and Ingestion+Rinse. Subjects were genotyped and classified as AA homozygotes or AC heterozygotes for the rs762551 polymorphism of the CYP1A2 gene involved in caffeine metabolism. Magnitude-based inferences were used to evaluate treatment differences in mean power output based on a predetermined meaningful treatment effect of 1.0%. AC heterozygotes (4.1%) and AA homozygotes (3.4%) benefited from Ingestion+Rinse, but only AC performed better with Ingestion (6.0%). Additionally, Rinse and Ingestion+Rinse elicited better performance relative to Placebo among subjects that performed prior to 10:00 h (Early) compared with after 10:00 h (Late). The present study provides additional evidence of genotype and time of day factors that affect the ergogenic value of caffeine intake that may allow for more personalized caffeine intake strategies to maximize performance. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. Dopamine transporter and vesicular monoamine transporter knockout mice : implications for Parkinson's disease.

    Miller, G W; Wang, Y M; Gainetdinov, R R; Caron, M G

    2001-01-01

    One of the most valuable methods for understanding the function of a particular protein is the generation of animals that have had the gene encoding for the protein of interest disrupted, commonly known as a "quo;knockout"quo; or null mutant. By incorporating a sequence of DNA (typically encoding antibiotic resistance to aid in the selection of the mutant gene) into embryonic stem cells by homologous recombination, the normal transcription of the gene is effectively blocked (Fig. 1). Since a particular protein is encoded by two copies of a gene, it is necessary to have the gene on both alleles "quo;knocked out."quo; This is performed by cross-breeding animals with one affected allele (heterozygote) to generate offspring that have inherited two mutant alleles (homozygote). This procedure has been used to generate animals lacking either the plasma membrane dopamine transporter (DAT; Fig. 2) or the vesicular monoamine transporter (VMAT2; Fig. 3). Both DAT and VMAT2 are essential for dopamine homeostasis and are thought to participate in the pathogenesis of Parkinson's disease (1-5). Fig. 1. Maps of the targeting vector and the mock construct. The mouse genomic fragment (clone 11) was isolated from a Stratagene 129 SvJ library by standard colony hybridization using a PCR probe from the 5' end of rat cDNA. The restriction site abbreviations are as follows: H, HindIII; N, NotI; Sc, SacI; Sn, SnaI; X, XbaI; and Xh, XhoI. The region between HindIII and SnaI on clone 11 containing the coding sequence from transmembrane domains 3 and 4 of VMAT2 was deleted and replaced with PGK-neo. The 3' fragment of clone 11 was reserved as an external probe for Southern analysis. To facilitate PCR screening of embryonic stem cell clones, a mock construct containing the SnaI/XbaI fragment and part of the Neo cassette was generated as a positive control. pPNT and pGEM4Z were used to construct knockout and mock vectors, respectively. (Reproduced with permission from ref. 1). Fig. 2. DAT and

  13. The search for evolutionary developmental origins of aging in zebrafish: a novel intersection of developmental and senescence biology in the zebrafish model system.

    Kishi, Shuji

    2011-09-01

    Senescence may be considered the antithesis of early development, but yet there may be factors and mechanisms in common between these two phenomena during the process of aging. We investigated whether any relationship exists between the regulatory mechanisms that function in early development and in senescence using the zebrafish (Danio rerio), a small freshwater fish and a useful model animal for genetic studies. We conducted experiments to isolate zebrafish mutants expressing an apparent senescence phenotype during embryogenesis (embryonic senescence). Some of the genes we thereby identified had already been associated with cellular senescence and chronological aging in other organisms, but many had not yet been linked to these processes. Complete loss-of-function of developmentally essential genes induce embryonic (or larval) lethality, whereas it seems like their partial loss-of-function (i.e., decrease-of-function by heterozygote or hypomorphic mutations) still remains sufficient to go through the early developmental process because of its adaptive plasticity or rather heterozygote advantage. However, in some cases, such partial loss-of-function of genes compromise normal homeostasis due to haploinsufficiency later in adult life having many environmental stress challenges. By contrast, any heterozygote-advantageous genes might gain a certain benefit(s) (much more fitness) by such partial loss-of-function later in life. Physiological senescence may evolutionarily arise from both genetic and epigenetic drifts as well as from losing adaptive developmental plasticity in face of stress signals from the external environment that interacts with functions of multiple genes rather than effects of only a single gene mutation or defect. Previously uncharacterized developmental genes may thus mediate the aging process and play a pivotal role in senescence. Moreover, unexpected senescence-related genes might also be involved in the early developmental process and

  14. BDNF-Val66Met-Polymorphism Impact on Cortical Plasticity in Schizophrenia Patients: A Proof-of-Concept Study

    Nitsche, Michael A.; Wobrock, Thomas; Bunse, Tilmann; Rein, Bettina; Herrmann, Maximiliane; Schmitt, Andrea; Nieratschker, Vanessa; Witt, Stephanie H.; Rietschel, Marcella; Falkai, Peter; Hasan, Alkomiet

    2015-01-01

    Background: Brain-derived neurotrophic factor (BDNF) has been shown to be a moderator of neuroplasticity. A frequent BDNF-polymorphism (Val66Met) is associated with impairments of cortical plasticity. In patients with schizophrenia, reduced neuroplastic responses following non-invasive brain stimulation have been reported consistently. Various studies have indicated a relationship between the BDNF-Val66Met-polymorphism and motor-cortical plasticity in healthy individuals, but schizophrenia patients have yet to be investigated. The aim of this proof-of-concept study was, therefore, to test the impact of the BDNF-Val66Met-polymorphism on inhibitory and facilitatory cortical plasticity in schizophrenia patients. Methods: Cortical plasticity was investigated in 22 schizophrenia patients and 35 healthy controls using anodal and cathodal transcranial direct-current stimulation (tDCS) applied to the left primary motor cortex. Animal and human research indicates that excitability shifts following anodal and cathodal tDCS are related to molecular long-term potentiation and long-term depression. To test motor-cortical excitability before and after tDCS, well-established single- and paired-pulse transcranial magnetic stimulation protocols were applied. Results: Our analysis revealed increased glutamate-mediated intracortical facilitation in met-heterozygotes compared to val-homozygotes at baseline. Following cathodal tDCS, schizophrenia met-heterozygotes had reduced gamma-amino-butyric-acid-mediated short-interval intracortical inhibition, whereas healthy met-heterozygotes displayed the opposite effect. The BDNF-Val66Met-polymorphism did not influence single-pulse motor-evoked potential amplitudes after tDCS. Conclusions: These preliminary findings support the notion of an association of the BDNF-Val66Met-polymorphism with observable alterations in plasticity following cathodal tDCS in schizophrenia patients. This indicates a complex interaction between inhibitory

  15. IL-33 polymorphisms are associated with increased risk of hay fever and reduced regulatory T cells in a birth cohort.

    Schröder, Paul C; Casaca, Vera I; Illi, Sabina; Schieck, Maximilian; Michel, Sven; Böck, Andreas; Roduit, Caroline; Frei, Remo; Lluis, Anna; Genuneit, Jon; Pfefferle, Petra; Roponen, Marjut; Weber, Juliane; Braun-Fahrländer, Charlotte; Riedler, Josef; Lauener, Roger; Vuitton, Dominique Angèle; Dalphin, Jean-Charles; Pekkanen, Juha; von Mutius, Erika; Kabesch, Michael; Schaub, Bianca

    2016-11-01

    IL-33 polymorphisms influence the susceptibility to asthma. IL-33 indirectly induces Th2-immune responses via dendritic cell activation, being important for development of atopic diseases. Furthermore, IL-33 upregulates regulatory T cells (Tregs), which are critical for healthy immune homeostasis. This study investigates associations between IL-33 polymorphisms during the development of childhood atopic diseases and underlying mechanisms including immune regulation of Tregs. Genotyping of IL-33-polymorphisms (rs928413, rs1342326) was performed by MALDI-TOF-MS in 880 of 1133 PASTURE/EFRAIM children. In 4.5-year-old German PASTURE/EFRAIM children (n = 99), CD4 + CD25 high FOXP3 + Tregs were assessed by flow cytometry following 24-h incubation of PBMCs with PMA/ionomycin, LPS or without stimuli (U). SOCS3, IL1RL1, TLR4 mRNA expression and sST2 protein levels ex vivo were measured in PASTURE/EFRAIM children by real-time PCR or ELISA, respectively. Health outcomes (hay fever, asthma) were assessed by questionnaires at the age of 6 years. rs928413 and rs1342326 were positively associated with hay fever (OR = 1.77, 95%CI = 1.02-3.08; OR = 1.79, 95%CI = 1.04-3.11) and CD4 + CD25 high FOXP3 + Tregs (%) decreased in minor allele homozygotes/heterozygotes compared to major allele homozygotes (p(U) = 0.004; p(LPS) = 0.005; p(U) = 0.001; p(LPS) = 0.012). SOCS3 mRNA expression increased in minor allele homozygotes and heterozygotes compared with major allele homozygotes for both IL-33-polymorphisms (p(rs928413) = 0.032, p(rs1342326) = 0.019) and negatively correlated to Tregs. IL-33-polymorphisms rs928413 and rs1342326 may account for an increased risk of hay fever with the age of 6 years. Lower Tregs and increased SOCS3 in combined heterozygotes and minor allele homozygotes may be relevant for hay fever development, pointing towards dysbalanced immune regulation and insufficient control of allergic inflammation. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. MiR-146a rs2910164 polymorphism increases the risk of digestive system cancer: A meta-analysis.

    Xie, Wen Qun; Wang, Xiao Fan

    2017-02-01

    There is merging evidence suggesting that the miR-146a polymorphism might be associated with susceptibility to digestive system cancer. However, previous published studies have failed to achieve a definitive conclusion. To address this issue, an updated meta-analysis was performed. A comprehensive electronic search was conducted using the following source to identify the eligible studies: PubMed, Embase, China BioMedicine, the Cochrane Library, and Google Scholar. Odds ratios and its corresponding 95% confidence interval (CI) was used in the quantitative synthesis. The database search identified 1344 eligible studies, of which 32 (comprising 12,541 cases and 15,925 controls) were included. The results indicate that the miR-146a rs2910164 polymorphism was significantly associated with increased risk of digestive system cancer in heterozygote comparison (GC vs. CC: OR=1.15, 95% CI: 1.02-1.30, P=0.02), and recessive model (GG vs. GC+CC: OR=1.11, 95% CI: 1.04-1.17, P=0.006). Subgroup analysis by cancer site revealed increased risk in gastric cancer above heterozygote comparison (GG vs. GC: OR=1.13, 95% CI: 1.02-1.25, P=0.02), and recessive model (GG vs. GC+CC: OR=1.15, 95% CI: 1.04-1.26, P=0.006). Similarly, increased cancer risk was observed in hepatocellular carcinoma when compared with homozygote comparison (GG vs. CC: OR=1.21, 95% CI: 1.04-1.42, P=0.02), heterozygote comparison (GC vs. CC: OR=1.15, 95% CI: 1.02-1.29, P=0.02), and dominant model (GG+GC vs. CC: OR=1.16, 95% CI: 1.04-1.29, P=0.009). When stratified by ethnicity and quality score, increased cancer risks were also observed among Asians, Caucasians and high quality studies subgroup. The current study revealed that miR-146a G/C genetic polymorphism was more likely to be associated with digestive system cancer risk. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  17. Val103Ile polymorphism of the melanocortin-4 receptor gene (MC4R) in cancer cachexia

    Knoll, Susanne; Zimmer, Sabiene; Hinney, Anke; Scherag, André; Neubauer, Andreas; Hebebrand, Johannes

    2008-01-01

    At present pathogenic mechanisms of cancer cachexia are poorly understood. Previous evidence in animal models implicates the melanocortin-4 receptor gene (MC4R) in the development of cancer cachexia. In humans, MC4R mutations that lead to an impaired receptor function are associated with obesity; in contrast, the most frequent polymorphism (Val103Ile, rs2229616; heterozygote frequency approximately 2%) was shown to be negatively associated with obesity. We tested if cancer patients that are homo-/heterozygous for the Val103Ile polymorphism are more likely to develop cachexia and/or a loss of appetite than non-carriers of the 103Ile-allele. BMI (body mass index in kg/m 2 ) of 509 patients (295 males) with malignant neoplasms was determined; additionally patients were asked about premorbid/pretherapeutical changes of appetite and weight loss. Cachexia was defined as a weight loss of at least 5% prior to initiation of therapy; to fulfil this criterion this weight loss had to occur independently of other plausible reasons; in single cases weight loss was the initial reason for seeing a physician. The average age in years (± SD) was 59.0 ± 14.5 (males: 58.8 ± 14.0, females 59.2 ± 14.0). Blood samples were taken for genotyping of the Val103Ile by PCR- RFLP. Most of the patients suffered from lymphoma, leukaemia and gastrointestinal tumours. 107 of the patients (21%) fulfilled our criteria for cancer cachexia. We did not detect association between the Val103Ile polymorphism and cancer cachexia. However, if we exploratively excluded the patients with early leucaemic stages, we detected a trend towards the opposite effect (p < 0.05); heterozygotes for the 103Ile-allele developed cancer cachexia less frequently in comparison to the rest of the study group. Changes of appetite were not associated with the 103Ile-allele carrier status (p > 0.39). Heterozygotes for the 103Ile-allele are not more prone to develop cancer cachexia than patients without this allele; possibly

  18. Val103Ile polymorphism of the melanocortin-4 receptor gene (MC4R) in cancer cachexia

    Knoll, Susanne; Zimmer, Sabiene [Department of Child and Adolescent Psychiatry, University of Duisburg-Essen (Germany); Department of Hematology/Oncology/Immunology, University of Marburg (Germany); Hinney, Anke [Department of Child and Adolescent Psychiatry, University of Duisburg-Essen (Germany); Scherag, André [Zentrum for clinical studies food (ZKSE) c/o Institute for Medical Informatics, Biometry and Epidemiology, University Duisburg-Essen, Essen (Germany); Neubauer, Andreas [Department of Hematology/Oncology/Immunology, University of Marburg (Germany); Hebebrand, Johannes [Department of Child and Adolescent Psychiatry, University of Duisburg-Essen (Germany)

    2008-03-31

    At present pathogenic mechanisms of cancer cachexia are poorly understood. Previous evidence in animal models implicates the melanocortin-4 receptor gene (MC4R) in the development of cancer cachexia. In humans, MC4R mutations that lead to an impaired receptor function are associated with obesity; in contrast, the most frequent polymorphism (Val103Ile, rs2229616; heterozygote frequency approximately 2%) was shown to be negatively associated with obesity. We tested if cancer patients that are homo-/heterozygous for the Val103Ile polymorphism are more likely to develop cachexia and/or a loss of appetite than non-carriers of the 103Ile-allele. BMI (body mass index in kg/m{sup 2}) of 509 patients (295 males) with malignant neoplasms was determined; additionally patients were asked about premorbid/pretherapeutical changes of appetite and weight loss. Cachexia was defined as a weight loss of at least 5% prior to initiation of therapy; to fulfil this criterion this weight loss had to occur independently of other plausible reasons; in single cases weight loss was the initial reason for seeing a physician. The average age in years (± SD) was 59.0 ± 14.5 (males: 58.8 ± 14.0, females 59.2 ± 14.0). Blood samples were taken for genotyping of the Val103Ile by PCR- RFLP. Most of the patients suffered from lymphoma, leukaemia and gastrointestinal tumours. 107 of the patients (21%) fulfilled our criteria for cancer cachexia. We did not detect association between the Val103Ile polymorphism and cancer cachexia. However, if we exploratively excluded the patients with early leucaemic stages, we detected a trend towards the opposite effect (p < 0.05); heterozygotes for the 103Ile-allele developed cancer cachexia less frequently in comparison to the rest of the study group. Changes of appetite were not associated with the 103Ile-allele carrier status (p > 0.39). Heterozygotes for the 103Ile-allele are not more prone to develop cancer cachexia than patients without this allele

  19. [Molecular genetic diagnostics and screening of hereditary hemochromatosis].

    Zlocha, J; Kovács, L; Pozgayová, S; Kupcová, V; Durínová, S

    2006-06-01

    Hereditary hemochromatosis is considered one of the most common hereditary diseases in population of Caucasian origin. In recent years, a candidate gene for HLA-linked hemochromatosis, HFE, has been cloned, and a single G-to-A mutation resulting in a cysteine-to-tyrosine substitution (C282Y) has been identified in up to 80% of study patients with type 1 hereditary hemochromatosis. The purpose of the paper was to confirm the importance of genetic testing for HFE mutations in making the diagnosis of hemochromatosis and find out a suitable diagnostic algorithm for the indication of this form of diagnostics in patients suspected of hereditary hemochromatosis. The examination of C282Y mutation was conducted in 500 subjects. The most frequent indications for DNA analysis were hepatopathy of unknown ethiology, liver cirrhosis, diabetes mellitus, bronze skin pigmentation in connection with high serum iron concentration, elevated transferrin saturation and elevated serum ferritin levels. In our group of patients, 29 homozygotes and 75 heterozygotes for C282Y mutation were identified, 10 patients carried both C282Y and H63D mutations of HFE gene (compound heterozygotes), whereas in 386 subjects the mutation was not found. The genotype-phenotype correlation showed that 22 homozygotes had liver affection proved by imaging and/or histologic methods. Except the liver disorders, the most common symptoms of these patients were type 2 diabetes mellitus or glucose tolerance disorder (10 patients), arthritis or joint pain (9 patients) and cardiovascular disorders, such as cardiomyopathy (2 patients). Bronze skin pigmentation was present in 9 homozygotes. Transferin saturation values were significantly higher in homozygotes for C282Y mutation as compared to C282Y heterozygotes (p diagnostics of this severe, but in early recognition curable disease. Early detection and phlebotomy treatment prior to the onset of cirrhosis can reduce morbidity and normalize life expectancy. It is readily

  20. Is 24-color FISH detection of in-vitro radiation-induced chromosomal aberrations suited to determine individual intrinsic radiosensitivity?

    Kuechler, A.; Wendt, T.G.; Neubauer, S.; Grabenbauer, G.G.; Sauer, R.; Claussen, U.; Liehr, T.

    2002-01-01

    Background: Reliable determination of intrinsic radiosensitivity in individual patients is a serious need in radiation oncology. Chromosomal aberrations are sensitive indicators of a previous exposure to ionizing irradiation. Former molecular cytogenetic studies showed that such aberrations as an equivalent of intrinsic radiosensitivity can be detected by fluorescence in-situ hybridization (FISH) techniques using whole chromosome painting (wcp) probes. However, only one up to three randomly chosen wcp probes have been applied for such approaches until now. As a random distribution of chromosomal rearrangements along the chromosomes is up to now still controversial, the power of the 24-color FISH approach should be elucidated in the present study. Methods and Material: Lymphocytes derived from lymphoblastoid cell lines of one patient with Nijmegen breakage syndrome (NBS homozygote) and of two NBS heterozygotes and peripheral blood lymphocytes of two controls were analyzed. Samples of each patient/control were irradiated in vitro with 0.0 Gy, 0.7 Gy or 2.0 Gy prior to cultivation. Chromosomal aberrations were analyzed in detail and quantified by means of 24-color FISH as an expression of the individual intrinsic radiosensitivity. Results: 24-color FISH analyses were done in a total of 1,674 metaphases. After in-vitro irradiation, 21% (0.7 Gy) or 57% (2.0 Gy) of the controls' cells, 15% (0.7 Gy) or 53% (2.0 Gy) of the heterozygotes' cells and 54% (0.7 Gy) or 79% (2.0 Gy) of the homozygote's cells contained aberrations. The highest average rates of breaks per mitosis [B/M] (0.7 Gy: 1.80 B/M, 2.0 Gy: 4.03 B/M) and complex chromosomal rearrangements [CCR] (0.7 Gy: 0.20 CCR/M, 2.0 Gy: 0.47 CCR/M) were observed in the NBS patient. Moreover, the proportion of different aberration types after irradiation showed a distinct increase in the rate of CCR combined with a decrease in dicentrics in the NBS homozygote. Conclusion: To come to a more complete picture of radiation

  1. Association between matrix metalloproteinases polymorphisms and ovarian cancer risk: A meta-analysis and systematic review.

    Xu-Ming Zhu

    Full Text Available Published data on the relationship between matrix metalloproteinases (MMPs polymorphisms and ovarian cancer risk have implicated inconclusive results. To evaluate the role of MMPs polymorphisms in ovarian cancer risk, a meta-analysis and systematic review were performed.MMPs polymorphisms which could be quantitatively synthesized were involved in meta-analysis. Five comparison models (homozygote model, heterozygote model, dominant model, recessive model, additive model were carried out, a subgroup analysis was performed to clarify heterogeneity source. The remaining polymorphisms which could not be quantitatively synthesized were involved in systematic review.10 articles with 20 studies were included in this paper. Among those studies, 8 studies involving MMP1 rs1799750 and MMP3 rs34093618 could be meta-analyzed and 12 studies involving 12 polymorphisms could not. Meta-analysis showed that no associations were found between MMP1 rs1799750 (homozygote model: OR = 0.93, 95%CI = 0.70-1.23, POR = 0.60; heterozygote model: OR = 1.09, 95%CI = 0.78-1.54, POR = 0.61; dominant model: OR = 1.02, 95%CI = 0.83-1.25, POR = 0.84; recessive model: OR = 0.95, 95%CI = 0.75-1.21, POR = 0.67; additive model: OR = 1.00, 95%CI = 0.85-1.17, POR = 0.99, MMP3 rs34093618 (homozygote model: OR = 1.25, 95%CI = 0.70-2.24, POR = 0.46; heterozygote model: OR = 1.08, 95%CI = 0.51-2.31, POR = 0.84; dominant model: OR = 0.97, 95%CI = 0.68-1.38, POR = 0.85; recessive model: OR = 1.12, 95%CI = 0.69-1.80, POR = 0.65; additive model: OR = 1.01, 95%CI = 0.79-1.31, POR = 0.91 and ovarian cancer. Furthermore, similar results were detected in subgroup analysis. The systematic review on 12 polymorphisms suggested that MMP2 C-735T, MMP7 A-181G, MMP8 rs11225395, MMP9 rs6094237, MMP12 rs2276109, MMP20 rs2292730, MMP20 rs12278250, MMP20 rs9787933 might have a potential effect on ovarian cancer risk.In summary, polymorphisms of MMPs might not be associated with ovarian cancer risk. However

  2. New mutation in the mouse Xpd/Ercc2 gene leads to recessive cataracts.

    Sarah Kunze

    Full Text Available Cataracts are the major eye disorder and have been associated mainly with mutations in lens-specific genes, but cataracts are also frequently associated with complex syndromes. In a large-scale high-throughput ENU mutagenesis screen we analyzed the offspring of paternally treated C3HeB/FeJ mice for obvious dysmorphologies. We identified a mutant suffering from rough coat and small eyes only in homozygotes; homozygous females turned out to be sterile. The mutation was mapped to chromosome 7 between the markers 116J6.1 and D7Mit294;4 other markers within this interval did not show any recombination among 160 F2-mutants. The critical interval (8.6 Mb contains 3 candidate genes (Apoe, Six5, Opa3; none of them showed a mutation. Using exome sequencing, we identified a c.2209T>C mutation in the Xpd/Ercc2 gene leading to a Ser737Pro exchange. During embryonic development, the mutant eyes did not show major changes. Postnatal histological analyses demonstrated small cortical vacuoles; later, cortical cataracts developed. Since XPD/ERCC2 is involved in DNA repair, we checked also for the presence of the repair-associated histone γH2AX in the lens. During the time, when primary lens fiber cell nuclei are degraded, γH2AX was strongly expressed in the cell nuclei; later, it demarcates clearly the border of the lens cortex to the organelle-free zone. Moreover, we analyzed also whether seemingly healthy heterozygotes might be less efficient in repair of DNA damage induced by ionizing radiation than wild types. Peripheral lymphocytes irradiated by 1Gy Cs137 showed 6 hrs after irradiation significantly more γH2AX foci in heterozygotes than in wild types. These findings demonstrate the importance of XPD/ERCC2 not only for lens fiber cell differentiation, but also for the sensitivity to ionizing radiation. Based upon these data, we hypothesize that variations in the human XPD/ERCC2 gene might increase the susceptibility for several disorders besides Xeroderma

  3. Genetic control of x-ray resistance in budding yeast cells

    Benathen, I.A.; Beam, C.A.

    1977-01-01

    Five x-ray-sensitive mutants were selected from 10,000 colonies arising from survivors of ultraviolet light. These were named XS5, XS6, XS7, XS8, and XS9. Mutant XS1 was donated by Nakai. These mutations affect the resistant budding cell survival component of the survival curve and, in diploids, the low-dose interdivisional cell shoulder. They are of two types: Class I, in which budding cells lack resistance; and Class II, in which budding cells show reduced resistance. When crossed with one another, they show a complex complementation pattern. Gene dosage effects are seen in XS1 heterozygotes, while budding but not between divisions. No direct correlation between radiation sensitivity, meiosis, and sporulation is observed; genes which influence radiation sensitivity do not affect meiotic recombination. A single mutation (XS1 or XS5) suppresses the shoulders of the survival curves of both budding haploid cells and diploid nonbudding cells

  4. High tobacco consumption is causally associated with increased all-cause mortality in a general population sample of 55 568 individuals, but not with short telomeres

    Rode, Line; Bojesen, Stig E; Weischer, Maren

    2014-01-01

    ,568 individuals including 32,823 ever smokers from the Danish general population, of whom 3430 died during 10 years of follow-up. All had telomere length measured, detailed information on smoking history, and CHRNA3 rs1051730 genotype, which is associated with tobacco consumption, determined. In a Mendelian...... randomization study, we conducted observational, genetic, and mediation analyses. RESULTS: First, tobacco consumption was 21.1 pack-years in non-carriers, 22.8 in heterozygotes and 24.8 in homozygotes (P-trend....12 [95% confidence interval (CI): 1.09, 1.15] per doubling in tobacco consumption. In Mendelian randomization analysis, the hazard ratio was 1.08 (1.02, 1.14) per minor CHRNA3 allele in ever smokers. Third, in observational analysis telomeres shortened with -13 base pairs (-18, -8) per doubling...

  5. LGMD2I in a North American population

    White Alexander J

    2007-11-01

    Full Text Available Abstract Background There is a marked variation in clinical phenotypes that have been associated with mutations in FKRP, ranging from severe congenital muscular dystrophies to limb-girdle muscular dystrophy type 2I (LGMD2I. Methods We screened the FKRP gene in two cohorts totaling 87 patients with the LGMD phenotype. Results The c.826C>A, p.L276I mutation was present in six patients and a compound heterozygote mutation in a seventh patient. Six patients had a mild LGMD2I phenotype, which resembles that of Becker muscular dystrophy. The other patient had onset before the age of 3 years, and thus may follow a more severe course. Conclusion These findings suggest that LGMD2I may be common in certain North American populations. This diagnosis should be considered early in the evaluation of LGMD.

  6. Isolation and characterization of the cDNA for cystic fibrosis antigen

    Dorin, J R

    1987-01-01

    Cystic fibrosis antigen (CFAg) is a protein which is present in the serum of cystic fibrosis (CF) patients and clinically normal heterozygotes, but not in normal individuals. CFAg has been shown to be a major granulocyte protein in normals, and the gene mapped to chromosome 1. This thesis describes the molecular cloning and subsequent characterization of the cDNA for CFAg. The availability of monoclonal antibodies to CFAg facilitated the identification of myeloid tissues which were actively synthesizing the protein. A specific radiolabeled protein could be immunoprecipitated from /sup 35/S-methionine labelled extracts of chronic myeloid leukemia cells (CML), normal granulocytes and HL-60 cells differentiated towards granulocytes. In CML and granulocytes, CFAg appeared to be one of the most abundantly synthesized proteins.

  7. Bg1II polymorphism of the epidermal growth factor receptor (EGF-R) gene

    Biunno, I; Pozzi, M R; Radice, P; Mondini, P; Pierotti, M A; Porta, G D [Istituto Nazionale Tumori, Milan (Italy); Haley, J; Waterfield, M D [Ludwig Institute for Cancer Research, London (England)

    1988-08-11

    A 770 bp cDNA fragment was derived from the cytoplasmic portion of the EGF-R (ref. Libermann et al., 1985). Bg1II identifies 4 invariant bands of 7.0, 5.0, 3.5 and 1.2 kb and a two allele polymorphism with a band of either 10.6 kb (lane 1) or 9.4 kb (lane 3). An heterozygote individual is represented. The frequency was analyzed in 78 unrelated European Caucasians. Its chromosomal location was determined. Co-dominant segregation was demonstrated in three families of 12 individuals. A rare variant of 8.3 kb was seen in one chromosome out of the 144 examined. This allelic form has not yet been fully characterized.

  8. Genetic evidence for two species of the genus Pimelodus Lacépède, 1803 (Siluriformes, Pimelodidae in the Iguaçu River (Brazil

    Renesto Erasmo

    2000-01-01

    Full Text Available The existence of reproductive isolation between two morphs of catfish, endemic to the Iguaçu River (Brazil, was examined by enzyme starch gel electrophoresis. Tissues of 19 catfish (Pimelodus ortmanni and 15 of a similar morph (Pimelodus sp., which differs from P. ortmanni by presenting larger and more scattered dusky spots on its skin, were analyzed. A Nei's (1978 genetic identity of 0.551 was determined by the analysis of 22 enzyme loci. The loci EST*1, EST*2, GDH*1, GPI*1, GPI*2, IDH*1, MDH*1, MDH*2, and PGM*1 were fixed for different alleles in each morph, that is, no heterozygote was found for these loci. The enzymatic patterns observed for the two morphs indicate both that the taxa are reproductively isolated and that they in fact represent separate species.

  9. Tobacco smoking is causally associated with antipsychotic medication use and schizophrenia, but not with antidepressant medication use or depression

    Wium-Andersen, Marie Kim; Ørsted, David Dynnes; Nordestgaard, Børge Grønne

    2015-01-01

    compared with non-carriers (CC). Furthermore, in ever-smokers homozygotes had increased risk of antipsychotic medication with an odds ratio (OR) of 1.16 [95% confidence interval (CI) 1.02-1.31] compared with non-carriers, whereas in never-smokers the corresponding OR was 1.07 (0.87-1.31) (P-interaction: 0......-old individuals from the Danish general population; 23,282 were never-smokers and 40,014 ever-smokers. For schizophrenia, we compared our results with those in the Psychiatric Genomics Consortium. RESULTS: In smokers, heterozygotes (CT) and homozygotes (TT) for rs1051730 genotype had higher smoking intensity...... OR for schizophrenia was 1.06 (1.04-1.08) in ever- and never-smokers combined. CONCLUSION: Our data suggest that tobacco smoking could influence the development of psychotic conditions causally, whereas an influence on depression seems unlikely....

  10. Pure Progressive Ataxia and Palatal Tremor (PAPT) Associated with a New Polymerase Gamma (POLG) Mutation.

    Nicastro, Nicolas; Ranza, Emmanuelle; Antonarakis, Stylianos E; Horvath, Judit

    2016-12-01

    Progressive ataxia with palatal tremor (PAPT) is a syndrome caused by cerebellar and brainstem lesions involving the dentato-rubro-olivary tract and associated with hypertrophic olivary degeneration. Etiologies include acquired posterior fossa lesions (e.g. tumors, superficial siderosis, and inflammatory diseases) and genetic disorders, such as glial fibrillary acidic protein (GFAP) and polymerase gamma (POLG) mutations. We describe the case of a 52-year-old man who developed pure progressive ataxia and palatal tremor. Genetic analysis has shown that he is compound heterozygote for a known pathogenic (W748S) and a novel POLG variant (I1185N). Patients with POLG recessive mutations usually manifest a more complex clinical picture, including polyneuropathy and epilepsy; our case emphasizes the need to consider a genetic origin in a seemingly sporadic and pure PAPT.

  11. Submicroscopic interstitial deletion of the X chromosome explains a complex genetic syndrome dominated by Norrie disease.

    Gal, A; Wieringa, B; Smeets, D F; Bleeker-Wagemakers, L; Ropers, H H

    1986-01-01

    Norrie disease (ND), an X-linked recessive disorder, is characterized by congenital blindness followed by bulbar atrophy. We have examined a three-generation family in which ND is part of a complex X-linked syndrome with severe mental retardation, hypogonadism, growth disturbances, and increased susceptibility to infections as additional features. This syndrome is apparently due to an interstitial deletion, as evidenced by the failure of the L1.28 DNA probe (DXS7 locus, Xp11.3) to detect complementary DNA sequences on the defective X chromosome of an affected male and of several obligatory heterozygotes. Attempts to further define this deletion with other DNA probes from the proximal short arm of the X chromosome or by prometaphase chromosome analysis were unsuccessful.

  12. Alternative splicing of exon 17 and a missense mutation in exon 20 of the insulin receptor gene in two brothers with a novel syndrome of insulin resistance (congenital fiber-type disproportion myopathy)

    Vorwerk, P; Christoffersen, C T; Müller, J

    1999-01-01

    to be compound heterozygotes for mutations in the IR gene. The maternal allele was alternatively spliced in exon 17 due to a point mutation in the -1 donor splice site of the exon. The abnormal skipping of exon 17 shifts the amino acid reading frame and leads to a truncated IR, missing the entire tyrosine kinase......The insulin receptor (IR) in two brothers with a rare syndrome of congenital muscle fiber type disproportion myopathy (CFTDM) associated with diabetes and severe insulin resistance was studied. By direct sequencing of Epstein-Barr virus-transformed lymphocytes both patients were found...... domain. In the correct spliced variant, the point mutation is silent and results in a normally translated IR. The paternal allele carries a missense mutation in the tyrosine kinase domain. All three cDNA variants were present in the lymphocytes of the patients. Purified IR from 293 cells overexpressing...

  13. Improvement of Fabry Disease-Related Gastrointestinal Symptoms in a Significant Proportion of Female Patients Treated with Agalsidase Beta

    Wilcox, William R; Feldt-Rasmussen, Ulla; Martins, Ana Maria

    2018-01-01

    of organ involvement. Although variable, gastrointestinal symptoms are among the most common and significant early clinical manifestations; they tend to persist into adulthood if left untreated. To further understand the effects of sustained enzyme replacement therapy (ERT) with agalsidase beta......Fabry disease, an X-linked inherited lysosomal storage disorder, is caused by mutations in the gene encoding α-galactosidase, GLA. In patients with Fabry disease, glycosphingolipids accumulate in various cell types, triggering a range of cellular and tissue responses that result in a wide spectrum...... on gastrointestinal symptoms in heterozygotes, a data analysis of female patients enrolled in the Fabry Registry was conducted. To be included, females of any age must have received agalsidase beta (average dose 1.0 mg/kg every 2 weeks) for at least 2.5 years. Measured outcomes were self-reported gastrointestinal...

  14. Frequency in Japan of carriers of the rare recessive gene causing actalasemia

    Hamilton, H B; Neel, J V; Kobara, T Y; Ozaki, Kyoko

    1961-05-17

    A rapid and simple method to detect the hypocatalasemic heterozygotes for the gene responsible for acatalasemia is described. A total of 13,647 blood specimens from individuals residing in Hiroshima and Nagasaki have been examined in this manner, and the frequency of hypocatalasemia found to be 0.09%. Surveys in other parts of Japan have revealed frequencies of the order of 1.4%. This unevenness in the distribution of a rare recessive gene, taken in conjunction with the known variation from locality to locality in the frequency of inbreeding, has important implications for the interpretation of data on inbreeding effects. Some of these implications are discussed. 17 references, 1 figure, 6 tables.

  15. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes

    Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Reynisdottir, Inga

    2007-01-01

    We conducted a genome-wide association study for type 2 diabetes (T2D) in Icelandic cases and controls, and we found that a previously described variant in the transcription factor 7-like 2 gene (TCF7L2) gene conferred the most significant risk. In addition to confirming two recently identified...... risk variants, we identified a variant in the CDKAL1 gene that was associated with T2D in individuals of European ancestry (allele-specific odds ratio (OR) = 1.20 (95% confidence interval, 1.13-1.27), P = 7.7 x 10(-9)) and individuals from Hong Kong of Han Chinese ancestry (OR = 1.25 (1.11-1.40), P = 0...... was approximately 20% lower than for heterozygotes or noncarriers, suggesting that this variant confers risk of T2D through reduced insulin secretion....

  16. Deletion of Xpter encompassing the SHOX gene and PAR1 region in familial patients with Leri-Weill Dyschondrosteosis syndrome.

    Mutesa, L; Vanbellinghen, J F; Hellin, A C; Segers, K; Jamar, M; Pierquin, G; Bours, V

    2009-01-01

    Heterozygote deletions or mutations of pseudoautosomal 1 region (PAR1) encompassing the short stature homeobox-containing (SHOX) gene cause Leri-Weill Dyschondrosteosis (LWD), which is a dominantly inherited osteochondroplasia characterized by short stature with mesomelic shortening of the upper and lower limbs and Madelung deformity of the wrists. SHOX is expressed by both sex chromosomes in males and females and plays an important role in bone growth and development. Clinically, the LWD expression is variable and more severe in females than males due to sex differences in oestrogen levels. Here, we report two familial cases of LWD with a large Xp terminal deletion (approximately 943 kb) of distal PAR1 encompassing the SHOX gene. In addition, the proband had mental retardation which appeared to be from recessive inheritance in the family.

  17. Why Do Sex Chromosomes Stop Recombining?

    Ponnikas, Suvi; Sigeman, Hanna; Abbott, Jessica K; Hansson, Bengt

    2018-04-28

    It is commonly assumed that sex chromosomes evolve recombination suppression because selection favours linkage between sex-determining and sexually antagonistic genes. However, although the role of sexual antagonism during sex chromosome evolution has attained strong support from theory, experimental and observational evidence is rare or equivocal. Here, we highlight alternative, often neglected, hypotheses for recombination suppression on sex chromosomes, which invoke meiotic drive, heterozygote advantage, and genetic drift, respectively. We contrast the hypotheses, the situations when they are likely to be of importance, and outline why it is surprisingly difficult to test them. Lastly, we discuss future research directions (including modelling, population genomics, comparative approaches, and experiments) to disentangle the different hypotheses of sex chromosome evolution. Copyright © 2018 Elsevier Ltd. All rights reserved.

  18. Allele coding in genomic evaluation

    Standen, Ismo; Christensen, Ole Fredslund

    2011-01-01

    Genomic data are used in animal breeding to assist genetic evaluation. Several models to estimate genomic breeding values have been studied. In general, two approaches have been used. One approach estimates the marker effects first and then, genomic breeding values are obtained by summing marker...... effects. In the second approach, genomic breeding values are estimated directly using an equivalent model with a genomic relationship matrix. Allele coding is the method chosen to assign values to the regression coefficients in the statistical model. A common allele coding is zero for the homozygous...... genotype of the first allele, one for the heterozygote, and two for the homozygous genotype for the other allele. Another common allele coding changes these regression coefficients by subtracting a value from each marker such that the mean of regression coefficients is zero within each marker. We call...

