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Sample records for hfe gene c282y

  1. Ancestral association between HLA and HFE H63D and C282Y gene mutations from northwest Colombia

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    Libia M Rodriguez

    2015-03-01

    Full Text Available A significant association between HFE gene mutations and the HLA-A*03-B*07 and HLA-A*29-B*44 haplotypes has been reported in the Spanish population. It has been proposed that these mutations are probably connected with Celtic and North African ancestry, respectively. We aimed to find the possible ancestral association between HLA alleles and haplotypes associated with the HFE gene (C282Y and H63D mutations in 214 subjects from Antioquia, Colombia. These were 18 individuals with presumed hereditary hemochromatosis (“HH” and 196 controls. The HLA-B*07 allele was in linkage disequilibrium (LD with C282Y, while HLA-A*23, A*29, HLA-B*44, and B*49 were in LD with H63D. Altogether, our results show that, although the H63D mutation is more common in the Antioquia population, it is not associated with any particular HLA haplotype, whereas the C282Y mutation is associated with HLA-A*03-B*07, this supporting a northern Spaniard ancestry.

  2. Clinical characteristics and analysis of HFE gene variants (C282Y ...

    African Journals Online (AJOL)

    Age-related macular degeneration (AMD) is a complex genetic disorder with multiple etiologies. Multiple genes as well as environmental effects are thought to play a role in causing AMD. Recent evidence pointed that elevated iron overload, resulting from hereditary defects of iron homeostasis, is associated with retinal ...

  3. Mutations in HAMP and HJV genes and their impact on expression of clinical hemochromatosis in a cohort of 100 Spanish patients homozygous for the C282Y mutation of HFE gene.

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    Altès, Albert; Bach, Vanessa; Ruiz, Angels; Esteve, Anna; Felez, Jordi; Remacha, Angel F; Sardà, M Pilar; Baiget, Montserrat

    2009-10-01

    Most hereditary hemochromatosis (HH) patients are homozygous for the C282Y mutation of the HFE gene. Nevertheless, penetrance of the disease is very variable. In some patients, penetrance can be mediated by concomitant mutations in other iron master genes. We evaluated the clinical impact of hepcidin (HAMP) and hemojuvelin mutations in a cohort of 100 Spanish patients homozygous for the C282Y mutation of the HFE gene. HAMP and hemojuvelin mutations were evaluated in all patients by bidirectional direct cycle sequencing. Phenotype-genotype interactions were evaluated. A heterozygous mutation of the HAMP gene (G71D) was found in only one out of 100 cases. Following, we performed a study of several members of that family, and we observed several members had a digenic inheritance of the C282Y mutation of the HFE gene and the G71D mutation of the HAMP gene. This mutation in the HAMP gene did not modify the phenotype of the individuals who were homozygous for the C282Y mutation. One other patient presented a new polymorphism in the hemojuvelin gene, without consequences in iron load or clinical course of the disease. In conclusion, HAMP and hemojuvelin mutations are rare among Spanish HH patients, and their impact in this population is not significant.

  4. Hepatocellular carcinoma and the penetrance of HFE C282Y mutations: a cross sectional study

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    Lonsdale Ray

    2005-06-01

    Full Text Available Abstract Background Although most patients with hereditary haemochromatosis have HFE C282Y mutations, the lifetime risk to HFE C282Y homozygotes of developing fatal diseases such as hepatocellular carcinoma is uncertain. We have carried out a cross-sectional study to determine the proportion of diagnosed hepatocellular carcinoma patients who are homozygous for the HFE C282Y mutation; and to estimate the penetrance of this genotype with respect to hepatocellular carcinoma in East Anglia. Methods Tissue biopsies were analysed from 144 cases of hepatocellular carcinoma for HFE C282Y mutations; the data produced were compared with the frequency of HFE mutations in a large sample of the local population. Data were also retrieved from the East Anglian Cancer Intelligence Unit to determine the annual incidence of hepatocellular carcinoma; and from appropriate life tables. Results Eight out of 144 of the cases were homozygous for the HFE C282Y mutation, all 8 cases were male. 6 of these 8 cases had a previous diagnosis of hereditary haemochromatosis. Male HFE C282Y homozygotes were more likely to be diagnosed with hepatocellular carcinoma (odds ratio [OR] = 14, 95% confidence interval [CI] = 5–37. For this population, we estimate that the penetrance of the HFE C282Y homozygous genotype, with respect to hepatocellular carcinoma, was between 1.31 % and 2.1% for males and was zero for females. Conclusion In this population, we found that only a very small proportion of homozygotes for the HFE C282Y mutation developed hepatocellular carcinoma. However, individuals with this genotype have a significantly increased risk of this rare disease relative to those who do not carry the mutations.

  5. HFE C282Y homozygosity is associated with an increased risk of total hip replacement for osteoarthritis.

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    Wang, Yuanyuan; Gurrin, Lyle C; Wluka, Anita E; Bertalli, Nadine A; Osborne, Nicholas J; Delatycki, Martin B; Giles, Graham G; English, Dallas R; Hopper, John L; Simpson, Julie A; Graves, Stephen; Allen, Katrina J; Cicuttini, Flavia M

    2012-06-01

    The evidence for an association between mutations in the HFE (hemochromatosis) gene and the risk of hip or knee osteoarthritis is inconsistent. Total joint replacement is considered a surrogate measure for symptomatic end-stage osteoarthritis. We examined the relationship between HFE gene mutations and risk of total hip and knee replacement using a prospective cohort study. The Melbourne Collaborative Cohort Study recruited participants between 1990 and 1994. Participants born in Australia, New Zealand, the United Kingdom, or Ireland (n = 27,848) were genotyped for the HFE C282Y mutation. Total hip and knee replacements for osteoarthritis during 2001 to 2009 were ascertained from the Australian Orthopaedic Association National Joint Replacement Registry. Hazard ratios (HR)/odds ratios (OR) and confidence intervals (CI) were obtained from Cox regression or logistic regression. Compared with those with no C282Y mutation, C282Y homozygotes had an increased risk of single total hip replacement (HR 1.94, 95% CI 1.04-3.62) and bilateral total hip replacement (OR 5.86, 95% CI 2.36-14.57) for osteoarthritis, adjusting for age, sex, body mass index, and educational level. Only 3 C282Y homozygotes had single total knee replacement; the HR was 0.51 (95% CI 0.16-1.57). C282Y/H63D compound heterozygosity was not related to the risk of total hip or knee replacement. HFE C282Y homozygosity was associated with an increased risk of both single and bilateral total hip replacement for osteoarthritis. Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.

  6. The origin and spread of the HFE-C282Y haemochromatosis mutation.

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    Distante, S; Robson, K J H; Graham-Campbell, J; Arnaiz-Villena, A; Brissot, P; Worwood, Mark

    2004-09-01

    The mutation responsible for most cases of genetic haemochromatosis in Europe (HFE C282Y) appears to have been originated as a unique event on a chromosome carrying HLA-A3 and -B7. It is often described as a "Celtic mutation"--originating in a Celtic population in central Europe and spreading west and north by population movement. It has also been suggested that Viking migrations were largely responsible for the distribution of this mutation. Two, initial estimates of the age of the mutation are compatible with either of these suggestions. Here we examine the evidence about HFE C282Y frequencies, extended haplotypes involving HLA-A and -B alleles, the validity of calculations of mutation age, selective advantage and current views on the relative importance of "demic-diffusion" (population migration) and "adoption-diffusion" (cultural change) in the neolithic transition in Europe and since then. We conclude that the HFE C282Y mutation occurred in mainland Europe before 4,000 BC.

  7. Expression of hereditary hemochromatosis C282Y HFE protein in HEK293 cells activates specific endoplasmic reticulum stress responses

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    Norris Suzanne

    2007-07-01

    Full Text Available Abstract Background Hereditary Hemochromatosis (HH is a genetic disease associated with iron overload, in which individuals homozygous for the mutant C282Y HFE associated allele are at risk for the development of a range of disorders particularly liver disease. Conformational diseases are a class of disorders associated with the expression of misfolded protein. HFE C282Y is a mutant protein that does not fold correctly and consequently is retained in the Endoplasmic Reticulum (ER. In this context, we sought to identify ER stress signals associated with mutant C282Y HFE protein expression, which may have a role in the molecular pathogenesis of HH. Results Vector constructs of Wild type HFE and Mutant C282Y HFE were made and transfected into HEK293 cell lines. We have shown that expression of C282Y HFE protein triggers both an unfolded protein response (UPR, as revealed by the increased GRP78, ATF6 and CHOP expression, and an ER overload response (EOR, as indicated by NF-κB activation. Furthermore, C282Y HFE protein induced apoptotic responses associated with activation of ER stress. Inhibition studies demonstrated that tauroursodeoxycholic acid, an endogenous bile acid, downregulates these events. Finally, we found that the co-existence of both C282Y HFE and Z alpha 1-antitrypsin protein (the protein associated with the liver disease of Z alpha 1-antitrypsin deficiency expression on ER stress responses acted as potential disease modifiers with respect to each other. Conclusion Our novel observations suggest that both the ER overload response (EOR and the unfolded protein response (UPR are activated by mutant C282Y HFE protein.

  8. Transferrin receptor 2 (TfR2) and HFE mutational analysis in non-C282Y iron overload: identification of a novel TfR2 mutation.

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    Mattman, Andre; Huntsman, David; Lockitch, Gillian; Langlois, Sylvie; Buskard, Noel; Ralston, Diana; Butterfield, Yaron; Rodrigues, Pedro; Jones, Steven; Porto, Graça; Marra, Marco; De Sousa, Maria; Vatcher, Greg

    2002-08-01

    Hereditary hemochromatosis (HH) is classically associated with a Cys282Tyr (C282Y) mutation of the HFE gene. Non-C282Y HH is a heterogeneous group accounting for 15% of HH in Northern Europe. Pathogenic mutations of the transferrin receptor 2 (TfR2) gene have been identified in 4 Italian pedigrees with the latter syndrome. The goal of this study was to perform a mutational analysis of the TfR2 and HFE genes in a cohort of non-C282Y iron overload patients of mixed ethnic backgrounds. Several sequence variants were identified within the TfR2 gene, including a homozygous missense change in exon 17, c2069 A-->C, which changes a glutamine to a proline residue at position 690. This putative mutation was found in a severely affected Portuguese man and 2 family members with the same genotype. In summary, pathologic TfR2 mutations are present outside of Italy, accounting for a small proportion of non-C282Y HH.

  9. Serum iron parameters, HFE C282Y genotype, and cognitive performance in older adults: results from the FACIT study

    NARCIS (Netherlands)

    Schiepers, Olga; Van Boxtel, Martin; De Groot, Renate; Jolles, Jelle; De Kort, Wim; Swinkels, Dorine; Kok, Frans; Verhoef, Petra; Durga, Jane

    2010-01-01

    Schiepers, O. J., Van Boxtel, M. P. J., De Groot, R. H. M., Jolles, J., De Kort, W. L., Swinkels, D. W., et al. (2010). Serum iron parameters, HFE C282Y genotype, and cognitive performance in older adults: results from the FACIT study. The Journals of gerontology. Series A, Biological sciences and

  10. Association Studies of HFE C282Y and H63D Variants with Oral Cancer Risk and Iron Homeostasis Among Whites and Blacks

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    Nathan R. Jones

    2015-12-01

    Full Text Available Background: Polymorphisms in the hemochromatosis (HFE gene are associated with excessive iron absorption from the diet, and pro-oxidant effects of iron accumulation are thought to be a risk factor for several types of cancer. Methods: The C282Y (rs1800562 and H63D (rs1799945 polymorphisms were genotyped in 301 oral cancer cases and 437 controls and analyzed in relation to oral cancer risk, and serum iron biomarker levels from a subset of 130 subjects. Results: Individuals with the C282Y allele had lower total iron binding capacity (TIBC (321.2 ± 37.2 µg/dL vs. 397.7 ± 89.0 µg/dL, p = 0.007 and higher percent transferrin saturation (22.0 ± 8.7 vs. 35.6 ± 22.9, p = 0.023 than wild type individuals. Iron and ferritin levels approached significantly higher levels for the C282Y allele (p = 0.0632 and p = 0.0588, respectively. Conclusions: Iron biomarker levels were elevated by the C282Y allele, but neither (rs1800562 nor (rs1799945 was associated with oral cancer risk in blacks and whites.

  11. Porphyria cutanea tarda associated with HFE C282Y homozygosity, iron overload, and use of a contraceptive vaginal ring

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    James C. Barton

    2016-02-01

    Full Text Available Porphyria cutanea tarda (PCT is characterized by decreased uroporphyrinogen decarboxylase activity in hepatocytes, uroporphyrin I and heptacarboxyl porphyrin III accumulation, photosensitivity dermatitis, and increased storage iron. In women, estrogen therapy, including oral contraceptives, postmenopausal hormone replacement, and tamoxifen for breast cancer treatment, is a risk factor for PCT. We report the case of a woman who presented with PCT, HFE C282Y homozygosity, and hepatic iron overload and was using a contraceptive vaginal ring containing ethinyl estradiol, an estrogen. We discuss this case in the context of characteristics of other persons with PCT, including common HFE mutations, iron overload, and estrogen exposure.

  12. Common variable immunodeficiency and IgG subclass deficiency in central Alabama hemochromatosis probands homozygous for HFE C282Y.

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    Barton, James C; Bertoli, Luigi F; Acton, Ronald T

    2003-01-01

    Eight hemochromatosis probands with HFE C282Y homozygosity had frequent, severe, or unusual infections and common variable immunodeficiency (CVID) or immunoglobulin (Ig) G subclass deficiency (IgGSD). Thus, we performed serum Ig isotyping and other characterization of 43 additional unselected probands, 5 human leukocyte antigen (HLA)-identical siblings, and 240 consecutive CVID or IgGSD index patients. C282Y allele frequencies were estimated in 58 CVID or IgGSD index patients without hemochromatosis phenotypes and in 341 controls. HLA-A and -B haplotypes and frequencies were determined in all 51 probands, 186 CVID or IgGSD index patients without hemochromatosis phenotypes, and 751 controls. Thirteen unselected probands (30%) had CVID or IgGSD. Among all 21 hemochromatosis probands with CVID (n = 4) or IgGSD (n = 17), Ig subclass deficiency patterns were IgG(1) (n = 5), IgG(1) and IgG(3) (n = 6), IgG(3) (n = 9), and IgG(1), IgG(3), and IgG(4) (n = 1). IgG(2) or IgA deficiency was not detected; one proband had IgM deficiency. Mean values of total IgG, IgG(1), and IgG(3) were significantly lower in probands with CVID or IgGSD. Mean values of age, transferrin saturation, and ferritin at diagnosis and phlebotomy units required to induce iron depletion were similar in probands with or without CVID or IgGSD; phlebotomy had no apparent effect on IgG levels. C282Y frequencies were similar in CVID or IgGSD index cases without hemochromatosis phenotypes and in controls. There was concordance of Ig and hemochromatosis phenotypes in probands and respective HLA-identical siblings. Eight of 240 CVID or IgGSD index patients had hemochromatosis phenotypes and C282Y homozygosity (3 vs 0.7% and 0.2% controls; P IgG abnormalities characteristic of CVID or IgGSD are common in hemochromatosis probands, and that the prevalence of hemochromatosis is increased in CVID and IgGSD index cases. These observations could be explained by the increased frequencies of HLA-A*03-B*07 in C282Y

  13. Transferrin receptor 2 (TfR2) and HFE mutational analysis in non‐C282Y iron overload: identification of a novel TfR2 mutation

    OpenAIRE

    Mattman, A.; Huntsman, D; Lockitch, G; Langlois, S.; Buskard, N; RALSTON, D.; BUTTERFIELD, Y.; Rodrigues, P; Jones, S.; Porto, G; Marra, M.; Sousa, M; VATCHER, G.

    2002-01-01

    Blood. 2002 Aug 1;100(3):1075-7. Transferrin receptor 2 (TfR2) and HFE mutational analysis in non-C282Y iron overload: identification of a novel TfR2 mutation. Mattman A, Huntsman D, Lockitch G, Langlois S, Buskard N, Ralston D, Butterfield Y, Rodrigues P, Jones S, Porto G, Marra M, De Sousa M, Vatcher G. SourceGenes, Elements, and Metabolism Program, Children and Women's Hospital of British Columbia, Vancouver, British Columbia, Canada. Abstract Hereditary hemochromatosis (HH...

  14. Prevalence of H63D, S65C and C282Y hereditary hemochromatosis gene mutations in Slovenian population by an improved high-throughput genotyping assay

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    Rupreht Ruth

    2007-11-01

    Full Text Available Abstract Background Hereditary hemochromatosis (HH is a common genetic disease characterized by excessive iron overload that leads to multi-organ failure. Although the most prevalent genotype in HH is homozygosity for C282Y mutation of the HFE gene, two additional mutations, H63D and S65C, appear to be associated with a milder form of HH. The aim of this study was to develop a high-throughput assay for HFE mutations screening based on TaqMan technology and to determine the frequencies of HFE mutations in the Slovenian population. Methods Altogether, 1282 randomly selected blood donors from different Slovenian regions and 21 HH patients were analyzed for the presence of HFE mutations by an in-house developed real-time PCR assay based on TaqMan technology using shorter non-interfering fluorescent single nucleotide polymorphism (SNP-specific MGB probes. The assay was validated by RFLP analysis and DNA sequencing. Results The genotyping assay of the H63D, S65C and C282Y mutations in the HFE gene, based on TaqMan technology proved to be fast, reliable, with a high-throughput capability and 100% concordant with genotypes obtained by RFLP and DNA sequencing. The observed frequency of C282Y homozygotes in the group of HH patients was only 48%, others were of the heterogeneous HFE genotype. Among 1282 blood donors tested, the observed H63D, S65C and C282Y allele frequency were 12.8% (95% confidence interval (CI 11.5 – 14.2%, 1.8% (95% CI 1.4 – 2.5% and 3.6% (95% CI 3.0 – 4.5%, respectively. Approximately 33% of the tested subjects had at least one of the three HH mutations, and 1% of them were C282Y homozygotes or compound heterozygotes C282Y/H63D or C282Y/S65C, presenting an increased risk for iron overload disease. A significant variation in H63D allele frequency was observed for one of the Slovenian regions. Conclusion The improved real-time PCR assay for H63D, S65C and C282Y mutations detection is accurate, fast, cost-efficient and ready for

  15. Prevalence of H63D, S65C and C282Y hereditary hemochromatosis gene mutations in Slovenian population by an improved high-throughput genotyping assay.

    Science.gov (United States)

    Cukjati, Marko; Vaupotic, Tomaz; Rupreht, Ruth; Curin-Serbec, Vladka

    2007-11-23

    Hereditary hemochromatosis (HH) is a common genetic disease characterized by excessive iron overload that leads to multi-organ failure. Although the most prevalent genotype in HH is homozygosity for C282Y mutation of the HFE gene, two additional mutations, H63D and S65C, appear to be associated with a milder form of HH. The aim of this study was to develop a high-throughput assay for HFE mutations screening based on TaqMan technology and to determine the frequencies of HFE mutations in the Slovenian population. Altogether, 1282 randomly selected blood donors from different Slovenian regions and 21 HH patients were analyzed for the presence of HFE mutations by an in-house developed real-time PCR assay based on TaqMan technology using shorter non-interfering fluorescent single nucleotide polymorphism (SNP)-specific MGB probes. The assay was validated by RFLP analysis and DNA sequencing. The genotyping assay of the H63D, S65C and C282Y mutations in the HFE gene, based on TaqMan technology proved to be fast, reliable, with a high-throughput capability and 100% concordant with genotypes obtained by RFLP and DNA sequencing. The observed frequency of C282Y homozygotes in the group of HH patients was only 48%, others were of the heterogeneous HFE genotype. Among 1282 blood donors tested, the observed H63D, S65C and C282Y allele frequency were 12.8% (95% confidence interval (CI) 11.5-14.2%), 1.8% (95% CI 1.4-2.5%) and 3.6% (95% CI 3.0-4.5%), respectively. Approximately 33% of the tested subjects had at least one of the three HH mutations, and 1% of them were C282Y homozygotes or compound heterozygotes C282Y/H63D or C282Y/S65C, presenting an increased risk for iron overload disease. A significant variation in H63D allele frequency was observed for one of the Slovenian regions. The improved real-time PCR assay for H63D, S65C and C282Y mutations detection is accurate, fast, cost-efficient and ready for routine screening and diagnostic procedures. The genotype frequencies in

  16. Serum hepcidin levels are innately low in HFE-related haemochromatosis but differ between C282Y-homozygotes with elevated and normal ferritin levels.

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    van Dijk, Boukje A C; Laarakkers, Coby M M; Klaver, Siem M; Jacobs, Esther M G; van Tits, Lambertus J H; Janssen, Mirian C H; Swinkels, Dorine W

    2008-09-01

    HFE C282Y-homozygosity has been associated with low hepcidin expression, leading to increased ferritin levels. However, serum hepcidin protein levels have not been documented in humans. In the current study, we compared serum hepcidin levels of newly diagnosed HFE C282Y-homozygotes with (N = 15) and without (N = 7) elevated serum ferritin levels to levels of 40 controls (20 heterozygotes and 20 wild types). In addition, hepcidin levels of four C282Y homozygotes were investigated during the course of all phlebotomy treatment phases. Serum hepcidin levels were lower in HFE C282Y-homozygotes (median; 25th-75th percentile: 1.88; 0.78-2.77 nmol/l) compared to controls (2.74; 1.45-5.39). Hepcidin/ferritin ratios were also lower in homozygotes. Homozygotes with an elevated serum ferritin had a higher serum hepcidin but a lower hepcidin/ferritin ratio than those with normal ferritin (2.28; 1.62-3.23 nmol/l hepcidin vs. 0.80; 0.60-1.29 and 3.63; 2.72-7.59 pmol hepcidin/microg ferritin vs. 13.2; 5.15-14.2). Serum hepcidin decreased during the depletion phase of phlebotomy and remained low during maintenance. This study showed that serum hepcidin is innately low in HFE-related haemochromatosis. Elevated ferritin levels were associated with increased hepcidin levels while erythropoiesis lead to lower hepcidin levels. During depletion, therefore, hepcidin levels are decreased, which may exacerbate intestinal iron absorption.