  19. Clinical Case of Immune Dysregulation, Polyendocrinopaty, Enteropathy, X-Linked (IPEX Syndrome with Severe Immune Deficiency and Late Onset of Endocrinopathy and Enteropathy

    R. Savova

    2014-01-01

    Full Text Available Objective. To describe the clinical characteristics of IPEX syndrome in a child with FOXP3 mutation. Clinical Case. A boy aged 2.3 years was born from first normal pregnancy with a weight of 3420 gr. Family History. Two brothers of the mother died before the age of 3 years with severe infections, diarrhea, erythroderma, and elevated immunoglobulins class E (IgEs. Since first month of life, our patient suffered from septicemia, pneumonias, pyelonephritis, and meningitis, accompanied with eczematous dermatitis and IgEs up to 4000 IU/L (normal A, p. (Arg337Gln, which confirmed IPEX syndrome. The same mutation in heterozygotic state was found in the mother. A prenatal diagnosis of her second pregnancy ensured a daughter carrier of the mutation.

  20. Relative autonomy of manifestation of welt mutation in imaginal discs of Drosophila

    Vikulova, V.K.

    1988-01-01

    Autonomy of manifestation of the temperature-sensitive lethal welt mutation was investigated during transplantation of imaginal discs of mutant larvae into normal recipients and in large clones of cells homozygous for welt induced by γ-irradiation in a dose of 1000 rd in y; fj wt/M(2)S7 T(1;2)sc s 2 heterozygotes. Three temperature regimes were used: 17 degree C, at which the welt mutation is not manifested; 29 degree C, at which it is manifested better; and 25 degree C. It was established that the welt mutation operates autonomously, but in restricted regions of imaginal discs. The possibility is discussed of nonautonomous manifestation of the mutation with direct contact of wt/wt cells with heteroxygous wt/+ tissue

  1. Biomarkers for exposure to ambient air pollution - Comparison of carcinogen-DNA adduct levels with other exposure markers and markers for oxidative stress

    Autrup, Herman; Daneshvar, Bahram; Dragsted, Lars Ove

    1999-01-01

    Human exposure to genotoxic compounds present in ambient air has been studied using selected biomarkers in nonsmoking Danish bus drivers and postal workers. A large interindividual variation in biomarker levels was observed. Significantly higher levels of bulky carcinogen-DNA adducts (75.42 adducts...... correlations were observed between bulky carcinogen-DNA adduct and PAM-albumin levels (p = 0.005), and between DNA adduct and gamma-glutamyl semialdehyde (GGS) in hemoglobin (p = 0.11). Highly significant correlations were found between PAM-albumin adducts and AAS in plasma (r = 0.001) and GGS in hemoglobin (p...... in the combined group. A significant negative correlation was only observed between bulky carcinogen-DNA adducts and PAM-albumin adducts (p = 0.02) and between DNA adduct and urinary mutagenic activity (p = 0.02) in the GSTM1 null group, bur not in the workers who were homozygotes or heterozygotes for GSTM1. Our...

  2. An Inherited Platelet Function Defect in Basset Hounds

    Johnstone, I. B.; Lotz, F.

    1979-01-01

    An inherited platelet function defect occurring in a family of basset hounds has been described. The trait is transmitted as an autosomal characteristic and appears to be expressed clinically only in the homozygous state. The characteristics of this platelet defect include: 1) marked bleeding tendencies and prolonged skin bleeding times in either male or female dogs. 2) normal blood coagulation mechanism. 3) adequate numbers of circulating platelets which appear morphologically normal by light microscopy. 4) normal whole blood clot retraction. 5) deficient in vivo platelet consumption and in vitro platelet retention in glass bead columns. 6) defective ADP-induced platelet aggregation in homozygotes, apparently normal ADP response in heterozygotes, and defective collagen-induced platelet aggregation in both. PMID:509382

  3. A case report of a patient carrying CYP2C9*3/4 genotype with extremely low warfarin dose requirement.

    Lee, Soo Youn; Nam, Myung Hyun; Kim, June Soo; Kim, Jong Won

    2007-06-01

    We report a case of intolerance to warfarin dosing due to impaired drug metabolism in a patient with CYP2C9*3/*4. A 73-yr-old woman with atrial fibrilation was taking warfarin. She attained a high prothrombin time international normalized ratio (INR) at the standard doses during the induction of anticoagulation and extremely low dose of warfarin (6.5 mg/week) was finally chosen to reach the target INR. Genotyping for CYP2C9 revealed that this patient had a genotype CYP2C9*3/*4. This is the first Korean compound heterozygote for CYP2C9*3 and *4. This case suggests the clinical usefulness of pharmacogenetic testing for individualized dosage adjustments of warfarin.

  4. The expanded clinical profile and the efficacy of colchicine therapy in Egyptian children suffering from familial mediterranean fever: a descriptive study

    Talaat Hala Salah El-Din

    2012-12-01

    Full Text Available Abstract Background Familial Mediterranean fever (FMF is an autosomal recessive disease characterized by self-limiting recurrent attacks of fever and serosal inflammation, leading to abdominal, thoracic or articular pain. Objective To detect variable clinical presentations and genotypic distribution of different groups of FMF patients and the efficacy of colchicine therapy in treatment of these groups of FMF after one year. Methods A cross-sectional study was conducted on 70 patients already diagnosed with FMF and following-up at the Rheumatology Clinic, Children's Hospital - Cairo University. Diagnosis of FMF was determined according to Tel Hashomer criteria for FMF. All patients were subjected to a questionnaire including detailed history with emphasis on clinical manifestations and colchicine dose to control attacks. Mutational analysis was performed for all study subjects covering 12 mutations in the MEFV gene: E148Q, P369S, F479L, M680I (G/C, M680I (G/A, I692del, M694V, M694I, K695R, V726A, A744S and R761H. Response to colchicine treatment was evaluated as complete, incomplete and unresponsive. Results Out of the 70 patients- 40 males and 30 females- fever was the most common presenting feature, followed by abdominal pain, and arthritis; documented in 95.7%, 94.3%, and 77.1% of cases respectively. Mutational analysis detected gene mutation on both alleles in 20 patients (homozygotes, on only 1 allele in 40 patients (heterozygotes, and on none of the alleles (uncharacterized cases. Mild to moderate disease severity score (according to Tel Hashomer key to severity score was detected in a significant proportion of heterozygotes and the uncharacterized group than the homozygotes. All patients received colchicine therapy; 22.9% of them showed complete response, 74.3% showed incomplete response and 2.9% showed no response to therapy. The colchicine dose needed to control attacks was significantly lower in heterozygotes than the homozygotes(P=0

  5. Radiation carcinogenesis in scid mice

    Ishii, Hiroko; Nishimura, Mayumi; Kobayashi, Shigeru; Tsuji, Hideo; Shimada, Yoshiya; Ogiu, Toshiaki [National Inst. of Radiological Sciences, Chiba (Japan); Suzuki, Fumio; Sado, Toshihiko

    1999-06-01

    Scid mice which have the defect of DNA-dependent protein kinase catalitic subunit, exhibit the limited activities of repair from DNA double strand breaks, and are sensitive to ionizing radiation. In order to study the relationship between repair capacity for DNA double strand breaks and carcinogenesis, the effects of ionizing radiation were studied using scid homozygotes (scid/scid), scid heterozygotes (scid/+) and CB-17 (+/+) mice. Both the Scid bone marrow cells and fibroblast cell lines from Scid embryos were highly sensitivity to acute effects of ionizing radiation. Carcinogenesis experiments showed the high incidence of thymic lymphomas (80 to 90%) in 1 to 3 Gy {sup 137}Cs-{gamma}-ray-irradiated Scid mice. (author)

  6. Analysis of the Fanconi anaemia complementation group A gene in acute myeloid leukaemia.

    Condie, Alison; Powles, Raymond L; Hudson, Chantelle D; Shepherd, Valerie; Bevan, Stephen; Yuille, Martin R; Houlston, Richard S

    2002-09-01

    Acute myeloid leukaemia (AML) is the most common acute leukaemia in adults. Around 10-15% of individuals with recessively inherited Fanconi anaemia (FA) develop AML. FA is one of a group of recessive syndromes characterized by excessive spontaneous chromosomal breakage in which heterozygote carriers appear to display an increased risk of cancer and there is some indirect evidence that FA carriers may also be at increased risk of AML. This suggests that FA genes may play a role in the development of AML in the wider context. To examine this proposition, further, we have screened samples from 79 AML patients for mutations in the major FA gene, FANCA. No truncating FANCA mutations were detected. One missense mutation previously designated as pathogenic and five novel missense mutations causing non-conservative amino acid substitutions were detected. The data suggests that while FANCA mutations are rare, FANCA mutations may contribute to the development of the disease in a subset of AML.

  7. Genetic influences on human body odor: from genes to the axillae.

    Preti, George; Leyden, James J

    2010-02-01

    Several groups have identified the characteristic axillary odorants and how they arrive on the skin surface, pre-formed, bound to water-soluble odorless precursors in apocrine secretions. In the current issue, Martin et al., (2010) describe the relationship between the production of axillary odorants and variants in the ABCC11 gene. Individuals who are homozygotic for a SNP (538G>A) were found to have significantly less of the characteristic axillary odorants than either individuals who were heterozygotic for this change or those who had the wild-type gene. The 538G>A SNP predominates in Asians who have nearly complete loss of typical body odor. ABCC11 is expressed and localized in apocrine sweat glands. These findings are remarkably similar to the ethnic distribution and expression patterns for apocrine apoD, a previously identified carrier of a characteristic axillary odorant.

  8. Meta-analysis for genome-wide association studies using case-control design: application and practice.

    Shim, Sungryul; Kim, Jiyoung; Jung, Wonguen; Shin, In-Soo; Bae, Jong-Myon

    2016-01-01

    This review aimed to arrange the process of a systematic review of genome-wide association studies in order to practice and apply a genome-wide meta-analysis (GWMA). The process has a series of five steps: searching and selection, extraction of related information, evaluation of validity, meta-analysis by type of genetic model, and evaluation of heterogeneity. In contrast to intervention meta-analyses, GWMA has to evaluate the Hardy-Weinberg equilibrium (HWE) in the third step and conduct meta-analyses by five potential genetic models, including dominant, recessive, homozygote contrast, heterozygote contrast, and allelic contrast in the fourth step. The 'genhwcci' and 'metan' commands of STATA software evaluate the HWE and calculate a summary effect size, respectively. A meta-regression using the 'metareg' command of STATA should be conducted to evaluate related factors of heterogeneities.

  9. Combinations of genetic variants associated with bipolar disorder

    Mellerup, Erling; Andreassen, Ole A; Bennike, Bente

    2017-01-01

    The main objective of the study was to find genetic variants that in combination are significantly associated with bipolar disorder. In previous studies of bipolar disorder, combinations of three and four single nucleotide polymorphisms (SNP) genotypes taken from 803 SNPs were analyzed, and five...... clusters of combinations were found to be significantly associated with bipolar disorder. In the present study, combinations of ten SNP genotypes taken from the same 803 SNPs were analyzed, and one cluster of combinations was found to be significantly associated with bipolar disorder. Combinations from......, heterozygote or variant homozygote. In the combinations containing 10 SNP genotypes almost all the genotypes were the normal homozygote. Such a finding may indicate that accumulation in the genome of combinations containing few SNP genotypes may be a risk factor for bipolar disorder when those combinations...

  10. The genetic profiles of two salmonid populations from Romania obtained through nuclear markers analysis

    Ramona Nechifor

    2017-05-01

    Full Text Available The Salmonidae fish family is well represented in Romanian fauna, with a total of six species in the wild and reared in fish farms. Among them, the brown trout (Salmo trutta fario can be found in all major Romanian river basins. However, anthropogenic activities might disrupt salmonids’ habitats, so that inbreeding and genetic isolation might easily occur in the wild populations. We analyzed two wild brown trout populations from rivers targeted by anthropogenic activities, by using nuclear markers and genotyping in order to observe their genetic structure. We analyzed nine microsatellites and we observed their alleles frequencies, number of private alleles, observed and expected heterozygosity, as well as their population structure. The two populations are not in Hardy-Weinberg equilibrium for most of the loci and the inbreeding coefficient for both populations suggests a heterozygote deficit. Further sequencing data are needed in order to have a better view upon their complete genetic structure.

  11. Effect of marine contamination on the genetic population structure of the bivalve Crassostrea angulata; Efecto de la contaminacion marina sobre la estructura genetica poblacional del bivalvo Crassostrea angulata

    Cross, Ismael; Rebordinos, Laureana [Laboratorio de Genetica, Facultad de Ciencias del Mar, Universidad de Cadiz, Cadiz (Spain)

    2003-06-15

    Seven enzyme loci were analyzed in three natural populations of Crassostrea angulata located on the southern Atlantic coast of the Iberian Peninsula. Two of the populations showed distinct levels of contamination by heavy metals, whereas the third was not contaminated and served as control. These seven loci were shown to be very variable in terms of the number of alleles, polymorphism and average heterozygosity. The Lap and Mdh1 loci presented null alleles. A significant positive correlation was found between the number of alleles and the concentration of iron that was fitted to a model of linear regression. However, this correlation was negative for the heterozygosity, and significant for cadmium and zinc. The Em, Lap, Mdh1 y Xdh loci showed a deficit of heterozygotes in all the populations. The values of heterozygotic deficit (D) were statistically significant between the contaminated populations and the control for Mdh1 and very close to a significant level for Em. In Pgm, a heterozygotic excess appeared in the control population and deficit, which was correlated to the increased levels of metal concentration, occurred in the other two populations. The differences between the D values of the three populations were also significant in this locus. Positive, negative and significant relationships were obtained between the concentration of metals and some alleles of the Em, Lap and Pgm loci. Also, the homozygotic genotypes of the alleles with positive correlation values were selected in the contaminated areas, while the heterozygotes were more favoured in the control population, showing an adaptive behavior and corroborating the utility of some of these loci as biomarkers in studies of population dynamics in areas subjected to environmental contamination. [Spanish] Se analizaron siete loci alozimicos en tres poblaciones naturales de Crassostrea angulata localizadas en la costa suratlantica de la Peninsula Iberica. Dos de las poblaciones mostraban distintos niveles

  12. Comparison of manual and automated AmpliSeq™ workflows in the typing of a Somali population with the Precision ID Identity Panel

    van der Heijden, Suzanne; de Oliveira, Susanne Juel; Kampmann, Marie-Louise

    2017-01-01

    to compare different AmpliSeq™ workflows to investigate the possibility of using automated library building in forensic genetic case work. In order to do so, the SNP typing of the Somalis was performed using three different workflows: 1) manual library building and sequencing on the Ion PGM™, 2) automated...... workflows. The Biomek(®)3000/Ion PGM™ workflow was found to perform similarly to the manual/Ion PGM™ workflow. This argues for the use of automated library building in forensic genetic case work. Automated library building decreases the workload of the laboratory staff, decreases the risk of pipetting...... library building using the Biomek(®)3000 and sequencing on the Ion PGM™, and 3) automated library building using the Ion Chef™ and sequencing on the Ion S5™. AmpliSeq™ workflows were compared based on coverage, locus balance, noise, and heterozygote balance. Overall, the Ion Chef™/Ion S5™ workflow...

  13. wtf genes are prolific dual poison-antidote meiotic drivers.

    Nuckolls, Nicole L; Bravo Núñez, María Angélica; Eickbush, Michael T; Young, Janet M; Lange, Jeffrey J; Yu, Jonathan S; Smith, Gerald R; Jaspersen, Sue L; Malik, Harmit S; Zanders, Sarah E

    2017-06-20

    Meiotic drivers are selfish genes that bias their transmission into gametes, defying Mendelian inheritance. Despite the significant impact of these genomic parasites on evolution and infertility, few meiotic drive loci have been identified or mechanistically characterized. Here, we demonstrate a complex landscape of meiotic drive genes on chromosome 3 of the fission yeasts Schizosaccharomyces kambucha and S. pombe . We identify S. kambucha wtf4 as one of these genes that acts to kill gametes (known as spores in yeast) that do not inherit the gene from heterozygotes. wtf4 utilizes dual, overlapping transcripts to encode both a gamete-killing poison and an antidote to the poison. To enact drive, all gametes are poisoned, whereas only those that inherit wtf4 are rescued by the antidote. Our work suggests that the wtf multigene family proliferated due to meiotic drive and highlights the power of selfish genes to shape genomes, even while imposing tremendous costs to fertility.

  14. An ace-1 gene duplication resorbs the fitness cost associated with resistance in Anopheles gambiae, the main malaria mosquito.

    Assogba, Benoît S; Djogbénou, Luc S; Milesi, Pascal; Berthomieu, Arnaud; Perez, Julie; Ayala, Diego; Chandre, Fabrice; Makoutodé, Michel; Labbé, Pierrick; Weill, Mylène

    2015-10-05

    Widespread resistance to pyrethroids threatens malaria control in Africa. Consequently, several countries switched to carbamates and organophophates insecticides for indoor residual spraying. However, a mutation in the ace-1 gene conferring resistance to these compounds (ace-1(R) allele), is already present. Furthermore, a duplicated allele (ace-1(D)) recently appeared; characterizing its selective advantage is mandatory to evaluate the threat. Our data revealed that a unique duplication event, pairing a susceptible and a resistant copy of the ace-1 gene spread through West Africa. Further investigations revealed that, while ace-1(D) confers less resistance than ace-1(R), the high fitness cost associated with ace-1(R) is almost completely suppressed by the duplication for all traits studied. ace-1 duplication thus represents a permanent heterozygote phenotype, selected, and thus spreading, due to the mosaic nature of mosquito control. It provides malaria mosquito with a new evolutionary path that could hamper resistance management.

  15. Final report of twenty-two years of AEC support, 1953--1975

    Herriott, R.M.

    1975-01-01

    Results are reported for: the partial clarification of many aspects of genetic transformation in H. influenzae; control of the many facets of the metabolic and genetic pathways of this organism; development of a totally defined medium for both growth and for competence; the discovery, analysis of kinetics and purification of the photphotoreactivating enzyme; the formation of new genetic units (heterozygotes) during renaturation of mixtures of transforming DNA and finally; the generation of mutations in free wild type DNA by nitrous acid or by thymine hydroperoxide. The latter mutagen is formed in DNA exposed to ionizing radiation and explains the mutations induced in genetic material by ionizing radiation. In addition to these research results, graduate students, postdoctorates and faculty have been trained in the molecular mechanisms of genetic processes through the study of transformation. (U.S.)

  16. Effect of low dose gamma radiation on stamen-hairs of different clones of Tradescantia presenting variability in the frequency of spontaneous mutations

    Takahashi, C.S.

    1976-01-01

    Changes in the frequency of spontaneous somatic mutations were studied for three different clones of Tradescantia heterozygotes for flower and stamen-hair color keeping them under controlled or natural conditions in order to verify the effect of different environmental conditions on the different genotypes. The effect of inflorescence age on the variation of spontaneous mutations was studied choosing young and old inflorescences of a same plant. Low dose irradiation experiments were carried out with those clones to elucidate the radiation effects on the clones presenting changes in the frequency of spontaneous mutations. The chronic-and acute irradiation effects of low dose irradiation of the stamen-hair of Tradescantia were also studied. Results are discussed. (M.A.) [pt

  17. Fitness of allozyme variants in Drosophila pseudoobscura. II. Selection at the Est-5, Odh and Mdh-2 loci

    Marinkovic, D; Ayala, F J

    1975-01-01

    We have studied the effects on fitness of allelic variation at three gene loci (Est-5, Odh, and Mdh-2) coding for enzymes in Drosophila pseudoobscura. Genotype has a significant effect on fitness for all six parameters measured (female fecundity, male mating capacity, egg-to-adult survival under near-optimal and under competitive conditions, and rate of development under near-optimal and under competitive conditions). No single genotype is best for all six fitness parameters; rather, genotypes with superior performance during a certain stage of the life-cycle may have low fitness at some other stage, or in different environmental conditions. Heterozygotes are sometimes best when all fitness parameters are considered. There are significant interactions between loci. The various forms of balancing selection uncovered in our experiments may account for the polymorphisms occurring in natural populations of D. pseudoobscura at the three loci studied. (auth)

  18. Oral CCR5 inhibitors: will they make it through?

    Biswas, Priscilla; Nozza, Silvia; Scarlatti, Gabriella; Lazzarin, Adriano; Tambussi, Giuseppe

    2006-05-01

    The therapeutic armamentarium against HIV has recently gained a drug belonging to a novel class of antiretrovirals, the entry inhibitors. The last decade has driven an in-depth knowledge of the HIV entry process, unravelling the multiple engagements of the HIV envelope proteins with the cellular receptorial complex that is composed of a primary receptor (CD4) and a co-receptor (CCR5 or CXCR4). The vast majority of HIV-infected subjects exhibit biological viral variants that use CCR5 as a co-receptor. Individuals with a mutated CCR5 gene, both homo- and heterozygotes, appear to be healthy. For these and other reasons, CCR5 represents an appealing target for treatment intervention, although certain challenges can not be ignored. Promising small-molecule, orally bioavailable CCR5 antagonists are under development for the treatment of HIV-1 infection.

  19. [Genetic diversity and mating system Pinus brutia var. Stankewiczii sukacz. in small localities of Sudak (Crimea)].

    Korshikov, I I; Kalafat, L A; Milchevskaya, Ya G

    2015-01-01

    A comparative analysis of genetic variation at 12 polymorphic isozyme loci, and the mating system has been carried out in mature trees and their seed progeny in three small localities of Pinus brutia var. stankewiczii Sukacz. near the town of Sudak--settlement of Novyi Svet in the Crimea. We found that embryos maintain the same allelic diversity as mother plants but their observed heterozygosity is lower on the average by 37.4%. The significant deviation of genotype distribution from the theoretically expected ratios caused by the deficiency of heterozygotes was observed at 8 out of 12 loci. Multilocus estimate of outcrossing rate (t(m)) in populations varied from 68.9 to 94.9% making on the average 80.7%.

  20. Boundaries of sustainability in simple and elaborate models of agricultural pest control with a pesticide and a non-toxic refuge.

    Mohammed-Awel, Jemal; Ringland, John; Bantle, John; Festinger, Aaron; Jo, Hee-Joon; Klafehn, Ryan

    2012-01-01

    In two models of pest control using a pesticidal crop along with a non-pesticidal refuge to prevent the development of resistance, we numerically compute the bifurcations that bound the region in parameter space where control is sustainable indefinitely. An exact formula for one of the bifurcation surfaces in one of the models is also found. One model is conceptual and as simple as possible. The other is realistic and very detailed. Despite the great differences in the models, we find the same distinctive bifurcation structure. We focus on the parameters that determine: (i) the restriction of pest exchange between the crop and the refuge, which we call 'screening' the refuge, and (ii) the recessiveness of the resistance trait. The screened refuge technique is seen to work in the models up to quite high values of fitness of resistant heterozygotes, that is, even when resistance is not strongly recessive.

  1. A sex-chromosome inversion causes strong overdominance for sperm traits that affect siring success.

    Knief, Ulrich; Forstmeier, Wolfgang; Pei, Yifan; Ihle, Malika; Wang, Daiping; Martin, Katrin; Opatová, Pavlína; Albrechtová, Jana; Wittig, Michael; Franke, Andre; Albrecht, Tomáš; Kempenaers, Bart

    2017-08-01

    Male reproductive success depends on the competitive ability of sperm to fertilize the ova, which should lead to strong selection on sperm characteristics. This raises the question of how heritable variation in sperm traits is maintained. Here we show that in zebra finches (Taeniopygia guttata) nearly half of the variance in sperm morphology is explained by an inversion on the Z chromosome with a 40% allele frequency in the wild. The sperm of males that are heterozygous for the inversion had the longest midpieces and the highest velocity. Furthermore, such males achieved the highest fertility and the highest siring success, both within-pair and extra-pair. Males homozygous for the derived allele show detrimental sperm characteristics and the lowest siring success. Our results suggest heterozygote advantage as the mechanism that maintains the inversion polymorphism and hence variance in sperm design and in fitness.

  2. [Effect of heterozygosity for insertions of homogeneously stained regions in chromosome 1 of the house mouse on synapsis in meiotic prophase].

    Borodin, P M; Ladygina, T Iu; Gorlov, I P

    1989-02-01

    Electron microscope analysis of surface-spread synaptonemal complexes (SC) in oocytes and spermatocytes from double cis heterozygotes for Is(HSR; 1C5)1Icg and Is(HSR; 1E3)2Icg was carried out. Aberrant chromosomes were isolated from the feral population of Mus musculus musculus of Novosibirsk. They contain homogeneously stained regions of total length of about 30% of Chr 1 mitotic metaphase. Heteromorphic bivalents of Chr1 with different lengths of the lateral elements of SC and the loop in the intermedial position were revealed in 4.4% spermatocytes and 20% oocytes of heterozygous animals. The loop size depends on the stage of meiosis: it is maximal at late zygotene and decreases up to disappearance during pachytene.

  3. Bloom's syndrome. VI. The disorder in Israel and an estimation of the gene frequency in the Ashkenazim.

    German, J; Bloom, D; Passarge, E; Fried, K; Goodman, R M; Katzenellenbogen, I; Laron, Z; Legum, C; Levin, S; Wahrman

    1977-01-01

    An effort was made to identify all individuals with Bloom's syndrome living in Israel between September 1971 and September 1972. Each of the eight individuals located were Jewish and could readily be classified Ashkenazic. The frequency of the Bloom's syndrome gene in Ashkenazim was estimated to be .0042 (minimum), implying a heterozygote frequency greater than 1 in 120. A striking distortion of the sex ratio (M/F = 7.0) may have been due to underascertainment of affected females. One of the affected individuals ascertained during the survey subsequently has died from cancer, which is in keeping with the recognized cancer proneness of this condition. Four of the affected have married, but no conception is known to have occurred, which suggests that sub- or infertility is a feature of the syndrome. PMID:930922

  4. Lipogenesis and glucose production in dwarf carrier and normal lines of chicks

    Rosebrough, R.W.; McMurtry, J.P.; Steele, N.C.

    1986-01-01

    Diets containing 13, 16, 19, or 23% protein and 70% carbohydrate calories were fed to dwarf heterozygote (dw) and normal (Dw) chickens to determine the effects of age (weeks) and protein on intermediary metabolism. In vitro lipogenesis (IVL) was determined by the incorporation of acetate (10 and 20 mM 2 14 C-Acet/2hr) into hepatic fatty acids. Net glucose production (NGP) was determined as the difference in media glucose in the presence or absence of 10 mM pyruvate. Values were expressed per unit of relative liver size (μmoles/100 g BWt). Serum insulin (INS; ng/ml) was determined by homologous radioimmunoassay. Results indicate that although INS was greater in Dw than in dw, this difference was not reflected in a decreased rate of glucose production to accompany the difference in IVL between the two lines. Moreover, an increase in dietary protein resulted in a decrease in IVL but an increase in INS

  5. Pectin Methylesterase Genes Influence Solid Wood Properties of Eucalyptus pilularis1[C][W][OA

    Sexton, Timothy R.; Henry, Robert J.; Harwood, Chris E.; Thomas, Dane S.; McManus, Luke J.; Raymond, Carolyn; Henson, Michael; Shepherd, Mervyn

    2012-01-01

    This association study of Eucalyptus pilularis populations provides empirical evidence for the role of Pectin Methylesterase (PME) in influencing solid wood characteristics of Eucalyptus. PME6 was primarily associated with the shrinkage and collapse of drying timber, which are phenotypic traits consistent with the role of pectin as a hydrophilic polysaccharide. PME7 was primarily associated with cellulose and pulp yield traits and had an inverse correlation with lignin content. Selection of specific alleles in these genes may be important for improving trees as sources of high-quality wood products. A heterozygote advantage was postulated for the PME7 loci and, in combination with haplotype blocks, may explain the absence of a homozygous class at all single-nucleotide polymorphisms investigated in this gene. PMID:22052017

  6. Phenotypic variability of Filipino beta(o)-thalassemia/HbE patients in Indonesia.

    Setianingsih, I; Williamson, R; Daud, D; Harahap, A; Marzuki, S; Forrest, S

    1999-09-01

    Three Indonesian patients with identical genotypes, each compound heterozygotes for Filipino beta(o)-thalassemia/HbE, expressed different clinical severities. One patient has mild disease and is transfusion independent, while the other two are severely affected and transfusion dependent. The size of the Filipino beta(o)-globin gene deletion was confirmed to be 45 kb, resolving conflicting values given in the literature. Neither ameliorating genetic factors such as alpha-globin gene deletions or the XmnI restriction site polymorphism at position -158 upstream of the (G)gamma-globin gene, nor differences in beta-globin gene haplotype, explain the phenotypic variation. These observations have implications for the development of antenatal diagnosis in Indonesia, as at present it is not possible to give an accurate prediction of severity of phenotype for this common genotype. Copyright 1999 Wiley-Liss, Inc.

  7. [THE INFLUENCE OF SEROTONIN TRANSPORTER AND MONOAMINE OXIDASE A GENES POLYMORPHISM ON PSYCHO-EMOTION AND KARYOLOGICAL STABILITY OF ATHLETES].

    Kalaev, V N; Nechaeva, M S; Korneeva, O S; Cherenkov, D A

    2015-11-01

    The influence of polymorphism of the serotonin transporter and monoamine oxidase A genes, associated with man's aggressiveness on the psycho-emotional state and karyological status of single combat athletes. It was revealed that the carriers of less active ("short"), monoamine oxidase A gene variant have a high motivation to succeed and less rigidity and frustrated, compared to the carriers of more active ("long") version of the gene. Heterozygote carriers of less active ("short") variant of the serotonin transporter gene 5-HTTL had more physical aggression, guilt and were less frustrated compared with carriers of two long alleles. It has been revealed the association of studied genes with the karyological status of athletes. So fighters who are carriers of the short and long alleles of the serotonin transporter gene had more cells with nuclear abnormalities in the buccal epithelium than single combat athletes which both alleles were long.

  8. Association of mutations in the hemochromatosis gene with shorter life expectancy

    Bathum, L; Christiansen, L; Nybo, H

    2001-01-01

    BACKGROUND: To investigate whether the frequency of carriers of mutations in the HFE gene associated with hereditary hemochromatosis diminishes with age as an indication that HFE mutations are associated with increased mortality. It is of value in the debate concerning screening for hereditary...... hemochromatosis to determine the significance of heterozygosity. METHODS: Genotyping for mutations in exons 2 and 4 of the HFE gene using denaturing gradient gel electrophoresis in 1784 participants aged 45 to 100 years from 4 population-based studies: all 183 centenarians from the Danish Centenarian Study, 601...... in the distribution of mutations in exon 2 in the different age groups. CONCLUSIONS: In a high-carrier frequency population like Denmark, mutations in HFE show an age-related reduction in the frequency of heterozygotes for C282Y, which suggests that carrier status is associated with shorter life expectancy....

  9. Early-onset ocular ochronosis in a girl with alkaptonuria (AKU) and a novel mutation in homogentisate 1,2-dioxygenase (HGD).

    Gucev, Z S; Slaveska, N; Laban, N; Danilovski, D; Tasic, V; Pop-Jordanova, N; Zatkova, A

    2011-01-01

    Alkaptonuria (AKU) is a disorder of phenylalanine/tyrosine metabolism due to a defect in the enzyme homogentisate 1,2-dioxygenase (HGD). This recessive disease is caused by mutations in the HGD gene. We report a 14-year-old girl who was referred after presenting black urine. Careful examination revealed ochronosis of the conjunctiva. There was no affection of the cardiac valves. Elevated excretion of homogentisic acid in urine was found. Sequence analysis of the HGD gene from genomic DNA revealed that the patient is a compound heterozygote with a previously described mutation (c.473C>T, p.Pro158Leu), and a novel one (c.821C>T, p.Pro274Leu). Her mother is heterozygous for the novel mutation, while the brother is heterozygous for the previously described mutation. In summary, we describe an alkaptonuric patient with ocular ochronosis and a novel HGD mutation, c.821C>T, p.Pro274Leu.

  10. Perfil de beta talassemia heterozigota obtido a partir de análise data mining em banco de dados The profile of beta thalassemia obtained by data mining analysis in a database

    Ana L. B. Domingos

    2010-02-01

    Full Text Available Variations in the phenotypic expression of heterozygous beta thalassemia reflect the formation of different populations. To better understand the profile of heterozygous beta-thalassemia of the Brazilian population, we aimed at establishing parameters to direct the diagnosis of carriers and calculate the frequency from information stored in an electronic database. Using a Data Mining tool, we evaluated information on 10,960 blood samples deposited in a relational database. Over the years, improved diagnostic technology has facilitated the elucidation of suspected beta thalassemia heterozygote cases with an average frequency of 3.5% of referred cases. We also found that the Brazilian beta thalassemia trait has classic increases of Hb A2 and Hb F (60%, mainly caused by mutations in beta zero thalassemia, especially in the southeast of the country.

  11. GFR and Blood Lead Levels in Gas Station Workers Based on δ-Alad Gene Polymorphisms

    Lantip Rujito

    2015-04-01

    showed that the proportion of ALAD genotype for ALAD 1-1, 1-2 and 2-2 were 94.7%, 5.3%, and 0% respectively. The mean of serum levels in homozygous 1-1 was 15.94 ppb and heterozygote 1-2 was 1.15 ppb. GFR of participants ranged from 71.11 mL/min to 185.20 mL/min with a mean of 117.34mL/min. There was no correlation between serum Pb and GFR (p = 0.19. Study also could not determine the correlation between GFR and ALAD gene Polymorphism. Discussion: Study then concluded that there was no correlation between blood lead levels in the GFR on each δ-ALAD genotypes. Keywords: Lead intoxication, GFR, δ-ALAD, gas station workers

  12. Workshop on The Epidemiology of the ATM Gene: Impact on Breast Cancer Risk and Treatment, Present Status and Future Focus, Lillehammer, Norway, 29 June 2002

    Bernstein, Jonine L; Seminara, Daniela; Børresen-Dale, Anne-Lise

    2002-01-01

    The role of ataxia-telangiectasia mutated (ATM) heterozygosity in cancer is uncertain. In vitro studies of cells from ATM heterozygotes provide strong evidence of radiation sensitivity. Some, but not all, clinical studies suggest an increased risk of breast cancer among ATM gene carriers, and this risk may be greater among those exposed to radiation. This possible excess risk of breast cancer associated with ATM heterozygosity constitutes the basis for several genetic epidemiological studies designed to clarify the role that the ATM gene plays in the etiology of breast and other cancers. The primary focus of this international, multidisciplinary, National Cancer Institute-sponsored workshop was to discuss ongoing and planned epidemiologic studies aimed at understanding the complexities of the ATM gene and its role in carcinogenesis. The invited participants were from diverse disciplines including molecular and clinical genetics, radiation biology and physics, epidemiology, biostatistics, pathology, and medicine. In the present meeting report, the aims of each project are described

  13. Wilson's disease: Rapid diagnosis and differentiation of heterozygous and homozygous carriers with 64CuCl2

    Wesch, H.; Przuntek, H.; Feist, D.; Wuerzburg Univ.; Heidelberg Univ.

    1980-01-01

    In the modified radiocopper test, a constant amount of copper and not of radioactivity is injected, a difference being made between males and females. The rate of incorporation of 64 Cu into caeruloplasmin and urinary excretion of nuclides is measured. It is a method with low radiation exposure, providing a definite diagnosis after 30 hours. This was demonstrated in 27 homozygous patients, 30 parents and 33 siblings, and 25 controls: a clear-cut diagnosis was made in all untreated homozygous patients. In five of eight patients treated with D-penicillamine for several years, the values were in the range of heterozygotes, so that the test makes treatment control possible. The recognition of heterozygous carriers is interfered with by contraceptives and infections. The results in control subjects were all widely outside the range for patients with Wilson's disease. (orig.) [de

  14. Early Renal Involvement in a Girl with Classic Fabry Disease.

    Perretta, Fernando; Antongiovanni, Norberto; Jaurretche, Sebastián

    2017-01-01

    Fabry disease is an X-linked lysosomal storage disorder resulting from the deficiency or absence of the enzyme alpha galactosidase A; this defect leads to the systemic accumulation of globotriaosylceramide and its metabolites. Organic involvement in men is well known, but in women it is controversial, mainly due to the random X-chromosome inactivation in each of their cells (Lyon hypothesis). This would explain why women (heterozygotes) present a wide variability in the severity of their phenotype. The manifestations are multisystemic and begin in early childhood, reaching a severe compromise in adulthood. Typical acroparesthesia in hands and feet, gastrointestinal symptoms, angiokeratomas, dyshidrosis, hearing loss, arrhythmias, hypertrophic cardiomyopathy, cerebrovascular accidents, and renal failure can be observed. Nephropathy is one of the major complications of Fabry disease. Glomerular and vascular changes are present before progression to overt proteinuria and decreased glomerular filtration rate, even in pediatric patients. A case of incipient renal involvement in a girl with classic Fabry disease is reported.

  15. New insights into how genetic disorders arise

    Unrau, P.

    1992-01-01

    One questionable assumption in genetic risk assessment is that all members of the population are equally at risk to the causative agent. The invalidity of this assumption can be demonstrated by considering data on the range of sensitivity to ionizing radiation of lymphoblastoid cell lines derived from various normal members of the population or from various disease groups associated with extreme radiosensitivity. Some 'normal' cell lines are as sensitive as those from the disease groups. A certain proportion of the normal population may be heterozygotic for many of the genes that lead to radiosensitivity. There are many cancer-facilitating genes in the population. These are made homozygotic by somatic mechanisms, or by breeding patterns. Mechanisms at the DNA level that lead to homozygosity change the risk within tissues and thus individuals. We need to measure heterozygosity, breeding effects, and molecular mechanisms to determine the causes of genetic and somatic risk. (L.L.)

  16. A common founder mutation in FANCA underlies the world's highest prevalence of Fanconi anemia in Gypsy families from Spain.

    Callén, Elsa; Casado, José A; Tischkowitz, Marc D; Bueren, Juan A; Creus, Amadeu; Marcos, Ricard; Dasí, Angeles; Estella, Jesús M; Muñoz, Arturo; Ortega, Juan J; de Winter, Johan; Joenje, Hans; Schindler, Detlev; Hanenberg, Helmut; Hodgson, Shirley V; Mathew, Christopher G; Surrallés, Jordi

    2005-03-01

    Fanconi anemia (FA) is a genetic disease characterized by bone marrow failure and cancer predisposition. Here we have identified Spanish Gypsies as the ethnic group with the world's highest prevalence of FA (carrier frequency of 1/64-1/70). DNA sequencing of the FANCA gene in 8 unrelated Spanish Gypsy FA families after retroviral subtyping revealed a homozygous FANCA mutation (295C>T) leading to FANCA truncation and FA pathway disruption. This mutation appeared specific for Spanish Gypsies as it is not found in other Gypsy patients with FA from Hungary, Germany, Slovakia, and Ireland. Haplotype analysis showed that Spanish Gypsy patients all share the same haplotype. Our data thus suggest that the high incidence of FA among Spanish Gypsies is due to an ancestral founder mutation in FANCA that originated in Spain less than 600 years ago. The high carrier frequency makes the Spanish Gypsies a population model to study FA heterozygote mutations in cancer.