  17. GNPAT p.D519G is independently associated with markedly increased iron stores in HFE p.C282Y homozygotes.

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    Barton, James C; Chen, Wen-Pin; Emond, Mary J; Phatak, Pradyumna D; Subramaniam, V Nathan; Adams, Paul C; Gurrin, Lyle C; Anderson, Gregory J; Ramm, Grant A; Powell, Lawrie W; Allen, Katrina J; Phillips, John D; Parker, Charles J; McLaren, Gordon D; McLaren, Christine E

    2017-03-01

    GNPAT p.D519G positivity is significantly increased in HFE p.C282Y homozygotes with markedly increased iron stores. We sought to determine associations of p.D519G and iron-related variables with iron stores in p.C282Y homozygotes. We defined markedly increased iron stores as serum ferritin >2247pmol/L (>1000μg/L) and either hepatic iron >236μmol/g dry weight or iron >10g by induction phlebotomy (men and women). We defined normal or mildly elevated iron stores as serum ferritin stores with these variables: age; iron supplement use (dichotomous); whole blood units donated; erythrocyte units received as transfusion; daily alcohol consumption, g; and p.D519G positivity (heterozygosity or homozygosity). The mean age of 56 participants (94.6% men) was 55±10 (SD) y; 41 had markedly increased iron stores. Prevalences of swollen/tender 2nd/3rd metacarpophalangeal joints and elevated aspartate or alanine aminotransferase were significantly greater in participants with markedly increased iron stores. Only participants with markedly increased iron stores had cirrhosis. In multivariable analyses, p.D519G positivity was the only exposure variable significantly associated with markedly increased iron stores (odds ratio 9.9, 95% CI [1.6, 60.3], p=0.0126). GNPAT p.D519G is strongly associated with markedly increased iron stores in p.C282Y homozygotes after correction for age, iron-related variables, and alcohol consumption. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. HFE, SLC40A1, HAMP, HJV, TFR2, and FTL mutations detected by denaturing high-performance liquid chromatography after iron phenotyping and HFE C282Y and H63D genotyping in 785 HEIRS Study participants.

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    Barton, James C; Lafreniere, Susie A; Leiendecker-Foster, Catherine; Li, Honggui; Acton, Ronald T; Press, Richard D; Eckfeldt, John H

    2009-11-01

    We sought to identify mutations that could explain iron phenotype heterogeneity in adults with previous HFE genotyping to detect C282Y and H63D. HEIRS Study participants genotyped for C282Y and H63D were designated as high transferrin saturation (TS) and/or serum ferritin (SF) (high TS/SF), low TS/SF, or controls. We grouped 191 C282Y homozygotes as high TS/SF, low TS/SF, or controls, and 594 other participants by race/ethnicity as high TS/SF or controls. Using denaturing high-performance liquid chromatography (DHPLC), we screened 20 regions of HFE, SLC40A1, HAMP, HJV, TFR2, and FTL in each participant. DHPLC analyses were successful in 99.3% of 791 participants and detected 117 different mutations. In C282Y homozygotes, 4.0% of high TS/SF participants had SLC40A1 Q248H, HAMP -72C>T, or HAMP R59G heterozygosity (0% Controls; P = 0.1200). In whites, 4.1% with high TS/SF and 1.3% of controls had HFE S65C or E168Q (P = 0.3049). HJV c.-6C>G and FTL L55L frequencies were greater in whites with high TS/SF than controls (0.0811 vs. 0.0200, P = 0.0144; 0.5743 vs. 0.4400, P = 0.0204, respectively). One Hispanic with high TS/SF (1.3%) had HAMP G71D heterozygosity. In blacks, SLC40A1 Q248H frequencies did not differ significantly between high TS/SF and control participants. Among Asians, 2.8% with high TS/SF were HFE V295A heterozygotes. Mutations other than HFE C282Y and H63D reported to be pathogenic were infrequently detected in high TS/SF participants. Genetic regions in linkage disequilibrium with HJV c.-6C>G and FTL L55L could partly explain high TS/SF phenotypes in whites. Am. J. Hematol., 2009. Published 2009 Wiley-Liss, Inc.

  19. Effect of Hereditary Hemochromatosis Gene H63D and C282Y Mutations on Iron Overload in Sickle Cell Disease Patients

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    Yunus Kasım Terzi

    2016-12-01

    Full Text Available Objective: Hemochromatosis is an autosomal recessive disease that is one of the most important reasons for iron overload. Sickle cell disease is a hemoglobinopathy that occurs as a result of a homozygous mutation in the hemoglobin gene. Erythrocyte transfusion is frequently used in the treatment of this disease. Iron overload as a result of transfusion is important in the mortality and morbidity of sickle cell anemia patients as well as in other hemoglobinopathies. In this study, the effect of hemochromatosis gene (HFE p.H63D and p.C282Y mutations on transfusion-related cardiac and liver iron overload in sickle cell disease patients who carry homozygous hemoglobin S mutation has been investigated. Materials and Methods: This is a prospective single-center crosssectional study in patients with homozygous hemoglobin S mutation between the years 2008 and 2013. The patients were divided into two groups. The first group (group A, n=31 was receiving chelation therapy and the second group (group B, n=13 was not. Direct and indirect iron loads were analyzed by magnetic resonance imaging and biochemically, respectively. HFE gene mutations were analyzed by polymerase chain reaction-restriction fragment length polymorphism method. Statistical analyses were performed by independent samples t-test. Results: p.H63D mutation was detected in 10 (32.3% patients in group A and in only 1 patient (7.7% in group B. When the 2 groups were compared for iron overload, iron deposition in the liver was significantly higher in group B (p=0.046. In addition, in group A, iron deposition was significantly higher in HFE mutation carriers compared to patients without the mutation (p=0.05. Conclusion: Results of this study showed that HFE gene mutations are important in iron deposition in the liver in patients with sickle cell disease.

  20. Effects of highly conserved major histocompatibility complex (MHC extended haplotypes on iron and low CD8+ T lymphocyte phenotypes in HFE C282Y homozygous hemochromatosis patients from three geographically distant areas.

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    Mónica Costa

    Full Text Available Hereditary Hemochromatosis (HH is a recessively inherited disorder of iron overload occurring commonly in subjects homozygous for the C282Y mutation in HFE gene localized on chromosome 6p21.3 in linkage disequilibrium with the human leukocyte antigen (HLA-A locus. Although its genetic homogeneity, the phenotypic expression is variable suggesting the presence of modifying factors. One such genetic factor, a SNP microhaplotype named A-A-T, was recently found to be associated with a more severe phenotype and also with low CD8(+T-lymphocyte numbers. The present study aimed to test whether the predictive value of the A-A-T microhaplotype remained in other population settings. In this study of 304 HH patients from 3 geographically distant populations (Porto, Portugal 65; Alabama, USA 57; Nord-Trøndelag, Norway 182, the extended haplotypes involving A-A-T were studied in 608 chromosomes and the CD8(+ T-lymphocyte numbers were determined in all subjects. Patients from Porto had a more severe phenotype than those from other settings. Patients with A-A-T seemed on average to have greater iron stores (p = 0.021, but significant differences were not confirmed in the 3 separate populations. Low CD8(+ T-lymphocytes were associated with HLA-A*03-A-A-T in Porto and Alabama patients but not in the greater series from Nord-Trøndelag. Although A-A-T may signal a more severe iron phenotype, this study was unable to prove such an association in all population settings, precluding its use as a universal predictive marker of iron overload in HH. Interestingly, the association between A-A-T and CD8(+ T-lymphocytes, which was confirmed in Porto and Alabama patients, was not observed in Nord-Trøndelag patients, showing that common HLA haplotypes like A*01-B*08 or A*03-B*07 segregating with HFE/C282Y in the three populations may carry different messages. These findings further strengthen the relevance of HH as a good disease model to search for novel candidate loci

  1. Prevalence of the C282Y mutation for haemochromatosis on the Island of Majorca.

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    Guix, P; Picornell, A; Parera, M; Tomás, C; Muncunill, J; Castro, J A; Rossell, J; Vaquer, P; Ramon, M M; Obrador, A

    2000-08-01

    The C282Y mutation of the HFE gene has been reported to be present in most of the patients with hereditary haemochromatosis (HH) of Northern European ancestry. HH affects approximately 1/300 individuals, but it is not evenly distributed in the different European countries. In the present study, polymerase chain reaction (PCR) and restriction-enzyme digestion were used to analyse the frequency of the most important mutation in haemochromatosis (C282Y) in subjects from Majorca (Balearic Islands, Spain) and patients with haemochromatosis. The results were compared with other studies from Spain and Europe. A total of 420 Majorcan chromosomes were analysed and the C282Y mutation was observed at a frequency of 2.62%+/-0.8 (11 heterozygotes: eight men and three women). In the group of hereditary haemochromatosis probands, 13 out of 14 were homozygous for the C282Y mutation. In the distribution of the C282Y mutation, a north-west to south-east cline was detected, supporting the Celtic origin of this mutation.

  2. Frequency of the HFE C282Y and H63D mutations in Danish patients with clinical haemochromatosis initially diagnosed by phenotypic methods

    DEFF Research Database (Denmark)

    Milman, Nils; Koefoed, Pernille; Pedersen, Palle

    2003-01-01

    diagnosis of clinical idiopathic haemochromatosis was made before blood samples were taken for HFE genotyping. The total series consisted of 58 patients (40 men and 18 women) with a median age of 60 yrs (range 18-74). HFE genotyping was performed by the polymerase chain reaction (PCR) technique. RESULTS...... idiopathic haemochromatosis diagnosed by phenotypic methods (serum transferrin saturation, serum ferritin, liver biopsy and mobilisable body iron stores). In 32 unrelated patients, frozen blood samples were available for genetic analysis. In a subsequent series of 26 unrelated Danish patients, a phenotypic...... appears to be the prevailing cause of clinically overt genetic haemochromatosis. This finding has implications both for the evaluation of patients with iron overload disorders and for the strategy in future population screening surveys....

  3. Study of the effect of HFE gene mutations on iron overload in ...

    African Journals Online (AJOL)

    Background: HFE gene mutations have been shown to be responsible for hereditary hemochromatosis. Their effect on iron load in β-thalassemia patients and carriers remains controversial. Objectives: We aimed to determine the prevalence of HFE gene mutations (C282Y and H63D) in β-thalassemia patients and carriers ...

  4. Study of the effect of HFE gene mutations on iron overload in ...

    African Journals Online (AJOL)

    Manal Michel Wilson

    2015-03-04

    Mar 4, 2015 ... Abstract Background: HFE gene mutations have been shown to be responsible for hereditary hemochromatosis. Their effect on iron load in b-thalassemia patients and carriers remains contro- versial. Objectives: We aimed to determine the prevalence of HFE gene mutations (C282Y and H63D) in.

  5. Analysis of HFE and non-HFE gene mutations in Brazilian patients with hemochromatosis

    Directory of Open Access Journals (Sweden)

    Paulo Lisboa Bittencourt

    2009-01-01

    Full Text Available BACKGROUND: Approximately one-half of Brazilian patients with hereditary hemochromatosis (HH are neither homozygous for the C282Y mutation nor compound heterozygous for the H63D and C282Y mutations that are associated with HH in Caucasians. Other mutations have been described in the HFE gene as well as in genes involved in iron metabolism, such as transferrin receptor 2 (TfR2 and ferroportin 1 (SCL40A1. AIMS: To evaluate the role of HFE, TfR2 and SCL40A1 mutations in Brazilian subjects with HH. PATIENTS AND METHODS: Nineteen male subjects (median age 42 [range: 20-72] years with HH were evaluated using the Haemochromatosis StripAssay A®. This assay is capable of detecting twelve HFE mutations, which are V53M, V59M, H63D, H63H, S65C, Q127H, P160delC, E168Q, E168X, W169X, C282Y and Q283, four TfR2 mutations, which are E60X, M172K, Y250X, AVAQ594-597del, and two SCL40A1 mutations, which are N144H and V162del. RESULTS: In our cohort, nine (47% patients were homozygous for the C282Y mutation, two (11% were heterozygous for the H63D mutation, and one each (5% was either heterozygous for C282Y or compound heterozygous for C282Y and H63D. No other mutations in the HFE, TfR2 or SCL40A1 genes were observed in the studied patients. CONCLUSIONS: One-third of Brazilian subjects with the classical phenotype of HH do not carry HFE or other mutations that are currently associated with the disease in Caucasians. This observation suggests a role for other yet unknown mutations in the aforementioned genes or in other genes involved in iron homeostasis in the pathogenesis of HH in Brazil.

  6. HFE-Related Hemochromatosis: The Haptoglobin 2-2 Type Has a Significant but Limited Influence on Phenotypic Expression of the Predominant p.C282Y Homozygous Genotype

    Directory of Open Access Journals (Sweden)

    Gérald Le Gac

    2009-01-01

    In this study we investigated influence of Hp2-2 and of potential confounders on the iron indices of 351 p.C282Y homozygous patients. We conclude that there is a cause-and-effect relationship between the Hp2-2 genotype and increased iron indices in p.C282Y homozygous patients. The Hp2-2 effect is, however, limited and only apparent in males.

  7. HFE gene mutations and iron status of Brazilian blood donors

    Directory of Open Access Journals (Sweden)

    P.C.J.L. Santos

    2010-01-01

    Full Text Available Mutations of the HFE and TFR2 genes have been associated with iron overload. HFE and TFR2 mutations were assessed in blood donors, and the relationship with iron status was evaluated. Subjects (N = 542 were recruited at the Hemocentro da Santa Casa de São Paulo, São Paulo, Brazil. Iron status was not influenced by HFE mutations in women and was independent of blood donation frequency. In contrast, men carrying the HFE 282CY genotype had lower total iron-binding capacity (TIBC than HFE 282CC genotype carriers. Men who donated blood for the first time and were carriers of the HFE 282CY genotype had higher transferrin saturation values and lower TIBC concentrations than those with the homozygous wild genotype for the HFE C282Y mutation. Moreover, in this group of blood donors, carriers of HFE 63DD plus 63HD genotypes had higher serum ferritin values than those with the homozygous wild genotype for HFE H63D mutation. Multiple linear regression analysis showed that HFE 282CY leads to a 17.21% increase (P = 0.018 and a 83.65% decrease (P = 0.007 in transferrin saturation and TIBC, respectively. In addition, serum ferritin is influenced by age (3.91%, P = 0.001 and the HFE 63HD plus DD genotype (55.84%, P = 0.021. In conclusion, the HFE 282Y and 65C alleles were rare, while the HFE 63D allele was frequent in Brazilian blood donors. The HFE C282Y and H63D mutations were associated with alterations in iron status in blood donors in a gender-dependent manner.

  8. Hemochromatosis (HFE gene mutations in Brazilian chronic hemodialysis patients

    Directory of Open Access Journals (Sweden)

    F.V. Perícole

    2005-09-01

    Full Text Available Patients with chronic renal insufficiency (CRI have reduced hemoglobin levels, mostly as a result of decreased kidney production of erythropoietin, but the relation between renal insufficiency and the magnitude of hemoglobin reduction has not been well defined. Hereditary hemochromatosis is an inherited disorder of iron metabolism. The importance of the association of hemochromatosis with treatment for anemia among patients with CRI has not been well described. We analyzed the frequency of the C282Y and H63D mutations in the HFE gene in 201 Brazilian individuals with CRI undergoing hemodialysis. The analysis of the effects of HFE mutations on iron metabolism and anemia with biochemical parameters was possible in 118 patients of this study (hemoglobin, hematocrit, ferritin levels, transferrin saturation, and serum iron. A C282Y heterozygous mutation was found in 7/201 (3.4% and H63D homozygous and heterozygous mutation were found in 2/201 (1.0% and 46/201 (22.9%, respectively. The allelic frequencies of the HFE mutations (0.017 for C282Y mutation and 0.124 for H63D mutation did not differ between patients with CRI and healthy controls. Regarding the biochemical parameters, no differences were observed between HFE heterozygous and mutation-negative patients, although ferritin levels were not higher among patients with the H63D mutation (P = 0.08. From what we observed in our study, C282Y/H63D HFE gene mutations are not related to degrees of anemia or iron stores in CRI patients receiving intravenous iron supplementation (P > 0.10. Nevertheless, the present data suggest that the H63D mutation may have an important function as a modulating factor of iron overload in these patients.

  9. The 16189 variant of mitochondrial DNA occurs more frequently in C282Y homozygotes with haemochromatosis than those without iron loading.

    Science.gov (United States)

    Livesey, K J; Wimhurst, V L C; Carter, K; Worwood, M; Cadet, E; Rochette, J; Roberts, A G; Pointon, J J; Merryweather-Clarke, A T; Bassett, M L; Jouanolle, A-M; Mosser, A; David, V; Poulton, J; Robson, K J H

    2004-01-01

    Patients with hereditary haemochromatosis (HH) are usually homozygous for the C282Y mutation in the HFE gene. They have variable expression of iron overload and present with a variety of complications, including liver disease, diabetes, arthropathy, fatigue, and cardiomyopathy. The mitochondrial 16189 variant is associated with diabetes, dilated cardiomyopathy, and low body fat at birth, and might contribute to genetic predisposition in further multifactorial disorders. The objective of this study was to determine the frequency of the 16189 variant in a range of patients with haemochromatosis, who had mutations in the HFE gene. Blood DNA was analysed for the presence of the 16189 variant in British, French, and Australian C282Y homozygotes and controls, with known iron status, and in birth cohorts. The frequency of the mitochondrial 16189 variant was found to be elevated in individuals with haemochromatosis who were homozygous for the C282Y allele, compared with population controls and with C282Y homozygotes who were asymptomatic (42/292 (14.4%); 102/1186 (8.6%) (p = 0.003); and 2/64 (3.1%) (p = 0.023), respectively). Iron loading in C282Y homozygotes with HH was exacerbated by the presence of the mitochondrial 16189 variant.

  10. Homozygosity For The C282Y Substitution In The HFE Gene: The Incomplete Penetrance And Variable Expressivity

    Directory of Open Access Journals (Sweden)

    Dilum Ekanayake

    2015-01-01

    Full Text Available The syndrome of hepatic cirrhosis diabetes and skin pigmentation (‘Bronze diabetes’ has been well documented, including its propensity to lead to hepatocellular cancer. However, this picture of advanced disease is much less common nowadays with increased awareness and early diagnosis. However, in addition to this, it has been increasingly recognised that in contrast to other diseases inherited as autosomal recessive traits, subjects carrying the genetic predisposition infrequently develop overt disease. This is due only in part to physiological and pathological blood loss, and further relevant genetic mutations have been anticipated. Indeed, an international consortium has recently identified that the genetic variant ( GNPAT has been identified as predisposing to iron overload related disease. Further mutations can be anticipated and will assist in early diagnosis and treatment as well as identifying subjects predisposed to significant iron overload.

  11. Precipitating factors of porphyria cutanea tarda in Brazil with emphasis on hemochromatosis gene (HFE) mutations. Study of 60 patients

    OpenAIRE

    Vieira, Fatima Mendonça Jorge; Nakhle, Maria Cristina; ABRANTES-LEMOS, Clarice Pires; Cançado,Eduardo Luiz Rachid; Reis,Vitor Manoel Silva dos

    2013-01-01

    BACKGROUND: Porphyria cutanea tarda is the most common form of porphyria, characterized by the decreased activity of the uroporphyrinogen decarboxylase enzyme. Several reports associated HFE gene mutations of hereditary hemochromatosis with porphyria cutanea tarda worldwide, although up to date only one study has been conducted in Brazil. OBJECTIVES: Investigation of porphyria cutanea tarda association with C282Y and H63D mutations in the HFE gene. Identification of precipitating factors...

  12. Study of the HFE gene common polymorphisms in French patients with sporadic amyotrophic lateral sclerosis.

    Science.gov (United States)

    Praline, Julien; Blasco, Hélène; Vourc'h, Patrick; Rat, Valérian; Gendrot, Chantal; Camu, William; Andres, Christian R

    2012-06-15

    Our objective was to investigate whether the C282Y (p.Cys 282 Tyr) and H63D (p. His 63 Asp) HFE polymorphisms were associated with sporadic amyotrophic lateral sclerosis (SALS) in the French population. We searched for a relation of HFE polymorphisms with the clinical characteristics of the disease. The HFE polymorphisms were studied in 824 patients with SALS and 583 controls. We compared the frequency of the polymorphisms between SALS and controls groups by univariate and multivariate statistics, taking into account gender, site, age-at-onset and survival. We did not observe significant difference in the frequency of H63D polymorphism between SALS and control group. We observed a significant difference for C282Y between patients and controls with a low frequency of the Y allele in patients (3.2%) compared to our control group (5.9%). Disease duration, distribution of gender, site-of-onset, age-at-onset did not differ between groups taking into account genotypes of each polymorphism. Our results in this large cohort of ALS patients indicate that H63D polymorphism is not associated with SALS in the French population. This conclusion does not exclude a weak effect of the HFE gene polymorphisms in certain ALS populations, or an effect of other rare HFE gene variants. Copyright © 2012 Elsevier B.V. All rights reserved.

  13. HFE gene polymorphisms and the risk for autism in Egyptian children and impact on the effect of oxidative stress.

    Science.gov (United States)

    Gebril, Ola H; Meguid, Nagwa A

    2011-01-01

    Autism is among the commonest neurodevelopmental childhood disorders worldwide; its aetiology is still unknown. Iron metabolism alteration in the central nervous system is recently implicated as a risk factor for several neurodegenerative disorders. Haemochromatosis HFE gene polymorphisms (p.H63D and p.C282Y) have shown significant association with several neurological diseases. Some evidences show altered iron related proteins in serum of autistic children. The aim of this work is to conduct a preliminary pilot study for the association of HFE polymorphisms and autism. All cases were referred from the clinic of special needs, National Research Centre, Cairo. Clinical diagnosis was based on the criteria for autistic disorder as defined in the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revision (DSM-IV-TR). Whole genome DNA was extracted; p.H63D and p.C282Y genotyping was studied using specific sequence amplification followed by restriction enzyme digestion on a sample of autism patients (25 cases) and twenty controls. The p.H63D is more abundant than the C282Y among both autism and control samples. No significant association of p.H63D nor p.C282Y polymorphism and autism was revealed. We here report on the first pilot study of the possible genetic association between autism and HFE gene polymorphisms among Egyptians. Although our results do not prove the role of HFE polymorphisms as risk factors for autism, yet this does not exclude the role of iron in this prevalent disorder. Further extended studies are recommended to include other iron metabolism genes.

  14. HFE gene mutations and iron metabolism in Wilson's disease.

    Science.gov (United States)

    Erhardt, Andreas; Hoffmann, Arne; Hefter, Harald; Häussinger, Dieter

    2002-12-01

    There is increasing evidence for an interaction between iron and copper metabolism. Iron indices (ferritin, transferrin saturation [TS], serum iron), liver parameters, the prevalence and significance of C282Y and H63D HFE mutations were studied in 40 unrelated, Caucasian patients with Wilson's disease and 295 healthy controls. Due to specific treatment Wilson's disease was well controlled in all but one patient. The allele frequencies for the C282Y (11.3% vs. 6.2%) and the H63D (18.8% vs. 16.4%) mutation did not differ between patients with Wilson's disease and healthy controls. One patient with C282Y homozygous HH and Wilson's disease was identified showing progressive liver disease despite reasonable venesection and copper chelation therapy. No differences in iron indices and liver values were seen between HFE heterozygous and HFE wildtype patients with Wilson's disease. Higher serum ferritin levels were noticed in patients with Wilson's disease compared to healthy controls (149 +/- 26 microg/l vs. 87 +/- 8 microg/l; P Wilson's disease in order to detect iron overload. HFE mutations other than C282Y homozygosity seem to have no impact on iron indices and liver parameters as long as Wilson's disease is controlled.