  17. NUTRIGENOMIC ANALYSIS OF C677T MUTATION OF MTHFR GENE IN SLOVAK POPULATION

    Jozef Bulla

    2011-04-01

    Full Text Available Total of 124 individuals originated from Slovak Republic has been nutrignomically analysed. Analysis was focused to mutation C677T of MTHFR gene detection and analysis of mutant genotypes frequency. Observed frequency of allele 677C was 0.6998 and allelic frequency of mutant variant 677T was 0.3992. Genotype frequency of mutant heterozygotes with 71% activity of MTHFR enzyme was 0,391 and mutant homozygotes with 33% MTHFR enzyme activity was 0.153. Result shows 64% of Slovak has decreased activity of enzyme MTHFR, and 14.3% of Slovak has predisposition to cancer, cardio vascular diseases, loss of fertility and many others complications according to improper nutrition, low folic acid and B12 vitamin intake.  doi:10.5219/136

  18. Genetic Variation in the Scavenger Receptor MARCO and Its Association with Chronic Obstructive Pulmonary Disease and Lung Infection in 10,604 Individuals

    Thomsen, Mette; Nordestgaard, Børge G; Kobzik, Lester

    2013-01-01

    Background: MARCO (macrophage receptor with collagenous structure) is a dominant receptor for unopsonized particles and bacteria in the lungs. Reduced function of this receptor due to genetic variation may be associated with susceptibility to chronic obstructive pulmonary disease (COPD) and lung...... infection. Objectives: To identify novel genetic variants in MARCO that are associated with reduced lung function, or increased risk of COPD or lung infection. Methods: We first screened 760 individuals with extreme lung phenotypes in a large general population study to identify novel variants in the MARCO...... the entire cohort for these variants, we found low minor allele frequencies ranging from 0.005 to 5%. None of the individual MARCO genotypes were associated with reduced lung function, or risk of COPD or lung infection. H101Q heterozygotes had an increased odds ratio for sepsis of 2.2 (95% CI: 1...

  19. Studies of malformation syndromes in man XXXX: multiple congenital anomalies/mental retardation syndrome or variant familial developmental pattern; differential diagnosis and description of the McDonough syndrome (with XXY son from XY/XXY father).

    Neuhäuser, G; Opitz, J M

    1975-11-13

    The McDonough syndrome is a "new" MCA/MR syndrome which was found in 3 children (1 girl, 2 boys) of non-consanguineous parents. The affected children were mentally retarded (IQ 47--67) and had congenital heart defect, sternal deformity, kyphosis and craniofacila anomalies (anteverted auricles, upward slanted palpebral fissures, squint); cryptorchidism was present in the 2 boys. In addition a possible VFDP is postulated as the explanation for similar features in affected and unaffected siblings and parents. However, the McDonough syndrome may be an autosomal recessive trait with minor manifestations in heterozygotes. The klinefelter syndrome in one affected boy and a 46,XY/47,XXY chromosome constitution in the father was a coincidental finding.

  20. Ectodermal Dysplasia: Report and Analysis of Eleven South Indian Patients with Review of Literature

    Renuka Ammanagi

    2010-01-01

    Full Text Available Ectodermal dysplasia represents a rare syndrome affecting two or more ectodermally derived structures. The condition is thought to occur in approximately 1 in every 100,000 live births. It affects men more frequently and severely, while women being the carriers and heterozygote usually show minor defects. There are more than 150 different variants of ectodermal dysplasia (ED reported in the literature. Most commonly encountered among them is hypohidrotic ED which frequently exhibits the most severe dental anomalies like hypodontia or anodontia along with hypohidrosis and hypotrichosis. Here we make an attempt to collectively report and discuss eleven South Indian patients who reported to our department during the year 1998 to 2004. An added emphasis is laid on family history of consanguineous marriage among the parents of these patients.

  1. Polycythemia in transgenic mice expressing the human erythropoietin gene

    Semenza, G.L.; Traystman, M.D.; Gearhart, J.D.; Antonarakis, S.E.

    1989-01-01

    Erythropoietin is a glycoprotein hormone that regulates mammalian erythropoiesis. To study the expression of the human erythropoietin gene, EPO, 4 kilobases of DNA encompassing the gene with 0.4 kilobase of 5' flanking sequence and 0.7 kilobase of 3' flanking sequence was microinjected into fertilized mouse eggs. Transgenic mice were generated that are polycythemic, with increased erythrocytic indices in peripheral blood, increased numbers of erythroid precursors in hematopoietic tissue, and increased serum erythropoietin levels. Transgenic homozygotes show a greater degree of polycythemia than do heterozygotes as well as striking extramedullary erythropoiesis. Human erythropoietin RNA was found not only in fetal liver, adult liver, and kidney but also in all other transgenic tissues analyzed. Anemia induced increased human erythropoietin RNA levels in liver but not kidney. These transgenic mice represent a unique model of polycythemia due to increased erythropoietin levels

  2. The effects of MSH2 deficiency on spontaneous and radiation-induced mutation rates in the mouse germline

    Burr, Karen L-A.; Duyn-Goedhart, Annemarie van; Hickenbotham, Peter; Monger, Karen; Buul, Paul P.W. van; Dubrova, Yuri E.

    2007-01-01

    Mutation rates at two expanded simple tandem repeat (ESTR) loci were studied in the germline of mismatch repair deficient Msh2 knock-out mice. Spontaneous mutation rates in homozygous Msh2 -/- males were significantly higher than those in isogenic wild-type (Msh2 +/+ ) and heterozygous (Msh2 +/- ) mice. In contrast, the irradiated Msh2 -/- mice did not show any detectable increases in their mutation rate, whereas significant ESTR mutation induction was observed in the irradiated Msh2 +/+ and Msh2 +/- animals. Considering these data and the results of other publications, we propose that the Msh2-deficient mice possess a mutator phenotype in their germline and somatic tissues while the loss of a single Msh2 allele does not affect the stability of heterozygotes

  3. Meta-analysis for genome-wide association studies using case-control design: application and practice

    Sungryul Shim

    2016-12-01

    Full Text Available This review aimed to arrange the process of a systematic review of genome-wide association studies in order to practice and apply a genome-wide meta-analysis (GWMA. The process has a series of five steps: searching and selection, extraction of related information, evaluation of validity, meta-analysis by type of genetic model, and evaluation of heterogeneity. In contrast to intervention meta-analyses, GWMA has to evaluate the Hardy–Weinberg equilibrium (HWE in the third step and conduct meta-analyses by five potential genetic models, including dominant, recessive, homozygote contrast, heterozygote contrast, and allelic contrast in the fourth step. The ‘genhwcci’ and ‘metan’ commands of STATA software evaluate the HWE and calculate a summary effect size, respectively. A meta-regression using the ‘metareg’ command of STATA should be conducted to evaluate related factors of heterogeneities.

  4. Microsatellite and HLA class II oligonucleotide typing in a population of Yanomami Indians.

    Roewer, L; Nagy, M; Schmidt, P; Epplen, J T; Herzog-Schröder, G

    1993-01-01

    We have used three different microsatellites (on chromosome 12 and Y) together with HLA class II oligonucleotide typing (DQA and DQB) to analyze families of Yanomami indians settling in villages in Southern Venezuela. There exist complex networks of biological relationship between villages as a result of wife exchange, village fissioning and changing patterns of alliances associated with inter-village warfare. Social status in this society is largely determined by the kinship system. Polygyny is common, especially among headmen, with additional wives, frequently being chosen among the sisters of the first wife. Our preliminary results mainly obtained from inhabitants of the village HAP show the expected allele distribution in populations with a high degree of consanguinity: (i) deficiency of observed heterozygotes at the autosomal loci and (ii) almost all men carry the same Y chromosomal allele. Nevertheless in the Yanomami village two thirds of the described autosomal microsatellite alleles were identified. Several paternities were clarified.

  5. Development and characterization of 21 polymorphic microsatellite markers for the barren-ground shrew, Sorex ugyunak (Mammalia: Sorcidae), through next-generation sequencing, and cross-species amplification in the masked shrew, S. cinereus

    Sonsthagen, Sarah A.; Sage, G. Kevin; Fowler, Megan C.; Hope, Andrew G.; Cook, J.A.; Talbot, Sandra L.

    2013-01-01

    We used next generation shotgun sequencing to develop 21 novel microsatellite markers for the barren-ground shrew (Sorex ugyunak), which were polymorphic among individuals from northern Alaska. The loci displayed moderate allelic diversity (averaging 6.81 alleles per locus) and heterozygosity (averaging 70 %). Two loci deviated from Hardy–Weinberg equilibrium (HWE) due to heterozygote deficiency. While the population did not deviate from HWE overall, it showed significant linkage disequilibrium suggesting this population is not in mutation-drift equilibrium. Nineteen of 21 loci were polymorphic in masked shrews (S. cinereus) from interior Alaska and exhibited linkage equilibrium and HWE overall. All loci yielded sufficient variability for use in population studies.

  6. The diploid genome sequence of an Asian individual

    Wang, Jun; Wang, Wei; Li, Ruiqiang

    2008-01-01

    Here we present the first diploid genome sequence of an Asian individual. The genome was sequenced to 36-fold average coverage using massively parallel sequencing technology. We aligned the short reads onto the NCBI human reference genome to 99.97% coverage, and guided by the reference genome, we...... used uniquely mapped reads to assemble a high-quality consensus sequence for 92% of the Asian individual's genome. We identified approximately 3 million single-nucleotide polymorphisms (SNPs) inside this region, of which 13.6% were not in the dbSNP database. Genotyping analysis showed that SNP...... identification had high accuracy and consistency, indicating the high sequence quality of this assembly. We also carried out heterozygote phasing and haplotype prediction against HapMap CHB and JPT haplotypes (Chinese and Japanese, respectively), sequence comparison with the two available individual genomes (J...

  7. Genetic Variants in KLOTHO Associate With Cognitive Function in the Oldest Old Group

    Mengel-From, Jonas; Sørensen, Mette; Nygaard, Marianne

    2016-01-01

    , for example, growth factor signaling. In the present study, 19 tagging gene variants in KL were studied in relation to 2 measures of cognitive function, a 5-item cognitive composite score and the Mini Mental State Examination, in 1,480 Danes 92-100 years of age. We found that heterozygotes for the previously......Decline in cognitive abilities is a major concern in aging individuals. A potential important factor for functioning of the central nervous system in late-life stages is the KLOTHO (KL) gene. KL is expressed in various organs including the brain and is involved in multiple biological processes...... reported KL-VS had poorer cognitive function than noncarriers. Two other variants positioned in the 5' end of the gene, rs398655 and rs562020, were associated with better cognitive function independently of KL-VS, and the common haplotype AG was associated with poorer cognition, consistently across two...

  8. Relative deformability of red blood cells in sickle cell trait and sickle cell anemia by trapping and dragging

    Solomon, Rance; Cooper, James; Welker, Gabriel; Aguilar, Elaura; Flanagan, Brooke; Pennycuff, Chelsey; Scott, David; Farone, Anthony; Farone, Mary; Erenso, Daniel; Mushi, Robert; del Pilar Aguinaga, Maria

    2013-06-01

    Genetic mutation of the β-globin gene or inheritance of this mutated gene changes the chemical composition of the oxygen-carrying hemoglobin molecule that could lead to either the heterozygote genotype, resulting in sickle cell trait (SCT), or the homozygote genotype, resulting in sickle cell anemia (SCA). These mutations could affect the reversible elastic deformations of the red blood cells (RBCs) which are vital for biological functions. We have investigated this effect by studying the differences in the deformability of RBCs from blood samples of an individual with SCT and an untreated patient with SCA along with hemoglobin quantitation of each blood sample. Infrared 1064 nm laser trap force along with drag shear force are used to induce deformation in the RBCs. Ultra2-High Performance Liquid Chromatography (UHPLC) is used for the hemoglobin quantitation.

  9. Maternal Inflammation Contributes to Brain Overgrowth and Autism-Associated Behaviors through Altered Redox Signaling in Stem and Progenitor Cells

    Janel E. Le Belle

    2014-11-01

    Full Text Available A period of mild brain overgrowth with an unknown etiology has been identified as one of the most common phenotypes in autism. Here, we test the hypothesis that maternal inflammation during critical periods of embryonic development can cause brain overgrowth and autism-associated behaviors as a result of altered neural stem cell function. Pregnant mice treated with low-dose lipopolysaccharide at embryonic day 9 had offspring with brain overgrowth, with a more pronounced effect in PTEN heterozygotes. Exposure to maternal inflammation also enhanced NADPH oxidase (NOX-PI3K pathway signaling, stimulated the hyperproliferation of neural stem and progenitor cells, increased forebrain microglia, and produced abnormal autism-associated behaviors in affected pups. Our evidence supports the idea that a prenatal neuroinflammatory dysregulation in neural stem cell redox signaling can act in concert with underlying genetic susceptibilities to affect cellular responses to environmentally altered cellular levels of reactive oxygen species.

  10. Meiotic events in Oenothera - a non-standard pattern of chromosome behaviour.

    Golczyk, Hieronim; Musiał, Krystyna; Rauwolf, Uwe; Meurer, Jörg; Herrmann, Reinhold G; Greiner, Stephan

    2008-11-01

    The genus Oenothera shows an intriguing extent of permanent translocation heterozygosity. Reciprocal translocations of chromosome arms in species or populations result in various kinds of chromosome multivalents in diakinesis. Early meiotic events conditioning such chromosome behaviour are poorly understood. We found a surprising uniformity of the leptotene-diplotene period, regardless of the chromosome configuration at diakinesis (ring of 14, 7 bivalents, mixture of bivalents and multivalents). It appears that the earliest chromosome interactions at Oenothera meiosis are untypical, since they involve pericentromeric regions. During early leptotene, proximal chromosome parts cluster and form a highly polarized Rabl configuration. Telomeres associated in pairs were seen at zygotene. The high degree of polarization of meiotic nuclei continues for an exceptionally long period, i.e., during zygotene-pachytene into the diplotene contraction stage. The Rabl-polarized meiotic architecture and clustering of pericentromeres suggest a high complexity of karyotypes, not only in structural heterozygotes but also in bivalent-forming homozygous species.

  11. Comparative human cellular radiosensitivity: Pt. 1

    Arlett, C.F.; Green, M.H.L.; Priestley, A.; Harcourt, S.A.; Mayne, L.V.

    1988-01-01

    The authors compared cell killing following 60 Co gamma irradiation in 22 primary human fibroblast strains, nine SV40-immortalized human fibroblast lines and seven SV40-transformed pre-crisis human fibroblast cultures from normal individuals, from ataxia-telangiectasia (A-T) patients and from A-T heterozygotes. They confirmed the greater sensitivity of A-T derived cells to gamma radiation. The distinction between A-T and normal cells is maintained in cells immortalized by SV40-virus but immortal cells are more gamma radiation resistant than corresponding primary fibroblasts. Cells transformed by plasmids (pSV3gpt and pSV3neo) expressing SV40 T-antigen, both pre- and post-crisis, show this increased resistance, indicating that expression of SV40 T-antigen, rather than immortalization per se is responsible for the change. (author)

  12. Variants of the ADRB2 Gene in COPD

    Nielsen, Anne Orholm; Steen Jensen, Camilla; Arredouani, Mohamed Simo

    2017-01-01

    The β2-adrenergic receptor (ADRB2) is an important regulator of airway smooth muscle tone in chronic obstructive pulmonary disease (COPD). Variants that impair ADRB2 function could increase disease risk or reduce the response to endogenous and inhaled adrenergic agonists in COPD. We performed...... a systematic review and three meta-analyses to assess whether three functional variants (Thr164Ile, Arg16Gly, and Gln27Glu) in the ADRB2 gene are associated with elevated risk of disease or reduced therapeutic response to inhaled β2-agonists in COPD. We searched the medical literature from 1966 to 2017...... and found 16 relevant studies comprising 85381 study subjects. The meta-analyses found no significant association between ADRB2 genotype and COPD risk. The summary odds ratios (ORs) for COPD in Thr164Ile homozygotes and heterozygotes were 2.57 (95% confidence interval (CI): 0.54-12.4) and 1.17 (95% CI: 0...

  13. Evaluation of the Precision ID Ancestry Panel for crime case work

    Pereira, Vania; Mogensen, Helle S; Børsting, Claus

    2017-01-01

    The application of massive parallel sequencing (MPS) methodologies in forensic genetics is promising and it is gradually being implemented in forensic genetic case work. One of the major advantages of these technologies is that several traditional electrophoresis assays can be combined into one...... single MPS assay. This reduces both the amount of sample used and the time of the investigations. This study assessed the utility of the Precision ID Ancestry Panel (Thermo Fisher Scientific, Waltham, USA) in forensic genetics. This assay was developed for the Ion Torrent PGM™ System and genotypes 165...... ancestry informative SNPs. The performance of the assay and the accompanying software solution for ancestry inference was assessed by typing 142 Danes and 98 Somalis. Locus balance, heterozygote balance, and noise levels were calculated and future analysis criteria for crime case work were estimated...

  14. A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma

    Smith, Dirk; Helgason, Hannes; Sulem, Patrick

    2017-01-01

    IL-33 is a tissue-derived cytokine that induces and amplifies eosinophilic inflammation and has emerged as a promising new drug target for asthma and allergic disease. Common variants at IL33 and IL1RL1, encoding the IL-33 receptor ST2, associate with eosinophil counts and asthma. Through whole......-C associates with lower eosinophil counts (β = -0.21 SD, P = 2.5×10-16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10-4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non...

  15. Association between the porcine Escherichia coli F18 receptor genotype and phenotype and susceptibility to colonisation and postweaning diarrhoea caused by E-coli O138 : F18

    Frydendahl, K.; Jensen, Tim Kåre; Andersen, Jens Strodl

    2003-01-01

    Porcine postweaning Escherichia coli enteritis is a cause of significant morbidity and mortality in pigs worldwide, and effective prevention remains an unsolved problem. This study examined the correlation between susceptibility of pigs to experimental infection with an E. coli F18 strain...... and the porcine intestinal F18 receptor genotypes. Thirty-one pigs classified as either belonging to the susceptible or the resistant genotype were inoculated with cultures of an E. coli 0138:F18 isolated from a pig with postweaning diarrhoea. Susceptibility to colonisation and diarrhoea was assessed by clinical...... and heterozygotic susceptible pigs. Faecal shedding of the challenge strain correlated with the genetic receptor profile. Twenty pigs examined immunohistochemically revealed focal to extensive small intestinal mucosal colonisation by E. coli O138:F18 in nine of 10 susceptible and three of 10 resistant pigs. Results...

  16. High frequency of a single nucleotide substitution (c.-6-180T>G) of the canine MDR1/ABCB1 gene associated with phenobarbital-resistant idiopathic epilepsy in Border Collie dogs.

    Mizukami, Keijiro; Yabuki, Akira; Chang, Hye-Sook; Uddin, Mohammad Mejbah; Rahman, Mohammad Mahbubur; Kushida, Kazuya; Kohyama, Moeko; Yamato, Osamu

    2013-01-01

    A single nucleotide substitution (c.-6-180T>G) associated with resistance to phenobarbital therapy has been found in the canine MDR1/ABCB1 gene in Border Collies with idiopathic epilepsy. In the present study, a PCR-restriction fragment length polymorphism assay was developed for genotyping this mutation, and a genotyping survey was carried out in a population of 472 Border Collies in Japan to determine the current allele frequency. The survey demonstrated the frequencies of the T/T wild type, T/G heterozygote, and G/G mutant homozygote to be 60.0%, 30.3%, and 9.8%, respectively, indicating that the frequency of the mutant G allele is extremely high (24.9%) in Border Collies. The results suggest that this high mutation frequency of the mutation is likely to cause a high prevalence of phenobarbital-resistant epilepsy in Border Collies.

  17. High Frequency of a Single Nucleotide Substitution (c.-6-180T>G of the Canine MDR1/ABCB1 Gene Associated with Phenobarbital-Resistant Idiopathic Epilepsy in Border Collie Dogs

    Keijiro Mizukami

    2013-01-01

    Full Text Available A single nucleotide substitution (c.-6-180T>G associated with resistance to phenobarbital therapy has been found in the canine MDR1/ABCB1 gene in Border Collies with idiopathic epilepsy. In the present study, a PCR-restriction fragment length polymorphism assay was developed for genotyping this mutation, and a genotyping survey was carried out in a population of 472 Border Collies in Japan to determine the current allele frequency. The survey demonstrated the frequencies of the T/T wild type, T/G heterozygote, and G/G mutant homozygote to be 60.0%, 30.3%, and 9.8%, respectively, indicating that the frequency of the mutant G allele is extremely high (24.9% in Border Collies. The results suggest that this high mutation frequency of the mutation is likely to cause a high prevalence of phenobarbital-resistant epilepsy in Border Collies.

  18. Effect Of G2706A and G1051A polymorphisms of the ABCA1 gene on the lipid, oxidative stress and homocystein levels in Turkish patients with polycystıc ovary syndrome.

    Karadeniz, Muammer; Erdoğan, Mehmet; Ayhan, Zengi; Yalcin, Murat; Olukman, Murat; Cetinkalp, Sevki; Alper, Gulinnaz E; Eroglu, Zuhal; Tetik, Asli; Cetintas, Vildan; Ozgen, Ahmet G; Saygili, Fusun; Yilmaz, Candeger

    2011-10-28

    Obesity, insulin resistance and hyperandrogenism, crucial parameters of Polycystic ovary syndrome (PCOS) play significant pathophysiological roles in lipidemic aberrations associated within the syndrome. Parts of the metabolic syndrome (low HDL and insulin resistance) appeared to facilitate the association between PCOS and coronary artery disease, independently of obesity. ABCA1 gene polymorphism may be altered this components in PCOS patients.In this study, we studied 98 PCOS patients and 93 healthy controls. All subjects underwent venous blood drawing for complete hormonal assays, lipid profile, glucose, insulin, malondialdehyde, nitric oxide, disulfide levels and ABCA genetic study. In PCOS group fasting glucose, DHEAS, 17-OHP, free testosterone, total-cholesterol, triglyceride, LDL-cholesterol and fibrinogen were significantly different compare to controls. The genotype ABCA G2706A distribution differed between the control group (GG 60.7%, GA 32.1%, AA 7.1%) and the PCOS patients (GG 8.7%, GA 8.7%, AA 76.8%). The frequency of the A allele (ABCAG2706A) was higher in PCOS patients than control group with 13,0% and 23,2%, respectively. In this study, the homocystein and insulin levels were significantly higher in PCOS patients with ABCA G1051A mutant genotype than those with heterozygote and wild genotypes. We found higher percentage of AA genotype and A allele of ABCA G2706A in PCOS patients compare to controls. The fasting insulin and homocystein levels were significantly higher in PCOS patients with ABCA G1051A mutant genotype than those with heterozygote and wild genotypes.

  19. Effect Of G2706A and G1051A polymorphisms of the ABCA1 gene on the lipid, oxidative stress and homocystein levels in Turkish patients with polycystıc ovary syndrome

    Tetik Asli

    2011-10-01

    Full Text Available Abstract Background Obesity, insulin resistance and hyperandrogenism, crucial parameters of Polycystic ovary syndrome (PCOS play significant pathophysiological roles in lipidemic aberrations associated within the syndrome. Parts of the metabolic syndrome (low HDL and insulin resistance appeared to facilitate the association between PCOS and coronary artery disease, independently of obesity. ABCA1 gene polymorphism may be altered this components in PCOS patients. In this study, we studied 98 PCOS patients and 93 healthy controls. All subjects underwent venous blood drawing for complete hormonal assays, lipid profile, glucose, insulin, malondialdehyde, nitric oxide, disulfide levels and ABCA genetic study. Results In PCOS group fasting glucose, DHEAS, 17-OHP, free testosterone, total-cholesterol, triglyceride, LDL-cholesterol and fibrinogen were significantly different compare to controls. The genotype ABCA G2706A distribution differed between the control group (GG 60.7%, GA 32.1%, AA 7.1% and the PCOS patients (GG 8.7%, GA 8.7%, AA 76.8%. The frequency of the A allele (ABCAG2706A was higher in PCOS patients than control group with 13,0% and 23,2%, respectively. In this study, the homocystein and insulin levels were significantly higher in PCOS patients with ABCA G1051A mutant genotype than those with heterozygote and wild genotypes. Conclusions We found higher percentage of AA genotype and A allele of ABCA G2706A in PCOS patients compare to controls. The fasting insulin and homocystein levels were significantly higher in PCOS patients with ABCA G1051A mutant genotype than those with heterozygote and wild genotypes.

  20. Population Screening and Prevention Strategies for Thalassemias and other Hemoglobinopathies of Eastern India: Experience of 18,166 cases.

    Chatterjee, Tridip; Chakravarty, Amit; Chakravarty, Sudipa

    2015-01-01

    We evaluated population screening programs (1999-2011), conducted by the Thalassaemia Foundation, Kolkata, India, for the first time in Eastern India in different districts of West Bengal, for prevention of thalassemia comprising screening of heterozygotes and β-thalassemia intermedia (β-TI) cases [β(+), β(++), β(0)/β(+), β(E)/β(E) (codon 26 or HBB: c.79G > A), Hb-E-β-thalassemia (Hb E-β-thal)]. Among 18,166 cases, we found 2092 heterozygotes and 2245 β-TI individuals (who had no information about their disorders). Results were evaluated with standard hematological analyses including erythrocyte indices, hemoglobin (Hb) typing and quantification. Participants were divided into five groups (children, pre-marriage cases, pre-pregnancy cases, affected family members, pregnant women). The objectives of this evaluation were to fix cut-off values of red blood cells (RBCs), mean corpuscular volume (MCV), mean corpuscular Hb (MCH), red blood cell distribution width (RDW) and Hb A2, as the standard World Health Organization (WHO) guidelines were not strictly followed in mass-scale screening programs. We have observed many dilemmas in considering the status of the thalassemia subject, due to presence of some other clinical conditions such as iron deficiency anemia, α-thalassemia (α-thal), δ-thalassemia (δ-thal), clinically silent Hb variants, and some cases of non hemoglobinopathies (such as pregnancy) along with thalassemia. The MCV values varied greatly in different conditions of hemoglobinopathies, whereas MCH provided a more stable measurement. We found an MCH value of <27.0 pg is a suitable cut-off point for screening in this population. Participants with an MCH of <27.0 pg should be investigated further to confirm or exclude a diagnosis of β-thal trait.

  1. Association of LMP/TAP gene polymorphisms with tuberculosis susceptibility in Li population in China.

    Danmei Wang

    Full Text Available BACKGROUND: Tuberculosis (TB is a contagious disease affected by multiple genetic and environmental factors. Several association studies have suggested that cellular immune response is vital for controlling and preventing of tuberculosis infection. Low molecular weight polypeptides (LMPs and transporters with antigen processing (TAPs are the main molecules in the processing and presentation pathway for intracellular antigens. This study was performed to elucidate whether these antigen-processing genes (LMP/TAP polymorphisms could be associated with the risk of tuberculosis infection in China. METHODOLOGY/PRINCIPAL FINDINGS: We recruited 205 active pulmonary tuberculosis patients and 217 normal controls from Li population for this study. Four polymorphisms of LMP/TAP genes were determined by PCR-RFLP assay and haplotypes were constructed by software PHASE 1.0. Of the total four polymorphisms, genotype frequencies of LMP7 AA homozygote and CA heterozygote were significantly greater among cases compared to controls, with odds ratio of 3.77 (95% CI: 1.60-8.89; P = 0.002 and 2.97 (95% CI: 1.80-4.90; P<0.0001, respectively. The genotypes of TAP1-2 GG homozygote and AG heterozygote were more frequent in subjects with TB than in controls, with odds ratio of 3.94 (95% CI: 1.82-8.53; P = 0.001 and 2.87 (95% CI: 1.75-4.71; P<0.0001, respectively. Similarly, we found that haplotype B which carried LMP7 and TAP1-2 variations significantly increased the susceptibility to TB (OR = 3.674, 95% CI: 2.254-5.988; P<0.0001. Moreover, it is noteworthy that the homozygote of wild haplotype A (A/A may be a strong protection for TB infection. CONCLUSIONS: Our findings suggested that LMP/TAP gene polymorphisms might be risk factors for TB infection among Li population in China.

  2. Genome-wide association study identifies nox3 as a critical gene for susceptibility to noise-induced hearing loss.

    Joel Lavinsky

    2015-04-01

    Full Text Available In the United States, roughly 10% of the population is exposed daily to hazardous levels of noise in the workplace. Twin studies estimate heritability for noise-induced hearing loss (NIHL of approximately 36%, and strain specific variation in sensitivity has been demonstrated in mice. Based upon the difficulties inherent to the study of NIHL in humans, we have turned to the study of this complex trait in mice. We exposed 5 week-old mice from the Hybrid Mouse Diversity Panel (HMDP to a 10 kHz octave band noise at 108 dB for 2 hours and assessed the permanent threshold shift 2 weeks post exposure using frequency specific stimuli. These data were then used in a genome-wide association study (GWAS using the Efficient Mixed Model Analysis (EMMA to control for population structure. In this manuscript we describe our GWAS, with an emphasis on a significant peak for susceptibility to NIHL on chromosome 17 within a haplotype block containing NADPH oxidase-3 (Nox3. Our peak was detected after an 8 kHz tone burst stimulus. Nox3 mutants and heterozygotes were then tested to validate our GWAS. The mutants and heterozygotes demonstrated a greater susceptibility to NIHL specifically at 8 kHz both on measures of distortion product otoacoustic emissions (DPOAE and on auditory brainstem response (ABR. We demonstrate that this sensitivity resides within the synaptic ribbons of the cochlea in the mutant animals specifically at 8 kHz. Our work is the first GWAS for NIHL in mice and elucidates the power of our approach to identify tonotopic genetic susceptibility to NIHL.

  3. Developing and Evaluating the HRM Technique for Identifying Cytochrome P450 2D6 Polymorphisms.

    Lu, Hsiu-Chin; Chang, Ya-Sian; Chang, Chun-Chi; Lin, Ching-Hsiung; Chang, Jan-Gowth

    2015-05-01

    Cytochrome P450 2D6 is one of the important enzymes involved in the metabolism of many widely used drugs. Genetic polymorphisms of CYP2D6 can affect its activity. Therefore, an efficient method for identifying CYP2D6 polymorphisms is clinically important. We developed a high-resolution melting (HRM) analysis to investigate CYP2D6 polymorphisms. Genomic DNA was extracted from peripheral blood samples from 71 healthy individuals. All nine exons of the CYP2D6 gene were sequenced before screening by HRM analysis. This method can detect the most genotypes (*1, *2, *4, *10, *14, *21 *39, and *41) of CYP2D6 in Chinese. All samples were successfully genotyped. The four most common mutant CYP2D6 alleles (*1, *2, *10, and *41) can be genotyped. The single nucleotides polymorphism (SNP) frequencies of 100C > T (rs1065852), 1039C > T (rs1081003), 1661G > C (rs1058164), 2663G > A (rs28371722), 2850C > T (rs16947), 2988G > A (rs28371725), 3181A > G, and 4180G > C (rs1135840) were 58%, 61%, 73%, 1%, 13%, 3%, 1%, 73%, respectively. We identified 100% of all heterozygotes without any errors. The two homozygous genotypes (1661G > C and 4180G > C) can be distinguished by mixing with a known genotype sample to generate an artificial heterozygote for HRM analysis. Therefore, all samples could be identified using our HRM method, and the results of HRM analysis are identical to those obtained by sequencing. Our method achieved 100% sensitivity, specificity, positive prediction value and negative prediction value. HRM analysis is a nongel resolution method that is faster and less expensive than direct sequencing. Our study shows that it is an efficient tool for typing CYP2D6 polymorphisms. © 2014 Wiley Periodicals, Inc.

  4. Comprehensive evaluation of SNP identification with the Restriction Enzyme-based Reduced Representation Library (RRL method

    Du Ye

    2012-02-01

    Full Text Available Abstract Background Restriction Enzyme-based Reduced Representation Library (RRL method represents a relatively feasible and flexible strategy used for Single Nucleotide Polymorphism (SNP identification in different species. It has remarkable advantage of reducing the complexity of the genome by orders of magnitude. However, comprehensive evaluation for actual efficacy of SNP identification by this method is still unavailable. Results In order to evaluate the efficacy of Restriction Enzyme-based RRL method, we selected Tsp 45I enzyme which covers 266 Mb flanking region of the enzyme recognition site according to in silico simulation on human reference genome, then we sequenced YH RRL after Tsp 45I treatment and obtained reads of which 80.8% were mapped to target region with an 20-fold average coverage, about 96.8% of target region was covered by at least one read and 257 K SNPs were identified in the region using SOAPsnp software. Compared with whole genome resequencing data, we observed false discovery rate (FDR of 13.95% and false negative rate (FNR of 25.90%. The concordance rate of homozygote loci was over 99.8%, but that of heterozygote were only 92.56%. Repeat sequences and bases quality were proved to have a great effect on the accuracy of SNP calling, SNPs in recognition sites contributed evidently to the high FNR and the low concordance rate of heterozygote. Our results indicated that repeat masking and high stringent filter criteria could significantly decrease both FDR and FNR. Conclusions This study demonstrates that Restriction Enzyme-based RRL method was effective for SNP identification. The results highlight the important role of bias and the method-derived defects represented in this method and emphasize the special attentions noteworthy.

  5. Mlh1 deficiency in normal mouse colon mucosa associates with chromosomally unstable colon cancer

    Pussila, Marjaana; Törönen, Petri; Einarsdottir, Elisabet; Katayama, Shintaro; Krjutškov, Kaarel; Holm, Liisa; Kere, Juha; Peltomäki, Päivi; Mäkinen, Markus J; Linden, Jere; Nyström, Minna

    2018-01-01

    Abstract Colorectal cancer (CRC) genome is unstable and different types of instabilities, such as chromosomal instability (CIN) and microsatellite instability (MSI) are thought to reflect distinct cancer initiating mechanisms. Although 85% of sporadic CRC reveal CIN, 15% reveal mismatch repair (MMR) malfunction and MSI, the hallmarks of Lynch syndrome with inherited heterozygous germline mutations in MMR genes. Our study was designed to comprehensively follow genome-wide expression changes and their implications during colon tumorigenesis. We conducted a long-term feeding experiment in the mouse to address expression changes arising in histologically normal colonic mucosa as putative cancer preceding events, and the effect of inherited predisposition (Mlh1+/−) and Western-style diet (WD) on those. During the 21-month experiment, carcinomas developed mainly in WD-fed mice and were evenly distributed between genotypes. Unexpectedly, the heterozygote (B6.129-Mlh1tm1Rak) mice did not show MSI in their CRCs. Instead, both wildtype and heterozygote CRC mice showed a distinct mRNA expression profile and shortage of several chromosomal segregation gene-specific transcripts (Mlh1, Bub1, Mis18a, Tpx2, Rad9a, Pms2, Cenpe, Ncapd3, Odf2 and Dclre1b) in their colon mucosa, as well as an increased mitotic activity and abundant numbers of unbalanced/atypical mitoses in tumours. Our genome-wide expression profiling experiment demonstrates that cancer preceding changes are already seen in histologically normal colon mucosa and that decreased expressions of Mlh1 and other chromosomal segregation genes may form a field-defect in mucosa, which trigger MMR-proficient, chromosomally unstable CRC. PMID:29701748

  6. Meiotic Recombination Analyses in Pigs Carrying Different Balanced Structural Chromosomal Rearrangements.

    Nicolas Mary

    Full Text Available Correct pairing, synapsis and recombination between homologous chromosomes are essential for normal meiosis. All these events are strongly regulated, and our knowledge of the mechanisms involved in this regulation is increasing rapidly. Chromosomal rearrangements are known to disturb these processes. In the present paper, synapsis and recombination (number and distribution of MLH1 foci were studied in three boars (Sus scrofa domestica carrying different chromosomal rearrangements. One (T34he was heterozygote for the t(3;4(p1.3;q1.5 reciprocal translocation, one (T34ho was homozygote for that translocation, while the third (T34Inv was heterozygote for both the translocation and a pericentric inversion inv(4(p1.4;q2.3. All three boars were normal for synapsis and sperm production. This particular situation allowed us to rigorously study the impact of rearrangements on recombination. Overall, the rearrangements induced only minor modifications of the number of MLH1 foci (per spermatocyte or per chromosome and of the length of synaptonemal complexes for chromosomes 3 and 4. The distribution of MLH1 foci in T34he was comparable to that of the controls. Conversely, the distributions of MLH1 foci on chromosome 4 were strongly modified in boar T34Inv (lack of crossover in the heterosynaptic region of the quadrivalent, and crossover displaced to the chromosome extremities, and also in boar T34ho (two recombination peaks on the q-arms compared with one of higher magnitude in the controls. Analyses of boars T34he and T34Inv showed that the interference was propagated through the breakpoints. A different result was obtained for boar T34ho, in which the breakpoints (transition between SSC3 and SSC4 chromatin on the bivalents seemed to alter the transmission of the interference signal. Our results suggest that the number of crossovers and crossover interference could be regulated by partially different mechanisms.

  7. Genetic polymorphisms in AS3MT and arsenic metabolism in residents of the Red River Delta, Vietnam

    Agusa, Tetsuro; Iwata, Hisato; Fujihara, Junko; Kunito, Takashi; Takeshita, Haruo; Minh, Tu Binh; Trang, Pham Thi Kim; Viet, Pham Hung; Tanabe, Shinsuke

    2009-01-01

    To elucidate the role of genetic factors in arsenic (As) metabolism, we studied associations of single nucleotide polymorphisms (SNPs) in As (+ 3 oxidation state) methyltransferase (AS3MT) with the As concentrations in hair and urine, and urinary As profile in residents in the Red River Delta, Vietnam. Concentrations of total As in groundwater were 0.7-502 μg/l. Total As levels in groundwater drastically decreased by using sand filter, indicating that the filter could be effective to remove As from raw groundwater. Concentrations of inorganic As (IAs) in urine and total As in hair of males were higher than those of females. A significant positive correlation between monomethylarsonic acid (MMA)/IAs and age in females indicates that older females have higher methylation capacity from IAs to MMA. Body mass index negatively correlated with urinary As concentrations in males. Homozygote for SNPs 4602AA, 35991GG, and 37853GG, which showed strong linkage disequilibrium (LD), had higher percentage (%) of dimethylarsinic acid (DMA) in urine. SNPs 4740 and 12590 had strong LD and associated with urinary %DMA. Although SNPs 6144, 12390, 14215, and 35587 comprised LD cluster, homozygotes in SNPs 12390GG and 35587CC had lower DMA/MMA in urine, suggesting low methylation capacity from MMA to DMA in homo types for these SNPs. SNPs 5913 and 8973 correlated with %MMA and %DMA, respectively. Heterozygote for SNP 14458TC had higher MMA/IAs in urine than TT homozygote, indicating that the heterozygote may have stronger methylation ability of IAs. To our knowledge, this is the first study on the association of genetic factors with As metabolism in Vietnamese.