  15. Changing aspects of HFE-related hereditary haemochromatosis and endeavours to early diagnosis

    NARCIS (Netherlands)

    Jacobs, E. M. G.; Verbeek, A. L. M.; Kreeftenberg, H. G.; van Deursen, C. Th. B. M.; Marx, J. J. M.; Stalenhoef, A. F. H.; Swinkels, D. W.; de Vries, R. A.

    2007-01-01

    HFE-related hereditary haernochromatosis (HH) is an iron overload disease attributed to the highly prevalent homozygosity for the C282Y mutation in the HFE gene. The pathophysiology of this error in iron metabolism is not completely elucidated yet, although deficiency of the iron regulatory hormone

  16. Changing aspects of HFE-related hereditary haemochromatosis and endeavours to early diagnosis.

    NARCIS (Netherlands)

    Jacobs, E.M.G.; Verbeek, A.L.M.; Kreeftenberg, H.G.; Deursen, C.T. van; Marx, J.J.M.; Stalenhoef, A.F.H.; Swinkels, D.W.; Vries, R.A. de

    2007-01-01

    HFE-related hereditary haemochromatosis (HH) is an iron overload disease attributed to the highly prevalent homozygosity for the C282Y mutation in the HFE gene. The pathophysiology of this error in iron metabolism is not completely elucidated yet, although deficiency of the iron regulatory hormone

  17. HFE-Associated Hereditary Haemochromatosis

    OpenAIRE

    Eijkelkamp, Emmeke J; Yapp, Thomas R; Powell, Lawrie W

    2000-01-01

    Hereditary hemochromatosis is a common inherited disorder of the iron metabolism. Screening studies indicate that it has a prevalence of one in 200 to 400, depending on the population studied, and a carrier rate of about one in seven to one in 10. Feder et al identified the hereditary hemochromatosis gene (HFE) in 1996 and two candidate mutations; the C282Y mutation has been shown to be responsible for the majority of the hereditary hemochromatosis cases worldwide. The gene discovery has led ...

  18. Preliminary investigation of bottlenose dolphins (Tursiops truncatus) for hfe gene-related hemochromatosis.

    Science.gov (United States)

    Phillips, Brianne E; Venn-Watson, Stephanie; Archer, Linda L; Nollens, Hendrik H; Wellehan, James F X

    2014-10-01

    Hemochromatosis (iron storage disease) has been reported in diverse mammals including bottlenose dolphins (Tursiops truncatus). The primary cause of excessive iron storage in humans is hereditary hemochromatosis. Most human hereditary hemochromatosis cases (up to 90%) are caused by a point mutation in the hfe gene, resulting in a C282Y substitution leading to iron accumulation. To evaluate the possibility of a hereditary hemochromatosis-like genetic predisposition in dolphins, we sequenced the bottlenose dolphin hfe gene, using reverse transcriptase-PCR and hfe primers designed from the dolphin genome, from liver of affected and healthy control dolphins. Sample size included two case animals and five control animals. Although isotype diversity was evident, no coding differences were identified in the hfe gene between any of the animals examined. Because our sample size was small, we cannot exclude the possibility that hemochromatosis in dolphins is due to a coding mutation in the hfe gene. Other potential causes of hemochromatosis, including mutations in different genes, diet, primary liver disease, and insulin resistance, should be evaluated.

  19. Incidence of cardiac arrhythmias in asymptomatic hereditary hemochromatosis subjects with C282Y homozygosity.

    Science.gov (United States)

    Shizukuda, Yukitaka; Tripodi, Dorothy J; Zalos, Gloria; Bolan, Charles D; Yau, Yu-Ying; Leitman, Susan F; Waclawiw, Myron A; Rosing, Douglas R

    2012-03-15

    It is not well known whether systemic iron overload per se in hereditary hemochromatosis (HH) is associated with cardiac arrhythmias before other signs and symptoms of cardiovascular disease occur. In the present study, we examined the incidence of cardiac arrhythmia in cardiac asymptomatic subjects with HH (New York Heart Association functional class I) and compared it to that in age- and gender-matched normal volunteers. The 42 subjects with HH and the 19 normal control subjects were recruited through the National Heart, Lung, and Blood Institute-sponsored "Heart Study of Hemochromatosis." They completed 48-hour Holter electrocardiography ambulatory monitoring at the baseline evaluation. The subjects with HH were classified as newly diagnosed (group A) and chronically treated (group B) subjects. All subjects with HH had C282Y homozygosity, and the normal volunteers lacked any HFE gene mutations known to cause HH. Although statistically insignificant, the incidence of ventricular and supraventricular ectopy tended to be greater in the combined HH groups than in the controls. Supraventricular ectopy was more frequently noted in group B compared to in the controls (ectopy rate per hour 11.1 ± 29.9 vs 1.5 ± 3.5, p cardiac arrhythmias was not significantly reduced after 6 months of intensive iron removal therapy in the group A subjects. No life-threatening arrhythmias were observed in our subjects with HH. In conclusion, our data suggest that the incidence of cardiac arrhythmias is, at most, marginally increased in asymptomatic subjects with HH. A larger clinical study is warranted to further clarify our observation. Published by Elsevier Inc.

  20. Precipitating factors of porphyria cutanea tarda in Brazil with emphasis on hemochromatosis gene (HFE) mutations. Study of 60 patients.

    Science.gov (United States)

    Vieira, Fatima Mendonça Jorge; Nakhle, Maria Cristina; Abrantes-Lemos, Clarice Pires; Cançado, Eduardo Luiz Rachid; Reis, Vitor Manoel Silva dos

    2013-01-01

    Porphyria cutanea tarda is the most common form of porphyria, characterized by the decreased activity of the uroporphyrinogen decarboxylase enzyme. Several reports associated HFE gene mutations of hereditary hemochromatosis with porphyria cutanea tarda worldwide, although up to date only one study has been conducted in Brazil. Investigation of porphyria cutanea tarda association with C282Y and H63D mutations in the HFE gene. Identification of precipitating factors (hepatitis C, HIV, alcoholism and estrogen) and their link with HFE mutations. An ambispective study of 60 patients with PCT was conducted during the period from 2003 to 2012. Serological tests for hepatitis C and HIV were performed and histories of alcohol abuse and estrogen intake were investigated. HFE mutations were identified with real-time PCR. Porphyria cutanea tarda predominated in males and alcohol abuse was the main precipitating factor. Estrogen intake was the sole precipitating factor present in 25% of female patients. Hepatitis C was present in 41.7%. All HIV-positive patients (15.3%) had a history of alcohol abuse. Allele frequency for HFE mutations, i.e., C282Y (p = 0.0001) and H63D (p = 0.0004), were significantly higher in porphyria cutanea tarda patients, compared to control group. HFE mutations had no association with the other precipitating factors. Alcohol abuse, hepatitis C and estrogen intake are prevalent precipitating factors in our porphyria cutanea tarda population; however, hemochromatosis in itself can also contribute to the outbreak of porphyria cutanea tarda, which makes the research for HFE mutations necessary in these patients.

  1. Analysis of HFE and TFR2 gene mutations in patients with acute leukemia.

    Science.gov (United States)

    Veneri, Dino; Franchini, Massimo; Krampera, Mauro; de Matteis, Giovanna; Solero, Pietro; Pizzolo, Giovanni

    2005-06-01

    There are increasing evidences regarding the association between iron overload and extra-hepatic malignancies. We studied the prevalence of 12 hereditary hemochromatosis (HH) gene mutations (C282Y, V53M, V59M, H63D, H63H, S56C, Q127H, E168Q, E168X, W169X and Q283P in the HFE gene and Y250X in the TFR2 gene) and its correlation with the iron status in 82 adult patients with acute leukemia (AL); 48 patients (58.5%) were affected by acute myeloid leukemia (AML) and 34 patients (41.5%) by acute lymphoblastic leukemia (ALL); 27 patients (32.9%) had at least one HH gene mutation (6 heterozygous for C282Y, 6 homozygous for H63D, 13 heterozygous for H63D and 2 heterozygous for S56C). Mean serum ferritin levels at diagnosis were increased (822.5+/-811.4 microg/L). However, there was no difference between patients positive or negative for the HH gene mutations. Similarly, we did not observe any statistically significant difference as far as iron status between AML and ALL patients. Our study does not support the evidence of an association between hemochromatosis gene mutations and iron overload in AL patients.

  2. HFE mutations in the elderly.

    Science.gov (United States)

    Willis, Gavin; Wimperis, Jennie Z; Smith, Katy; Fellows, Ian W; Jennings, Barbara A

    2003-01-01

    Most individuals diagnosed with hereditary hemochromatosis have mutations in both copies of the HFE gene, with such mutations being common in populations of north European origin. The number of individuals currently diagnosed and treated for hemochromatosis is small relative to the number carrying two HFE mutations. Studies searching for undiagnosed hemochromatosis cases among disease cohorts have generally failed to find the number of cases that would be expected if disease were the commonest outcome for individuals with two C282Y HFE mutations. Our aim was to test the hypothesis that individuals with two HFE mutations would be under-represented in an elderly population because many would have died from disease caused by hemochromatosis before they reached old age. This is a cross-sectional study of elderly patients referred for full blood counts at the Norfolk and Norwich University Hospital. We screened blood samples from 1,000 elderly men (aged 85 and over) and women (aged 89 and over) for the C282Y, H63D, and S65C mutations of the HFE gene. We also analyzed any recent laboratory data relevant to signs of hemochromatosis. None of the ten possible genotypes was significantly under- or over-represented compared to the expected frequency calculated from the Hardy-Weinberg equation. Four C282Y homozygotes were found. There were few significant differences in the laboratory findings between the genotypes. Our data suggest that most people with HFE mutations survive to old age and do not suffer from signs of iron overload and hemochromatosis.

  3. high prevalence of the cys282tyr hfe mutation facilitates an improved ...

    African Journals Online (AJOL)

    screened for two common haemochromatosis (HFE) gene mutations. The local frequencies of mutations C282Y and. H63D were determined and the DNA results correlated with biochemical parameters. Setting. Patients were referred from private practitioners, health workers and pathologists for a molecular diagnosis of.

  4. Lack of evidence for the pathogenic role of iron and HFE gene mutations in Brazilian patients with nonalcoholic steatohepatitis

    Directory of Open Access Journals (Sweden)

    M.M. Deguti

    2003-06-01

    Full Text Available The hypothesis of the role of iron overload associated with HFE gene mutations in the pathogenesis of nonalcoholic steatohepatitis (NASH has been raised in recent years. In the present study, biochemical and histopathological evidence of iron overload and HFE mutations was investigated in NASH patients. Thirty-two NASH patients, 19 females (59%, average 49.2 years, 72% Caucasians, 12% Mulattoes and 12% Asians, were submitted to serum aminotransferase and iron profile determinations. Liver biopsies were analyzed for necroinflammatory activity, architectural damage and iron deposition. In 31 of the patients, C282Y and H63D mutations were tested by PCR-RFLP. Alanine aminotransferase levels were increased in 30 patients, 2.42 ± 1.12 times the upper normal limit on average. Serum iron concentration, transferrin saturation and ferritin averages were 99.4 ± 31.3 g/dl, 33.1 ± 12.7% and 219.8 ± 163.8 µg/dl, respectively, corresponding to normal values in 93.5, 68.7 and 78.1% of the patients. Hepatic siderosis was observed in three patients and was not associated with architectural damage (P = 0.53 or with necroinflammatory activity (P = 0.27. The allelic frequencies (N = 31 found were 1.6 and 14.1% for C282Y and H63D, respectively, which were compatible with those described for the local population. In conclusion, no evidence of an association of hepatic iron overload and HFE mutations with NASH was found. Brazilian NASH patients comprise a heterogeneous group with many associated conditions such as hyperinsulinism, environmental hepatotoxin exposure and drugs, but not hepatic iron overload, and their disease susceptibility could be related to genetic and environmental features other than HFE mutations.

  5. Analysis of HFE and TFR2 mutations in selected blood donors with biochemical parameters of iron overload.

    Science.gov (United States)

    De Gobbi, Marco; Daraio, Filomena; Oberkanins, Christian; Moritz, Anne; Kury, Fritz; Fiorelli, Gemino; Camaschella, Clara

    2003-04-01

    Hereditary hemochromatosis is a recessive condition characterized by iron accumulation in several organs, followed by organ damage and failure. The disorder is prevalently due to C282Y and H63D mutations in the HFE gene, but additional HFE and TFR2 mutations have been reported. Early iron overload may be assessed by biochemical parameters such as increased transferrin saturation and serum ferritin. Taking advantage of the collection of 178 DNA samples selected for increased transferrin saturation (>50% in males and >45% in females) from a previous large scale screening of Italian blood donors, we simultaneously assessed the presence of 14 hemochromatosis-associated molecular defects (11 of HFE and 3 of TFR2) by a reverse hybridization-based strip assay. In the series studied the overall C282Y allele frequency was 9% and that of the H63D and S65C was 22.2% and 1.4%, respectively. One rare HFE allele (E168Q), but no TFR2 mutation was detected. When checked at a second examination, transferrin saturation was significantly higher in C282Y homozygotes, H63D/ C282Y compound heterozygotes and H63D homozygotes as compared to wild-type subjects (pTFR2 mutations was identified in this series confirming the preliminary indication of their rare occurrence. Subjects with hemochromatosis-associated genotypes show a persistently higher mean transferrin saturation than do those with wild type genotypes.

  6. Mutations in the HFE, TFR2, and SLC40A1 genes in patients with hemochromatosis.

    Science.gov (United States)

    Del-Castillo-Rueda, Alejandro; Moreno-Carralero, María-Isabel; Cuadrado-Grande, Nuria; Alvarez-Sala-Walther, Luis-Antonio; Enríquez-de-Salamanca, Rafael; Méndez, Manuel; Morán-Jiménez, María-Josefa

    2012-10-15

    Hereditary hemochromatosis causes iron overload and is associated with a variety of genetic and phenotypic conditions. Early diagnosis is important so that effective treatment can be administered and the risk of tissue damage avoided. Most patients are homozygous for the c.845G>A (p.C282Y) mutation in the HFE gene; however, rare forms of genetic iron overload must be diagnosed using a specific genetic analysis. We studied the genotype of 5 patients who had hyperferritinemia and an iron overload phenotype, but not classic mutations in the HFE gene. Two patients were undergoing phlebotomy and had no iron overload, 1 with metabolic syndrome and no phlebotomy had mild iron overload, and 2 patients had severe iron overload despite phlebotomy. The patients' first-degree relatives also underwent the analysis. We found 5 not previously published mutations: c.-408_-406delCAA in HFE, c.1118G>A (p.G373D), c.1473G>A (p.E491E) and c.2085G>C (p.S695S) in TFR2; and c.-428_-427GG>TT in SLC40A1. Moreover, we found 3 previously published mutations: c.221C>T (p.R71X) in HFE; c.1127C>A (p.A376D) in TFR2; and c.539T>C (p.I180T) in SLC40A1. Four patients were double heterozygous or compound heterozygous for the mutations mentioned above, and the patient with metabolic syndrome was heterozygous for a mutation in the TFR2 gene. Our findings show that hereditary hemochromatosis is clinically and genetically heterogeneous and that acquired factors may modify or determine the phenotype. Copyright © 2012. Published by Elsevier B.V.

  7. La mutacion H63D del gen HFE se asocia con un riesgo aumentado de carcinoma hepatocelular The H63D mutation of the HFE gene is related to the risk of hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    P. Ropero

    2007-07-01

    Full Text Available Objetivo: comprobar si las mutaciones del gen HFE, que pueden inducir sobrecarga hepática de hierro, guardan relación con el riesgo de desarrollar carcinoma hepatocelular (CHC en sujetos predispuestos a sufrir este tumor. Material y métodos: se han incluido 196 pacientes (161 varones diagnosticados de CHC. Ninguno estaba diagnosticado de hemocromatosis. El grupo control estaba constituido por 181 sujetos sanos. Todos los sujetos eran españoles de raza blanca.Las mutaciones C282Y y H63D del gen HFE se identificaron mediante reacción en cadena de polimerasa (PCR sobre ADN genómico leucocitario utilizando enzimas de restricción específicas. Resultados (casos/controles: 1. Distribución genotípica: a mutación C282Y: 1/0 homocigotos, 12/23 heterocigotos, 183/158 normales (p = 0,07, n.s.; y b mutación H63D: 9/5 homocigotos, 85/52 heterocigotos, 102/124 normales (odds ratio 2,00, IC95% 1,29-3,12, p = 0,002. Cuatro casos y seis controles eran heterocigotos compuestos. 2. Frecuencias alélicas: a mutación C282Y: normales 378/339, mutados 14/23 (p = 0,11, n.s.; b mutación H63D: normales 289/300; mutados 103/62 (odds ratio 1,72, IC95% 1,19-2,50, p = 0,004. No se observaron diferencias en relación con el sexo, la edad o la etiología (VHC, VHB, etílica o mixta de la hepatopatía previa. Conclusiones: la mutación C282Y no guarda relación con el riesgo de desarrollar CHC en sujetos sin hemocromatosis conocida. La posesión de la mutación H63D se asocia con un riesgo aumentado de desarrollar CHC independientemente de la etiología de la hepatopatía crónica subyacente.Aim: to disclose whether mutations in the HFE gene inducing liver iron overload are related to the risk of hepatocellular carcinoma (HCC in otherwise predisposed patients. Patients and methods: one hundred and ninety-six patients (161 males diagnosed with HCC and 181 healthy controls were included in the study. All subjects were white Spaniards. C282Y and H63D mutations in the

  8. Four variants in transferrin and HFE genes as potential markers of iron deficiency anaemia risk: an association study in menstruating women

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    Arroyo-Pardo Eduardo

    2011-10-01

    Full Text Available Abstract Background Iron deficiency anaemia is a worldwide health problem in which environmental, physiologic and genetic factors play important roles. The associations between iron status biomarkers and single nucleotide polymorphisms (SNPs known to be related to iron metabolism were studied in menstruating women. Methods A group of 270 Caucasian menstruating women, a population group at risk of iron deficiency anaemia, participated in the study. Haematological and biochemical parameters were analysed and 10 selected SNPs were genotyped by minisequencing assay. The associations between genetic and biochemical data were analysed by Bayesian Model Averaging (BMA test and decision trees. Dietary intake of a representative subgroup of these volunteers (n = 141 was assessed, and the relationship between nutrients and iron biomarkers was also determined by linear regression. Results Four variants, two in the transferrin gene (rs3811647, rs1799852 and two in the HFE gene (C282Y, H63D, explain 35% of the genetic variation or heritability of serum transferrin in menstruating women. The minor allele of rs3811647 was associated with higher serum transferrin levels and lower transferrin saturation, while the minor alleles of rs1799852 and the C282Y and H63D mutations of HFE were associated with lower serum transferrin levels. No association between nutrient intake and iron biomarkers was found. Conclusions In contrast to dietary intake, these four SNPs are strongly associated with serum transferrin. Carriers of the minor allele of rs3811647 present a reduction in iron transport to tissues, which might indicate higher iron deficiency anaemia risk, although the simultaneous presence of the minor allele of rs1799852 and HFE mutations appear to have compensatory effects. Therefore, it is suggested that these genetic variants might potentially be used as markers of iron deficiency anaemia risk.

  9. АЛЛЕЛИ 282Y И H63D ГЕНА HFE И ПРЕДРАСПОЛОЖЕННОСТЬ К СИНДРОМУ ХРОНИЧЕСКОЙ ПЕРЕГРУЗКИ ЖЕЛЕЗОМ И НАРУШЕНИЮ ПОРФИРИНОВОГО ОБМЕНА ПРИ НЕАЛКОГОЛЬНОЙ ЖИРОВОЙ БОЛЕЗНИ ПЕЧЕНИ

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    А. Б. Кривошеев

    2012-01-01

    Full Text Available Testing for carriers of mutations C282Y and H63D HFE gene in 57 patients with nonalcoholic fatty liver disease was completed. Abnormalities in the metabolism of porphyrins were detected in 39 (68.4% patients, mutations C282Y and H63D were detected in 16 (28.1% patients, of whom 12 patients with metabolic disorders of porphyrins and symptoms of the syndrome of chronic iron overload. In 41 (71.9% patients without the mutations found disorders metabolism of porphyrins were in 27 (65.8% patients. They had no symptoms of the syndrome of chronic iron overload. Detection of C282Y and H63D mutations in the gene HFE in conjunction with disorders of porphyrin metabolism in association with the syndrome of chronic iron overload, but the probability will consider these patients as candidates for inclusion in the higher risk of formation of liver fibrosis.

  10. Coincident natural selection of CCR532 and C282Y in Europe: to ...

    Indian Academy of Sciences (India)

    Keywords. CCR532; C282Y; natural selection; Black Death; plague. Author Affiliations. Marjan Gharagozloo1 Abbas Ghaderi1. Department of Immunology, Shiraz University of Medical Sciences, P.O. Box 71345 1798, Shiraz, Iran. Dates. Manuscript received: 30 November 2004; Manuscript revised: 9 February 2005 ...

  11. Time-course analysis of serum hepcidin, iron and cytokines in a C282Y homozygous patient with Schnitzler's syndrome treated with IL-1 receptor antagonist.

    Science.gov (United States)

    van Deuren, Marcel; Kroot, Joyce J C; Swinkels, Dorine W

    2009-09-01

    It is currently unknown if the increase of the hepatic iron regulatory hormone hepcidin during inflammation in man depends on an intact HFE-protein. Here we describe the temporal relationship of serum hepcidin, serum iron and cytokines in a patient with HFE-related (C282Y homozygous) hereditary hemochromatosis who was treated for an auto-inflammatory condition, i.e. variant Schnitzler's syndrome, with the potent anti-inflammatory cytokine inter-leukin-1 receptor antagonist (IL-1ra, anakinra). The patient had bouts of fever with peaking serum IL-6 concentrations followed by peaking serum hepcidin levels, while serum iron was low. Upon treatment, these peaks disappeared and hepcidin levels became non-detectable, consistent with HFE deficiency. In conclusion, this in vivo human model: i) supports the importance of an HFE-independent IL-6-hepcidin axis in the development of hypoferremia and anemia of inflammation; and ii) suggests that chronic inflammation protects patients with HFE-related hereditary hemochromatosis from iron accumulation.

  12. Time-course analysis of serum hepcidin, iron and cytokines in a C282Y homozygous patient with Schnitzler’s syndrome treated with IL-1 receptor antagonist

    Science.gov (United States)

    van Deuren, Marcel; Kroot, Joyce J. C.; Swinkels, Dorine W.