  8. Fibulin-1 Binds to Fibroblast Growth Factor 8 with High Affinity: EFFECTS ON EMBRYO SURVIVAL.

    Fresco, Victor M; Kern, Christine B; Mohammadi, Moosa; Twal, Waleed O

    2016-09-02

    Fibulin-1 (FBLN1) is a member of a growing family of extracellular matrix glycoproteins that includes eight members and is involved in cellular functions such as adhesion, migration, and differentiation. FBLN1 has also been implicated in embryonic heart and valve development and in the formation of neural crest-derived structures, including aortic arch, thymus, and cranial nerves. Fibroblast growth factor 8 (FGF8) is a member of a large family of growth factors, and its functions include neural crest cell (NCC) maintenance, specifically NCC migration as well as patterning of structures formed from NCC such as outflow tract and cranial nerves. In this report, we sought to investigate whether FBLN1 and FGF8 have cooperative roles in vivo given their influence on the development of the same NCC-derived structures. Surface plasmon resonance binding data showed that FBLN1 binds tightly to FGF8 and prevents its enzymatic degradation by ADAM17. Moreover, overexpression of FBLN1 up-regulates FGF8 gene expression, and down-regulation of FBLN1 by siRNA inhibits FGF8 expression. The generation of a double mutant Fbln1 and Fgf8 mice (Fbln1(-/-) and Fgf8(-/-)) showed that haplo-insufficiency (Fbln1(+/-) and Fgf8(+/-)) resulted in increased embryonic mortality compared with single heterozygote crosses. The mortality of the FGF8/Fbln1 double heterozygote embryos occurred between 14.5 and 16.5 days post-coitus. In conclusion, FBLN1/FGF8 interaction plays a role in survival of vertebrate embryos, and reduced levels of both proteins resulted in added mortality in utero The FBLN1/FGF8 interaction may also be involved in the survival of neural crest cell population during development. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. Associations of Cigarette Smoking and Polymorphisms in Brain-Derived Neurotrophic Factor and Catechol-O-Methyltransferase with Neurocognition in Alcohol Dependent Individuals during Early Abstinence

    Timothy eDurazzo

    2012-10-01

    Full Text Available Chronic cigarette smoking and polymorphisms in brain-derived neurotrophic factor (BDNF and catechol-o-methyltransferase (COMT are associated with neurocognition in normal controls and those with various neuropsychiatric conditions. The influence of these polymorphisms on neurocognition in alcohol dependence is unclear. The goal of this report was to investigate the associations of single nucleotide polymorphisms (SNP in BDNF Val66Met and COMT Val158Met with neurocognition in a treatment-seeking alcohol dependent cohort and determine if neurocognitive differences between non-smokers and smokers previously observed in this cohort persist when controlled for these functional SNPs. Genotyping was conducted on 70 primarily male treatment-seeking alcohol dependent participants (ALC who completed a comprehensive neuropsychological battery after 33 ± 9 days of monitored abstinence. Smoking ALC performed significantly worse than non-smoking ALC on the domains of auditory-verbal and visuospatial learning and memory, cognitive efficiency, general intelligence, processing speed and global neurocognition. In smoking ALC, greater number of years of smoking over lifetime was related to poorer performance on multiple domains. COMT Met homozygotes were superior to Val homozygotes on measures of executive skills and showed trends for higher general intelligence and visuospatial skills, while COMT Val/Met heterozygotes showed significantly better general intelligence than Val homozygotes. COMT Val homozygotes performed better than heterozygotes on auditory-verbal memory. BDNF genotype was not related to any neurocognitive domain. The findings are consistent with studies in normal controls and neuropsychiatric cohorts that observed COMT Met carriers showed better performance on measures of executive skills and general intelligence. Overall, the findings support to the expanding clinical movement to make smoking cessation programs available at the inception of

  10. Genetic contribution of CISH promoter polymorphisms to susceptibility to tuberculosis in Chinese children.

    Lin Sun

    Full Text Available Tuberculosis (TB is the leading cause of death due to an infectious disease worldwide, particularly in developing countries. A series of candidate genes have been suggested to be associated with development of TB disease. Among them, the human Cytokine-inducible Src homology 2(SH2 domain protein (CISH gene has been very recently reported to be involved in T cell activation and differentiation in response to Mycobacterium tuberculosis infection. Here, we studied the association between CISH promoter polymorphisms and pediatric TB. A case-control study enrolled 352 TB patients and 527 healthy controls, who were of Han Chinese ethnicity and aged from 0.2 to 18 years. CISH gene promoter SNPs rs414171, rs622502 and rs809451 were genotyped in all subjects and transcriptional activity, mRNA level, and plasma cytokine level of subjects with different genotypes were further examined. Carriers with rs414171TT homozygotes and rs809451GC heterozygotes had a 1.78-fold (95% CI,1.16-2.74 and 1.86-fold (95% CI, 1.26-2.74 excess risk of developing TB compared to those with wild-type genotypes. A greater risk of TB disease was observed in population carrying C(-809451-T(-414171-C(-622502 haplotype (OR 3.66, 95% CI:2.12-6.32. The G(-809451-A(-414171-C(-622502-containing CISH promoter drove a 5.43-fold increased reporter expression compared to the C(-809451-T(-414171-C(-622502-containing counterpart in Hela cell lines (P = 0.0009. PBMCs carrying rs414171TT homozygotes and rs809451GC heterozygotes showed a reduced CISH mRNA level compared to cells carrying wild type genotypes. Individuals with the rs414171TT genotype had significantly increased IL-12p40 and IL-10 production. In conclusion, CISH promoter rs414171 and rs809451 polymorphisms may play a vital role in mediating individual susceptibility to tuberculosis.

  11. Genetic contribution of CISH promoter polymorphisms to susceptibility to tuberculosis in Chinese children.

    Sun, Lin; Jin, Ya-qiong; Shen, Chen; Qi, Hui; Chu, Ping; Yin, Qing-qin; Li, Jie-qiong; Tian, Jian-ling; Jiao, Wei-wei; Xiao, Jing; Shen, A-dong

    2014-01-01

    Tuberculosis (TB) is the leading cause of death due to an infectious disease worldwide, particularly in developing countries. A series of candidate genes have been suggested to be associated with development of TB disease. Among them, the human Cytokine-inducible Src homology 2(SH2) domain protein (CISH) gene has been very recently reported to be involved in T cell activation and differentiation in response to Mycobacterium tuberculosis infection. Here, we studied the association between CISH promoter polymorphisms and pediatric TB. A case-control study enrolled 352 TB patients and 527 healthy controls, who were of Han Chinese ethnicity and aged from 0.2 to 18 years. CISH gene promoter SNPs rs414171, rs622502 and rs809451 were genotyped in all subjects and transcriptional activity, mRNA level, and plasma cytokine level of subjects with different genotypes were further examined. Carriers with rs414171TT homozygotes and rs809451GC heterozygotes had a 1.78-fold (95% CI,1.16-2.74) and 1.86-fold (95% CI, 1.26-2.74) excess risk of developing TB compared to those with wild-type genotypes. A greater risk of TB disease was observed in population carrying C(-809451)-T(-414171)-C(-622502) haplotype (OR 3.66, 95% CI:2.12-6.32). The G(-809451)-A(-414171)-C(-622502)-containing CISH promoter drove a 5.43-fold increased reporter expression compared to the C(-809451)-T(-414171)-C(-622502)-containing counterpart in Hela cell lines (P = 0.0009). PBMCs carrying rs414171TT homozygotes and rs809451GC heterozygotes showed a reduced CISH mRNA level compared to cells carrying wild type genotypes. Individuals with the rs414171TT genotype had significantly increased IL-12p40 and IL-10 production. In conclusion, CISH promoter rs414171 and rs809451 polymorphisms may play a vital role in mediating individual susceptibility to tuberculosis.

  12. Cancer incidence in relatives of British Fanconi Anaemia patients

    Hodgson Shirley V

    2008-09-01

    Full Text Available Abstract Background Fanconi anemia (FA is an autosomal recessive DNA repair disorder with affected individuals having a high risk of developing acute myeloid leukaemia and certain solid tumours. Thirteen complementation groups have been identified and the genes for all of these are known (FANCA, B, C, D1/BRCA2, D2, E, F, G, I, J/BRIP1, L, M and N/PALB2. Previous studies of cancer incidence in relatives of Fanconi anemia cases have produced conflicting results. A study of British FA families was therefore carried out to investigate this question, since increases in cancer risk in FA heterozygotes would have implications for counselling FA family members, and possibly also for the implementation of preventative screening measures in FA heterozygotes. Methods Thirty-six families took part and data was collected on 575 individuals (276 males, 299 females, representing 18,136 person years. In this cohort, 25 males and 30 females were reported with cancer under the age of 85 years, and 36 cancers (65% could be confirmed from death certificates, cancer registries or clinical records. Results A total of 55 cancers were reported in the FA families compared to an estimated incidence of 56.95 in a comparable general population cohort, and the relative risk of cancer was 0.97 (95% C.I. = 0.71–1.23, p = 0.62 for FA family members. Analysis of relative risk for individual cancer types in each carrier probability group did not reveal any significant differences with the possible exception of prostate cancer (RR = 3.089 (95% C.I. = 1.09 – 8.78; Χ2 = 4.767, p = 0.029. Conclusion This study has not shown a significant difference in overall cancer risk in FA families.

  13. Severe hypertriglyceridemia due to two novel loss-of-function lipoprotein lipase gene mutations (C310R/E396V) in a Chinese family associated with recurrent acute pancreatitis.

    Lun, Yu; Sun, Xiaofang; Wang, Ping; Chi, Jingwei; Hou, Xu; Wang, Yangang

    2017-07-18

    Lipoprotein lipase (LPL) is widely expressed in skeletal muscles, cardiac muscles as well as adipose tissue and involved in the catabolism of triglyceride. Herein we have systematically characterized two novel loss-of-function mutations in LPL from a Chinese family in which afflicted members were manifested by severe hypertriglyceridemia and recurrent pancreatitis. DNA sequencing revealed that the proband was a heterozygote carrying a novel c.T928C (p.C310R) mutation in exon 6 of the LPL gene. Another member of the family was detected to be a compound heterozygote who along with the c.T928C mutation also carried a novel missense mutation c.A1187T (p.E396V) in exon 8 of the LPL gene. Furthermore, COS-1 cells were transfected with lentiviruses containing the mutant LPL genes. While C310R markedly reduced the overall LPL protein level, COS-1 cells carrying E396V or double mutations contained similar overall LPL protein levels to the wild-type. The specific activity of the LPL mutants remained at comparable magnitude to the wild-type. However, few LPL were detected in the culture medium for the mutants, suggesting that both mutations caused aberrant triglyceride catabolism. More specifically, E396V and double mutations dampened the transport of LPL to the cell surface, while for the C310R mutation, reducing LPL protein level might be involved. By characterizing these two novel LPL mutations, this study has expanded our understanding on the pathogenesis of familial hypertriglyceridemia (FHTG).

  14. Frequency of distribution of leptin receptor gene polymorphism in obstructive sleep apnea patients.

    Popko, K; Gorska, E; Wasik, M; Stoklosa, A; Pływaczewski, R; Winiarska, M; Gorecka, D; Sliwinski, P; Demkow, U

    2007-11-01

    Leptin is an adipocyte-derived hormone regulating energy homeostasis and body weight. Leptin concentration is increased in patients with the obstructive sleep apnea syndrome (OSAS). Leptin receptor (LEPR) is a single transmembrane protein belonging to the superfamily of cytokine receptors related by a structure to the hemopoietin receptor family. The aim of the present study was to evaluate the frequency of distribution of leptin receptor gene polymorphism GLN223ARG in OSAS patients compared with healthy controls. The examined group included 179 subjects: 102 OSAS patients (74 men and 28 women) and 77 non-apneic controls (39 men and 38 women). Genomic DNA was isolated with the use of a column method and genotyping of DNA sequence variation was carried out by restriction enzyme analysis of PCR-amplified DNA. The results revealed a significant correlation between the polymorphism of LEPR and OSAS. Carriers of Arg allele in homozygotic genotype Arg/Arg and heterozygotic genotype Gln/Arg were more often obese and developed OSAS than the group of carriers of homozygotic Gln/Gln genotype. This tendency was observed in the whole examined population and in the group of obese women. We also found the highest levels of total cholesterol, LDL, HDL, and triglycerides in the group of homozygotic Arg/Arg genotype carriers, lower in heterozygotic Gln/Arg genotype carriers, and the lowest in the group of persons carring homozygotic Gln/Gln genotype. The presence of Arg allel seems linked to a higher risk of obesity and higher lipid levels in OSAS patients. OSAS may have a strong genetic basis due to the effects from a variety of genes including those for leptin receptor.

  15. Prevalence of hereditary factors predisposing to thrombosis in 260 patients diagnosed as thrombosis and investigated at Hospital Israelita Albert Einstein, São Paulo, Brazil

    João Carlos de Campos Guerra

    2005-06-01

    Full Text Available Objective: To evaluate the prevalence of genetic polymorphism incoagulation factors in thromboembolic disease in patients withclinical suspicion of thrombosis. Methods: A retrospective casecollection was performed searching all patients with clinicalsuspicion of thrombosis who were submitted to coagulation factoranalysis at the Hospital Israelita Albert Einstein from November2003 to April 2004. We included 260 patients, 118 male and 142female, mean age of 46 years. Prothrombin mutation and Leiden Vfactor were evaluated with multiplex PCR. Protein C, S and lupusanticoagulant were studied in coagulation assays. AntithrombinIII was studied by chromogenic assay. Anticardiolipin was evaluatedthrough an immunoenzymatic method and homocysteine by animmunometric method. Results: Factor V Leiden was found in 22cases (8.3 %, one homozygote and 21 heterozygotes. Prothrombinmutation was found in 18 cases (6.8%, one homozygote and 17heterozygotes. Forty cases with genetic alteration showed 34 caseswith thrombosis (85%, 29 venous thrombosis and 4 arterialthrombosis. One hundred and seven patients were tested foranticardiolipin antibodies: 21 were anticardiolipin antibody positives(19.6%, and 15 of them had IgG antibodies, 3 IgM and 3 IgA. Sixteenof the 21 patients had thrombosis, 11 venous thrombosis and 5arterial thrombosis. Lupus anticoagulant was found in two patients,both with thrombosis. There was only one case ofhyperhomocystinemia, with thrombosis. Protein C, protein S andantithrombin III deficiencies were found in 63 cases (12%. Out of31 cases with thrombosis (49,2 %, 26 cases had venous thrombosisand 5 had arterial thrombosis. Conclusion: Thromboembolicdisease is clearly associated with genetic factors but there isconsensus its cause is multifactorial. Genetic alterations, however,should be studied when there is clinical evidence of thrombosis,at least in young patients.

  16. Consequences of Marfan mutations to expression of fibrillin gene and to the structure of microfibrils

    Peltonen, L.; Karttunen, L.; Rantamaeki, T. [NPHI, Helsinki (Finland)] [and others

    1994-09-01

    Marfan syndrome (MFS) is a dominantly inherited connective tissue disorder which is caused by mutations in the fibrillin-1 gene (FBN1). Over 40 family-specific FBN1 mutations have been identified. We have characterized 18 different heterozygous mutations including amino acid substitutions, premature stop, and splicing defects leading to deletions or one insertion, and one compound heterozygote with two differently mutated FBN1 alleles inherited from his affected parents. To unravel the consequences of FBN1 mutations to the transcription of FBN1 gene, we have measured the steady state levels of mRNA transcribed from the normal and mutated alleles. The missense mutations do not affect the transcription of the allele while the nonsense mutation leads to lower steady state amount of mutated allele. For the dissection of molecular pathogenesis of FBN1 mutations we have performed rotary shadowing of the microfibrils produced by the cell cultures from MFS patients. The cells from the neonatal patients with established mutations produced only disorganized fibrillin aggregates but no clearly defined microfibrils could be detected, suggesting a major role of this gene region coding for exons 24-26 in stabilization and organization of the bead structure of microfibrils. From the cells of a rare compound heterozygote case carrying two different mutations, no detectable microfibrils could be detected whereas the cells of his parents with heterozygous mutations were able to form identifiable but disorganized microfibrils. In the cells of an MFS case caused by a premature stop removing the C-terminus of fibrillin, the microfibril assembly takes place but the appropriate packing of the microfibrils is disturbed suggesting that C-terminae are actually located within the interbead domain of the microfibrils.

  17. Surfactant protein B deficiency and gene mutations for neonatal respiratory distress syndrome in China Han ethnic population

    Yin, Xiaojuan; Meng, Fanping; wang, Yan; Xie, Lu; Kong, Xiangyong; Feng, Zhichun

    2013-01-01

    Objective: To determine whether the SP-B deficiency and gene mutations in exon 4 is associated with neonatal RDS in China Han ethnic population. Methods: The study population consisted of 40 neonates with RDS and 40 neonates with other diseases as control in China Han ethnic population. We Compared SP-B expression in lung tissue and bronchoalveolar lavage fluid with immunoblotting, and analyzed mutations in the SP-B gene with polymerase chain reaction (PCR) and gene sequencing. Results: In RDS group, low mature Surfactant protein B was found in both lung tissue and bronchoalveolar lavage fluid in 8 neonates. In control group, only 4 neonates with low mature Surfactant protein B in both lung tissue and bronchoalveolar lavage fluid. In RDS group, 20 neonates were found to have mutations in exon 4, 12 homozygous mutations with C/C genotype and 8 heterozygous mutations with C/T genotype in surfactant protein B gene+1580 polymorphism. There were 8 cases mutations in control group, 1 in C/C and 7 in C/T genotype. The frequency of homozygotes with C/C genotype was 0.3 and frequency of heterozygotes with C/T genotype was 0.02 in RDS group. In control group, frequency of homozygotes with C/C genotype was 0.025 and frequency of heterozygote with C/T genotype was 0.175. Conclusion: Low mature Surfactant protein B is associated with the pathogenesis of neonatal respiratory distress syndrome (RDS) in China Han ethnic population. Mutations in exon 4 of the surfactant protein B gene demonstrate an association between homozygous mutations with C/C genotype in SP-B gene and neonatal RDS. PMID:23330012

  18. Thrombophilia testing in young patients with ischemic stroke.

    Pahus, Sidse Høst; Hansen, Anette Tarp; Hvas, Anne-Mette

    2016-01-01

    The possible significance of thrombophilia in ischemic stroke remains controversial. We aimed to study inherited and acquired thrombophilias as risk factors for ischemic stroke, transient ischemic attack (TIA) and amaurosis fugax in young patients. We included patients aged 18 to 50 years with ischemic stroke, TIA or amaurosis fugax referred to thrombophilia investigation at Aarhus University Hospital, Denmark from 1 January 2004 to 31 December 2012 (N=685). Clinical information was obtained from the Danish Stroke Registry and medical records. Thrombophilia investigation results were obtained from the laboratory information system. Absolute thrombophilia prevalences and associated odds ratios (OR) with 95% confidence intervals (95% CI) were reported for ischemic stroke (N=377) and TIA or amaurosis fugax (N=308). Thrombophilia prevalences for the general population were obtained from published data. No strong associations were found between thrombophilia and ischemic stroke, but patients with persistent presence of lupus anticoagulant (3%) had an OR at 2.66 (95% CI 0.84-9.15) for ischemic stroke. A significantly higher risk of TIA/amaurosis fugax was found for factor V Leiden heterozygote (12%) (OR: 1.99 (95% CI 1.14-3.28)). No other inherited or acquired thrombophilia was associated with ischemic stroke, TIA or amaurosis fugax. In young patients, thrombophilia did not infer an increased risk of ischemic stroke. Only factor V Leiden heterozygote patients had an increased risk of TIA/amaurosis fugax, and persistent presence of lupus anticoagulant was likely associated with ischemic stroke. We suggest the testing restricted to investigation of persistent presence of lupus anticoagulant. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Analysis of the relationship between single nucleotide polymorphism of the CD209, IL-10, IL-28 and CCR5 D32 genes with the human predisposition to developing tick-borne encephalitis

    Piotr Czupryna

    2017-01-01

    Full Text Available Introduction: It is known that in the pathogenesis of tick-borne encephalitis (TBE various molecules play a significant role. The most prominent factors include IL-10, IL-28B, CD-209 and CCR5. It is reasonable to search for genetic predispositions to the development of various clinical forms of TBE related to the genetic variation of IL-10, IL-28B, CD-209 and CCR5. In this study we aimed to search for the relationship between single nucleotide polymorphism in the promoter region of the CD209, IL-10, IL-28 and 32 base pair deletion in CCR5 coding region (Δ 32 with the human predisposition to development of various clinical presentations of TBE. We tried to assess the relation between the presence of particular alleles and genotypes with laboratory and clinical parameters. Material/Methods 59 patients with TBE and 57 people, bitten by a tick who never developed TBE (Polish cohort, were included in the study. To assess the distribution of single nucleotide polymorphisms, TaqMan SNP genotyping assays were used for IL10: rs1800872 and rs1800896, for CD 209 rs4804803 and rs2287886, rs12979860 for IL 28B SNPs according to the manufacturer’s protocol using real-time PCR technology on the StepOne thermal cycler. Results Comparison between TBE patients and CG showed that in SNP rs2287886 CD 209 AG heterozygotes were more frequent in the TBE group, while homozygotes GG were more frequent in the CG group. Conclusions SNP rs2287886 CD 209 AG heterozygotes predispose humans to develop TBE. Single nucleotide polymorphism in the promoter region of the CD209, IL-10, IL-28 and CCR5 D32 genes does not correlate with the severity of TBE.

  20. Beta 2 adrenergic receptor polymorphisms, at codons 16 and 27, and bronchodilator responses in adult Venezuelan asthmatic patients.

    Larocca, Nancy; Moreno, Dolores; Garmendia, Jenny Valentina; Velasquez, Olga; Martin-Rojo, Joana; Talamo, Carlos; Garcia, Alexis; De Sanctis, Juan Bautista

    2013-12-01

    One of the gene polymorphisms often studied in asthmatic patients is the β2 adrenergic receptor (ADRβ2). Even though in the Venezuelan Mestizo population there is a high incidence of asthma, there are no direct reports of ADRβ2 gene polymorphism, and treatment response. The aim of this study was to assess, in this population, the gene frequency of ADRβ2 polymorphisms at codons 16 Arg/Gly and 27 Gln/Glu, allergen sensitization, and its relationship to bronchodilator response. Purified genomic DNA was obtained form 105 Mestizo asthmatic and 100 Mestizo healthy individuals from Venezuela. The two polymorphisms were assessed by PCR-RFLP. Patient sensitization to aeroallergens and their response to bronchodilatation were correlated. Significant differences between patients and controls were recorded in: 1) the prevalence of Arg/Arg at codon 16 (28.6% in patients vs. 47% in controls, P<0.01), 2) the frequency of heterozygotes Arg/Gly (55% in patients vs. 35% in controls, P<0.01). Conversely, no differences in polymorphism frequencies were found at codon 27. The haplotypes Arg/Gly-Gln/Gln were more common in patients than controls (P <0.01), whereas the Arg/Arg-Gln/Glu combination prevailed in the control group (P<0.01). The Arg/Gly and Gln/Glu genotypes were associated with better responses after salbutamol. The asthmatic homozygotes Arg/Arg have higher sensitivity to aeroallergens. The difference in Arg/Arg frequency between groups suggests that this could be a protective genotype although the asthmatic group had a higher sensitivity to aeroallergens. The asthmatic heterozygotes had better bronchodilator responses than the homozygotes.

  1. Cell biological study on ataxia-telangiectasia

    Ohta, Shigeru; Katsura, Tadahiko; Shimada, Morimi; Shima, Akihiro; Chishiro, Hiroko; Kasahara, Yoshitaka.

    1985-01-01

    Diagnosis of ataxia-telangiectasia (AT) has largely been dependent on the clinical findings such as cerebellar ataxia, telangiectasia, and immunological deficiency. However, diagnosis of AT by these ordinary criteria is sometimes not sufficient because of the lack of immunological abnormalities. We examined three cases of AT by ordinary clinical criteria and also by X-ray sensitivity of cultured skin fibroblasts. Case 1, a 9-year-old boy, revealed typical clinical features of AT. However, he had no abnormality in serum IgA or IgE. Case 2, a 10-year-old boy, showed decreased serum IgA level. Case 3, a 19-year-old female, had typical clinical features of AT with normal serum IgA, and developed papillary adenocarcinoma of thyroid which was surgically removed. Fibroblast strains derived from these three cases of AT and from the parents of Case 3 were examined with regard to X-ray sensitivity. Three fibroblast strains derived from AT patients (AT homozygotes) showed remarkable hypersensitivity to X-ray. Fibroblast strains derived from the parents (AT heterozygotes) of Case 3, however, showed normal X-ray sensitivity. Recently, AT fibroblasts have been known to show hypersensitivity also to some mutagen like neocarzinostazin as reported by Shiloh et al. Fibroblasts from Case 3 revealed hypersensitivity to neocarzinostazin. However, the sensitivity of the strains from AT heterozygotes (the parents of Case 3) showed no apparent difference from that of control cells. The assay system for mutagen is quite unstable and proper conditioning of the seeding cell number is important for the carrier detection. However, the diagnosis of AT homozygotes was definitely established by X-ray irradiation to cultured fibroblasts from patients. (author)

  2. Atm heterozygous mice are more sensitive to radiation-induced cataracts than are their wild-type counterparts

    Worgul, Basil V.; Smilenov, Lubomir; Brenner, David J.; Junk, Anna; Zhou, Wei; Hall, Eric J.

    2002-01-01

    It is important to know whether the human population includes genetically predisposed radiosensitive subsets. In vitro studies have shown that cells from individuals homozygous for ataxia telangiectasia (A-T) are much more radiosensitive than cells from unaffected individuals. Although cells heterozygous for the ATM gene (ATM(+/-)) may be slightly more radiosensitive in vitro, it remained to be determined whether the greater susceptibility of ATM(+/-) cells translates into an increased sensitivity for late effects in vivo, though there is a suggestion that radiotherapy patients that are heterozygous for the ATM gene may be more at risk of developing late normal tissue damage. We chose cataractogenesis in the lens as a means to assay for the effects of ATM deficiency in a late-responding tissue. One eye of wild-type, Atm heterozygous and homozygous knockout mice was exposed to 0.5-, 1.0-, 2.0-, or 4.0-Gy x rays. The animals were followed weekly for cataract development by conventional slit-lamp biomicroscopy. Cataract development in the animals of all three groups was strongly dependent on dose. The lenses of homozygous mice were the first to opacify at any given dose. Most important in the present context is that cataracts appeared earlier in the heterozygous versus wild-type animals. The data suggest that ATM heterozygotes in the human population may also be radiosensitive. This may influence the choice of individuals destined to be exposed to higher than normal doses of radiation, such as astronauts, and may also suggest that radiotherapy patients who are ATM heterozygotes could be predisposed to increased late normal tissue damage.

  3. Genetic interactions between planar cell polarity genes cause diverse neural tube defects in mice

    Jennifer N. Murdoch

    2014-10-01

    Full Text Available Neural tube defects (NTDs are among the commonest and most severe forms of developmental defect, characterized by disruption of the early embryonic events of central nervous system formation. NTDs have long been known to exhibit a strong genetic dependence, yet the identity of the genetic determinants remains largely undiscovered. Initiation of neural tube closure is disrupted in mice homozygous for mutations in planar cell polarity (PCP pathway genes, providing a strong link between NTDs and PCP signaling. Recently, missense gene variants have been identified in PCP genes in humans with NTDs, although the range of phenotypes is greater than in the mouse mutants. In addition, the sequence variants detected in affected humans are heterozygous, and can often be detected in unaffected individuals. It has been suggested that interactions between multiple heterozygous gene mutations cause the NTDs in humans. To determine the phenotypes produced in double heterozygotes, we bred mice with all three pairwise combinations of Vangl2Lp, ScribCrc and Celsr1Crsh mutations, the most intensively studied PCP mutants. The majority of double-mutant embryos had open NTDs, with the range of phenotypes including anencephaly and spina bifida, therefore reflecting the defects observed in humans. Strikingly, even on a uniform genetic background, variability in the penetrance and severity of the mutant phenotypes was observed between the different double-heterozygote combinations. Phenotypically, Celsr1Crsh;Vangl2Lp;ScribCrc triply heterozygous mutants were no more severe than doubly heterozygous or singly homozygous mutants. We propose that some of the variation between double-mutant phenotypes could be attributed to the nature of the protein disruption in each allele: whereas ScribCrc is a null mutant and produces no Scrib protein, Celsr1Crsh and Vangl2Lp homozygotes both express mutant proteins, consistent with dominant effects. The variable outcomes of these genetic

  4. Two novel partial deletions of LDL-receptor gene in Italian patients with familial hypercholesterolemia (FH Siracusa and FH Reggio Emilia).

    Garuti, R; Lelli, N; Barozzini, M; Tiozzo, R; Ghisellini, M; Simone, M L; Li Volti, S; Garozzo, R; Mollica, F; Vergoni, W; Bertolini, S; Calandra, S

    1996-03-01

    In the present study we report two novel partial deletions of the LDL-R gene. The first (FH Siracusa), found in an FH-heterozygote, consists of a 20 kb deletion spanning from the 5' flanking region to the intron 2 of the LDL-receptor gene. The elimination of the promoter and the first two exons prevents the transcription of the deleted allele, as shown by Northern blot analysis of LDL-R mRNA isolated from the proband's fibroblasts. The second deletion (FH Reggio Emilia), which eliminates 11 nucleotides of exon 10, was also found in an FH heterozygote. The characterization of this deletion was made possible by a combination of techniques such as single strand conformation polymorphism (SSCP) analysis, direct sequence of exon 10 and cloning of the normal and deleted exon 10 from the proband's DNA. The 11 nt deletion occurs in a region of exon 10 which contains three triplets (CTG) and two four-nucleotides (CTGG) direct repeats. This structural feature might render this region more susceptible to a slipped mispairing during DNA duplication. Since this deletion causes a shift of the BamHI site at the 5' end of exon 10, a method has been devised for its rapid screening which is based on the PCR amplification of exon 10 followed by BamHI digestion. FH Reggio Emilia deletion produces a shift in the reading frame downstream from Lys458, leading to a sequence of 51 novel amino acids before the occurrence of a premature stop codon (truncated receptor). However, since RT-PCR failed to demonstrate the presence of the mutant LDL-R mRNA in proband fibroblasts, it is likely that the amount of truncated receptor produced in these cells is negligible.

  5. Investigation of inversion polymorphisms in the human genome using principal components analysis.

    Ma, Jianzhong; Amos, Christopher I

    2012-01-01

    Despite the significant advances made over the last few years in mapping inversions with the advent of paired-end sequencing approaches, our understanding of the prevalence and spectrum of inversions in the human genome has lagged behind other types of structural variants, mainly due to the lack of a cost-efficient method applicable to large-scale samples. We propose a novel method based on principal components analysis (PCA) to characterize inversion polymorphisms using high-density SNP genotype data. Our method applies to non-recurrent inversions for which recombination between the inverted and non-inverted segments in inversion heterozygotes is suppressed due to the loss of unbalanced gametes. Inside such an inversion region, an effect similar to population substructure is thus created: two distinct "populations" of inversion homozygotes of different orientations and their 1:1 admixture, namely the inversion heterozygotes. This kind of substructure can be readily detected by performing PCA locally in the inversion regions. Using simulations, we demonstrated that the proposed method can be used to detect and genotype inversion polymorphisms using unphased genotype data. We applied our method to the phase III HapMap data and inferred the inversion genotypes of known inversion polymorphisms at 8p23.1 and 17q21.31. These inversion genotypes were validated by comparing with literature results and by checking Mendelian consistency using the family data whenever available. Based on the PCA-approach, we also performed a preliminary genome-wide scan for inversions using the HapMap data, which resulted in 2040 candidate inversions, 169 of which overlapped with previously reported inversions. Our method can be readily applied to the abundant SNP data, and is expected to play an important role in developing human genome maps of inversions and exploring associations between inversions and susceptibility of diseases.

  6. Genetic testing for cystic fibrosis in adult patients

    Marina Mencinger

    2006-02-01

    Full Text Available Background: Cystic fibrosis (CF is an autosomal recessive disease caused by mutations in gene encoding cystic fibrosis transmembrane regulator (CFTR protein. Over 1400 mutations found in the gene contribute to the complexity of the CF phenotypes ranging from a classic multiorgan disease commonly involving respiratory, gastrointestinal and reproductive tract to mild and monosymptomatic presentations. Pilocarpine iontophoresis is considered as standard diagnostic test for CF, but it often fails in atypical forms of CF.Methods: In order to provide an additional diagnostic test to assure the diagnosis and provide patients with a proper medical care, we performed a genetic testing on 16 adults suspected to have atypical form of CF. Following counselling, parents of patients with possible homozygote variant of mutations were tested. On a personal request testing was also performed in an adult sibling of a patient with two known mutations to investigate possible carrier hood. The allele specific polymerase chain reaction method (PCR was used to detect 29 most common mutations in the cftr gene.Results: The diagnosis was proved in 3 individuals, a homozygote for Δ F508, and two compound heterozygotes Δ F508/R1162X and Δ F508/3849+10kbC>T. In three cases only one mutation was found: I148T, 2789+5G>A and Δ F508 in a heterozygote form.Conclusions: The genetic testing for CF is a valuable diagnostic tool in atypical forms of CF. Exclusion of possible differential diagnosis is warranted because of a variable CF phenotype. In cases where only one or no mutation was detected a necessity of whole gene sequencing is indicated to exclude rare mutations and polymorphisms that could be implicated in the pathogenesis of atypical CF.

  7. A dominant-negative mutation of mouse Lmx1b causes glaucoma and is semi-lethal via LDB1-mediated dimerization [corrected].

    Sally H Cross

    2014-05-01

    Full Text Available Mutations in the LIM-homeodomain transcription factor LMX1B cause nail-patella syndrome, an autosomal dominant pleiotrophic human disorder in which nail, patella and elbow dysplasia is associated with other skeletal abnormalities and variably nephropathy and glaucoma. It is thought to be a haploinsufficient disorder. Studies in the mouse have shown that during development Lmx1b controls limb dorsal-ventral patterning and is also required for kidney and eye development, midbrain-hindbrain boundary establishment and the specification of specific neuronal subtypes. Mice completely deficient for Lmx1b die at birth. In contrast to the situation in humans, heterozygous null mice do not have a mutant phenotype. Here we report a novel mouse mutant Icst, an N-ethyl-N-nitrosourea-induced missense substitution, V265D, in the homeodomain of LMX1B that abolishes DNA binding and thereby the ability to transactivate other genes. Although the homozygous phenotypic consequences of Icst and the null allele of Lmx1b are the same, heterozygous Icst elicits a phenotype whilst the null allele does not. Heterozygous Icst causes glaucomatous eye defects and is semi-lethal, probably due to kidney failure. We show that the null phenotype is rescued more effectively by an Lmx1b transgene than is Icst. Co-immunoprecipitation experiments show that both wild-type and Icst LMX1B are found in complexes with LIM domain binding protein 1 (LDB1, resulting in lower levels of functional LMX1B in Icst heterozygotes than null heterozygotes. We conclude that Icst is a dominant-negative allele of Lmx1b. These findings indicate a reassessment of whether nail-patella syndrome is always haploinsufficient. Furthermore, Icst is a rare example of a model of human glaucoma caused by mutation of the same gene in humans and mice.

  8. Phenotypic Analysis and Virulence of Candida albicans LIG4 Mutants

    Andaluz, Encarnación; Calderone, Richard; Reyes, Guadalupe; Larriba, Germán

    2001-01-01

    In previous studies, we reported the isolation and preliminary characterization of a DNA ligase-encoding gene of Candida albicans. This gene (LIG4) is the structural and functional homologue of both yeast and human ligase IV, which is involved in nonhomologous end joining (NHEJ) of DNA double-strand breaks. In the present study, we have shown that there are no other LIG4 homologues in C. albicans. In order to study the function of LIG4 in morphogenesis and virulence, we constructed gene deletions. LIG4 transcript levels were reduced in the heterozygote and were completely absent in null strains. Concomitantly, the heterozygote showed a pronounced defect in myceliation, which was slightly greater in the null strain. This was true with several solid and liquid media, such as Spider medium, medium 199, and 2% glucose–1% yeast extract–2% Bacto Peptone, at several pHs. Reintroduction of the wild-type allele into the null mutant partially restored the ability of cells to form hyphae. In agreement with the positive role of LIG4 in morphogenesis, we detected a significant rise in mRNA levels during the morphological transition. LIG4 is not essential for DNA replication or for the repair of DNA damage induced by ionizing radiation or UV light, indicating that these lesions are repaired primarily by homologous recombination. However, our data show that the NHEJ apparatus of C. albicans may control morphogenesis in this diploid organism. In addition, deletion of one or both copies of LIG4 resulted in attenuation of virulence in a murine model of candidiasis. PMID:11119499

  9. Association Analysis of the Leptin and Ghrelin Receptor Gene Polymorphism in the Human with BMI

    Zuzana Lieskovská

    2011-05-01

    Full Text Available The aim of this work was identification of Leptin and Ghrelin receptor gene polymorphism in the population. Leptin is a product of obese (ob gene expression that plays a role in energy metabolism and body weight. The human leptin gene is located in the 17 chromosome. The restriction site is located at the position 2549 bp (C→A. Ghrelin, a peptide hormone predominantly produced by the stomach, was isolated as the endogenous ligand for the growth hormone secretagogue receptor. Ghrelin is a potent stimulator of growth hormone (GH secretion and is the only circulatory hormone known to potently enhance feeding and weight gain and to regulate energy homeostasis following central and systemic administration. Therapeutic intervention with ghrelin in catabolic situations may induce a combination of enhanced food intake, increased gastric emptying and nutrient storage, coupled with an increase in GH thereby linking nutrient partitioning with growth and repair processes. The present study included 35 human samples. The average value of BMI was estimate on 24.45. The size of amplified PCR product is 242bp. Subsequently we used the specific restriction enzyme HhaI and length of fragments is 181+61 bp in the homozygote CC, 242+181+61 bp in the heterozygote AC and 242 bp in the homozygote AA. The restriction site is located at the position 171T/C. Examination of the polymorphism of the GHSR gene was accomplished used PCR-RFLP method. We used amplified the 593 bp product, which was subsequently digested with restriction enzyme LweI and length of fragmetnts is 593 bp in the homozygote TT, 593+567+26 bp in the heterozygote TC and 593+26 bp in the homozygote CC. We assume that this mutation has connection with human obesity level.

  10. Assessment of dysmyelination with RAFFn MRI: application to murine MPS I.

    David Satzer

    Full Text Available Type I mucopolysaccharidosis (MPS I is an autosomal recessive lysosomal storage disorder with neurological features. Humans and laboratory animals with MPS I exhibit various white matter abnormalities involving the corpus callosum and other regions. In this study, we first validated a novel MRI technique, entitled Relaxation Along a Fictitious Field in the rotating frame of rank n (RAFFn, as a measure of myelination and dysmyelination in mice. We then examined differences between MPS I mice and heterozygotes using RAFF5 and histology. RAFF5 (i.e., RAFFn with n = 5 relaxation time constants were highly correlated with histological myelin density (R2 = 0.68, P<0.001, and RAFF5 clearly distinguished between the hypomyelinated and dysmyelinated shiverer mouse and the wild-type mouse. Bloch-McConnell theoretical analysis revealed slower exchange correlation times and smaller exchange-induced relaxation rate constants for RAFF4 and RAFF5 compared to RAFF1-3, T1ρ, and T2ρ. These data suggest that RAFF5 may assess methylene protons in myelin lipids and proteins, though other mechanisms (e.g. detection of myelin-bound water may also explain the sensitivity of RAFF5 to myelin. In MPS I mice, mean RAFF5 relaxation time constants were significantly larger for the striatum (P = 0.004 and internal capsule (P = 0.039, and marginally larger for the fornix (P = 0.15. Histological assessment revealed no differences between MPS I mice and heterozygotes in myelin density or corpus callosum thickness. Taken together, these findings support subtle dysmyelination in the brains of mice with MPS I. Dysmyelination may result from myelin lipid abnormalities caused by the absence of α-L-iduronidase. Our findings may help to explain locomotor and cognitive deficits seen in mice with MPS I.

  11. Population genetic structure of the major malaria vector Anopheles darlingi (Diptera: Culicidae from the Brazilian Amazon, using microsatellite markers

    Vera Margarete Scarpassa

    2007-06-01

    Full Text Available The population genetic structure of Anopheles darlingi, the major human malaria vector in the Neotropics, was examined using seven microsatellite loci from nine localities in central and western Amazonian Brazil. High levels of genetic variability were detected (5-25 alleles per locus; H E = 0.519-0.949. There was deviation from Hardy-Weinberg Equilibrium for 59.79% of the tests due to heterozygote deficits, while the analysis of linkage disequilibrium was significant for only two of 189 (1.05% tests, most likely caused by null alleles. Genetic differentiation (F ST = 0.001-0.095; Nm = 4.7-363.8 indicates that gene flow is extensive among locations < 152 km apart (with two exceptions and reduced, but not absent, at a larger geographic scale. Genetic and geographic distances were significantly correlated (R² = 0.893, P < 0.0002, supporting the isolation by distance (IBD model. The overall estimate of Ne was 202.4 individuals under the linkage disequilibrium model, and 8 under the heterozygote excess model. Analysis of molecular variance showed that nearly all variation (~ 94% was within sample locations. The UPGMA phenogram clustered the samples geographically, with one branch including 5/6 of the state of Amazonas localities and the other branch the Acre, Rondônia, and remaining Amazonas localities. Taken together, these data suggest little genetic structure for An. darlingi from central and western Amazonian Brazil. These findings also imply that the IBD model explains nearly all of the differentiation detected. In practical terms, populations of An. darlingi at distances < 152 km should respond similarly to vector control measures, because of high gene flow.

  12. Who's behind that mask and cape? The Asian leopard cat's Agouti (ASIP) allele likely affects coat colour phenotype in the Bengal cat breed.

    Gershony, L C; Penedo, M C T; Davis, B W; Murphy, W J; Helps, C R; Lyons, L A

    2014-12-01

    Coat colours and patterns are highly variable in cats and are determined mainly by several genes with Mendelian inheritance. A 2-bp deletion in agouti signalling protein (ASIP) is associated with melanism in domestic cats. Bengal cats are hybrids between domestic cats and Asian leopard cats (Prionailurus bengalensis), and the charcoal coat colouration/pattern in Bengals presents as a possible incomplete melanism. The complete coding region of ASIP was directly sequenced in Asian leopard, domestic and Bengal cats. Twenty-seven variants were identified between domestic and leopard cats and were investigated in Bengals and Savannahs, a hybrid with servals (Leptailurus serval). The leopard cat ASIP haplotype was distinguished from domestic cat by four synonymous and four non-synonymous exonic SNPs, as well as 19 intronic variants, including a 42-bp deletion in intron 4. Fifty-six of 64 reported charcoal cats were compound heterozygotes at ASIP, with leopard cat agouti (A(P) (be) ) and domestic cat non-agouti (a) haplotypes. Twenty-four Bengals had an additional unique haplotype (A2) for exon 2 that was not identified in leopard cats, servals or jungle cats (Felis chaus). The compound heterozygote state suggests the leopard cat allele, in combination with the recessive non-agouti allele, influences Bengal markings, producing a darker, yet not completely melanistic coat. This is the first validation of a leopard cat allele segregating in the Bengal breed and likely affecting their overall pelage phenotype. Genetic testing services need to be aware of the possible segregation of wild felid alleles in all assays performed on hybrid cats. © 2014 The Authors. Animal Genetics published by John Wiley & Sons Ltd on behalf of Stichting International Foundation for Animal Genetics.

  13. Association of COL1A1 rs1800012 polymorphism with musculoskeletal degenerative diseases: a meta-analysis.

    Zhong, Binlong; Huang, Donghua; Ma, Kaige; Deng, Xiangyu; Shi, Deyao; Wu, Fashuai; Shao, Zengwu

    2017-09-26

    It has been reported that the single nucleotide polymorphism (SNP) rs1800012 in COL1A1 gene might be linked to the susceptibility of musculoskeletal degenerative diseases, such as osteoarthritis (OA) and intervertebral disc degeneration (IVDD). However, the data from different studies is contradictory. Here we aimed to comprehensively summarize and clarify the relationship between the SNP and musculoskeletal degenerative diseases. Seven eligible studies including 1339 cases and 5406 controls were screened out from PubMed, Web Of Science and Cochrane library databases. Significant association was identified in sub group analysis of IVDD in homozygote model (GG versus TT: OR = 0.33, 95% CI 0.14-0.78, P = 0.012), heterozygote model (GT versus TT: OR = 0.29, 95% CI 0.11-0.72, P = 0.008) and dominant model (GG/GT versus TT: OR = 0.31, 95% CI 0.13-0.74, P = 0.008). Additionally, significant relationship was also found in sub group analysis of severe degree of IVDD in homozygote model (GG versus TT: OR = 0.37, 95% CI 0.15-0.91, P = 0.031), heterozygote model (GT versus TT: OR = 0.33, 95% CI 0.13-0.87, P = 0.024) and dominant model (GG/GT versus TT: OR = 0.36, 95% CI 0.14-0.88, P = 0.025). Although no significance was observed, there is a trend that the more G allele at COL1A1 rs1800012 site, the less possibility of IVDD and severe IVDD would happen. Our results indicate that COL1A1 rs1800012 polymorphism associates with the susceptibility of IVDD. However, this polymorphism may not be associated with OA risk.

  14. ADHD and Disruptive behavior scores – associations with MAO-A and 5-HTT genes and with platelet MAO-B activity in adolescents

    Larsson Jan-Olov

    2008-04-01

    Full Text Available Abstract Background Pharmacological and genetic studies suggest the importance of the dopaminergic, serotonergic, and noradrenergic systems in the pathogenesis of Attention Deficit Hyperactivity Disorder (ADHD and Disruptive Behavior Disorder (DBD. We have, in a population-based sample, studied associations between dimensions of the ADHD/DBD phenotype and Monoamine Oxidase B (MAO-B activity in platelets and polymorphisms in two serotonergic genes: the Monoamine Oxidase A Variable Number of Tandem Repeats (MAO-A VNTR and the 5-Hydroxytryptamine Transporter gene-Linked Polymorphic Region (5-HTT LPR. Methods A population-based sample of twins, with an average age of 16 years, was assessed for ADHD/DBD with a clinical interview; Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL. Blood was drawn from 247 subjects and analyzed for platelet MAO-B activity and polymorphisms in the MAO-A and 5-HTT genes. Results We found an association in girls between low platelet MAO-B activity and symptoms of Oppositional Defiant Disorder (ODD. In girls, there was also an association between the heterozygote long/short 5-HTT LPR genotype and symptoms of conduct disorder. Furthermore the heterozygote 5-HTT LPR genotype in boys was found to be associated with symptoms of Conduct Disorder (CD. In boys, hemizygosity for the short MAO-A VNTR allele was associated with disruptive behavior. Conclusion Our study suggests that the serotonin system, in addition to the dopamine system, should be further investigated when studying genetic influences on the development of Disruptive Behavior Disorders.

  15. Parasite-mediated selection drives an immunogenetic tradeoff in plains zebra (Equus quagga)

    Kamath, Pauline L.; Turner, Wendy C.; Küsters, Martina; Getz, Wayne M.

    2014-01-01

    Pathogen evasion of the host immune system is a key force driving extreme polymorphism in genes of the major histocompatibility complex (MHC). Although this gene family is well characterized in structure and function, there is still much debate surrounding the mechanisms by which MHC diversity is selectively maintained. Many studies have investigated relationships between MHC variation and specific pathogens, and have found mixed support for and against the hypotheses of heterozygote advantage, frequency-dependent or fluctuating selection. Few, however, have focused on the selective effects of multiple parasite types on host immunogenetic patterns. Here, we examined relationships between variation in the equine MHC gene, ELA-DRA, and both gastrointestinal (GI) and ectoparasitism in plains zebras (Equus quagga). Specific alleles present at opposing population frequencies had antagonistic effects, with rare alleles associated with increased GI parasitism and common alleles with increased tick burdens. These results support a frequency-dependent mechanism, but are also consistent with fluctuating selection. Maladaptive GI parasite ‘susceptibility alleles’ were reduced in frequency, suggesting that these parasites may play a greater selective role at this locus. Heterozygote advantage, in terms of allele mutational divergence, also predicted decreased GI parasite burden in genotypes with a common allele. We conclude that an immunogenetic trade-off affects resistance/susceptibility to parasites in this system. Because GI and ectoparasites do not directly interact within hosts, our results uniquely show that antagonistic parasite interactions can be indirectly modulated through the host immune system. This study highlights the importance of investigating the role of multiple parasites in shaping patterns of host immunogenetic variation.

  16. Parasite-mediated selection drives an immunogenetic trade-off in plains zebras (Equus quagga).

    Kamath, Pauline L; Turner, Wendy C; Küsters, Martina; Getz, Wayne M

    2014-05-22

    Pathogen evasion of the host immune system is a key force driving extreme polymorphism in genes of the major histocompatibility complex (MHC). Although this gene family is well characterized in structure and function, there is still much debate surrounding the mechanisms by which MHC diversity is selectively maintained. Many studies have investigated relationships between MHC variation and specific pathogens, and have found mixed support for and against the hypotheses of heterozygote advantage, frequency-dependent or fluctuating selection. Few, however, have focused on the selective effects of multiple parasite types on host immunogenetic patterns. Here, we examined relationships between variation in the equine MHC gene, ELA-DRA, and both gastrointestinal (GI) and ectoparasitism in plains zebras (Equus quagga). Specific alleles present at opposing population frequencies had antagonistic effects, with rare alleles associated with increased GI parasitism and common alleles with increased tick burdens. These results support a frequency-dependent mechanism, but are also consistent with fluctuating selection. Maladaptive GI parasite 'susceptibility alleles' were reduced in frequency, suggesting that these parasites may play a greater selective role at this locus. Heterozygote advantage, in terms of allele mutational divergence, also predicted decreased GI parasite burden in genotypes with a common allele. We conclude that an immunogenetic trade-off affects resistance/susceptibility to parasites in this system. Because GI and ectoparasites do not directly interact within hosts, our results uniquely show that antagonistic parasite interactions can be indirectly modulated through the host immune system. This study highlights the importance of investigating the role of multiple parasites in shaping patterns of host immunogenetic variation.

  17. Association of gene variants in TLR4 and IL-6 genes with Perthes disease

    Srzentić Sanja

    2014-01-01

    Full Text Available Introduction. Perthes disease is idiopathic avascular osteonecrosis of the hip in children, with unknown etiology. Inflammation is present during development of Perthes disease and it is known that this process influences bone remodeling. Objective. Since genetic studies related to inflammation have not been performed in Perthes disease so far, the aim of this study was to analyze the association of frequencies of genetic variants of immune response genes, toll-like receptor 4 (TLR4 and interleukin-6 (IL-6, with this disease. Methods. The study cohort consisted of 37 patients with Perthes disease and 50 healthy controls. Polymorphisms of well described inflammatory mediators: TLR4 (Asp299Gly, Thr399Ile and IL-6 (G-174C, G- 597A were determined by polymerase chain reaction restriction fragment length polymorphism method. Results. IL-6 G-174C and G-597A polymorphisms were in complete linkage disequilibrium. A statistically significant increase of heterozygote subjects for IL-6 G-174C/G-597A was found in controls in comparison to Perthes patient group (p=0.047, OR=2.49, 95% CI=1.00-6.21. Also, the patient group for IL-6 G-174C/G- 597A polymorphisms was not in Hardy-Weinberg equilibrium. No statistically significant differences were found between patient and control groups for TLR4 analyzed polymorphisms. A stratified analysis by the age at disease onset also did not reveal any significant difference for all analyzed polymorphisms. Conclusion. Our study revealed that heterozygote subjects for the IL-6 G-174C/G-597A polymorphisms were significantly overrepresented in the control group than in the Perthes patient group. Consequently, we concluded that children who are heterozygous for these polymorphisms have a lower chance of developing Perthes disease than carriers of both homozygote genotypes. [Projekat Ministarstva nauke Republike Srbije, br. III41004

  18. Genetic heterogeneity of hemoglobin AEBart's disease: a large cohort data from a single referral center in northeast Thailand.

    Chaibunruang, Attawut; Karnpean, Rossarin; Fucharoen, Goonnapa; Fucharoen, Supan

    2014-04-01

    AEBart's disease is a thalassemia intermedia usually characterized by the interaction of α(0)-thalassemia with either deletional or non-deletional α(+)-thalassemia in Hb E heterozygote. Genotypic and phenotypic features are heterogeneous. We studied the hematologic and molecular characteristics of this disease in a cohort of 173 Thai patients encountered at our center in northeast Thailand. Hemoglobin and DNA analyses identified patients with deletional AEBart's disease (n=84), Hb Constant Spring AEBart's disease (n=81), Hb Paksé-AEBart's disease (n=5), AEBart's disease with codon 30 mutation (n=1) and two hitherto un-described forms of AEBart's disease due to interaction of Hb E heterozygote and α(0)-thalassemia with the -α(16.6)kb deletional α(+)-thalassemia (n=1) and Hb Q-Thailand (n=1). Different phenotypic expression of these AEBart's diseases with low Hb, Hct and MCV and increased RDW values with marked reduction in Hb E levels were observed. It was found that all these forms of AEBart's disease showed similar thalassemia intermedia phenotypes but those with non-deletional forms were relatively more anemic. Our data confirm that in such area with high prevalence of hemoglobinopathies such as Southeast Asia, identification of rare thalassemia alleles in a thalassemia intermedia patient should not be ignored. Careful consideration of different phenotypic expression may help in providing presumptive diagnosis of this disease where access to molecular testing is limited. However, molecular diagnostic is useful for predicting the clinical outcome and improving genetic counseling of these complex hemoglobinopathies. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. Variation in the HFE gene is associated with the development of bleomycin-induced pulmonary toxicity in testicular cancer patients.

    van der Schoot, Gabriela G F; Westerink, Nico-Derk L; Lubberts, Sjoukje; Nuver, Janine; Zwart, Nynke; Walenkamp, Annemiek M E; Wempe, Johan B; Meijer, Coby; Gietema, Jourik A

    2016-05-01

    Bleomycin and cisplatin are of key importance in testicular cancer treatment. Known potential serious adverse effects are bleomycin-induced pulmonary toxicity (BIP) and cisplatin-induced renal toxicity. Iron handling may play a role in development of this toxicity. Carriage of allelic variants of the HFE gene induces altered iron metabolism and may contribute to toxicity. We investigated the association between two common allelic variants of the HFE gene, H63D and C282Y, with development of pulmonary and renal toxicity during and after treatment with bleomycin- and cisplatin-containing chemotherapy. In 369 testicular cancer patients treated with bleomycin and cisplatin at the University Medical Center Groningen between 1978 and 2006, H63D and/or C282Y genotypes were determined with an allelic discrimination assay. Data were collected on development of BIP, pulmonary function parameters, renal function, and survival. BIP developed more frequently in patients who were heterozygote (16 in 75, 21%) and homozygote (2 in 4, 50%) for the H63D variant, compared with those who had the HFE wild-type gene (31 in 278, 11%) (p = 0.012). Overall survival, testicular cancer-related survival, and change in renal function were not associated with the H63D variant. We observed an association between presence of one or both H63D alleles and development of BIP in testicular cancer patients treated with bleomycin combination chemotherapy. In patients heterozygote and homozygote for the H63D variant, BIP occurred more frequently compared with wild-type patients. When validated and confirmed, HFE H63D genotyping may be used to identify patients with increased risk for pulmonary bleomycin toxicity. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. HFE gene C282Y, H63D and S65C mutations frequency in the Transylvania region, Romania.

    Trifa, Adrian P; Popp, Radu A; Militaru, Mariela S; Farcaş, Marius F; Crişan, Tania O; Gana, Ionuţ; Cucuianu, Andrei; Pop, Ioan V

    2012-06-01

    HFE-associated haemochromatosis is one of the most frequent autosomal recessive disorders in the Caucasian population. Although most of the cases are homozygous individuals for the C282Y mutation, another two mutations, H63D and S65C, have been reported to be associated with milder forms of the disease. This study was a first attempt to evaluate the distribution of these HFE gene mutations in the Transylvania region. Two-hundred and twenty-five healthy, unrelated volunteers originating from the Transylvania region, Romania, were screened for the HFE gene C282Y, H63D and S65C mutations, using molecular genetics assays (Polymerase Chain Reaction-Restriction Fragments Length Polymorphism). For the C282Y mutation, 7 heterozygotes (3.1%) were found, but no homozygous individual. In the case of the H63D mutation, 40 heterozygotes (17.8%) and 4 homozygotes (1.75%) for the mutant allele were evidenced. We found a compound heterozygous genotype (C282Y/H63D) in one individual (0.45%). Thus, the allele frequencies of the C282Y and H63D were 1.75% and 10.9%, respectively. Three individuals (1.3%) were found to harbour the S65C mutation in a heterozygous state, but none in a homozygous state: the allele frequency of the mutant allele was 0.75%. The distribution of the HFE gene C282Y, H63D and S65C mutations found in our group matches the tendencies observed in other European countries: a decreasing gradient from Northern to Southern Europe for the C282Y mutation; high frequency for the H63D mutation, and low frequency for the S65C mutation in most of the countries.

  1. Loss-of-function mutations in the thyrotropin receptor gene as a major determinant of hyperthyrotropinemia in a consanguineous community.

    Tenenbaum-Rakover, Yardena; Grasberger, Helmut; Mamanasiri, Sunee; Ringkananont, Usanee; Montanelli, Lucia; Barkoff, Marla S; Dahood, Ahmad Mahameed-Hag; Refetoff, Samuel

    2009-05-01

    Resistance to TSH (RTSH) is a condition of impaired responsiveness of the thyroid gland to TSH, characterized by elevated serum TSH, low or normal thyroid hormone levels, and hypoplastic or normal-sized thyroid gland. The aim of the study was to evaluate the clinical course and the genotype-phenotype relationship of RTSH caused by two different TSH receptor (TSHR) gene mutations in a consanguineous population. We conducted a clinical and genetic investigation of 46 members of an extended family and 163 individuals living in the same town. In vitro functional studies of the mutant TSHRs were also performed. Two TSHR gene mutations (P68S and L653V) were identified in 33 subjects occurring as homozygous L653V (five subjects), heterozygous L653V (20 subjects), heterozygous P68S (four subjects), and compound heterozygous L653V/P68S (four subjects). With the exception of one individual with concomitant autoimmune thyroid disease, all homozygotes and compound heterozygotes presented with compensated RTSH (high TSH with free T(4) and T(3) in the normal range). Only nine of 24 heterozygotes had mild hyperthyrotropinemia. The L653V mutation resulted in a higher serum TSH concentration and showed a more severe in vitro abnormality than P68S. Haplotype analysis predicted a founder of the L653V six to seven generations earlier, whereas the P68S is older. Cross-sectional and prospective longitudinal studies indicate that TSH and T(4) concentrations remain stable over time. High frequency hyperthyrotropinemia in an Israeli Arab-Muslim consanguineous community is attributed to two inactivating TSHR gene mutations. Concordant genotype-phenotype was demonstrated clinically and by in vitro functional analysis. Retrospective and prospective studies indicate that in the absence of concomitant autoimmune thyroid disease, elevated TSH levels reflect stable compensated RTSH.

  2. Churg-Strauss Syndrome as an Unusual Aetiology of Stroke with Haemorrhagic Transformation in a Patient with No Cardiovascular Risk Factors

    Tiina Sairanen

    2011-01-01

    Full Text Available Background: We present here a case of haemorrhagic brain infarction in a middle-aged and physically active male, who had never smoked. This case report aims to remind the internist and neurologist to bear in mind unusual aetiologies of brain infarcts in patients without classical cardiovascular risk factors. Case Description: A 49-year-old male with pulmonary asthma and a prior history of nasal polyps had a wake-up stroke with left-sided symptoms and speech disturbance. A head MRI and MR angiography revealed a recent haemorrhagic infarct in the right putamen and corona radiata. The left hemiparesis progressed to sensory-motor hemiplegia on the 4th day. In the head CT, it was shown that the haemorrhagic infarct had progressed to a large haematoma. A pansinusitis was also diagnosed. The aetiological investigations revealed a minor atrial septal defect (ASD with shunting and a heterozygotic clotting factor V R506Q mutation. A remarkable blood eosinophilia of 9.80 E9/l (42% together with fever, sinusitis, wide-spread bilateral nodular pulmonary infiltrates that did not respond to wide-spectrum antimicrobial treatment, positive anti-neutrophilic cytoplasmic antibodies, a high myeloperoxidase antibody level and slightly positive anti-proteinase 3 antibodies suggested the diagnosis of Churg-Strauss syndrome. These inflammatory symptoms and findings promptly responded to treatment with corticosteroids and cyclophosphamide. Conclusions: Even after the concomitant findings of the low risk factors, i.e. small ASD and heterozygotic clotting factor mutation, continued search for the final aetiology of stroke revealed Churg-Strauss syndrome, which was the key to the treatment.

  3. Churg-Strauss Syndrome as an Unusual Aetiology of Stroke with Haemorrhagic Transformation in a Patient with No Cardiovascular Risk Factors

    Sairanen, Tiina; Kanerva, Mari; Valanne, Leena; Lyytinen, Jukka; Pekkonen, Eero

    2011-01-01

    Background We present here a case of haemorrhagic brain infarction in a middle-aged and physically active male, who had never smoked. This case report aims to remind the internist and neurologist to bear in mind unusual aetiologies of brain infarcts in patients without classical cardiovascular risk factors. Case Description A 49-year-old male with pulmonary asthma and a prior history of nasal polyps had a wake-up stroke with left-sided symptoms and speech disturbance. A head MRI and MR angiography revealed a recent haemorrhagic infarct in the right putamen and corona radiata. The left hemiparesis progressed to sensory-motor hemiplegia on the 4th day. In the head CT, it was shown that the haemorrhagic infarct had progressed to a large haematoma. A pansinusitis was also diagnosed. The aetiological investigations revealed a minor atrial septal defect (ASD) with shunting and a heterozygotic clotting factor V R506Q mutation. A remarkable blood eosinophilia of 9.80 E9/l (42%) together with fever, sinusitis, wide-spread bilateral nodular pulmonary infiltrates that did not respond to wide-spectrum antimicrobial treatment, positive anti-neutrophilic cytoplasmic antibodies, a high myeloperoxidase antibody level and slightly positive anti-proteinase 3 antibodies suggested the diagnosis of Churg-Strauss syndrome. These inflammatory symptoms and findings promptly responded to treatment with corticosteroids and cyclophosphamide. Conclusions Even after the concomitant findings of the low risk factors, i.e. small ASD and heterozygotic clotting factor mutation, continued search for the final aetiology of stroke revealed Churg-Strauss syndrome, which was the key to the treatment. PMID:21468361

  4. Involvement of H- and N-Ras isoforms in transforming growth factor-β1-induced proliferation and in collagen and fibronectin synthesis

    Martinez-Salgado, Carlos; Fuentes-Calvo, Isabel; Garcia-Cenador, Begona; Santos, Eugenio; Lopez-Novoa, Jose M.

    2006-01-01

    Transforming growth factor β1 (TGF-β1) has a relevant role in the origin and maintenance of glomerulosclerosis and tubule-interstitial fibrosis. TGF-β and Ras signaling pathways are closely related: TGF-β1 overcomes Ras mitogenic effects and Ras counteracts TGF-β signaling. Tubule-interstitial fibrosis is associated to increases in Ras, Erk, and Akt activation in a renal fibrosis model. We study the role of N- and H-Ras isoforms, and the involvement of the Ras effectors Erk and Akt, in TGF-β1-mediated extracellular matrix (ECM) synthesis and proliferation, using embrionary fibroblasts from double knockout (KO) mice for H- and N-Ras (H-ras -/- /N-ras -/- ) isoforms and from heterozygote mice (H-ras +/- /N-ras +/- ). ECM synthesis is increased in basal conditions in H-ras -/- /N-ras -/- fibroblasts, this increase being higher after stimulation with TGF-β1. TGF-β1-induced fibroblast proliferation is smaller in H-ras -/- /N-ras -/- than in H-ras +/- /N-ras +/- fibroblasts. Erk activation is decreased in H-ras -/- /N-ras -/- fibroblasts; inhibition of Erk activation reduces fibroblast proliferation. Akt activation is higher in double KO fibroblasts than in heterozygotes; inhibition of Akt activation also inhibits ECM synthesis. We suggest that H- and N-Ras isoforms downregulate ECM synthesis, and mediate proliferation, in part through MEK/Erk activation. PI3K-Akt pathway activation may be involved in the increase in ECM synthesis observed in the absence of H- and N-Ras

  5. NOS3 Glu298Asp genotype and blood pressure response to endurance training: the HERITAGE family study.

    Rankinen, T; Rice, T; Pérusse, L; Chagnon, Y C; Gagnon, J; Leon, A S; Skinner, J S; Wilmore, J H; Rao, D C; Bouchard, C

    2000-11-01

    Endothelium-dependent vasodilation is a mechanism that may affect blood pressure response to endurance training. Because NO plays a central role in this process, the endothelial NO synthase gene is a good candidate for the regulation of exercise blood pressure. We investigated the associations between an endothelial NO synthase gene polymorphism (Glu298Asp) and endurance training-induced changes in resting and submaximal exercise blood pressure in 471 white subjects of the HERITAGE Family Study. Two submaximal exercise tests at 50 W were conducted both before and after a 20-week endurance training program. Steady-state exercise blood pressure was measured twice in each test with an automated unit. The Glu298Asp polymorphism was typed with a PCR-based method and digestion with BAN:II. Both systolic and diastolic blood pressure at 50 W decreased in response to the training program, whereas resting blood pressure remained unchanged. The decrease in diastolic blood pressure at 50 W was greater (P=0.0005, adjusted for age, gender, baseline body mass index, and baseline diastolic blood pressure at 50 W) in the Glu/Glu homozygotes (4.4 [SEM 0.4] mm Hg, n=187) than in the heterozygotes (3.1 [0.4] mm Hg, n=213) and the Asp/Asp homozygotes (1.3 [0.7] mm Hg, n=71). The genotype accounted for 2.3% of the variance in diastolic blood pressure at 50 W training response. Both the Glu298 homozygotes and the heterozygotes had a greater (P=0.013) training-induced reduction in rate-pressure product at 50 W than the Asp298 homozygotes. These data suggest that DNA sequence variation in the endothelial NO synthase gene locus is associated with the endurance training-induced decreases in submaximal exercise diastolic blood pressure and rate-pressure product in sedentary normotensive white subjects.

  6. Analysis of mating system in two Pinus cembra L. populations of the Ukrainian Carpathians

    Dmitri V. Politov

    2008-09-01

    Full Text Available In natural pine populations, a mixed mating system is typical,characterized by the proportions of selfed and outcrossed seeds. Swiss stone pine(Pinus cembra L. is one of the least studied European conifers in this respect. The mating system of six polymorphic allozyme loci were studied in haploid megagametophytes and diploid open-pollinated embryos in two stands located in theEast Carpathians. In the 'Gorgany' population (24 trees, 198 seeds the mean singlelocus estimated outcrossing rate (ts was 0.731, and the multilocus estimate (tm was 0.773. In the 'Yayko' population the outcrossing rate was lower (27 trees, 213 seeds, ts=0.645, tm=0.700, suggesting 23-30% of seeds are self-pollinated. Correlation ofoutcrossing rate estimates among loci was less than 1, (0.300 in 'Gorgany' and 0.469 in 'Yayko' indicating biparental inbreeding occurred. Differences between tm and ts (0.042 in 'Gorgany' and 0.056 in 'Yayko' can also be influenced by consanguineous mating, indicated by the presence of spatial and genetic family structure. In small isolated populations of Pinus cembra, which are typical for the Carpathian part of the species' range, inbreeding depression may negatively affect seed quality. The high proportion of selfed seeds observed here can be expected in any seedlot of this species and should be taken into account while planning gene conservation orreforestation measures. Maternal trees in these populations showed no heterozygote deficiency at these allozyme loci, and instead showed increased proportions of heterozygotes (inbreeding coefficient FIS = -0.200 in 'Gorgany' and -0.142 in 'Yayko'. Balancing selection may explain heterozygosity levels up to and above equilibrium proportions.

  7. Origin and spread of the 1278insTATC mutation causing Tay-Sachs disease in Ashkenazi Jews: genetic drift as a robust and parsimonious hypothesis.

    Frisch, Amos; Colombo, Roberto; Michaelovsky, Elena; Karpati, Mazal; Goldman, Boleslaw; Peleg, Leah

    2004-03-01

    The 1278insTATC is the most prevalent beta-hexosaminidase A ( HEXA) gene mutation causing Tay-Sachs disease (TSD), one of the four lysosomal storage diseases (LSDs) occurring at elevated frequencies among Ashkenazi Jews (AJs). To investigate the genetic history of this mutation in the AJ population, a conserved haplotype (D15S981:175-D15S131:240-D15S1050:284-D15S197:144-D15S188:418) was identified in 1278insTATC chromosomes from 55 unrelated AJ individuals (15 homozygotes and 40 heterozygotes for the TSD mutation), suggesting the occurrence of a common founder. When two methods were used for analysis of linkage disequilibrium (LD) between flanking polymorphic markers and the disease locus and for the study of the decay of LD over time, the estimated age of the insertion was found to be 40+/-12 generations (95% confidence interval: 30-50 generations), so that the most recent common ancestor of the mutation-bearing chromosomes would date to the 8th-9th century. This corresponds with the demographic expansion of AJs in central Europe, following the founding of the Ashkenaz settlement in the early Middle Ages. The results are consistent with the geographic distribution of the main TSD mutation, 1278insTATC being more common in central Europe, and with the coalescent times of mutations causing two other LSDs, Gaucher disease and mucolipidosis type IV. Evidence for the absence of a determinant positive selection (heterozygote advantage) over the mutation is provided by a comparison between the estimated age of 1278insTATC and the probability of the current AJ frequency of the mutant allele as a function of its age, calculated by use of a branching-process model. Therefore, the founder effect in a rapidly expanding population arising from a bottleneck provides a robust parsimonious hypothesis explaining the spread of 1278insTATC-linked TSD in AJ individuals.

  8. Frequency of Fanconi anemia in Brazil and efficacy of screening for the FANCA 3788-3790del mutation

    N. Magdalena

    2005-05-01

    Full Text Available Fanconi anemia (FA is an autosomal recessive genetic disease characterized by progressive bone marrow failure, susceptibility to cancer and multiple congenital anomalies. There is important clinical variability among patients and the knowledge of factors which might predict outcome would greatly help the decision making regarding the choices of treatment and the appropriate time to start it. Future studies of the possible correlation between specific mutations with specific clinical presentations will provide the answer to one of these factors. At our Center we standardized a rapid and precise screening test using a mismatch PCR assay for a specific mutation (3788-3790del in exon 38 of gene FANCA in Brazilian FA patients. We present the results obtained after screening 80 non-consanguineous FA patients referred from all regions of Brazil with a clinical diagnosis of FA supported by cellular hypersensitivity to diepoxybutane. We were able to detect the 3788-3790del allele in 24 of the 80 (30% FA patients studied. Thirteen of the 80 (16.25% were homozygotes and 11 of the 80 (13.75% were compound heterozygotes, thus confirming the high frequency of the FANCA 3788-3790del mutation in Brazilian FA patients. The identification of patients with specific mutations in the FA genes may lead to a better clinical description of this condition, also providing data for genotype-phenotype correlations, to a better understanding of the interaction of this specific mutation with other mutations in compound heterozygote patients, and ultimately to the right choices of treatment for each patient with improvement of the prognosis on future studies.

  9. Frequency of Fanconi anemia in Brazil and efficacy of screening for the FANCA 3788-3790del mutation.

    Magdalena, N; Pilonetto, D V; Bitencourt, M A; Pereira, N F; Ribeiro, R C; Jeng, M; Pasquini, R

    2005-05-01

    Fanconi anemia (FA) is an autosomal recessive genetic disease characterized by progressive bone marrow failure, susceptibility to cancer and multiple congenital anomalies. There is important clinical variability among patients and the knowledge of factors which might predict outcome would greatly help the decision making regarding the choices of treatment and the appropriate time to start it. Future studies of the possible correlation between specific mutations with specific clinical presentations will provide the answer to one of these factors. At our Center we standardized a rapid and precise screening test using a mismatch PCR assay for a specific mutation (3788-3790del in exon 38 of gene FANCA) in Brazilian FA patients. We present the results obtained after screening 80 non-consanguineous FA patients referred from all regions of Brazil with a clinical diagnosis of FA supported by cellular hypersensitivity to diepoxybutane. We were able to detect the 3788-3790del allele in 24 of the 80 (30%) FA patients studied. Thirteen of the 80 (16.25%) were homozygotes and 11 of the 80 (13.75%) were compound heterozygotes, thus confirming the high frequency of the FANCA 3788-3790del mutation in Brazilian FA patients. The identification of patients with specific mutations in the FA genes may lead to a better clinical description of this condition, also providing data for genotype-phenotype correlations, to a better understanding of the interaction of this specific mutation with other mutations in compound heterozygote patients, and ultimately to the right choices of treatment for each patient with improvement of the prognosis on future studies.

  10. Genetic Polymorphisms and Weight Loss in Obesity: A Randomised Trial of Hypo-Energetic High- versus Low-Fat Diets

    Sørensen, Thorkild I. A; Boutin, Philippe; Taylor, Moira A; Larsen, Lesli H; Verdich, Camilla; Petersen, Liselotte; Holst, Claus; Echwald, Søren M; Dina, Christian; Toubro, Søren; Petersen, Martin; Polak, Jan; Clément, Karine; Martínez, J. Alfredo; Langin, Dominique; Oppert, Jean-Michel; Stich, Vladimir; Macdonald, Ian; Arner, Peter; Saris, Wim H. M; Pedersen, Oluf; Astrup, Arne; Froguel, Philippe

    2006-01-01

    Objectives: To study if genes with common single nucleotide polymorphisms (SNPs) associated with obesity-related phenotypes influence weight loss (WL) in obese individuals treated by a hypo-energetic low-fat or high-fat diet. Design: Randomised, parallel, two-arm, open-label multi-centre trial. Setting: Eight clinical centres in seven European countries. Participants: 771 obese adult individuals. Interventions: 10-wk dietary intervention to hypo-energetic (−600 kcal/d) diets with a targeted fat energy of 20%–25% or 40%–45%, completed in 648 participants. Outcome Measures: WL during the 10 wk in relation to genotypes of 42 SNPs in 26 candidate genes, probably associated with hypothalamic regulation of appetite, efficiency of energy expenditure, regulation of adipocyte differentiation and function, lipid and glucose metabolism, or production of adipocytokines, determined in 642 participants. Results: Compared with the noncarriers of each of the SNPs, and after adjusting for gender, age, baseline weight and centre, heterozygotes showed WL differences that ranged from −0.6 to 0.8 kg, and homozygotes, from −0.7 to 3.1 kg. Genotype-dependent additional WL on low-fat diet ranged from 1.9 to −1.6 kg in heterozygotes, and from 3.8 kg to −2.1 kg in homozygotes relative to the noncarriers. Considering the multiple testing conducted, none of the associations was statistically significant. Conclusions: Polymorphisms in a panel of obesity-related candidate genes play a minor role, if any, in modulating weight changes induced by a moderate hypo-energetic low-fat or high-fat diet. PMID:16871334

  11. Autophagy and UPR in alpha-crystallin mutant knock-in mouse models of hereditary cataracts.

    Andley, Usha P; Goldman, Joshua W

    2016-01-01

    Knock-in mice provide useful models of congenital and age-related cataracts caused by α-crystallin mutations. R49C αA-crystallin and R120G αB-crystallin mutations are linked with hereditary cataracts. Knock-in αA-R49C+/- heterozygotes develop cataracts by 1-2months, whereas homozygote mice have cataracts at birth. The R49C mutation drastically reduces lens protein water solubility and causes cell death in knock-in mouse lenses. Mutant crystallin cannot function as a chaperone, which leads to protein aggregation and lens opacity. Protein aggregation disrupts the lens fiber cell structure and normal development and causes cell death in epithelial and fiber cells. We determined what aspects of the wild-type phenotype are age-dependently altered in the mutant lens. Wild-type, heterozygote (αA-R49C+/-), and homozygote (αA-R49C+/+) mouse lenses were assessed pre- and postnatally for lens morphology (electron microscopy, immunohistochemistry), and autophagy or unfolded protein response markers (immunoblotting). Morphology was altered by embryonic day 17 in R49C+/+ lenses; R49C+/- lens morphology was unaffected at this stage. Active autophagy in the lens epithelium of mutant lenses was indicated by the presence of autophagosomes using electron microscopy. Protein p62 levels, which are degraded specifically by autophagy, increased in αA-R49C mutant versus wild-type lenses, suggesting autophagy inhibition in the mutant lenses. The unfolded protein response marker XBP-1 was upregulated in adult lenses of αB-R120G+/+ mice, suggesting its role in lens opacification. Mutated crystallins alter lens morphology, autophagy, and stress responses. Therapeutic modulation of autophagic pathways may improve protein degradation in cataractous lenses and reduce lens opacity. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Hybridization in the Ensatina Ring Species, Strong selection against hybrids at a hybrid zone in the ensatina ring species complex and its evolutionary implications

    Alexandrino, Joao; Baird, Stuart J.E.; Lawson, Lucinda; Macey, J. Robert; Moritz, Craig; Wake, David B.