    2009-01-01

    It is currently unknown if the increase of the hepatic iron regulatory hormone hepcidin during inflammation in man depends on an intact HFE-protein. Here we describe the temporal relationship of serum hepcidin, serum iron and cytokines in a patient with HFE-related (C282Y homozygous) hereditary hemochromatosis who was treated for an auto-inflammatory condition, i.e. variant Schnitzler’s syndrome, with the potent anti-inflammatory cytokine inter-leukin-1 receptor antagonist (IL-1ra, anakinra). The patient had bouts of fever with peaking serum IL-6 concentrations followed by peaking serum hepcidin levels, while serum iron was low. Upon treatment, these peaks disappeared and hepcidin levels became non-detectable, consistent with HFE deficiency. In conclusion, this in vivo human model: i) supports the importance of an HFE-independent IL-6-hepcidin axis in the development of hypoferremia and anemia of inflammation; and ii) suggests that chronic inflammation protects patients with HFE-related hereditary hemochromatosis from iron accumulation. PMID:19608676

  13. H63D mutation in HFE gene is common in Indians and is associated ...

    Indian Academy of Sciences (India)

    inated in a Celtic population in central Europe and spread west and north by population movement. There are ... mutation with the C282Y mutation is a known risk factor for iron overload (Pointon et al. 2000) The H63D ... gene causally associated with the disease may aid in resolv- ing its single or multiple origins within a ...

  14. Was the C282Y mutation an Irish Gaelic mutation that the Vikings helped disseminate?

    DEFF Research Database (Denmark)

    Olsson, Karl Sigvard; Konar, Jan; Dufva, Inge Hoegh

    2011-01-01

    The HLA-related hemochromatosis mutation C282Y is thought to have originated in Ireland in a person with HLA-A3-B14 and was spread by Vikings. Irish people with two HLA-A3 alleles had a high risk of hemochromatosis. In this study, from west Sweden, we wanted to test these hypotheses.......The HLA-related hemochromatosis mutation C282Y is thought to have originated in Ireland in a person with HLA-A3-B14 and was spread by Vikings. Irish people with two HLA-A3 alleles had a high risk of hemochromatosis. In this study, from west Sweden, we wanted to test these hypotheses....

  15. Porfiria cutánea tarda: asociación con mutaciones HFE, hepatitis virales, alcohol y otros factores de riesgo en Guipúzcoa, País Vasco Porphyria cutanea tarda: An analysis of HFE gene mutations, hepatitis viruses, alcohol intake, and other risk factors in 54 patients from Guipúzcoa, Basque Country, Spain

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    A. Castiella

    2008-12-01

    Full Text Available Objetivo: estudiar la frecuencia de las mutaciones en el gen HFE (C282Y, H63D, S65C en un grupo de 54 pacientes con porfiria cutánea tarda (PCT y en un grupo de controles sanos (donantes de sangre en Guipúzcoa. También analizar su relación con los virus de la hepatitis B y C (VHB, VHC, alcohol y otros factores de riesgo reconocidos. Métodos: el análisis de las mutaciones se hizo mediante PCR. Se compararon las frecuencias alélicas y genotípicas. Se determinaron la probabilidad y el test de Chi cuadrado. Resultados: no encontramos asociación entre C282Y y PCT (5,76 vs. 5% controles. Se observó una alta frecuencia alélica en la mutación H63D en PCT (34,25%, pero sin ser estadísticamente significativa (controles 29,31%, debido a la alta prevalencia de esta mutación en la población vasca. La mutación S65C fue menor en PCT que en controles. Encontramos una idéntica presencia de H63D en heterocigosis en ambos grupos (38,8 vs. 38,8%. La asociación con el VHC se objetivó en el 35,18% de los pacientes y la infección por VHB en el 7,4%. Un 55,55% de los pacientes tenía un hábito alcohólico de más de 60 g etanol día. Todos eran negativos para el virus de la inmunodeficiencia humana (VIH y 1 de las 5 mujeres con PCT tomaba estrógenos. Conclusión: las mutaciones C282Y y H63D no tienen un papel relevante en los pacientes con PCT en Guipúzcoa. Los factores externos (consumo importante de alcohol y VHC parecen jugar un papel fundamental en el desarrollo de la PCT en nuestra población.Aim: to study the frequency of HFE gene mutations (C282Y, H63D, S65C in a group of 54 sporadic PCT patients and in a group of healthy controls (blood donors from Guipúzcoa, Spain. We studied the association of PCT with HCV, HBV, alcohol abuse, and other established risk factors. Methods: the analysis of mutations was made by PCR. Allelic and genotypic frequencies were compared. Probability was determined and a Chi-squared test was performed. Results

  16. HFE gene mutations and Wilson's disease in Sardinia.

    Science.gov (United States)

    Sorbello, Orazio; Sini, Margherita; Civolani, Alberto; Demelia, Luigi

    2010-03-01

    Hypocaeruloplasminaemia can lead to tissue iron storage in Wilson's disease and the possibility of iron overload in long-term overtreated patients should be considered. The HFE gene encodes a protein that is intimately involved in intestinal iron absorption. The aim of this study was to determine the prevalence of the HFE gene mutation, its role in iron metabolism of Wilson's disease patients and the interplay of therapy in copper and iron homeostasis. The records of 32 patients with Wilson's disease were reviewed for iron and copper indices, HFE gene mutations and liver biopsy. Twenty-six patients were negative for HFE gene mutations and did not present significant alterations of iron metabolism. The HFE mutation was significantly associated with increased hepatic iron content (Pgene wild-type. The HFE gene mutations may be an addictional factor in iron overload in Wilson's disease. Our results showed that an adjustment of dosage of drugs could prevent further iron overload induced by overtreatment only in patients HFE wild-type. 2009. Published by Elsevier Ltd.

  17. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22.

    Science.gov (United States)

    Camaschella, C; Roetto, A; Calì, A; De Gobbi, M; Garozzo, G; Carella, M; Majorano, N; Totaro, A; Gasparini, P

    2000-05-01

    Haemochromatosis is a common recessive disorder characterized by progressive iron overload, which may lead to severe clinical complications. Most patients are homozygous for the C282Y mutation in HFE on 6p (refs 1-5). A locus for juvenile haemochromatosis (HFE2) maps to 1q (ref. 7). Here we report a new locus (HFE3) on 7q22 and show that a homozygous nonsense mutation in the gene encoding transferrin receptor-2 (TFR2) is found in people with haemochromatosis that maps to HFE3.

  18. The effect of the hemochromatosis (HFE genotype on lead load and iron metabolism among lead smelter workers.

    Directory of Open Access Journals (Sweden)

    Guangqin Fan

    Full Text Available Both an excess of toxic lead (Pb and an essential iron disorder have been implicated in many diseases and public health problems. Iron metabolism genes, such as the hemochromatosis (HFE gene, have been reported to be modifiers for lead absorption and storage. However, the HFE gene studies among the Asian population with occupationally high lead exposure are lacking.To explore the modifying effects of the HFE genotype (wild-type, H63D variant and C282Y variant on the Pb load and iron metabolism among Asian Pb-workers with high occupational exposure.Seven hundred and seventy-one employees from a lead smelter manufacturing company were tested to determine their Pb intoxication parameters, iron metabolic indexes and identify the HFE genotype. Descriptive and multivariate analyses were conducted.Forty-five H63D variant carriers and no C282Y variant carrier were found among the 771 subjects. Compared with subjects with the wild-type genotype, H63D variant carriers had higher blood lead levels, even after controlling for factors such as age, sex, marriage, education, smoking and lead exposure levels. Multivariate analyses also showed that the H63D genotype modifies the associations between the blood lead levels and the body iron burden/transferrin.No C282Y variant was found in this Asian population. The H63D genotype modified the association between the lead and iron metabolism such that increased blood lead is associated with a higher body iron content or a lower transferrin in the H63D variant. It is indicated that H63D variant carriers may be a potentially highly vulnerable sub-population if they are exposed to high lead levels occupationally.

  19. The evolutionary adaptation of the C282Y mutation to culture and climate during the European Neolithic.

    Science.gov (United States)

    Heath, Kathleen M; Axton, Jacob H; McCullough, John M; Harris, Nathan

    2016-05-01

    The C282Y allele is the major cause of hemochromatosis as a result of excessive iron absorption. The mutation arose in continental Europe no earlier than 6,000 years ago, coinciding with the arrival of the Neolithic agricultural revolution. Here we hypothesize that this new Neolithic diet, which originated in the sunny warm and dry climates of the Middle East, was carried by migrating farmers into the chilly and damp environments of Europe where iron is a critical micronutrient for effective thermoregulation. We argue that the C282Y allele was an adaptation to this novel environment. To address our hypothesis, we compiled C282Y allele frequencies, known Neolithic sites in Europe and climatic data on temperature and rainfall for statistical analysis. Our findings indicate that the geographic cline for C282Y frequency in Europe increases as average temperatures decrease below 16°C, a critical threshold for thermoregulation, with rainy days intensifying the trend. The results indicate that the deleterious C282Y allele, responsible for most cases of hemochromatosis, may have evolved as a selective advantage to culture and climate during the European Neolithic. © 2016 The Authors American Journal of Physical Anthropology Published by Wiley Periodicals, Inc.

  20. Influence of HFE variants and cellular iron on monocyte chemoattractant protein-1

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    Simmons Zachary

    2009-02-01

    Full Text Available Abstract Background Polymorphisms in the MHC class 1-like gene known as HFE have been proposed as genetic modifiers of neurodegenerative diseases that include neuroinflammation as part of the disease process. Variants of HFE are relatively common in the general population and are most commonly associated with iron overload, but can promote subclinical cellular iron loading even in the absence of clinically identified disease. The effects of the variants as well as the resulting cellular iron dyshomeostasis potentially impact a number of disease-associated pathways. We tested the hypothesis that the two most common HFE variants, H63D and C282Y, would affect cellular secretion of cytokines and trophic factors. Methods We screened a panel of cytokines and trophic factors using a multiplexed immunoassay in human neuroblastoma SH-SY5Y cells expressing different variants of HFE. The influence of cellular iron secretion on the potent chemokine monocyte chemoattractant protein-1 (MCP-1 was assessed using ferric ammonium citrate and the iron chelator, desferroxamine. Additionally, an antioxidant, Trolox, and an anti-inflammatory, minocycline, were tested for their effects on MCP-1 secretion in the presence of HFE variants. Results Expression of the HFE variants altered the labile iron pool in SH-SY5Y cells. Of the panel of cytokines and trophic factors analyzed, only the release of MCP-1 was affected by the HFE variants. We further examined the relationship between iron and MCP-1 and found MCP-1 secretion tightly associated with intracellular iron status. A potential direct effect of HFE is considered because, despite having similar levels of intracellular iron, the association between HFE genotype and MCP-1 expression was different for the H63D and C282Y HFE variants. Moreover, HFE genotype was a factor in the effect of minocycline, a multifaceted antibiotic used in treating a number of neurologic conditions associated with inflammation, on MCP-1

  1. Autoimmune Conditions in 235 Hemochromatosis Probands with HFE C282Y Homozygosity and Their First-Degree Relatives

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    James C. Barton

    2015-01-01

    Full Text Available We performed a retrospective study of autoimmune conditions (ACs in 235 hemochromatosis probands at diagnosis by analyzing age, sex, ACs, history of first-degree family members with ACs (FH, diabetes, heavy ethanol consumption, elevated serum ALT/AST, nonalcoholic fatty liver disease, viral hepatitis, cirrhosis, iron removed to achieve iron depletion (QFe, and positivity for human leukocyte antigen (HLA haplotypes A∗01, B∗08; A∗02, B∗44; A∗03, B∗07; A∗03, B∗14; and A∗29, B∗44. There were 138 men (58.7%. Median followup was 19.6 y. One or more of 19 ACs were diagnosed in each of 35 probands (14.9%. Prevalences of Hashimoto’s thyroiditis, rheumatoid arthritis, and ankylosing spondylitis were 8.1% (95% CI: [5.1, 12.5], 1.7% [0.6, 4.6], and 0.0085 [0.0015, 0.0337], respectively. Eighteen probands (7.7% had a FH. Eight probands with ACs had 9 family members with ACs. In a logistic regression, ACs were less likely in men (odds ratio (OR 0.3 [0.1, 0.6] and more likely in probands with a FH (OR 4.1 [1.4, 11.8]. Overall ACs risk was not significantly associated with QFe or HLA haplotypes. Estimated survival of probands with and without ACs did not differ significantly. We conclude that ACs are common in hemochromatosis probands, especially women and probands with a FH.