    2005-04-22

    The analysis of interactions between lineages at varying levels of genetic divergence can provide insights into the process of speciation through the accumulation of incompatible mutations. Ring species, and especially the Ensatina eschscholtzii system exemplify this approach. The plethodontid salamanders Ensatina eschscholtzii xanthoptica and Ensatina eschscholtzii platensis hybridize in the Central Sierran foothills of California. We compared the genetic structure across two transects (southern and northern Calaveras Co.), one of which was re-sampled over 20 years, and examined diagnostic molecular markers (eight allozyme loci and mitochondrial DNA) and a diagnostic quantitative trait (color pattern). Key results across all studies were: (i) cline centers for all markers were coincident and the zones were narrow, with width estimates of 730m to 2000m; (ii) cline centers at the northern Calaveras transect were coincident between 1981 and 2001, demonstrating repeatability over 5 generations; (iii) there are very few if any putative F1's, but a relatively high number of backcrossed individuals (57-86 percent) in the central portion of transects; (iv) we found substantial linkage disequilibrium in all three studies and strong heterozygote deficit both in northern Calaveras, in 2001, and southern Calaveras. Both linkage disequilibrium and heterozygote deficit show maximum values near the center of the zones (R and Fis, approx. equal to 0.5). Using estimates of cline width and dispersal, we infer strong selection against hybrids (s* approx. equal to 46-75 percent). This is sufficient to promote accumulation of differences at loci that are neutral or under divergent selection, but would still allow for introgression of adaptive alleles. The evidence for strong, but incomplete isolation across this centrally located contact is consistent with theory suggesting a gradual increase in postzygotic incompatibility between allopatric populations subject to divergent

  13. Retinoschisislike alterations in the mouse eye caused by gene targeting of the Norrie disease gene.

    Ruether, K; van de Pol, D; Jaissle, G; Berger, W; Tornow, R P; Zrenner, E

    1997-03-01

    To investigate the retinal function and morphology of mice carrying a replacement mutation in exon 2 of the Norrie disease gene. Recently, Norrie disease mutant mice have been generated using gene targeting technology. The mutation removes the 56 N-terminal amino acids of the Norrie gene product. Ganzfeld electroretinograms (ERGs) were obtained in five animals hemizygous or homozygous for the mutant gene and in three female animals heterozygous for the mutant gene. As controls, three males carrying the wild-type gene were examined. Electroretinogram testing included rod a- and b-wave V-log I functions, oscillatory potentials, and cone responses. The fundus morphology has been visualized by scanning laser ophthalmoscopy. Rod and cone ERG responses and fundus morphology were not significantly different among female heterozygotes and wild-type mice. In contrast, the hemizygous mice displayed a severe loss of ERG b-wave, leading to a negatively shaped scotopic ERG and a marked reduction of oscillatory potentials. The a-wave was normal at low intensities, and only with brighter flashes was there a moderate amplitude loss. Cone amplitudes were barely recordable in the gene-targeted males. Ophthalmoscopy revealed snowflakelike vitreal changes, retinoschisis, and pigment epithelium irregularities in hemizygotes and homozygotes, but no changes in female heterozygotes. The negatively shaped scotopic ERG in male mice with a Norrie disease gene mutation probably was caused by retinoschisis. Pigment epithelial changes and degenerations of the outer retina are relatively mild. These findings may be a clue to the embryonal retinoschisislike pathogenesis of Norrie disease in humans or it may indicate a different expression of the Norrie disease gene defect in mice compared to that in humans.

  14. Genetic variation in hormone metabolizing genes and risk of testicular germ cell tumors.

    Figueroa, Jonine D; Sakoda, Lori C; Graubard, Barry I; Chanock, Stephen; Rubertone, Mark V; Erickson, R Loren; McGlynn, Katherine A

    2008-11-01

    Testicular germ cell tumors (TGCT) that arise in young men are composed of two histologic types, seminomas and nonseminomas. Risk patterns for the two types appear to be similar and may be related to either endogenous or exogenous hormonal exposures in utero. Why similar risk patterns would result in different histologic types is unclear, but could be related to varying genetic susceptibility profiles. Genetic variation in hormone metabolizing genes could potentially modify hormonal exposures, and thereby affect which histologic type a man develops. To examine this hypothesis, 33 single nucleotide polymorphisms (SNPs) in four hormone metabolism candidate genes (CYP1A1, CYP17A1, HSD17B1, HSD17B4) and the androgen receptor gene (AR) were genotyped. Associations with TGCT were evaluated among 577 TGCT cases (254 seminoma, 323 nonseminoma) and 707 controls from the US Servicemen's Testicular Tumor Environmental and Endocrine Determinants (STEED) study. There were no significant associations with TGCT overall based on a test using an additive model. However, compared to homozygotes of the most common allele, two nonredundant SNPs in CYP1A1 were inversely associated with nonseminoma: CYP1A1 promoter SNP rs4886605 OR = 0.75 (95% CI = 0.54-1.04) among the heterozygotes and OR = 0.37, 95% CI = 0.12-1.11 among the homozygotes with a p-value for trend = 0.02; rs2606345 intron 1 SNP, OR = 0.69 (95% CI = 0.51-0.93) among heterozygotes and OR = 0.70 (95% CI = 0.42-1.17) among homozygotes, with a p-value for trend = 0.02. Caution in interpretation is warranted until findings are replicated in other studies; however, the results suggest that genetic variation in CYP1A1 may be associated with nonseminoma.

  15. Enamelin (Enam) is essential for amelogenesis: ENU-induced mouse mutants as models for different clinical subtypes of human amelogenesis imperfecta (AI).

    Masuya, Hiroshi; Shimizu, Kunihiko; Sezutsu, Hideki; Sakuraba, Yoshiyuki; Nagano, Junko; Shimizu, Aya; Fujimoto, Naomi; Kawai, Akiko; Miura, Ikuo; Kaneda, Hideki; Kobayashi, Kimio; Ishijima, Junko; Maeda, Takahide; Gondo, Yoichi; Noda, Tetsuo; Wakana, Shigeharu; Shiroishi, Toshihiko

    2005-03-01

    Amelogenesis imperfecta (AI) is a group of commonly inherited defects of dental enamel formation, which exhibits marked genetic and clinical heterogeneity. The genetic basis of this heterogeneity is still poorly understood. Enamelin, the affected gene product in one form of AI (AIH2), is an extracellular matrix protein that is one of the components of enamel. We isolated three ENU-induced dominant mouse mutations, M100395, M100514 and M100521, which caused AI-like phenotypes in the incisors and molars of the affected individuals. Linkage analyses mapped each of the three mutations to a region of chromosome 5 that contained the genes encoding enamelin (Enam) and ameloblastin (Ambn). Sequence analysis revealed that each mutation was a single-base substitution in Enam. M100395 (Enam(Rgsc395)) and M100514 (Enam(Rgsc514)) were putative missense mutations that caused S to I and E to G substitutions at positions 55 and 57 of the translated protein, respectively. Enam(Rgsc395) and Enam(Rgsc514) heterozygotes showed severe breakage of the enamel surface, a phenotype that resembled local hypoplastic AI. The M100521 mutation (Enam(Rgsc521)) was a T to A substitution at the splicing donor site in intron 4. This mutation resulted in a frameshift that gave rise to a premature stop codon. The transcript of the Enam(Rgsc521) mutant allele was degraded, indicating that Enam(Rgsc521) is a loss-of-function mutation. Enam(Rgsc521) heterozygotes showed a hypomaturation-type AI phenotype in the incisors, possibly due to haploinsufficiency of Enam. Enam(Rgsc521) homozygotes showed complete loss of enamel on the incisors and the molars. Thus, we report here that the Enam gene is essential for amelogenesis, and that mice with different point mutations at Enam may provide good animal models to study the different clinical subtypes of AI.

  16. Expression of embryonic hemoglobin genes in mice heterozygous for α-thalassemia or β-duplication traits and in mice heterozygous for both traits

    Popp, R.A.; Marsh, C.L.; Skow, L.C.

    1981-01-01

    Hemoglobins of mouse embryos at 11.5 through 16.5 days of gestation were separated by electrophoresis on cellulose acetate and quantitated by a scanning densitometer to study the effects of two radiation-induced mutations on the expression of embryonic hemoglobin genes in mice. Normal mice produce three kinds of embryonic hemoglobins. In heterozygous α-thalassemic embryos, expression of EI (x 2 y 2 ) and EII (α 2 y 2 ) is deficient because the x- and α-globin genes of one of the allelic pairs of Hba on chromosome 11 was deleted or otherwise inactivated by X irradiation. Simultaneous inactivation of the x- and α-globin genes indicates that these genes must be closely linked. Reduced x- and α-chain synthesis results in an excess of y chains that associate as homotetramers. This unique y 4 hemoglobin also appears in β-duplication embryos where excess y chains are produced by the presence of three rather than two functional alleles of y- and β-globin genes. In double heterozygotes, which have a single functional allele of x- and α-globin genes and three functional alleles of y- and β-globin genes, synthesis of α and non-α chains is severely imbalanced and half of the total hemoglobin is y 4 . Mouse y 4 has a high affinity for oxygen, P 50 of less than 10 mm Hg, but it lacks cooperativity so is inefficient for oxygen transport. The death of double heterozygotes in late fetal or neonatal life may be in large part to oxygen deprivation to the tissues

  17. Longitudinal data analysis of polymorphisms in the κ-casein and β-lactoglobulin genes shows differential effects along the trajectory of the lactation curve in tropical dairy goats.

    Cardona, Samir Julián Calvo; Cadavid, Henry Cardona; Corrales, Juan David; Munilla, Sebastián; Cantet, Rodolfo J C; Rogberg-Muñoz, Andrés

    2016-09-01

    The κ-casein (CSN-3) and β-lactoglobulin (BLG) genes are extensively polymorphic in ruminants. Several association studies have estimated the effects of polymorphisms in these genes on milk yield, milk composition, and cheese-manufacturing properties. Usually, these results are based on production integrated over the lactation curve or on cross-sectional studies at specific days in milk (DIM). However, as differential expression of milk protein genes occurs over lactation, the effect of the polymorphisms may change over time. In this study, we fitted a mixed-effects regression model to test-day records of milk yield and milk quality traits (fat, protein, and total solids yields) from Colombian tropical dairy goats. We used the well-characterized A/B polymorphisms in the CSN-3 and BLG genes. We argued that this approach provided more efficient estimators than cross-sectional designs, given the same number and pattern of observations, and allowed exclusion of between-subject variation from model error. The BLG genotype AA showed a greater performance than the BB genotype for all traits along the whole lactation curve, whereas the heterozygote showed an intermediate performance. We observed no such constant pattern for the CSN-3 gene between the AA homozygote and the heterozygote (the BB genotype was absent from the sample). The differences among the genotypic effects of the BLG and the CSN-3 polymorphisms were statistically significant during peak and mid lactation (around 40-160 DIM) for the BLG gene and only for mid lactation (80-145 DIM) for the CSN-3 gene. We also estimated the additive and dominant effects of the BLG locus. The locus showed a statistically significant additive behavior along the whole lactation trajectory for all quality traits, whereas for milk yield the effect was not significant at later stages. In turn, we detected a statistically significant dominance effect only for fat yield in the early and peak stages of lactation (at about 1-45 DIM

  18. Association between sequence variations of the Mediterranean fever gene and the risk of migraine: a case–control study

    Coşkun S

    2016-08-01

    Full Text Available Salih Coşkun,1 Sefer Varol,2 Hasan H Özdemir,2 Sercan Bulut Çelik,3 Metin Balduz,4 Mehmet Akif Camkurt,5 Abdullah Çim,1 Demet Arslan,2 Mehmet Uğur Çevik2 1Department of Medical Genetics, 2Department of Neurology, Faculty of Medicine, Dicle University, Diyarbakir, 3Family Health Center, Batman, 4Department of Neurology, Şanlıurfa Education and Research Hospital, Şanlıurfa, 5Department of Psychiatry, Afsin State Hospital, Kahramanmaraş, Turkey Abstract: Migraine pathogenesis involves a complex interaction between hormones, neurotransmitters, and inflammatory pathways, which also influence the migraine phenotype. The Mediterranean fever gene (MEFV encodes the pyrin protein. The major role of pyrin appears to be in the regulation of inflammation activity and the processing of the cytokine pro-interleukin-1β, and this cytokine plays a part in migraine pathogenesis. This study included 220 migraine patients and 228 healthy controls. Eight common missense mutations of the MEFV gene, known as M694V, M694I, M680I, V726A, R761H, K695R, P369S, and E148Q, were genotyped using real-time polymerase chain reaction with 5' nuclease assays, which include sequence specific primers, and probes with a reporter dye. When mutations were evaluated separately among the patient and control groups, only the heterozygote E148Q carrier was found to be significantly higher in the control group than in the patient group (P=0.029, odds ratio [95% confidence interval] =0.45 [0.21–0.94]. In addition, the frequency of the homozygote and the compound heterozygote genotype carrier was found to be significantly higher in patients (n=8, 3.6% than in the control group (n=1, 0.4% (P=0.016, odds ratio [95% confidence interval] =8.57 [1.06–69.07]. However, there was no statistically significant difference in the allele frequencies of MEFV mutations between the patients and the healthy control group (P=0.964. In conclusion, the results of the present study suggest that

  19. Association of matrix metalloproteinase-3 -1171(5A>6A polymorphism with cancer risk: a meta-analysis of 41 studies.

    Xin Yang

    Full Text Available BACKGROUND AND OBJECTIVE: Evidence has shown that matrix metalloproteinases-3 (MMP3 is important for cancer progression. Recent studies about the association between the -1171(5A>6A polymorphism in MMP3 promoter region and cancer risk have yielded conflicting results. METHODOLOGY/PRINCIPAL FINDINGS: We performed a meta-analysis of 41 studies including 11112 cases and 11091 controls to determine whether the -1171(5A>6A polymorphism of MMP3 was associated with cancer risk. We assessed the strength of association and performed sub-group analyses by cancer types, ethnicity, smoking status, genotyping method, source of controls and sample size. The pooled results revealed that no significant association of the -1171(5A>6A polymorphism with overall cancer risk in any of four models. Further sub-group analysis revealed that individuals with the 6A allele had lower risk of gastrointestinal cancer in two models: heterozygote comparison (6A/5A vs. 5A/5A: OR=0.74, 95%CI: 0.60-0.91; I(2=1.9%, and dominant model (6A/6A+6A/5A vs. 5A/5A: OR=0.77, 95%CI: 0.64-0.94; I(2=29.0%. Additionally, the associations were significant in Asian populations for three models: homozygote comparison (6A/6A vs. 5A/5A, OR=0.68, 95%CI: 0.52-0.90; I(2=26.7%, heterozygote comparison (6A/5A vs. 5A/5A: OR=0.75, 95%CI: 0.58-0.98; I(2=0.0%, and dominant model (6A/6A+6A/5A vs. 5A/5A: OR=0.69, 95%CI: 0.54-0.88; I(2=0.5%. It was noteworthy that we had a contrary finding in non-smokers: the variant 6A/6A homozygote might statistically increase cancer risk compared with 6A/5A+5A/5A genotype (OR=1.92, 95%CI: 1.25-2.96; I(2=72.7%. CONCLUSION: This meta-analysis suggests that the -1171(5A>6A polymorphism in MMP3 promoter region is not associated with overall cancer risk, but it may contribute to decreased cancer risk in Asian population when compared with Caucasian population and significantly reduce the risk of gastrointestinal cancer.

  20. Beneficial role of D allele in controlling ACE levels: a study among Brahmins of north India.

    Kumari, Shobha; Sharma, Nidhi; Thakur, Sunil; Mondal, Prakash R; Saraswathy, Kallur N

    2016-06-01

    India being a country with vast diversity is expected to have different dietary and life style patterns which in turn may lead to population-specific environmental risk factors. Further, the interaction of these risk factors with the genetic makeup of population makes it either susceptible or resistant to cardiovascular disease. One such candidate gene is angiotensin converting enzyme (ACE) for various cardiovascular mechanisms. ACE is the key enzyme of the renin angiotensin aldosterone system pathway which maintains homeostasis blood pressure in the body and any variation in the levels is reported to be associated with various complex diseases. The DD genotype is found to increase ACE levels, which is associated with cardiovascular diseases and decrease in ACE levels are associated with kidney diseases. The aim of this study was to understand the distribution of ACE I/D polymorphism and ACE levels among Brahmins of National Capital Region (NCR) north India, with respect to age and sex ratio distribution. In this study, 136 subjects of which 50 males and 86 females, who were unrelated up to first cousin, aged 25 to70 years were studied. ACE gene was found to be polymorphic with high frequency of heterozygote (ID) followed by II and DD genotypes. The studied population was found to be in Hardy-Weinberg equilibrium with respect to ACE I/D polymorphism (P = 0.55). I allele frequency was found to be higher (0.560) than the D allele (0.44). The median level of ACE was found to be 65.96 ng/mL (48.12-86.24) which is towards lower side of the normal range. ACE levels were found to be increased among individual having either of the homozygotes that is II or DD and higher frequency of heterozygote (ID) is indicative of advantage in the population by maintaining lower ACE levels. The limitation of the present study is low sample size, however, the merit is that the subjects belonged to a Mendalian population with a common gene pool.

  1. A new CYP21A1P/CYP21A2 chimeric gene identified in an Italian woman suffering from classical congenital adrenal hyperplasia form

    Concolino, Paola; Mello, Enrica; Minucci, Angelo; Giardina, Emiliano; Zuppi, Cecilia; Toscano, Vincenzo; Capoluongo, Ettore

    2009-01-01

    Background More than 90% of Congenital Adrenal Hyperplasia (CAH) cases are associated with mutations in the 21-hydroxylase gene (CYP21A2) in the HLA class III area on the short arm of chromosome 6p21.3. In this region, a 30 kb deletion produces a non functional chimeric gene with its 5' and 3' ends corresponding to CYP21A1P pseudogene and CYP21A2, respectively. To date, five different CYP21A1P/CYP21A2 chimeric genes have been found and characterized in recent studies. In this paper, we describe a new CYP21A1P/CYP21A2 chimera (CH-6) found in an Italian CAH patient. Methods Southern blot analysis and CYP21A2 sequencing were performed on the patient. In addition, in order to isolate the new CH-6 chimeric gene, two different strategies were used. Results The CYP21A2 sequencing analysis showed that the patient was homozygote for the g.655C/A>G mutation and heterozygote for the p.P30L missense mutation. In addition, the promoter sequence revealed the presence, in heterozygosis, of 13 SNPs generally produced by microconversion events between gene and pseudogene. Southern blot analysis showed that the woman was heterozygote for the classic 30-kb deletion producing a new CYP21A1P/CYP21A2 chimeric gene (CH-6). The hybrid junction site was located between the end of intron 2 pseudogene, after the g.656C/A>G mutation, and the beginning of exon 3, before the 8 bp deletion. Consequently, CH-6 carries three mutations: the weak pseudogene promoter region, the p.P30L and the g.655C/A>G splice mutation. Conclusion We describe a new CYP21A1P/CYP21A2 chimera (CH-6), associated with the HLA-B15, DR13 haplotype, in a young Italian CAH patient. PMID:19624807

  2. Association of L-ficolin levels and FCN2 genotypes with chronic Chagas disease.

    Paola R Luz

    Full Text Available BACKGROUND: L-ficolin (encoded by FCN2 binds to acetylated sugar moieties of many pathogens, including Trypanosoma cruzi, promoting their phagocytosis and lysis by the complement system. METHODS: We investigated L-ficolin levels in 160 T. cruzi infected patients with chronic Chagas disease and 71 healthy individuals, and FCN2 polymorphisms (-986 G>A, -602 G>A, and -4 A>G in the promoter and A258S in exon 8 in 243 patients, being 88 indeterminate (asymptomatic, 96 with cardiac, 23 with digestive and 33 with cardiodigestive manifestations (two were unspecified and 305 controls (135 for A258S. RESULTS: Patients presented lower L-ficolin plasma levels than controls (p<0.0001. Among the different groups of cardiac commitment, individuals with moderate forms had higher L-ficolin levels than the severe forms (P = 0.039. Lower L-ficolin levels were found associated with the 258S variant in the patients (P = 0.034. We found less -4A/G heterozygotes in the cardiac patients, than in the controls (OR = 0.56 [95% CI = 0.33-0.94], P = 0.034. Heterozygote -4A/G genotypes with the 258S variant and 258SS homozygotes were nevertheless more frequent among cardiodigestive patients than in controls (OR = 14.1 [95% CI = 3.5-56.8], P = 0.0001 and in indeterminate patients (OR = 3.2 [95% CI = 1.1-9.4], P = 0.037. We also found an association of the allelic frequency of the 258S variant with cardiodigestive Chagas disease compared to controls (OR = 2.24 [95% CI = 1.1-4.5], P = 0.037. Thus, decreased patient levels of L-ficolin reflect not only protein consumption due to the disease process, but also the higher frequency of the 258S variant in patients with cardiodigestive symptoms. CONCLUSION: The very first study on Brazilian cohort associates both L-ficolin plasma levels and FCN2 variants to Chagas disease and subsequent disease progression. The prognostic value of L-ficolin levels and the FCN2*A258S polymorphism

  3. Association between immunoglobulin GM and KM genotypes and placental malaria in HIV-1 negative and positive women in western Kenya.

    Nnaemeka C Iriemenam

    Full Text Available Immunoglobulin (Ig GM and KM allotypes, genetic markers of γ and κ chains, are associated with humoral immune responsiveness. Previous studies have shown the relationships between GM6-carrying haplotypes and susceptibility to malaria infection in children and adults; however, the role of the genetic markers in placental malaria (PM infection and PM with HIV co-infection during pregnancy has not been investigated. We examined the relationship between the gene polymorphisms of Ig GM6 and KM allotypes and the risk of PM infection in pregnant women with known HIV status. DNA samples from 728 pregnant women were genotyped for GM6 and KM alleles using polymerase chain reaction-restriction fragment length polymorphism method. Individual GM6 and KM genotypes and the combined GM6 and KM genotypes were assessed in relation to PM in HIV-1 negative and positive women, respectively. There was no significant effect of individual GM6 and KM genotypes on the risk of PM infection in HIV-1 negative and positive women. However, the combination of homozygosity for GM6(+ and KM3 was associated with decreased risk of PM (adjusted OR, 0.25; 95% CI, 0.08-0.8; P = 0.019 in HIV-1 negative women while in HIV-1 positive women the combination of GM6(+/- with either KM1-3 or KM1 was associated with increased risk of PM infection (adjusted OR, 2.10; 95% CI, 1.18-3.73; P = 0.011. Hardy-Weinberg Equilibrium (HWE tests further showed an overall significant positive F(is (indication of deficit in heterozygotes for GM6 while there was no deviation for KM genotype frequency from HWE in the same population. These findings suggest that the combination of homozygous GM6(+ and KM3 may protect against PM in HIV-1 negative women while the HIV-1 positive women with heterozygous GM6(+/- combined with KM1-3 or KM1 may be more susceptible to PM infection. The deficit in heterozygotes for GM6 further suggests that GM6 could be under selection likely by malaria infection.

  4. A novel FKRP-related muscular dystrophy founder mutation in South African Afrikaner patients with a phenotype suggestive of a dystrophinopathy

    M M Mudau

    2017-01-01

    Full Text Available Background. Fukutin-related protein (FKRP muscular dystrophy is an autosomal recessive disorder caused by mutations in the FKRP gene. The condition is often misdiagnosed as a dystrophinopathy. A previously unreported mutation, c.1100T>C in exon 4 of FKRP, had been identified in homozygous form in two white South African (SA Afrikaner patients clinically diagnosed with a dystrophinopathy. Objectives. To investigate whether the c.1100T>C mutation and the common European FKRP mutation c.826C>A are present in other patients of Afrikaner origin with suspected dystrophinopathy, and whether a founder haplotype exists. Methods. The c.1100T>C mutation was initially tested for using an amplification refractory mutation system technique in 45 white SA Afrikaner patients who had tested negative using multiplex ligation probe amplification screening for exonic deletions/duplications in the dystrophin gene. Sequencing analysis was used to confirm the c.1100T>C mutation and screen for the c.826C>A mutation. Two cohorts (each numbering 100 of Afrikaans and other white controls were screened for the c.1100T>C and c.826C>A mutations, respectively. Results. Of the 45 patients, 8 patients (17.8% were homozygous for c.1100T>C, 2 (4.4% were compound heterozygotes for c.1100T>C and c.826C>A, and 1 (2.2% was heterozygous for c.1100T>C with a second unidentified mutation. The c.1100T>C mutation was found in 1/100 controls, but no heterozygotes for the c.826C>A mutation were identified. Linked marker analysis for c.1100T>C showed a common haplotype, suggesting a probable founder mutation in the SA Afrikaner population. Conclusion. FKRP mutations may be relatively common in Afrikaners, and screening should be considered in patients who have a suggestive phenotype and test negative for a dystrophinopathy. This test will be useful for offering diagnostic, carrier and prenatal testing for affected individuals and their families. As FKRP muscular dystrophy is autosomal

  5. Hb I-Toulouse in association with homozygosity for the α3.7 deletion in a Pacific Island woman

    Beverley Pullon

    2016-11-01

    Full Text Available Only four cases of Hb I-Toulouse have been reported to date. Current literature associates Hb I-Toulouse in the heterozygote with a mild chronic hemolytic anemia. The variant is mildly unstable with a tendency to form metHb. The quantity of the variant in heterozygotes has been reported as varying between 33 to 40%. This report confirms the finding from a single case, that a reduced percentage of Hb IToulouse along with microcytosis can be attributed to the co-inheritance of an abnormal α globin genotype. This current case was found in a woman of Pacific People ethnicity residing in New Zealand. There is a high prevalence of α thalassemia in this ethnic group and New Zealand has the highest Pacific population in the world. Therefore, if a reduced percentage of Hb I-Toulouse is found with microcytosis and normal iron studies, co-inheritance with α thalassemia should be considered. 目前仅有四例Hb I-Toulouse的病例报告。 当前的文献将杂合子中的Hb I-Toulouse与慢性溶血性贫血相关联。 这种变异体轻度不稳定,有形成高铁血红蛋白(metHb)的倾向。 杂合子中变异体数量据报道为33%至40%不等。 本报告证实从单一病例得到的结果,即伴有小红细胞症的更低Hb I-Toulouse百分比可被归结为异常α球蛋白基因型的合并遗传。 该例当前病例在一名居住在新西兰的太平洋诸岛族裔女性身上发现。 在这个族群中存在较高的α地中海贫血患病率,而在全世界新西兰的太平洋诸岛族裔人口最多。 因此,如果发现Hb I-Toulouse的百分比更低,同时伴有小红细胞症并且检查铁含量正常,则应考虑α地中海贫血的合并遗传。

  6. A simplified high-throughput method for pyrethroid knock-down resistance (kdr) detection in Anopheles gambiae

    Lynd, Amy; Ranson, Hilary; McCall, P J; Randle, Nadine P; Black, William C; Walker, Edward D; Donnelly, Martin J

    2005-01-01

    Background A single base pair mutation in the sodium channel confers knock-down resistance to pyrethroids in many insect species. Its occurrence in Anopheles mosquitoes may have important implications for malaria vector control especially considering the current trend for large scale pyrethroid-treated bednet programmes. Screening Anopheles gambiae populations for the kdr mutation has become one of the mainstays of programmes that monitor the development of insecticide resistance. The screening is commonly performed using a multiplex Polymerase Chain Reaction (PCR) which, since it is reliant on a single nucleotide polymorphism, can be unreliable. Here we present a reliable and potentially high throughput method for screening An. gambiae for the kdr mutation. Methods A Hot Ligation Oligonucleotide Assay (HOLA) was developed to detect both the East and West African kdr alleles in the homozygous and heterozygous states, and was optimized for use in low-tech developing world laboratories. Results from the HOLA were compared to results from the multiplex PCR for field and laboratory mosquito specimens to provide verification of the robustness and sensitivity of the technique. Results and Discussion The HOLA assay, developed for detection of the kdr mutation, gives a bright blue colouration for a positive result whilst negative reactions remain colourless. The results are apparent within a few minutes of adding the final substrate and can be scored by eye. Heterozygotes are scored when a sample gives a positive reaction to the susceptible probe and the kdr probe. The technique uses only basic laboratory equipment and skills and can be carried out by anyone familiar with the Enzyme-linked immunosorbent assay (ELISA) technique. A comparison to the multiplex PCR method showed that the HOLA assay was more reliable, and scoring of the plates was less ambiguous. Conclusion The method is capable of detecting both the East and West African kdr alleles in the homozygous and

  7. Albinism and disease causing pathogens in Tanzania: are alleles that are associated with OCA2 being maintained by balancing selection?

    Tuli, Abbas M; Valenzuela, Robert K; Kamugisha, Erasmus; Brilliant, Murray H

    2012-12-01

    Oculocutaneous albinism type 2 (OCA2) is present at significantly higher frequencies in sub-Saharan African populations compared to populations in other regions of the world. In Tanzania and other sub-Saharan countries, most OCA2 is associated with a common 2.7kb deletion allele. Leprosy is also in high prevalence in sub-Saharan African populations. The infectious agent of leprosy, Mycobacterium leprae, contains a gene, 38L, that is similar to OCA2. Hypopigmented patches of skin are early symptoms that present with infection of leprosy. In consideration of both the genetic similarity of OCA2 and the 38L gene of M. leprae and the involvement of pigmentation in both disorders, we hypothesized that the high rates of OCA2 may be due to heterozygote advantage. Hence, we hypothesized that carriers of the 2.7kb deletion allele of OCA2 may provide a protective advantage from infection with leprosy. We tested this hypothesis by determining the carrier frequency of the 2.7kb deletion allele from a sample of 240 individuals with leprosy from Tanzania. The results were inconclusive due to the small sample size; however, they enabled us to rule out a large protective effect, but perhaps not a small advantage. Mycobacterium tuberculosis is another infectious organism prevalent in sub-Saharan Africa that contains a gene, arsenic-transport integral membrane protein that is also similar to OCA2. Interestingly, chromosomal region 15q11-13, which also contains OCA2, was reported to be linked to tuberculosis susceptibility. Although variants within OCA2 were tested for association, the 2.7kb deletion allele of OCA2 was not tested. This led us to hypothesize that the deletion allele may confer resistance to susceptibility. Confirmation of our hypothesis would enable development of novel pharmocogenetic therapies for the treatment of tuberculosis, which in turn, may enable development of drugs that target other pathogens that utilize a similar infection mechanism as M. tuberculosis

  8. Two Variants in SLC24A5 Are Associated with “Tiger-Eye” Iris Pigmentation in Puerto Rican Paso Fino Horses

    Maura Mack

    2017-08-01

    Full Text Available A unique eye color, called tiger-eye, segregates in the Puerto Rican Paso Fino (PRPF horse breed and is characterized by a bright yellow, amber, or orange iris. Pedigree analysis identified a simple autosomal recessive mode of inheritance for this trait. A genome-wide association study (GWAS with 24 individuals identified a locus on ECA 1 reaching genome-wide significance (Pcorrected = 1.32 × 10−5. This ECA1 locus harbors the candidate gene, Solute Carrier Family 24 (Sodium/Potassium/Calcium Exchanger, Member 5 (SLC24A5, with known roles in pigmentation in humans, mice, and zebrafish. Humans with compound heterozygous mutations in SLC24A5 have oculocutaneous albinism (OCA type 6 (OCA6, which is characterized by dilute skin, hair, and eye pigmentation, as well as ocular anomalies. Twenty tiger-eye horses were homozygous for a nonsynonymous mutation in exon 2 (p.Phe91Tyr of SLC24A5 (called here Tiger-eye 1, which is predicted to be deleterious to protein function. Additionally, eight of the remaining 12 tiger-eye horses heterozygous for the p.Phe91Tyr variant were also heterozygous for a 628 bp deletion encompassing all of exon 7 of SLC24A5 (c.875-340_1081+82del, which we will call here the Tiger-eye 2 allele. None of the 122 brown-eyed horses were homozygous for either tiger-eye-associated allele or were compound heterozygotes. Further, neither variant was detected in 196 horses from four related breeds not known to have the tiger-eye phenotype. Here, we propose that two mutations in SLC24A5 affect iris pigmentation in tiger-eye PRPF horses. Further, unlike OCA6 in humans, the Tiger-eye 1 mutation in its homozygous state or as a compound heterozygote (Tiger-eye 1/Tiger-eye 2 does not appear to cause ocular anomalies or a change in coat color in the PRPF horse.

  9. Heterozygosity for the Mood Disorder-Associated Variant Gln460Arg Alters P2X7 Receptor Function and Sleep Quality.

    Metzger, Michael W; Walser, Sandra M; Dedic, Nina; Aprile-Garcia, Fernando; Jakubcakova, Vladimira; Adamczyk, Marek; Webb, Katharine J; Uhr, Manfred; Refojo, Damian; Schmidt, Mathias V; Friess, Elisabeth; Steiger, Axel; Kimura, Mayumi; Chen, Alon; Holsboer, Florian; Arzt, Eduardo; Wurst, Wolfgang; Deussing, Jan M

    2017-11-29

    A single nucleotide polymorphism substitution from glutamine (Gln, Q) to arginine (Arg, R) at codon 460 of the purinergic P2X7 receptor (P2X7R) has repeatedly been associated with mood disorders. The P2X7R-Gln460Arg variant per se is not compromised in its function. However, heterologous expression of P2X7R-Gln460Arg together with wild-type P2X7R has recently been demonstrated to impair receptor function. Here we show that this also applies to humanized mice coexpressing both human P2X7R variants. Primary hippocampal cells derived from heterozygous mice showed an attenuated calcium uptake upon agonist stimulation. While humanized mice were unaffected in their behavioral repertoire under basal housing conditions, mice that harbor both P2X7R variants showed alterations in their sleep quality resembling signs of a prodromal disease stage. Also healthy heterozygous human subjects showed mild changes in sleep parameters. These results indicate that heterozygosity for the wild-type P2X7R and its mood disorder-associated variant P2X7R-Gln460Arg represents a genetic risk factor, which is potentially able to convey susceptibility to mood disorders. SIGNIFICANCE STATEMENT Depression and bipolar disorder are the most common mood disorders. The P2X7 receptor (P2X7R) regulates many cellular functions. Its polymorphic variant Gln460Arg has repeatedly been associated with mood disorders. Genetically engineered mice, with human P2X7R, revealed that heterozygous mice (i.e., they coexpress the disease-associated Gln460Arg variant together with its normal version) have impaired receptor function and showed sleep disturbances. Human participants with the heterozygote genotype also had subtle alterations in their sleep profile. Our findings suggest that altered P2X7R function in heterozygote individuals disturbs sleep and might increase the risk for developing mood disorders. Copyright © 2017 the authors 0270-6474/17/3711688-13$15.00/0.

  10. Whole-exome sequencing of a rare case of familial childhood acute lymphoblastic leukemia reveals putative predisposing mutations in Fanconi anemia genes.

    Spinella, Jean-François; Healy, Jasmine; Saillour, Virginie; Richer, Chantal; Cassart, Pauline; Ouimet, Manon; Sinnett, Daniel

    2015-07-23

    Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. While the multi-step model of pediatric leukemogenesis suggests interplay between constitutional and somatic genomes, the role of inherited genetic variability remains largely undescribed. Nonsyndromic familial ALL, although extremely rare, provides the ideal setting to study inherited contributions to ALL. Toward this goal, we sequenced the exomes of a childhood ALL family consisting of mother, father and two non-twinned siblings diagnosed with concordant pre-B hyperdiploid ALL and previously shown to have inherited a rare form of PRDM9, a histone H3 methyltransferase involved in crossing-over at recombination hotspots and Holliday junctions. We postulated that inheritance of additional rare disadvantaging variants in predisposing cancer genes could affect genomic stability and lead to increased risk of hyperdiploid ALL within this family. Whole exomes were captured using Agilent's SureSelect kit and sequenced on the Life Technologies SOLiD System. We applied a data reduction strategy to identify candidate variants shared by both affected siblings. Under a recessive disease model, we focused on rare non-synonymous or frame-shift variants in leukemia predisposing pathways. Though the family was nonsyndromic, we identified a combination of rare variants in Fanconi anemia (FA) genes FANCP/SLX4 (compound heterozygote - rs137976282/rs79842542) and FANCA (rs61753269) and a rare homozygous variant in the Holliday junction resolvase GEN1 (rs16981869). These variants, predicted to affect protein function, were previously identified in familial breast cancer cases. Based on our in-house database of 369 childhood ALL exomes, the sibs were the only patients to carry this particularly rare combination and only a single hyperdiploid patient was heterozygote at both FANCP/SLX4 positions, while no FANCA variant allele carriers were identified. FANCA is the most commonly mutated gene in FA and is essential for

  11. Contribution of genetic diversity for improvement of some abiotic stresses in wheat (abstract)

    Kazi, M.; Swati, Z.A.

    2005-01-01

    Wheat improvement has predominantly been accomplished through conventional plant breeding methodologies. This approach shall continue to be the predominant procedure in the future. Genetic diversity is crucial for crop improvement and in the Triticeae family it resides in the primary, secondary and tertiary gene pools. These gene pools can be utilize for wheat improvement by producing genetic stocks where the alien gene pools can be combined with durum and bread wheat cultivars via interspecific and intergeneric hybridization. Adopting the interspecific route strategies has led to the production of several genetic stocks, which are elucidated here. The categories include the amphiploids of the A, B, and D genomes with durum cultivars (AAAABB, AABBBB, AABBDD) and new AADD tetraploids. Tertiary gene pool species (more complex to utilize) are a potent resource for gene pyramiding, which contribute towards stress durability and addresses sustainable agricultural aspects. The conventional classical protocols of introgressing alien genetic diversity into wheat are complex, and long-term in generating farmer usable products. The gene transfer procedures are further complicated when the stress trait has multigenic control associated with several alien chromosomes. Our current approach has incorporated a novel strategy for promoting alien chromosome introgression involving wheat/alien homeologous as well as non-homeologous chromosomes. The protocol comprises of hybridizing the Phph based amphiploid with the phph Chinese Spring wheat genetic stock to yield heterozygote Phph derivatives. From selfing of the heterozygotes or from their derived haploids via wheat/maize crosses the ph derivatives are identified by a PCR diagnostic. The ph seedlings form the reservoir of wheat/alien chromosome translocations which are identified by Giemsa C-banding / fluorescent in situ hybridization (FISH). Plants with translocations are step-wise advanced by backcrosses to elite wheat cultivars

  12. ASSOCIATION OF INTERLEUKIN-10 -1082 A/G (RS1800896) POLYMORPHISM WITH SUSCEPTIBILITY TO GASTRIC CANCER: META-ANALYSIS OF 6,101 CASES AND 8,557 CONTROLS.

    Namazi, Abolfazl; Forat-Yazdi, Mohammad; Jafari, Mohammadali; Farahnak, Soudabeh; Nasiri, Rezvan; Foroughi, Elnaz; Abolbaghaei, Seyed Mojtaba; Neamatzadeh, Hossein

    2018-01-01

    The promoter -1082 A/G (rs1800896) polymorphism of Interleukin-10 (IL-10) gene have been widely reported and considered to have a significant role on gastric cancer risk, but the results are inconsistent. To clarify the association, we conducted a meta-analysis to investigate the associations IL-10 -1082 A/G polymorphism with gastric cancer. Eligible articles were identified by searching databases including PubMed, Web of Science, and Google Scholar up to August 03, 2017. Odds ratios (OR) with corresponding 95% confidence intervals (CIs) were used to assess the association. A total of 30 case-control studies with 6,101 cases and 8,557 controls were included in this meta-analysis. Overall, a significant association between IL-10 -1082 A/G polymorphism and gastric cancer risk was observed under the allele model (G vs A: OR=1.305, 95% CI=1.076-1.584; P=0.007), heterozygote model and (GA vs AA: OR=1.252, 95% CI=1.252-1.054; P=0.011) and dominant model (GG+GA vs AA: OR=1.264, 95% CI=1.053-1.516; P=0.012). In the subgroup analysis by ethnicity, increased gastric cancer risk were found in Asians under the allele model (G vs A: OR=1.520, 95% CI=1.172-1.973; P=0.002), homozygote model (GG+GA vs AA: OR=1.571, 95% CI=1.023-2.414; P= 0.039), heterozygote model (GA vs AA: OR=1.465, 95% CI=1.192-1.801; P≤0.001) and dominant model (GG+GA vs AA: OR=1.448, 95% CI=1.152-1.821; P=0.002), but not among Caucasian and Latinos populations. These results suggested that the IL-10 -1082 A/G (rs1800896) polymorphism might contribute to the gastric cancer susceptibility, especially among Asians.

  13. Resistance of neuronal nitric oxide synthase-deficient mice to methamphetamine-induced dopaminergic neurotoxicity.

    Itzhak, Y; Gandia, C; Huang, P L; Ali, S F

    1998-03-01

    Methamphetamine (METH) is a powerful psychostimulant that produces dopaminergic neurotoxicity manifested by a decrease in the levels of dopamine, tyrosine hydroxylase activity and dopamine transporter (DAT) binding sites in the nigrostriatal system. We have recently reported that blockade of the neuronal nitric oxide synthase (nNOS) isoform by 7-nitroindazole provides protection against METH-induced neurotoxicity in Swiss Webster mice. The present study was undertaken to investigate the effect of a neurotoxic dose of METH on mutant mice lacking the nNOS gene [nNOS(-/-)] and wild-type controls. In addition, we sought to investigate the behavioral outcome of exposure to a neurotoxic dose of METH. Homozygote nNOS(-/-), heterozygote nNOS(+/-) and wild-type animals were administered either saline or METH (5 mg/kg x 3). Dopamine, DOPAC and HVA levels, as well as DAT binding site levels, were determined in striatal tissue derived 72 h after the last METH injection. This regimen of METH given to nNOS(-/-) mice affected neither the tissue content of dopamine and its metabolites nor the number of DAT binding sites. Although a moderate reduction in the levels of dopamine (35%) and DAT binding sites (32%) occurred in striatum of heterozygote nNOS(+/-) mice, a more profound depletion of the dopaminergic markers (up to 68%) was observed in the wild-type animals. METH-induced hyperthermia was observed in all animal strains examined except the nNOS(-/-) mice. Investigation of the animals' spontaneous locomotor activity before and after administration of the neurotoxic dose of METH (5 mg/kg x 3) revealed no differences. A low dose of METH (1.0 mg/kg) administered to naive animals (nNOS(-/-) and wild-type) resulted in a similar intensity of locomotor stimulation. However, 68 to 72 h after exposure to the high-dose METH regimen, a marked sensitized responses to a challenge METH injection was observed in the wild-type mice but not in the nNOS(-/-) mice. Taken together, these results

  14. Diversidad genética de piracanjuba usada en programas de repoblación con marcadores microsatélites Genetic diversity of piracanjuba used in stock enhancement programs with microsatellite markers

    Maria del Pilar Rodriguez-Rodriguez

    2010-01-01

    that there is less genetic distance between parental and larvae and a decrease of genetic variability in the fingerlings. Deviations in the EHW and disequilibrium ligation were observed in six pairs of loci. Inbreeding coefficient showed excess of heterozygotes in parental and larvae and heterozygote deficiencies in fingerlings. The broodstock is in process of allele losses and the genetic variability decreased between larva and fingerling stages.

  15. Polymorphisms in XPD (Asp312Asn and Lys751Gln) genes, sunburn and arsenic-related skin lesions.

    McCarty, Kathleen M; Smith, Thomas J; Zhou, Wei; Gonzalez, Ernesto; Quamruzzaman, Quazzi; Rahman, Mahmuder; Mahiuddin, Golam; Ryan, Louise; Su, Li; Christiani, David C

    2007-08-01

    Single-nucleotide polymorphisms in genes related to DNA repair capacity and ultraviolet exposure have not been well investigated in relation to skin lesions associated with arsenic exposure. This population based case-control study, of 600 cases and 600 controls, frequency matched on age and gender in Pabna, Bangladesh, in 2001-2002, investigated the association and potential effect modification between polymorphisms in Xeroderma Pigmentosum complementation group D (XPD) (Lys751Gln and Asp312Asn) genes, tendency to sunburn and arsenic-related skin lesions. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). No significant association was observed between skin lesions and the XPD 312 Asp/Asn (adjusted OR = 0.87, 95% CI = 0.65-1.15) Asn/Asn (adjusted OR = 0.76, 95% CI = 0.50-1.15) (referent Asp/Asp); XPD 751 Lys/Gln (adjusted OR = 0.92, 95% CI = 0.69-1.23) Gln/Gln (adjusted OR = 0.98, 95% CI = 0.66-1.45) (referent Lys/Lys). While we did not observe any evidence of effect modification of these polymorphisms on the association between well arsenic concentration and skin lesions, we did observe effect modification between these polymorphisms and sunburn tendency and arsenic-related skin lesions. Individuals with the heterozygote or homozygote variant forms (Asp/Asn or Asn/Asn) had half the risk of skin lesions (OR = 0.45, 95% CI = 0.29-0.68) compared with those with the wild-type XPDAsp312Asn genotype (Asp/Asp) and individuals with heterozygote or homozygote variant forms (Lys/Gln or Gln/Gln) had half the risk of skin lesions (OR = 0.47, 95% CI = 0.31-0.72) compared with those with the wild-type XPDLys751Gln genotype (Lys/Lys), within the least sensitive strata of sunburn severity. We observed effect modification on the multiplicative scale for XPD 751 and XPD 312. XPD polymorphisms modified the relationship between tendency to sunburn and skin lesions in an arsenic exposed population. Further study is necessary

  16. Dual core quantum dots for highly quantitative ratiometric detection of trypsin activity in cystic fibrosis patients

    Castelló Serrano, Iván; Stoica, Georgiana; Matas Adams, Alba; Palomares, Emilio

    2014-10-01

    We present herein two colour encoded silica nanospheres (2nanoSi) for the fluorescence quantitative ratiometric determination of trypsin in humans. Current detection methods for cystic fibrosis diagnosis are slow, costly and suffer from false positives. The 2nanoSi proved to be a highly sensitive, fast (minutes), and single-step approach nanosensor for the screening and diagnosis of cystic fibrosis, allowing the quantification of trypsin concentrations in a wide range relevant for clinical applications (25-350 μg L-1). Furthermore, as trypsin is directly related to the development of cystic fibrosis (CF), different human genotypes, i.e. CF homozygotic, CF heterozygotic, and unaffected, respectively, can be determined using our 2nanoSi nanospheres. We anticipate the 2nanoSi system to be a starting point for non-invasive, easy-to-use and cost effective ratiometric fluorescent biomarkers for recessive genetic diseases like human cystic fibrosis. In a screening program in which the goal is to detect disease and also the carrier status, early diagnosis could be of great help.We present herein two colour encoded silica nanospheres (2nanoSi) for the fluorescence quantitative ratiometric determination of trypsin in humans. Current detection methods for cystic fibrosis diagnosis are slow, costly and suffer from false positives. The 2nanoSi proved to be a highly sensitive, fast (minutes), and single-step approach nanosensor for the screening and diagnosis of cystic fibrosis, allowing the quantification of trypsin concentrations in a wide range relevant for clinical applications (25-350 μg L-1). Furthermore, as trypsin is directly related to the development of cystic fibrosis (CF), different human genotypes, i.e. CF homozygotic, CF heterozygotic, and unaffected, respectively, can be determined using our 2nanoSi nanospheres. We anticipate the 2nanoSi system to be a starting point for non-invasive, easy-to-use and cost effective ratiometric fluorescent biomarkers for

  17. The Importance of G Protein-Coupled Receptor Kinase 4 (GRK4 in Pathogenesis of Salt Sensitivity, Salt Sensitive Hypertension and Response to Antihypertensive Treatment

    Brian Rayner

    2015-03-01

    two major hypertension studies, the 65Leu/142Val heterozygote predicted a significantly decreased response to atenolol treatment, and the 65Leu/142Val heterozygote and 486Val homozygote were associated in an additive fashion with adverse cardiovascular outcomes, independent of BP. In conclusion, there is considerable evidence that GRK4 variants are linked to impaired Na excretion, hypertension in animal models and humans, therapeutic response to dietary Na restriction and response to antihypertensive drugs. It may also underlie the difference in hypertension between different geographically derived population groups, and form a basis for pharmacogenomic approaches to treatment of hypertension.

  18. [Prevalence survey and molecular characterization of alpha and beta thalassemia in Liuzhou city of Guangxi].

    Cai, Ren; Li, Liyan; Liang, Xin; Liu, Zhongying; Su, Liu; Li, Wenjun; Zhu, Qiangui; Mo, Qiuhua; Pan, Lizhen; Ouyang, Hong; Huang, Lihua; Xu, Xiangmin

    2002-08-01

    To investigate the gene frequencies and mutation patterns of alpha thalassemia (alpha-thal) and beta thalassemia (beta-thal) in Liuzhou city of Guangxi Zhuang Autonomous Region. Cluster sampling was used. A total of 1 028 of umbilical blood samples were collected for a prevalence study of alpha-thal and a total of 1 312 healthy young people when receiving pre-marriage consultation were recruited for a beta-thal prevalence survey. Individuals live in city or town area of Liuzhou. A complete blood count as well as hemoglobin electrophoresis analysis were done in all of samples for phenotyping of alpha and beta-thals. Those with Hb Bart's for alpha-thal indicator and those with both microcytosis (MCV /=4.0%) for beta-thal were further studied by DNA analysis. PCR-based methodologies were used to characterize the mutation contributions of alpha and beta-thals. All the subjects were tested for the state of carrying beta-thala alleles for evaluating the situation of the compound heterozygotes of alpha-thal with beta-thal. Of 1 028 random samples of umbilical blood screened, 112 of subjects were defined to be the gene carriers of alpha-thal. The alpha-thal carrier rate was as high as 11.19% including 3 compound heterozygotes. Five well-known types of alpha-thal alleles were detected with gene contributions of 37.4% (--(SEA) deletion), 31.3% (-alpha(3.7) deletion), 17.4% (-alpha(4.2) deletion), 12.1% (alpha(CS)alpha mutation), and 0.9% (alpha(QS)alpha mutation), successively. Of the 1 312 adult specimens studied, 89 with beta-thal including 14 of the compound higher Hb F subjects were detected. All of the 89 phenotypic beta-thal carriers had the mutations in the beta-globin gene, making the overall prevalence 6.78%. The commonly seen three mutations, beta CD41 - 42 (-CTTT) frameshift, beta CD17 (T-A) nonsense mutation and beta-28 (A-G) promoter variation were accounted for 90% of the beta-thal alleles in Liuzhou. Of these beta-thal subjects, 16 (accounting for 18%) were

  19. Synthetic analysis of associations between IL-10 polymorphisms and skin cancer risk.

    Zhao, Hongbo; Yang, Jiaoli; Yu, Zhenzhen; Shen, Hui; Huang, Xinlin; Zhang, Mi; Long, Teng; Cailing, A; Wang, Wenhui

    2018-01-23

    The current study was designed to quantitatively summarize the evidence for the strength of the associations between common IL-10 functional polymorphisms and skin cancer risk. Relevant publications concerning the associations between common IL-10 functional polymorphisms(-1082G>A, -819C>T and -592C>A) and skin cancer were retrieved by a comprehensive electronic literature search in PubMed, Web of Science, EBSCO, Embase, China National Knowledge Infrastructure, Wanfang, Chinese Biomedical Database (CBM). The odds ratio (OR) and 95% confidence interval (CI) were utilized to assess the strength of the relationship. A total of 26 studies including 4090 cases and 4133 controls (-1082G>A, 10 studies with 1809 cases and 1830 controls; -819C>T, 7 studies with 862 cases and 957 controls; -592C>A, 9 studies with 1419 cases and 1346 controls) were enrolled in the meta-analysis. Overall, the results revealed a borderline decreased risk of skin cancer in heterozygote model (OR = 0.82, 95CI = 0.67-1.00, p = 0.05). The subgroup analysis also presented similar association for non-melanoma skin cancer in heterozygote model (OR = 0.67, 95CI = 0.50-0.91, p = 0.01). Moreover, the further analysis based on the histological type of non-melanoma skin cancer indicated a significantly decreased risk of BCC in allele model (OR = 0.67, 95% CI = 0.50-0.91, p = 0.02) and dominant model (OR = 0.68, 95% CI = 0.48-0.98, p = 0.04). However, neither overall analysis nor subgroup analysis based on cancer subtype revealed a significant association of -1082G>A or -592C>A polymorphisms with skin cancer. The present study suggested a potential association between IL-10 -819C>T polymorphism and decreased risk of skin cancer, but a lack of association for -1082G>A and -592C>A polymorphisms. Further invalidation is urgently needed.

  20. Meiotic Studies on Combinations of Chromosomes With Different Sized Centromeres in Maize

    Fangpu Han

    2018-06-01

    Full Text Available Multiple centromere misdivision derivatives of a translocation between the supernumerary B chromosome and the short arm of chromosome 9 (TB-9Sb permit investigation of how centromeres of different sizes behave in meiosis in opposition or in competition with each other. In the first analysis, heterozygotes were produced between the normal TB-9Sb and derivatives of it that resulted from centromere misdivision that reduced the amounts of centromeric DNA. These heterozygotes could test whether these drastic differences would result in meiotic drive of the larger chromosome in female meiosis. Cytological determinations of the segregation of large and small centromeres among thousands of progeny of four combinations were made. The recovery of the larger centromere was at a few percent higher frequency in two of four combinations. However, examination of phosphorylated histone H2A-Thr133, a characteristic of active centromeres, showed a lack of correlation with the size of the centromeric DNA, suggesting an expansion of the basal protein features of the kinetochore in two of the three cases despite the reduction in the size of the underlying DNA. In the second analysis, plants containing different sizes of the B chromosome centromere were crossed to plants with TB-9Sb with a foldback duplication of 9S (TB-9Sb-Dp9. In the progeny, plants containing large and small versions of the B chromosome centromere were selected by FISH. A meiotic “tug of war” occurred in hybrid combinations by recombination between the normal 9S and the foldback duplication in those cases in which pairing occurred. Such pairing and recombination produce anaphase I bridges but in some cases the large and small centromeres progressed to the same pole. In one combination, new dicentric chromosomes were found in the progeny. Collectively, the results indicate that the size of the underlying DNA of a centromere does not dramatically affect its segregation properties or its ability

  1. Effect of the 3'APOB-VNTR polymorphism on the lipid profiles in the Guangxi Hei Yi Zhuang and Han populations

    Ruixing, Yin; Guangqin, Chen; Yong, Wang; Weixiong, Lin; Dezhai, Yang; Shangling, Pan

    2007-01-01

    Background Apolipoprotein (Apo) B is the major component of low-density lipoprotein (LDL), very low-density lipoprotein (VLDL) and chylomicrons. Many genetic polymorphisms of the Apo B have been described, associated with variation of lipid levels. However, very few studies have evaluated the effect of the variable number of tandem repeats region 3' of the Apo B gene (3'APOB-VNTR) polymorphism on the lipid profiles in the special minority subgroups in China. Thus, the present study was undertaken to study the effect of the 3'APOB-VNTR polymorphism on the serum lipid levels in the Guangxi Hei Yi Zhuang and Han populations. Methods A total of 548 people of Hei Yi Zhuang were surveyed by a stratified randomized cluster sampling. The epidemiological survey was performed using internationally standardized methods. Serum lipid and apolipoprotein levels were measured. The 3'APOB-VNTR alleles were determined by polymerase chain reaction (PCR) followed by electrophoresis in polyacrylamide gels, and classified according to the number of repeats of a 15-bp hypervariable elements (HVE). The sequence of the most common allele was determined using the PCR and direct sequencing. The possible association between alleles of the 3'APOB-VNTR and lipid variables was examined. The results were compared with those in 496 people of Han who also live in that district. Results Nineteen alleles ranging from 24 to 64 repeats were detected in both Hei Yi Zhuang and Han. HVE56 and HVE58 were not be detected in Hei Yi Zhuang whereas HVE48 and HVE62 were totally absent in Han. The frequencies of HVE26, HVE30, HVE46, heterozygote, and short alleles (VNTR-LS (carrier of one long and one short alleles) than in VNTR-LL (the individual carrying two long alleles) genotypes. The levels of TC, triglycerides (TG), LDL cholesterol, and Apo B in Hei Yi Zhuang were higher in both HVE34 and HVE36 alleles than in HVE32 allele. The levels of TC, TG, HDL-C and Apo B in Hei Yi Zhuang were also higher in

  2. Pri-let-7a-1 rs10739971 polymorphism is associated with gastric cancer prognosis and might affect mature let-7a expression

    Li Y

    2016-07-01

    Full Text Available Ying Li, Qian Xu, Jingwei Liu, Caiyun He, Quan Yuan, Chengzhong Xing, Yuan Yuan Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University, Liaoning Provincial Education Department, Shenyang, People’s Republic of China Abstract: The relationship between the pri-let-7a-1 rs10739971 polymorphism and gastric cancer (GC risk has been reported. However, the role of this polymorphism in the prognosis of GC remains largely elusive. Sequenom MassARRAY platform method and the polymerase chain reaction (PCR-restriction fragment length polymorphism were used to investigate pri-let-7a-1 rs10739971 G→A in 334 GC patients. Real-time PCR detected expression of mature let-7a in serum and tissue. Patients with AA or GA+AA genotypes of the pri-let-7a-1 rs10739971 polymorphism demonstrated significantly longer survival time than those with the wild GG genotype. Stratified analysis indicated that survival time was significantly longer in women with AA or GA+AA genotypes and in Borrmann type I/II patients with GA heterozygote or GA+AA genotypes. AA genotype was more frequent in the lymphatic-metastasis-negative subgroup. Serum mature let-7a expression in healthy people with the GA heterozygote and the GA+AA genotype was higher than in those with the GG genotype, and the difference remained significant in the female healthy subgroup. Pri-let-7a-1 rs10739971 polymorphism might be a biomarker for GC prognosis, especially for female and Borrmann type I/II patients. The pri-let-7a-1 rs10739971 polymorphism might affect serum mature let-7a expression, and partly explain the mechanism of the relationship between the pri-let-7a-1 rs10739971 polymorphism and GC survival. Keywords: miRNA, let-7a, polymorphism, gastric cancer, prognosis, expression

  3. Risk of Pediatric Celiac Disease According to HLA Haplotype and Country

    Liu, Edwin; Lee, Hye-Seung; Aronsson, Carin A.; Hagopian, William A.; Koletzko, Sibylle; Rewers, Marian J.; Eisenbarth, George S.; Bingley, Polly J.; Bonifacio, Ezio; Simell, Ville; Agardh, Daniel

    2014-01-01

    BACKGROUND The presence of HLA haplotype DR3–DQ2 or DR4–DQ8 is associated with an increased risk of celiac disease. In addition, nearly all children with celiac disease have serum antibodies against tissue transglutaminase (tTG). METHODS We studied 6403 children with HLA haplotype DR3–DQ2 or DR4–DQ8 prospectively from birth in the United States, Finland, Germany, and Sweden. The primary end point was the development of celiac disease autoimmunity, which was defined as the presence of tTG antibodies on two consecutive tests at least 3 months apart. The secondary end point was the development of celiac disease, which was defined for the purpose of this study as either a diagnosis on biopsy or persistently high levels of tTG antibodies. RESULTS The median follow-up was 60 months (interquartile range, 46 to 77). Celiac disease autoimmunity developed in 786 children (12%). Of the 350 children who underwent biopsy, 291 had confirmed celiac disease; an additional 21 children who did not undergo biopsy had persistently high levels of tTG antibodies. The risks of celiac disease autoimmunity and celiac disease by the age of 5 years were 11% and 3%, respectively, among children with a single DR3–DQ2 haplotype, and 26% and 11%, respectively, among those with two copies (DR3–DQ2 homozygosity). In the adjusted model, the hazard ratios for celiac disease autoimmunity were 2.09 (95% confidence interval [CI], 1.70 to 2.56) among heterozygotes and 5.70 (95% CI, 4.66 to 6.97) among homozygotes, as compared with children who had the lowest-risk genotypes (DR4–DQ8 heterozygotes or homozygotes). Residence in Sweden was also independently associated with an increased risk of celiac disease autoimmunity (hazard ratio, 1.90; 95% CI, 1.61 to 2.25). CONCLUSIONS Children with the HLA haplotype DR3–DQ2, especially homozygotes, were found to be at high risk for celiac disease autoimmunity and celiac disease early in childhood. The higher risk in Sweden than in other countries

  4. Association of the polymorphisms of the IL-1B, IL-1RN, IL-10 and p53 genes with risk of gastric cancer in a population of high risk of Costa Rica

    Alpizar Alpizar, Wagner

    2004-01-01

    Factors that increase the risk to develop gastric cancer are studied: associated factors to diet, nitrous compounds endogenous formation, genetic predisposition, infection by Helicobacter pylori and polymorphic mixes pickles in the cut out gen of p53 tumour. Also it describes like Helicobacter pylori causes inflammation and its magnitude depends of the reaction mechanisms of the innkeeper in answer to the pathogen. The study aim was to determined the association of polymorphisms of the IL-1B, IL-IRN, IL-10 and p53 genes with the gastric cancer and gastric harms in a population of high risk in Costa Rica. Blood samples of 58 patients diagnosed with gastric cancer were analysed, 99 people with no suspicions of gastric cancer according to the diagnosis by x-Ray (contrast double gastroduodenal series), 41 patients histologically classified as I and II groups in a accordance with the Japanese classification. The analyses was carried out from DNA extracted of leucocytes. Association of the polymorphisms IL-1B-31, IL-1B-511, IL-10-592, IL-10-819 and IL-10-1082 were not found with risk to develop gastric cancer in the studied population. For IL-IB+3954, it was determined that the people with the heterozygote genotype for the T allele present more risk to develop gastric cancer (OR 3.7; IC 95% 1.34-10.2; p=0.007). For the polymorphism of IL-IRN gene it was observed that heterozygote genotype carrier people for the allele 2, present more risk to develop the illness (OR 2.94; IC 1.09-7.93; p=0.03). The allele frequencies that have been related with increase of the pro inflammatory answer are higher in the total population studied here than in other populations. According with the got results it will be necessary to carry out studies with more size of sample, with representative samples of the Costa Rican population and with samples of regions of low and high risk. (author) [es

  5. Enhanced low-template DNA analysis conditions and investigation of allele dropout patterns.

    Hedell, Ronny; Dufva, Charlotte; Ansell, Ricky; Mostad, Petter; Hedman, Johannes

    2015-01-01

    Forensic DNA analysis applying PCR enables profiling of minute biological samples. Enhanced analysis conditions can be applied to further push the limit of detection, coming with the risk of visualising artefacts and allele imbalances. We have evaluated the consecutive increase of PCR cycles from 30 to 35 to investigate the limitations of low-template (LT) DNA analysis, applying the short tandem repeat (STR) analysis kit PowerPlex ESX 16. Mock crime scene DNA extracts of four different quantities (from around 8-84 pg) were tested. All PCR products were analysed using 5, 10 and 20 capillary electrophoresis (CE) injection seconds. Bayesian models describing allele dropout patterns, allele peak heights and heterozygote balance were developed to assess the overall improvements in EPG quality with altered PCR/CE settings. The models were also used to evaluate the impact of amplicon length, STR marker and fluorescent label on the risk for allele dropout. The allele dropout probability decreased for each PCR cycle increment from 30 to 33 PCR cycles. Irrespective of DNA amount, the dropout probability was not affected by further increasing the number of PCR cycles. For the 42 and 84 pg samples, mainly complete DNA profiles were generated applying 32 PCR cycles. For the 8 and 17 pg samples, the allele dropouts decreased from 100% using 30 cycles to about 75% and 20%, respectively. The results for 33, 34 and 35 PCR cycles indicated that heterozygote balance and stutter ratio were mainly affected by DNA amount, and not directly by PCR cycle number and CE injection settings. We found 32 and 33 PCR cycles with 10 CE injection seconds to be optimal, as 34 and 35 PCR cycles did not improve allele detection and also included CE saturation problems. We find allele dropout probability differences between several STR markers. Markers labelled with the fluorescent dyes CXR-ET (red in electropherogram) and TMR-ET (shown as black) generally have higher dropout risks compared with those

  6. A dominant mutation in mediator of paramutation2, one of three second-largest subunits of a plant-specific RNA polymerase, disrupts multiple siRNA silencing processes.

    Sidorenko, Lyudmila; Dorweiler, Jane E; Cigan, A Mark; Arteaga-Vazquez, Mario; Vyas, Meenal; Kermicle, Jerry; Jurcin, Diane; Brzeski, Jan; Cai, Yu; Chandler, Vicki L

    2009-11-01

    Paramutation involves homologous sequence communication that leads to meiotically heritable transcriptional silencing. We demonstrate that mop2 (mediator of paramutation2), which alters paramutation at multiple loci, encodes a gene similar to Arabidopsis NRPD2/E2, the second-largest subunit of plant-specific RNA polymerases IV and V. In Arabidopsis, Pol-IV and Pol-V play major roles in RNA-mediated silencing and a single second-largest subunit is shared between Pol-IV and Pol-V. Maize encodes three second-largest subunit genes: all three genes potentially encode full length proteins with highly conserved polymerase domains, and each are expressed in multiple overlapping tissues. The isolation of a recessive paramutation mutation in mop2 from a forward genetic screen suggests limited or no functional redundancy of these three genes. Potential alternative Pol-IV/Pol-V-like complexes could provide maize with a greater diversification of RNA-mediated transcriptional silencing machinery relative to Arabidopsis. Mop2-1 disrupts paramutation at multiple loci when heterozygous, whereas previously silenced alleles are only up-regulated when Mop2-1 is homozygous. The dramatic reduction in b1 tandem repeat siRNAs, but no disruption of silencing in Mop2-1 heterozygotes, suggests the major role for tandem repeat siRNAs is not to maintain silencing. Instead, we hypothesize the tandem repeat siRNAs mediate the establishment of the heritable silent state-a process fully disrupted in Mop2-1 heterozygotes. The dominant Mop2-1 mutation, which has a single nucleotide change in a domain highly conserved among all polymerases (E. coli to eukaryotes), disrupts both siRNA biogenesis (Pol-IV-like) and potentially processes downstream (Pol-V-like). These results suggest either the wild-type protein is a subunit in both complexes or the dominant mutant protein disrupts both complexes. Dominant mutations in the same domain in E. coli RNA polymerase suggest a model for Mop2-1 dominance

  7. Polymorphism of ORM1 is associated with the pharmacokinetics of telmisartan.

    Wang-Qing Chen

    Full Text Available The pharmacokinetics (PKs and pharmacodynamics (PDs of telmisartan varies among the individuals, and the main causes remain unknown. The aim of this study was to evaluate the impact of ORM1, as well as ABCC2, ABCB1, ABCG2 and SLCO1B3 polymorphisms, on the disposition of the drug and BP change after taking 40 mg telmisartan in 48 healthy Chinese males.A total of 48 healthy males were included in this trial. Every volunteer ingested a single dose of 40 mg telmisartan, and the plasma drug concentration and blood pressure (BP were measured up to 48 h.In this study, the area under the plasma concentration-time curve (AUC in the heterozygotes of ORM1 113AG was higher than that in the wild-type homozygotes, AUC(0-48 (113AA vs. 113AG, 1,549.18±859.84 ng·h/ml vs. 2,313.54±1,257.71 ng·h/ml, P = 0.033, AUC(0-∞ (113AA vs. 113AG, 1,753.13±1,060.60 ng·h/ml vs. 2,686.90±1,401.87 ng·h/ml, P = 0.016, and the change(% of the diastolic blood pressure (DBP from the baseline BP value also showed a significant difference between the ORM1 113AG and 113AA genotypes at 5 h after taking telmisartan (P = 0.026. This study also showed that the allele of ABCC2 C3972T would affected the disposition of telmsiartan and the DBP change significantly after taking the drug. However, the common SNPs of ABCG2 C421, ABCB1 C3435T, and SLCO1B3 T334G showed no impacts on the PKs of telmisartan or BP change(% in our trial.The ORM1 A113G polymorphism was associated with the PKs variability after taking telmsiartan, as well as ABCC2 C3972T. The heterozygotes of ORM1 113AG showed a larger AUC and a notable BP change(% from the baseline compared with the wild-type.Chinese Clinical Trial Registry ChiCTR-TNC-10000898.

  8. A simplified high-throughput method for pyrethroid knock-down resistance (kdr detection in Anopheles gambiae

    Walker Edward D

    2005-03-01

    Full Text Available Abstract Background A single base pair mutation in the sodium channel confers knock-down resistance to pyrethroids in many insect species. Its occurrence in Anopheles mosquitoes may have important implications for malaria vector control especially considering the current trend for large scale pyrethroid-treated bednet programmes. Screening Anopheles gambiae populations for the kdr mutation has become one of the mainstays of programmes that monitor the development of insecticide resistance. The screening is commonly performed using a multiplex Polymerase Chain Reaction (PCR which, since it is reliant on a single nucleotide polymorphism, can be unreliable. Here we present a reliable and potentially high throughput method for screening An. gambiae for the kdr mutation. Methods A Hot Ligation Oligonucleotide Assay (HOLA was developed to detect both the East and West African kdr alleles in the homozygous and heterozygous states, and was optimized for use in low-tech developing world laboratories. Results from the HOLA were compared to results from the multiplex PCR for field and laboratory mosquito specimens to provide verification of the robustness and sensitivity of the technique. Results and Discussion The HOLA assay, developed for detection of the kdr mutation, gives a bright blue colouration for a positive result whilst negative reactions remain colourless. The results are apparent within a few minutes of adding the final substrate and can be scored by eye. Heterozygotes are scored when a sample gives a positive reaction to the susceptible probe and the kdr probe. The technique uses only basic laboratory equipment and skills and can be carried out by anyone familiar with the Enzyme-linked immunosorbent assay (ELISA technique. A comparison to the multiplex PCR method showed that the HOLA assay was more reliable, and scoring of the plates was less ambiguous. Conclusion The method is capable of detecting both the East and West African kdr alleles

  9. Forensic genetic SNP typing of low-template DNA and highly degraded DNA from crime case samples.

    Børsting, Claus; Mogensen, Helle Smidt; Morling, Niels

    2013-05-01

    Heterozygote imbalances leading to allele drop-outs and disproportionally large stutters leading to allele drop-ins are known stochastic phenomena related to STR typing of low-template DNA (LtDNA). The large stutters and the many drop-ins in typical STR stutter positions are artifacts from the PCR amplification of tandem repeats. These artifacts may be avoided by typing bi-allelic markers instead of STRs. In this work, the SNPforID multiplex assay was used to type LtDNA. A sensitized SNP typing protocol was introduced, that increased signal strengths without increasing noise and without affecting the heterozygote balance. Allele drop-ins were only observed in experiments with 25 pg of DNA and not in experiments with 50 and 100 pg of DNA. The allele drop-in rate in the 25 pg experiments was 0.06% or 100 times lower than what was previously reported for STR typing of LtDNA. A composite model and two different consensus models were used to interpret the SNP data. Correct profiles with 42-49 SNPs were generated from the 50 and 100 pg experiments, whereas a few incorrect genotypes were included in the generated profiles from the 25 pg experiments. With the strict consensus model, between 35 and 48 SNPs were correctly typed in the 25 pg experiments and only one allele drop-out (error rate: 0.07%) was observed in the consensus profiles. A total of 28 crime case samples were selected for typing with the sensitized SNPforID protocol. The samples were previously typed with old STR kits during the crime case investigation and only partial profiles (0-6 STRs) were obtained. Eleven of the samples could not be quantified with the Quantifiler™ Human DNA Quantification kit because of partial or complete inhibition of the PCR. For eight of these samples, SNP typing was only possible when the buffer and DNA polymerase used in the original protocol was replaced with the AmpFℓSTR(®) SEfiler Plus™ Master Mix, which was developed specifically for challenging forensic samples. All

  10. Theoretical and Practical Studies on a Possible Genetic Method for Tsetse Fly Control

    Curtis, C. F. [Tsetse Research Laboratory, School of Veterinary Science, University Of Bristol, Langford, Bristol (United Kingdom); Hill, W. G. [Institute of Animal Genetics, Edinburgh (United Kingdom)

    1968-06-15

    Chromosome translocations may be useful in pest control because they are a common type of mutation in a variety of organisms and, frequently, the heterozygote is semi-sterile and the homo- zygote folly fertile. It might be possible to induce such a translocation in a pest species, to breed from a selected ancestral pair of translocation homozygotes a large number of the homozygotes and to release these into a wild population. This would cause the production of heterozygotes in the wild population and hence would reduce the fertility of the population. This reduction would persist for a number of generations. Calculations, based on simplified assumptions, showed that this method of fertility reduction might be more economical than the use of sterilized males. In the present paper a theoretical comparison is made of the translocation and sterilized-male methods for the control of tsetse flies (Glossina sp.). A computer model has been set up which simulates, as far as possible, the known facts about birth, mating and death in a wild tsetse population. The predicted effects of releases of sterilized males and of translocation homozygotes are described and the modifications which would be caused by density-dependent mortality, migration and reduced viability of the translocation genotypes and sterilized males are indicated. It is concluded that to eradicate a well isolated wild population the numbers of translocation homozygotes required might well be considerably less than the number of sterilized males required for the same task. However, immigration into the population would greatly reduce the efficiency of the translocation method. The progress so far in attempting to produce a suitable translocation in Glossina austeni is described. Males have been treated with 5-7 krad of gamma radiation and a number of semi-sterile individuals have been selected from among their progeny. The semi-sterility is inherited and, by analogy with the results in other organisms, is

  11. Deposição pulmonar de tobramicina inalatória antes e após fisioterapia respiratória e uso de salbutamol inalatório em pacientes com fibrose cística colonizados por Pseudomonas aeruginosa Pulmonary deposition of inhaled tobramycin prior to and after respiratory therapy and use of inhaled albuterol in cystic fibrosis patients colonized with Pseudomonas aeruginosa

    Milena Baptistella Grotta

    2009-01-01

    Full Text Available OBJETIVO: Avaliar se a fisioterapia respiratória seguida do uso de salbutamol inalatório modifica a deposição pulmonar de tobramicina inalatória em pacientes com fibrose cística (FC e se a deposição pulmonar apresenta correlação com a gravidade da doença ou com o genótipo. MÉTODOS: Um estudo prospectivo foi realizado com pacientes com FC maiores de 6 anos e colonizados por Pseudomonas aeruginosa. Os critérios de exclusão foram exacerbação pulmonar, mudança terapêutica entre as fases do estudo e FEV1 OBJECTIVE: To evaluate whether respiratory therapy followed by the use of inhaled albuterol modifies the pulmonary deposition of inhaled tobramycin in patients with cystic fibrosis (CF and whether pulmonary deposition correlates with disease severity or genotype. METHODS: A prospective study was carried out including patients with CF older than 6 years of age and colonized with Pseudomonas aeruginosa. Exclusion criteria were pulmonary exacerbation, changes in therapy between the study phases and FEV1 < 25%. All patients were submitted to pulmonary scintigraphy by means of a scintillation camera equipped with a low energy all purpose collimator in order to evaluate drug penetration following the administration of inhaled 99mTc-tobramycin, as well as to pulmonary perfusion with 99mTc-macroaggregated albumin (phase 1. One month later, the same procedure was performed following respiratory therapy and administration of inhaled albuterol (phase 2. RESULTS: We included 24 patients (12 males aged 5-27 years (mean ± SD: 12.85 ± 6.64 years. The Shwachman score (SS was excellent/good in 8 patients, moderate/fair in 16 and poor in 0. Genotyping revealed that 7 patients were ΔF508 homozygotes, 13 were ΔF508 heterozygotes; and 4 presented other mutations. In all patients, lung deposition of tobramycin decreased in phase 2, especially in those with moderate/fair SS (p = 0.017 and in heterozygotes (p = 0.043. CONCLUSIONS: The use of a

  12. Genetic variations in the MCT1 (SLC16A1) gene in the Chinese population of Singapore.

    Lean, Choo Bee; Lee, Edmund Jon Deoon

    2009-01-01

    MCT1(SLC16A1) is the first member of the monocarboxylate transporter (MCT) and its family is involved in the transportation of metabolically important monocarboxylates such as lactate, pyruvate, acetate and ketone bodies. This study identifies genetic variations in SLC16A1 in the ethnic Chinese group of the Singaporean population (n=95). The promoter, coding region and exon-intron junctions of the SLC16A1 gene encoding the MCT1 transporter were screened for genetic variation in the study population by DNA sequencing. Seven genetic variations of SLC16A1, including 4 novel ones, were found: 2 in the promoter region, 2 in the coding exons (both nonsynonymous variations), 2 in the 3' untranslated region (3'UTR) and 1 in the intron. Of the two mutations detected in the promoter region, the -363-855T>C is a novel mutation. The 1282G>A (Val(428)Ile) is a novel SNP and was found as heterozygotic in 4 subjects. The 1470T>A (Asp(490)Glu) was found to be a common polymorphism in this study. Lastly, IVS3-17A>C in intron 3 and 2258 (755)A>G in 3'UTR are novel mutations found to be common polymorphisms in the local Chinese population. To our knowledge, this is the first report of a comprehensive analysis on the MCT1 gene in any population.

  13. Negative-assortative mating for color in wolves.

    Hedrick, Philip W; Smith, Douglas W; Stahler, Daniel R

    2016-04-01

    There is strong negative-assortative mating for gray and black pelage color in the iconic wolves in Yellowstone National Park. This is the first documented case of significant negative-assortative mating in mammals and one of only a very few cases in vertebrates. Of 261 matings documented from 1995 to 2015, 63.6% were between gray and black wolves and the correlation between mates for color was -0.266. There was a similar excess of matings of both gray males × black females and black males × gray females. Using the observed frequency of negative-assortative mating in a model with both random and negative-assortative mating, the estimated proportion of negative-assortative mating was 0.430. The estimated frequency of black wolves in the population from 1996 to 2014 was 0.452 and these frequencies appear stable over this 19-year period. Using the estimated level of negative-assortative mating, the predicted equilibrium frequency of the dominant allele was 0.278, very close to the mean value of 0.253 observed. In addition, the patterns of genotype frequencies, that is, the observed proportion of black homozygotes and the observed excess of black heterozygotes, are consistent with negative-assortative mating. Importantly these results demonstrate that negative-assortative mating could be entirely responsible for the maintenance of this well-known color polymorphism. © 2016 The Author(s). Evolution © 2016 The Society for the Study of Evolution.

  14. Dopamine D3 receptor status modulates sexual dimorphism in voluntary wheel running behavior in mice.

    Klinker, Florian; Ko Hnemann, Kathrin; Paulus, Walter; Liebetanz, David

    2017-08-30

    Sexual dimorphism has been described in various aspects of physiological and pathophysiological processes involving dopaminergic signaling. This might account for the different disease characteristics in men and women in e.g. Parkinson's disease or ADHD. A better understanding might contribute to the future individualization of therapy. We examined spontaneous wheel running activity of male and female mice, homo- and heterozygote for dopamine D3 receptor deficiency (D3R -/- and D3R+/-), and compared them to wild type controls. We found higher wheel running activity in female mice than in their male littermates. D3-/- mice, irrespective of sex, were also hyperactive compared to both D3+/- and wild type animals. Hyperactivity of D3-/- female mice was pronounced during the first days of wheel running but then decreased while their male counterparts continued to be hyperactive. Physical activity was menstrual cycle-dependent. Activity fluctuations were also seen in D3 receptor knockout mice and are therefore presumably independent of D3 receptor activation. Our data underscore the complex interaction of dopaminergic signaling and gonadal hormones that leads to specific running behavior. Furthermore, we detected sex- and D3 receptor status-specific reactions during novel exposure to the running wheel. These findings suggest the need for adapting dopaminergic therapies to individual factors such as sex or even menstrual cycle to optimize therapeutic success. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Prevention of Hb Bart's (γ4) Disease Associated with the - -(THAI) α(0)-Thalassemia Deletion in Mainland China.

    Li, Dong-Zhi; Li, Yan; Li, Jian; Li, Shu-Chen; Li, Ru

    2015-01-01

    α-Thalassemia (α-thal) is a common inherited disease in southern China. The severest form is Hb Bart's (γ4) disease, in which the affected fetuses almost always die in utero or shortly after birth, and the mothers are at high risk for severe morbidity. The most common type of α(0)-thalassemia (α(0)-thal) in southern China is Southeast Asian (- -(SEA)) deletion. Occasionally, Hb Bart's disease, caused by a compound heterozygosity for the - -(SEA) and - -(THAI) α(0)-thal deletions, can also be encountered. In this study, we report our experience with the prevention of Hb Bart's disease associated with the - -(THAI) α(0)-thal deletion. A total of 385 couples at risk for Hb Bart's disease, including seven who tested positive for the - -(SEA) deletion in one partner and the - -(THAI) deletion in the other, were found. Different prenatal procedures were offered, depending on the gestational age at presentation. Sixty-six affected fetuses were diagnosed prenatally; among these, two cases of Hb Bart's disease were compound heterozygotes for the - -(SEA) and - -(THAI) deletions. All affected pregnancies were terminated in time. We also presented a diagnostic protocol for identification of α(0)-thal trait that can reduce the number of samples for detection of the - -(THAI) deletion.

  16. An unusual insertion/deletion in the gene encoding the β-subunit of propionyl-CoA carboxylase is a frequent mutation in Caucasian propionic acidemia

    Tahara, T.; Kraus, J.P.; Rosenberg, L.E.

    1990-01-01

    Propionic acidemia is an inherited disorder of organic acid metabolism that is caused by deficiency of propionly-CoA carboxylase. Affected patients fall into two complementation groups, pccA and pccBC (subgroups B, C, and BC), resulting from deficiency of the nonidentical α and β subunits of PCC, respectively. The authors have detected an unusual insertion/deletion in the DNA of patients from the pccBC and pccC subgroups that replaces 14 nucleotides in the coding sequence of the β subunit with 12 nucleotides unrelated to this region of the gene. Among 14 unrelated Caucasian patients in the pccBc complementation group, this unique mutation was found in 8 of 28 mutant alleles examined. Mutant allele-specific oligonucleotide hybridization to amplified genomic DNAs revealed that the inserted 12 nucleotides do not originate in an ∼1000-bp region around the mutation. In the course of the investigation, they identified another mutation in the same exon: a 3-bp in-frame deletion that eliminates one of two isoleucine codons immediately preceding the Msp I site. Two unrelated patients were compound heterozygotes for this single-codon deletion and for the insertion/deletion described above. They conclude that either there is a propensity for the PCC β-subunit gene to undergo mutations of this sort at this position or, more likely, the mutations in all of the involved Caucasian patients have a common origin in preceding generations

  17. Whole-Exome Sequencing Reveals Clinically Relevant Variants in Family Affected with Autism Spectrum Disorder

    Jiaxiu Zhou

    2016-10-01

    Full Text Available Chromosomal microarray (CMA has been suggested as a first tier clinical diagnostic test for ASD. High-throughput sequencing (HTS has associated hundreds of genes associated with ASD. Whole Exome Sequencing (WES was used in combination with CMA to identify clinically-relevant ASD variants. In prior work, a trio-based (father, mother, and proband WGS (Whole Genome Sequencing was used to reveal clinically-relevant de novo, or inherited, rare variants in half (16 / 32 of the ASD families in which all probands had normal, or VOUS (Variant of Uncertain Clinical Significance, CMA results. In this study, after CMA screening chromosome structural abnormalities of a proband affected with ASD, a WES was performed on the patient and parents. Some rare de novo, and inherited, variants were detected using trio-based bioinformatics analysis. ASD variants were ranked by SFARI Gene score, HPO (human phenotype ontology, protein function damage, and manual searching PubMed. Sanger sequencing was used to validated some candidate variants in family members. A de novo homozygous mutation in SPG11 (p.C209F, two inherited, compound-heterozygote mutations in SCN9A (p.Q10R and p.R1893H and BEST1 (p.A135V and p.A297V were confirmed. Heterozygous mutations in TSC1 (p.S487C and SHANK2 (p.Arg569His inherited from mother were also confirmed.

  18. Functional significance of rare neuroligin 1 variants found in autism.

    Moe Nakanishi

    2017-08-01

    Full Text Available Genetic mutations contribute to the etiology of autism spectrum disorder (ASD, a common, heterogeneous neurodevelopmental disorder characterized by impairments in social interaction, communication, and repetitive and restricted patterns of behavior. Since neuroligin3 (NLGN3, a cell adhesion molecule at the neuronal synapse, was first identified as a risk gene for ASD, several additional variants in NLGN3 and NLGN4 were found in ASD patients. Moreover, synaptopathies are now known to cause several neuropsychiatric disorders including ASD. In humans, NLGNs consist of five family members, and neuroligin1 (NLGN1 is a major component forming a complex on excitatory glutamatergic synapses. However, the significance of NLGN1 in neuropsychiatric disorders remains unknown. Here, we systematically examine five missense variants of NLGN1 that were detected in ASD patients, and show molecular and cellular alterations caused by these variants. We show that a novel NLGN1 Pro89Leu (P89L missense variant found in two ASD siblings leads to changes in cellular localization, protein degradation, and to the impairment of spine formation. Furthermore, we generated the knock-in P89L mice, and we show that the P89L heterozygote mice display abnormal social behavior, a core feature of ASD. These results, for the first time, implicate rare variants in NLGN1 as functionally significant and support that the NLGN synaptic pathway is of importance in the etiology of neuropsychiatric disorders.

  19. Lack of evidence to support the association of a single IL28B genotype SNP rs12979860 with the HTLV-1 clinical outcomes and proviral load

    Sanabani Sabri Saeed

    2012-12-01

    Full Text Available Abstract Background The Interleukin 28B (IL28B rs12979860 polymorphisms was recently reported to be associated with the human T-cell leukemia virus type 1 (HTLV-1 proviral load (PvL and the development of the HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP. Methods In an attempt to examine this hypothesis, we assessed the association of the rs12979860 genotypes with HTLV-1 PvL levels and clinical status in 112 unrelated Brazilian subjects (81 HTLV-1 asymptomatic carriers, 24 individuals with HAM/TSP and 7 with Adult T cell Leukemia/Lymphoma (ATLL. Results All 112 samples were successfully genotyped and their PvLs compared. Neither the homozygote TT nor the heterozygote CT mutations nor the combination genotypes (TT/CT were associated with a greater PvL. We also observed no significant difference in allele distribution between asymptomatic carriers and patients with HTLV-1 associated HAM/TSP. Conclusions Our study failed to support the previously reported positive association between the IL28B rs12979860 polymorphisms and an increased risk of developing HAM/TSP in the Brazilian population.

  20. Auxin-dependent microtubule responses and seedling development are affected in a rice mutant resistant to EPC

    Nick, P.; Yatou, O.; Furuya, M.; Lambert, A.M.

    1994-01-01

    Mutants in rice (Oryza sativa L. cv. japonica) were used to study the role of the cytoskeleton in signal-dependent morphogenesis. Mutants obtained by gamma ray irradiation were selected that failed to show inhibition of coleoptile elongation by the anti microtubular drug ethyl-N-phenylcarbamate (EPC). The mutation EPC-Resistant 31 (ER31), isolated from such a screen, caused lethality in putatively homozygous embryos. Heterozygotes exhibited drug resistance, impaired development of crown roots, and characteristic changes in the pattern of cell elongation: cell elongation was enhanced in mesocotyls and leaf sheaths, but inhibited in coleoptiles. The orientation of cortical microtubules changed correspondingly: for etiolated seedlings, compared with the wild-type, they were more transverse with respect to the long cell axis in mesocotyls and leaf sheaths, but more longitudinal in coleoptiles. In mutant coleoptiles, in contrast to wild-type, microtubules did not reorient in response to auxin, and their response to microtubule-eliminating and microtubule-stabilizing drugs was conspicuously reduced. In contrast, they responded normally to other stimuli such as gibberellins or red light. Auxin sensitivity as assayed by the dose-response for callus induction did not show any significant differences between wild-type and mutant. The mutant phenotype is interpreted in terms of an interrupted link between auxin-triggered signal transduction and microtubule reorientation. (author)

  1. Involvement of Gaucher Disease Mutations in Parkinson Disease.

    Vilageliu, Lluisa; Grinberg, Daniel

    2017-01-01

    Gaucher disease is an autosomal recessive lysosomal storage disorder, caused by mutations in the GBA gene. The frequency of Gaucher disease patients and heterozygote carriers that developed Parkinson disease has been found to be above that of the control population. This fact suggests that mutations in the GBA gene can be involved in Parkison's etiology. Analysis of large cohorts of patients with Parkinson disease has shown that there are significantly more cases bearing GBA mutations than those found among healthy individuals. Functional studies have proven an interaction between α-synuclein and GBA, the levels of which presented an inverse correlation. Mutant GBA proteins cause increases in α-synuclein levels, while an inhibition of GBA by α-synuclein has been also demonstrated. Saposin C, a coactivator of GBA, has been shown to protect GBA from this inhibition. Among the GBA variants associated with Parkinson disease, E326K seems to be one of the most prevalent. Interestingly, it is involved in Gaucher disease only when it forms part of a double-mutant allele, usually with the L444P mutation. Structural analyses have revealed that both residues (E326 and L444) interact with Saposin C and, probably, also with α-synuclein. This could explain the antagonistic role of these two proteins in relation to GBA. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  2. The genetics of aging in optimal and stressful environments

    Parsons, P.A.

    1978-01-01

    The genetic basis of aging in Drosophila varies according to environment, as shown by variations in temperatures and levels of 60 Co-γ irradiation. Under conditions of extreme stress large additive differences occur not found under less acute stresses. In addition, longevities of strains are not necessarily correlated across levels of 60 C0-γ irradiation or temperatures, so that studies of the genetics of aging are not only relevant to the environment selected. Given these results on experimental animals, it appears impossible to separate clearly genetic and environmental factors determining longevity in man - a conclusion that in any case appears likely from human studies. In experimental organisms such as Drosophila, differences between genotypes for longevity are magnified under stress compared with optimal environments. Hybrid and heterozygote superiority frequently occur for density-independent physical stresses of the environment as well as density-dependent behavioral stresses due to crowding levels. It is argued that these conclusions apply to man, so that for maximum longevity genotypes are likely to be highly heterozygous. (author)

  3. Detection of early atherosclerosis with radiolabeled monocyte chemoattractant protein-1 in prediabeteic Zucker rats

    Blankenberg, F.G. [Div. of Pediatric Radiology, Stanford, CA (United States); Wen, P.; Dai, M.; Zhu, D.; Panchal, S.N.; Valantine, H.A. [Division of Cardiovascular Medicine, Department of Medicine, Stanford, California (United States); Tait, J.F. [Dept. of Laboratory Medicine, Univ. of Washington, Seattle (United States); Post, A.M.; Strauss, H.W. [Div. of Nuclear Medicine, Stanford Univ., CA (United States)

    2001-12-01

    Background: Migration of monocytes into the arterial wall is an early finding of atherosclerosis. Monocytes are attracted to sites of vascular endothelial cell injury, the initiating event in the development of atheromatous disease, by a chemokine known as monocyte chemoattractant protein-1 (MCP-1). Injured vascular endothelial and smooth muscle cells selectively secrete MCP-1. Objective: This study was performed to determine if radiolabeled MCP-1 would co-localize at sites of monocyte/macrophage concentration in an experimental model of transplant-induced vasculopathy in diabetic animals. Materials and methods: Hearts from 3-month-old male Zucker rats, heterozygote (Lean) or homozygote (Fat) for the diabetes-associated gene fa, were transplanted into the abdomens of genetically matched recipients. Lean and Fat animals were then fed normal or high-fat diets for 90 days. Results: At 90 days significant increases (P < 0.013) of MCP-1 graft uptake were seen at imaging and confirmed on scintillation gamma well counting studies in Lean (n = 5) and Fat (n = 12) animals, regardless of diet, 400 % and 40 %, above control values, respectively. MCP-1 uptake of native and grafted hearts correlated with increased numbers of perivascular macrophages (P < 0.02), as seen by immunostaining with an antibody specific for macrophages (ED 2). Conclusion: Radiolabeled MCP-1 can detect abnormally increased numbers of perivascular mononuclear cells in native and grafted hearts in prediabetic rats. MCP-1 may be useful in the screening of diabetic children for early atherosclerotic disease. (orig.)

  4. Complex Mhc-based mate choice in a wild passerine

    Bonneaud, Camille; Chastel, Olivier; Federici, Pierre; Westerdahl, Helena; Sorci, Gabriele

    2006-01-01

    The extreme polymorphism of the vertebrate major histocompatibility complex (Mhc) is famous for protecting hosts against constantly evolving pathogens. Mate choice is often evoked as a means of maintaining Mhc variability through avoidance of partners with similar Mhc alleles or preference for heterozygotes. Evidence for these two hypotheses mostly comes from studies on humans and laboratory mice. Here, we tested these hypotheses in a wild outbred population of house sparrows (Passer domesticus). Females were not more or less closely related to the males they paired with when considering neutral genetic variation. However, males failed to form breeding pairs when they had too few Mhc alleles and when they were too dissimilar from females at Mhc loci (i.e. had no common alleles). Furthermore, pairs did not form at random as Mhc diversity positively correlated in mating pairs. These results suggest that mate choice evolves in response to (i) benefits in terms of parasite resistance acquired from allelic diversity, and (ii) costs associated with the disruption of co-adapted genes. PMID:16600889

  5. Assignment of the Nance-Horan syndrome to the distal short arm of the X chromosome.

    Zhu, D; Alcorn, D M; Antonarakis, S E; Levin, L S; Huang, P C; Mitchell, T N; Warren, A C; Maumenee, I H

    1990-11-01

    There are three types of X-linked cataracts recorded in Mendelian Inheritance in Man (McKusick 1988): congenital total, with posterior sutural opacities in heterozygotes; congenital, with microcornea or slight microphthalmia; and the cataract-dental syndrome or Nance-Horan (NH) syndrome. To identify a DNA marker close to the gene responsible for the NH syndrome, linkage analysis on 36 members in a three-generation pedigree including seven affected males and nine carrier females was performed using 31 DNA markers. A LOD score of 1.662 at theta = 0.16 was obtained with probe 782 from locus DXS85 on Xp22.2-p22.3. Negative LOD scores were found at six loci on the short arm, one distal to DXS85, five proximal, and six probes spanning the long arm were highly negative. These results make the assignment of the locus for NH to the distal end of the short arm of the X chromosome likely.

  6. Association between vitamin D concentration and levels of sex hormones in an elderly Polish population with different genotypes of VDR polymorphisms (rs10735810, rs1544410, rs7975232, rs731236).

    Laczmanski, Lukasz; Lwow, Felicja; Mossakowska, Malgorzata; Puzianowska-Kuznicka, Monika; Szwed, Małgorzata; Kolackov, Katarzyna; Krzyzanowska-Swiniarska, Barbara; Bar-Andziak, Ewa; Chudek, Jerzy; Sloka, Natalia; Milewicz, Andrzej

    2015-03-15

    Vitamin D co-regulates the synthesis of sex hormones in part by interaction with its nuclear receptor. The aim of this study was to determine whether there is an association of vitamin D concentration vs the level of sex hormones in elderly Polish individuals with different genotypes of the vitamin D receptor (VDR) gene. Rs10735810, rs1544410, rs7975232, and rs731236 polymorphisms of VDR, the serum sex hormone level, free estrogen index (FEI) and free androgen index (FAI) as well as vitamin D, were evaluated in 766 persons (362 women and 404 men) selected from 5695 Polish population, aged 65-90years from the PolSenior survey. We observed that women with GG (rs731236), TT (rs7975232), BB (rs1544410) and FF (rs10735810) genotypes were characterized by a significant correlation between vitamin D vs testosterone concentration and FAI value. We found a significant correlation between testosterone level and FAI vs vitamin D concentration in men with heterozygote AG in the rs731236 polymorphism and in the GG (rs7975232), the BB (rs1544410), and the Ff (rs10735810) genotypes. In elderly selected Polish population with different genotypes of VDR polymorphisms, a statistically significant relationship between vitamin D concentration vs testosterone level was observed. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. The inhibition of polo kinase by matrimony maintains G2 arrest in the meiotic cell cycle.

    Youbin Xiang

    2007-12-01

    Full Text Available Many meiotic systems in female animals include a lengthy arrest in G2 that separates the end of pachytene from nuclear envelope breakdown (NEB. However, the mechanisms by which a meiotic cell can arrest for long periods of time (decades in human females have remained a mystery. The Drosophila Matrimony (Mtrm protein is expressed from the end of pachytene until the completion of meiosis I. Loss-of-function mtrm mutants result in precocious NEB. Coimmunoprecipitation experiments reveal that Mtrm physically interacts with Polo kinase (Polo in vivo, and multidimensional protein identification technology mass spectrometry analysis reveals that Mtrm binds to Polo with an approximate stoichiometry of 1:1. Mutation of a Polo-Box Domain (PBD binding site in Mtrm ablates the function of Mtrm and the physical interaction of Mtrm with Polo. The meiotic defects observed in mtrm/+ heterozygotes are fully suppressed by reducing the dose of polo+, demonstrating that Mtrm acts as an inhibitor of Polo. Mtrm acts as a negative regulator of Polo during the later stages of G2 arrest. Indeed, both the repression of Polo expression until stage 11 and the inactivation of newly synthesized Polo by Mtrm until stage 13 play critical roles in maintaining and properly terminating G2 arrest. Our data suggest a model in which the eventual activation of Cdc25 by an excess of Polo at stage 13 triggers NEB and entry into prometaphase.

  8. Variation in heterozygosity predicts variation in human substitution rates between populations, individuals and genomic regions.

    William Amos

    Full Text Available The "heterozygote instability" (HI hypothesis suggests that gene conversion events focused on heterozygous sites during meiosis locally increase the mutation rate, but this hypothesis remains largely untested. As humans left Africa they lost variability, which, if HI operates, should have reduced the mutation rate in non-Africans. Relative substitution rates were quantified in diverse humans using aligned whole genome sequences from the 1,000 genomes project. Substitution rate is consistently greater in Africans than in non-Africans, but only in diploid regions of the genome, consistent with a role for heterozygosity. Analysing the same data partitioned into a series of non-overlapping 2 Mb windows reveals a strong, non-linear correlation between the amount of heterozygosity lost "out of Africa" and the difference in substitution rate between Africans and non-Africans. Putative recent mutations, derived variants that occur only once among the 80 human chromosomes sampled, occur preferentially at the centre of 2 Kb windows that have elevated heterozygosity compared both with the same region in a closely related population and with an immediately adjacent region in the same population. More than half of all substitutions appear attributable to variation in heterozygosity. This observation provides strong support for HI with implications for many branches of evolutionary biology.

  9. Joint Analysis of Strain and Parent-of-Origin Effects for Recombinant Inbred Intercrosses Generated from Multiparent Populations with the Collaborative Cross as an Example.

    Liu, Yanyan; Xiong, Sican; Sun, Wei; Zou, Fei

    2018-02-02

    Multiparent populations (MPP) have become popular resources for complex trait mapping because of their wider allelic diversity and larger population size compared with traditional two-way recombinant inbred (RI) strains. In mice, the collaborative cross (CC) is one of the most popular MPP and is derived from eight genetically diverse inbred founder strains. The strategy of generating RI intercrosses (RIX) from MPP in general and from the CC in particular can produce a large number of completely reproducible heterozygote genomes that better represent the (outbred) human population. Since both maternal and paternal haplotypes of each RIX are readily available, RIX is a powerful resource for studying both standing genetic and epigenetic variations of complex traits, in particular, the parent-of-origin (PoO) effects, which are important contributors to many complex traits. Furthermore, most complex traits are affected by >1 genes, where multiple quantitative trait locus mapping could be more advantageous. In this paper, for MPP-RIX data but taking CC-RIX as a working example, we propose a general Bayesian variable selection procedure to simultaneously search for multiple genes with founder allelic effects and PoO effects. The proposed model respects the complex relationship among RIX samples, and the performance of the proposed method is examined by extensive simulations. Copyright © 2018 Liu et al.

  10. A missense mutation in the human liver/bone/kidney alkaline phosphatase gene causing a lethal form of hypophosphatasia

    Weiss, M.J.; Cole, D.E.C.; Ray, K.; Whyte, M.P.; Lafferty, M.A.; Mulivor, R.A.; Harris, H.

    1988-01-01

    Hypophosphatasia is an inherited disorder characterized by defective bone mineralization and a deficiency of serum and tissue liver/bone/kidney alkaline phosphatase (L/B/K ALP) activity. Clinical severity is variable, ranging from death in utero (due to severe rickets) to pathologic fractures first presenting in adult life. Affected siblings, however, are phenotypically similar. Severe forms of the disease are inherited in an autosomal recessive fashion; heterozygotes often show reduced serum ALP activity. The specific gene defects in hypophosphatasia are unknown but are thought to occur either at the L/B/K ALP locus or within another gene that regulates L/B/K ALP expression. The authors used the polymerase chain reaction to examine L/B/K ALP cDNA from a patient with a perinatal (lethal) form of the disease. They observed a guanine-to-adenine transition in nucleotide 711 of the cDNA that converts alanine-162 of the mature enzyme to threonine. The affected individual, whose parents are second cousins, is homozygous for the mutant allele. Introduction of this mutation into an otherwise normal cDNA by site-directed mutagenesis abolished the expression of active enzyme, demonstrating that a defect in the L/B/K ALP gene results in hypophosphatasia and that the enzyme is, therefore, essential for normal skeletal mineralization

  11. [Identification of novel compound heterozygous mutations of USH2A gene in a family with Usher syndrome type II].

    Jiang, Haiou; Ge, Chuanqin; Wang, Yiwang; Tang, Genyun; Quan, Qingli

    2015-06-01

    To identify potential mutations in a Chinese family with Usher syndrome type II. Genomic DNA was obtained from two affected and four unaffected members of the family and subjected to amplification of the entire coding sequence and splicing sites of USH2A gene. Mutation detection was conducted by direct sequencing of the PCR products. A total of 100 normal unrelated individuals were used as controls. The patients were identified to be a compound heterozygote for two mutations: c.8272G>T (p.E2758X) in exon 42 from his mother and c.12376-12378ACT>TAA(p.T4126X) in exon 63 of the USH2A gene from his father. Both mutations were not found in either of the two unaffected family members or 100 unrelated controls, and had completely co-segregated with the disease phenotype in the family. Neither mutation has been reported in the HGMD database. The novel compound heterozygous mutations c.8272G>T and c.12376-12378ACT>TAA within the USH2A gene may be responsible for the disease. This result may provide new clues for molecular diagnosis of this disease.

  12. Features of Brain MRI in Dogs with Treated and Untreated Mucopolysaccharidosis Type I

    Vite, Charles H; Nestrasil, Igor; Mlikotic, Anton; Jens, Jackie K; Snella, Elizabeth M; Gross, William; Shapiro, Elsa G; Kovac, Victor; Provenzale, James M; Chen, Steven; Le, Steven Q; Kan, Shih-hsin; Banakar, Shida; Wang, Raymond Y; Haskins, Mark E; Ellinwood, N Matthew; Dickson, Patricia I

    2013-01-01

    The mucopolysaccharidosis type I (MPS I) dog model has been important in the development of therapies for human patients. We treated dogs with enzyme replacement therapy (ERT) by various approaches. Dogs assessed included untreated MPS I dogs, heterozygous carrier dogs, and MPS I dogs treated with intravenous ERT as adults (beginning at age 13 to 16 mo), intrathecal and intravenous ERT as adults (beginning at age 13 to 16 mo), or intrathecal ERT as juveniles (beginning at age 4 mo). We then characterized the neuroimaging findings of 32 of these dogs (age, 12 to 30 mo). Whole and midsagittal volumes of the corpus callosum, measured from brain MRI, were significantly smaller in affected dogs compared with unaffected heterozygotes. Corpus callosum volumes in dogs that were treated with intrathecal ERT from 4 mo until 21 mo of age were indistinguishable from those of age-matched carrier controls. Dogs with MPS I showed cerebral ventricular enlargement and cortical atrophy as early as 12 mo of age. Ventricular enlargement was greater in untreated MPS I dogs than in age-matched dogs treated with intrathecal ERT as juveniles or adults. However, treated dogs still showed some ventricular enlargement or cortical atrophy (or both). Understanding the progression of neuroimaging findings in dogs with MPS I and their response to brain-directed therapy may improve preclinical studies for new human-directed therapies. In particular, corpus callosum volumes may be useful quantitative neuroimaging markers for MPS-related brain disease and its response to therapy. PMID:23582423

  13. Serum Homocysteine, Vitamin B12, Folic Acid Levels and Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphism in Vitiligo

    Yasar, Ali; Gunduz, Kamer; Onur, Ece; Calkan, Mehmet

    2012-01-01

    The aim of this study was to determine serum vitamin B12, folic acid and homocysteine (Hcy) levels as well as MTHFR (C677, A1298C) gene polymorphisms in patients with vitiligo, and to compare the results with healthy controls. Forty patients with vitiligo and 40 age and sex matched healthy subjects were studied. Serum vitamin B12 and folate levels were determined by enzyme-linked immunosorbent assay. Plasma Hcy levels and MTHFR polymorphisms were determined by chemiluminescence and real time PCR methods, respectively. Mean serum vitamin B12 and Hcy levels were not significantly different while folic acid levels were significantly lower in the control group. There was no significant relationship between disease activity and vitamin B12, folic acid and homocystein levels. No significant difference in C677T gene polymorphism was detected. Heterozygote A1298C gene polymorphism in the patient group was statistically higher than the control group. There was no significant relationship between MTHFR gene polymorphisms and vitamin B12, folic acid and homocysteine levels. In conclusion, vitamin B12, folate and Hcy levels are not altered in vitiligo and MTHFR gene mutations (C677T and A1298C) do not seem to create susceptibility for vitiligo. PMID:22846211

  14. Serum Homocysteine, Vitamin B12, Folic Acid Levels and Methylenetetrahydrofolate Reductase (MTHFR Gene Polymorphism in Vitiligo

    Ali Yasar

    2012-01-01

    Full Text Available The aim of this study was to determine serum vitamin B12, folic acid and homocysteine (Hcy levels as well as MTHFR (C677, A1298C gene polymorphisms in patients with vitiligo, and to compare the results with healthy controls. Forty patients with vitiligo and 40 age and sex matched healthy subjects were studied. Serum vitamin B12 and folate levels were determined by enzyme-linked immunosorbent assay. Plasma Hcy levels and MTHFR polymorphisms were determined by chemiluminescence and real time PCR methods, respectively. Mean serum vitamin B12 and Hcy levels were not significantly different while folic acid levels were significantly lower in the control group. There was no significant relationship between disease activity and vitamin B12, folic acid and homocystein levels. No significant difference in C677T gene polymorphism was detected. Heterozygote A1298C gene polymorphism in the patient group was statistically higher than the control group. There was no significant relationship between MTHFR gene polymorphisms and vitamin B12, folic acid and homocysteine levels. In conclusion, vitamin B12, folate and Hcy levels are not altered in vitiligo and MTHFR gene mutations (C677T and A1298C do not seem to create susceptibility for vitiligo.

  15. Polymorphisms in tumor necrosis factor genes and susceptibility to visceral leishmaniasis in Moroccan children

    Rajaa Ejghal

    2015-05-01

    Full Text Available Objective: To examine whether polymorphic alleles at these two loci are involved in the susceptibility to visceral leishmaniasis (VL in Moroccan children. Methods: We have genotyped polymorphisms by PCR-restricted fragment length polymorphisms in 102 patients with VL, 92 asymptomatic carriers [positive skin test delayedtype hypersensitivity (DTH+] and 40 healthy controls (negative skin test delayed-type hypersensitivity, with no history of Leishmania infection. Results: Regression analysis showed no significant association between polymorphisms of tumor necrosis factors-ααwhen comparing VL and DTH + group (P > 0.05. The associations were detected between VL and negative skin test delayed-type hypersensitivity for the heterozygote genotype (P = 0.021, the recessive model: 1/2 + 2/2 (P = 0.044 and the minor allele 2 (P = 0.019. The resistance to VL was found to be under the recessive model 1/2 + 2/2 of tumor necrosis factors-β, when comparing VL and DTH + group (odds ratios: 0.558, 95%; confidence interval: 0.316-0.987; P = 0.044. Conclusions: These results must be regarded to preliminary but suggestive that further study with larger populations is worthwhile.

  16. Fatal ammonia toxicity in an adult due to an undiagnosed urea cycle defect: under-recognition of ornithine transcarbamylase deficiency.

    Thurlow, Vanessa R; Asafu-Adjaye, Michelle; Agalou, Stamatina; Rahman, Yusof

    2010-05-01

    There is a lack of awareness of acutely presenting inborn errors of metabolism in adults, of which the X-linked urea cycle defect ornithine transcarbamylase (OTC) deficiency is an example, many comparatively mild mutations having been identified. In male hemizygotes clinical manifestations and age at presentation vary and depend on the mutation. In female heterozygotes the clinical spectrum depends on the extent to which the abnormal gene is expressed. Milder versions of the defect may not cause clear clinical symptoms and may remain unrecognized until the person is subjected to an unusually high nitrogen load when they develop severe hyperammonaemia. During acute episodes liver enzymes may be normal or only slightly elevated and occasionally accompanied by coagulopathy, but the key finding is hyperammonaemia. Boys with these milder forms may exhibit abnormal behaviour and be diagnosed with attention deficit hyperactivity disorder. This case illustrates how late presentation of OTC deficiency in a non-specialist centre can be difficult to differentiate from drug abuse, psychiatric illness or encephalopathy. Failure to measure blood ammonia in adults with unexplained key symptoms - particularly prolonged vomiting without diarrhoea and altered mental state/hallucinations, or to recognize the significance of elevated blood ammonia without evidence of liver decompensation can lead to delayed or missed diagnosis.

  17. A Comparison Between Denaturing Gradient Gel Electrophoresis and Denaturing High Performance Liquid Chromatography in Detecting Mutations in Genes Associated with Hereditary Non-Polyposis Colorectal Cancer (HNPCC and the Identification of 9 New Mutations Previously Unidentified by DGGE

    Meldrum Cliff J

    2003-12-01

    Full Text Available Abstract Denaturing high performance liquid chromatography is a relatively new method by which heteroduplex structures formed during the PCR amplification of heterozygote samples can be rapidly identified. The use of this technology for mutation detection in hereditary non-polyposis colorectal cancer (HNPCC has the potential to appreciably shorten the time it takes to analyze genes associated with this disorder. Prior to acceptance of this method for screening genes associated with HNPCC, assessment of the reliability of this method should be performed. In this report we have compared mutation and polymorphism detection by denaturing gradient gel electrophoresis (DGGE with denaturing high performance liquid chromatography (DHPLC in a set of 130 families. All mutations/polymorphisms representing base substitutions, deletions, insertions and a 23 base pair inversion were detected by DHPLC whereas DGGE failed to identify four single base substitutions and a single base pair deletion. In addition, we show that DHPLC has been used for the identification of 5 different mutations in exon 7 of hMSH2 that could not be detected by DGGE. From this study we conclude that DHPLC is a more effective and rapid alternative to the detection of mutations in hMSH2 and hMLH1 with the same or better accuracy than DGGE. Furthermore, this technique offers opportunities for automation, which have not been realised for the majority of other methods of gene analysis.

  18. Using Random Amplified Polymorphic DNA to Assess Genetic Diversity and Structure of Natural Calophyllum brasiliense (Clusiaceae Populations in Riparian Forests

    Evânia Galvão Mendonça

    2014-01-01

    Full Text Available The objective of this study was to assess the genetic variability in two natural populations of Calophyllum brasiliense located along two different rivers in the state of Minas Gerais, Brazil, using RAPD molecular markers. Eighty-two polymorphic fragments were amplified using 27 primers. The values obtained for Shannon index (I were 0.513 and 0.530 for the populations located on the margins of the Rio Grande and Rio das Mortes, respectively, demonstrating the high genetic diversity in the studied populations. Nei’s genetic diversity (He was 0.341 for the Rio Grande population and 0.357 for the Rio das Mortes population. These results were not significantly different between populations and suggest a large proportion of heterozygote individuals within both populations. AMOVA showed that 70.42% of the genetic variability is found within populations and 29.58% is found among populations (ФST=0.2958. The analysis of kinship coefficients detected the existence of family structures in both populations. Average kinship coefficients between neighboring individuals were 0.053 (P<0.001 in Rio das Mortes and 0.040 (P<0.001 in Rio Grande. This could be due to restricted pollen and seed dispersal and the history of anthropogenic disturbance in the area. These factors are likely to contribute to the relatedness observed among these genotypes.

  19. A novel albumin gene mutation (R222I) in familial dysalbuminemic hyperthyroxinemia.

    Schoenmakers, Nadia; Moran, Carla; Campi, Irene; Agostini, Maura; Bacon, Olivia; Rajanayagam, Odelia; Schwabe, John; Bradbury, Sonia; Barrett, Timothy; Geoghegan, Frank; Druce, Maralyn; Beck-Peccoz, Paolo; O'Toole, Angela; Clark, Penelope; Bignell, Michelle; Lyons, Greta; Halsall, David; Gurnell, Mark; Chatterjee, Krishna

    2014-07-01

    Familial dysalbuminemic hyperthyroxinemia, characterized by abnormal circulating albumin with increased T4 affinity, causes artefactual elevation of free T4 concentrations in euthyroid individuals. Four unrelated index cases with discordant thyroid function tests in different assay platforms were investigated. Laboratory biochemical assessment, radiolabeled T4 binding studies, and ALB sequencing were undertaken. (125)I-T4 binding to both serum and albumin in affected individuals was markedly increased, comparable with known familial dysalbuminemic hyperthyroxinemia cases. Sequencing showed heterozygosity for a novel ALB mutation (arginine to isoleucine at codon 222, R222I) in all four cases and segregation of the genetic defect with abnormal biochemical phenotype in one family. Molecular modeling indicates that arginine 222 is located within a high-affinity T4 binding site in albumin, with substitution by isoleucine, which has a smaller side chain predicted to reduce steric hindrance, thereby facilitating T4 and rT3 binding. When tested in current immunoassays, serum free T4 values from R222I heterozygotes were more measurably abnormal in one-step vs two-step assay architectures. Total rT3 measurements were also abnormally elevated. A novel mutation (R222I) in the ALB gene mediates dominantly inherited dysalbuminemic hyperthyroxinemia. Susceptibility of current free T4 immunoassays to interference by this mutant albumin suggests likely future identification of individuals with this variant binding protein.

  20. Prevalence of MTHFR gene polymorphisms (C677T and A1298C) among Tamilians.

    Angeline, T; Jeyaraj, Nirmala; Granito, Selena; Tsongalis, Gregory J

    2004-10-01

    We have investigated the incidence of the C677T and A1298C methylene tetrahydrofolate reductase (MTHFR) gene single nucleotide polymorphisms (SNPs) in the South Indian Tamil Nadu population with a total number of 72 individuals. The MTHFR genotyping was performed using the polymerase chain reaction followed by restriction enzyme analysis. Homozygosity for the MTHFR A1298C SNP was detected in 15.3% (11/72) of the individuals tested, and 47.2% (34/72) were heterozygous for this SNP. Homozygosity for the C677T MTHFR SNP was detected in 1.38%(1/72), and the frequency of the C677T heterozygotes was 18.1%(13/72). When we analyzed the combined frequency of the two SNPs, the frequency of double heterozygosity was19.6%, and the frequency of double homozygosity was completely absent among the study group. The 'C' allele frequency for MTHFR A1298C was 0.389, and the 'T' allele frequency for C677T mutation was 0.104. Out of the 72 individuals included in the study, 52 were acute myocardial infarction (AMI) patients and 20 were healthy individuals with no documented history of heart disease. The results of this study indicate that the MTHFR A1298C SNP is more prevalent among the Tamilians when compared to the MTHFR C677T SNP, suggesting a possible role of MTHFR A1298C in the pathogenesis of heart diseases.