  2. HFE H63D polymorphism as a modifier of the effect of cumulative lead exposure on pulse pressure: the Normative Aging Study.

    Science.gov (United States)

    Zhang, Aimin; Park, Sung Kyun; Wright, Robert O; Weisskopf, Marc G; Mukherjee, Bhramar; Nie, Huiling; Sparrow, David; Hu, Howard

    2010-09-01

    Cumulative lead exposure is associated with a widened pulse pressure (PP; the -difference between systolic and diastolic blood pressure), a marker of arterial stiffness and a predictor of cardiovascular disease. Polymorphisms in the hemochromatosis gene (HFE) have been shown to modify the impact of cumulative lead exposure on measures of adult cognition and cardiac function. We examined whether the HFE mutations modify the impact of lead on PP in -community-dwelling older men. We examined 619 participants with a total of 1,148 observations of PP from a substudy of bone lead levels (a measure of cumulative exposure, measured by in vivo K-shell X-ray fluorescence) and health in the Normative Aging Study between 1991 and 2001. Linear mixed-effects regression models with random intercepts were constructed. Of the 619 subjects, 138 and 72 carried the HFE H63D and C282Y variants, respectively. After adjusting for age; education; alcohol intake; smoking; daily intakes of calcium, sodium, and potassium; total calories; family history of hypertension; diabetes; height; heart rate; high-density lipoprotein (HDL); total cholesterol:HDL ratio; and waist circumference, baseline bone lead levels were associated with steeper increases in PP in men with at least one H63D allele (p-interaction = 0.03 for tibia and 0.02 for patella) compared with men with only the wild types or C282Y variant. The HFE H63D polymorphism, but not the C282Y mutation, appears to enhance susceptibility to the deleterious impact of cumulative lead on PP, possibly via prooxidative or pro-inflammatory mechanisms.

  3. HFE Genotyping in Patients with Elevated Serum Iron Indices and Liver Diseases

    Directory of Open Access Journals (Sweden)

    Andreia Silva Evangelista

    2015-01-01

    Full Text Available Iron abnormalities in chronic liver disease may be the result of genetic diseases or secondary factors. The present study aimed to identify subjects with HFE-HH in order to describe the frequency of clinical manifestations, identify risk factors for iron elevation, and compare the iron profile of HFE-HH to other genotypes in liver disease patients. A total of 108 individuals with hepatic disease, transferrin saturation (TS > 45%, and serum ferritin (SF > 350 ng/mL were tested for HFE mutations. Two groups were characterized: C282Y/C282Y or C282Y/H63D genotypes (n=16 were the HFE hereditary hemochromatosis (HFE-HH group; and C282Y and H63D single heterozygotes, the H63D/H63D genotype, and wild-type were considered group 2 (n=92. Nonalcoholic liver disease, alcoholism, and chronic hepatitis C were detected more frequently in group 2, whereas arthropathy, hepatocarcinoma, diabetes, and osteoporosis rates were significantly higher in the HFE-HH group. TS > 82%, SF > 2685 ng/mL, and serum iron > 178 μg/dL were the cutoffs for diagnosis of HFE-HH in patients with liver disease. Thus, in non-Caucasian populations with chronic liver disease, HFE-HH diagnosis is more predictable in those with iron levels higher than those proposed in current guidelines for the general population.

  4. A time course of hepcidin response to iron challenge in patients with HFE and TFR2 hemochromatosis.

    Science.gov (United States)

    Girelli, Domenico; Trombini, Paola; Busti, Fabiana; Campostrini, Natascia; Sandri, Marco; Pelucchi, Sara; Westerman, Mark; Ganz, Tomas; Nemeth, Elizabeta; Piperno, Alberto; Camaschella, Clara

    2011-04-01

    Inadequate hepcidin production leads to iron overload in nearly all types of hemochromatosis. We explored the acute response of hepcidin to iron challenge in 25 patients with HFE-hemochromatosis, in two with TFR2-hemochromatosis and in 13 controls. Sixteen patients (10 C282Y/C282Y homozygotes, 6 C282Y/H63D compound heterozygotes) had increased iron stores, while nine (6 C282Y/C282Y homozygotes, 3 C282Y/H63D compound heterozygotes) were studied after phlebotomy-induced normalization of iron stores. We analyzed serum iron, transferrin saturation, and serum hepcidin by both enzyme-linked immunosorbent assay and mass-spectrometry at baseline, and 4, 8, 12 and 24 hours after a single 65-mg dose of oral iron. Serum iron and transferrin saturation significantly increased at 4 hours and returned to baseline values at 8-12 hours in all groups, except in the iron-normalized patients who showed the highest and longest increase of both parameters. The level of hepcidin increased significantly at 4 hours and returned to baseline at 24 hours in controls and in the C282Y/H63D compound heterozygotes at diagnosis. The hepcidin response was smaller in C282Y-homozygotes than in controls, barely detectable in the patients with iron-depleted HFE-hemochromatosis and absent in those with TFR2-hemochromatosis. Conclusions Our results are consistent with a scenario in which TFR2 plays a prominent and HFE a contributory role in the hepcidin response to a dose of oral iron. In iron-normalized patients with HFE hemochromatosis, both the low baseline hepcidin level and the weak response to iron contribute to hyperabsorption of iron.

  5. Haplotype analysis of the HFE gene among populations of Northern Eurasia, in patients with metabolic disorders or stomach cancer, and in long-lived people.

    Science.gov (United States)

    Mikhailova, S V; Babenko, V N; Ivanoshchuk, D E; Gubina, M A; Maksimov, V N; Solovjova, I G; Voevoda, M I

    2016-06-17

    Previously, it was shown that the HFE gene (associated with human hereditary hemochromatosis) has several haplotypes of intronic polymorphisms. Some haplotype frequencies are race specific and hence can be used in phylogenetic analysis. We assumed that analysis of Caucasoid patients-living now in Western Siberia and having diseases associated with dietary habits and metabolic rate-will allow us to understand the processes of possible selection during settling of the northern part of Asia. Haplotype analysis of Northern Eurasian native and recently settled ethnic groups was performed on polymorphisms rs1799945, rs1800730, rs1800562, rs2071303, rs1800708, rs1572982, rs2794719, rs807209, and rs2032451 of this gene. The CCA haplotype of the rs2071303, rs1800708, and rs1572982 was found to be associated with HLA-A2 (39 %) in Asian populations. Haplotype analysis for the rs1799945, rs1800730, rs1800562, rs2071303, rs1800708, and rs1572982 was performed on Russian patients with some metabolic disorders or stomach cancer and among long-lived people. Decreased frequencies of the TTA haplotype (T in rs2071303, T in rs1800708, and A in rs1572982) were observed in the groups of patients with diseases associated with overweight (fatty liver disease, type 2 diabetes mellitus, or metabolic syndrome + arterial hypertension) as compared with the control sample. We detected significant differences in this haplotype's frequency between the patients with type 2 diabetes mellitus and Russian adolescents, elderly citizens, and long-lived people (χ(2) P value = 0.003, 0.010, and 0.015, respectively). No significant differences in frequencies of the alleles with mutations in coding regions of the HFE gene (C282Y, H63D, and S65C) were detected between the analyzed patients (with stomach cancer, metabolic syndrome, fatty liver disease, or type 2 diabetes mellitus) and the control Caucasoid sample. Monophyletic origin of H63D (rs1799945) was confirmed in Caucasoids and Northern

  6. Best practice guidelines for the molecular genetic diagnosis of Type 1 (HFE-related hereditary haemochromatosis

    Directory of Open Access Journals (Sweden)

    Barton David E

    2006-11-01

    Full Text Available Abstract Background Hereditary haemochromatosis (HH is a recessively-inherited disorder of iron over-absorption prevalent in Caucasian populations. Affected individuals for Type 1 HH are usually either homozygous for a cysteine to tyrosine amino acid substitution at position 282 (C282Y of the HFE gene, or compound heterozygotes for C282Y and for a histidine to aspartic acid change at position 63 (H63D. Molecular genetic testing for these two mutations has become widespread in recent years. With diverse testing methods and reporting practices in use, there was a clear need for agreed guidelines for haemochromatosis genetic testing. The UK Clinical Molecular Genetics Society has elaborated a consensus process for the development of disease-specific best practice guidelines for genetic testing. Methods A survey of current practice in the molecular diagnosis of haemochromatosis was conducted. Based on the results of this survey, draft guidelines were prepared using the template developed by UK Clinical Molecular Genetics Society. A workshop was held to develop the draft into a consensus document. The consensus document was then posted on the Clinical Molecular Genetics Society website for broader consultation and amendment. Results Consensus or near-consensus was achieved on all points in the draft guidelines. The consensus and consultation processes worked well, and outstanding issues were documented in an appendix to the guidelines. Conclusion An agreed set of best practice guidelines were developed for diagnostic, predictive and carrier testing for hereditary haemochromatosis and for reporting the results of such testing.

  7. Porfiria cutánea tarda: asociación con mutaciones HFE, hepatitis virales, alcohol y otros factores de riesgo en Guipúzcoa, País Vasco Porphyria cutanea tarda: An analysis of HFE gene mutations, hepatitis viruses, alcohol intake, and other risk factors in 54 patients from Guipúzcoa, Basque Country, Spain

    OpenAIRE

    A. Castiella; Zapata, E.; M. D. de Juan; F. Múgica; Barrio, J.; P. Otazua; J. A. Arriola; A. Cosme; E. Elosegui; Fernández, J.; L. Zubiaurre; L. F. Alzate; Utrilla, E.

    2008-01-01

    Objetivo: estudiar la frecuencia de las mutaciones en el gen HFE (C282Y, H63D, S65C) en un grupo de 54 pacientes con porfiria cutánea tarda (PCT) y en un grupo de controles sanos (donantes de sangre) en Guipúzcoa. También analizar su relación con los virus de la hepatitis B y C (VHB, VHC), alcohol y otros factores de riesgo reconocidos. Métodos: el análisis de las mutaciones se hizo mediante PCR. Se compararon las frecuencias alélicas y genotípicas. Se determinaron la probabilidad y el test d...

  8. Coincident natural selection of CCR5∆32 and C282Y in Europe: to ...

    Indian Academy of Sciences (India)

    Unknown

    CCR5 is a member of the G protein-coupled chemokine receptor superfamily which acts as one of the major co- receptors for HIV-1 infection. A 32-base pair deletion (∆32) in the CCR5 gene results in defective expression of the receptor on the cell surface and blocks entry of the virus. The inactive CCR5∆32 allele confers ...

  9. Identification of novel mutations in HFE, HFE2, TfR2, and SLC40A1 genes in Chinese patients affected by hereditary hemochromatosis.

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    Wang, Yongwei; Du, Yali; Liu, Gang; Guo, Shanshan; Hou, Bo; Jiang, Xianyong; Han, Bing; Chang, Yanzhong; Nie, Guangjun

    2017-04-01

    Hereditary hemochromatosis (HH) is a group of inherited iron-overload disorders associated with pathogenic defects in the genes encoding hemochromatosis (HFE), hemojuvelin (HJV/HFE2), hepcidin (HAMP), transferrin receptor 2 (TfR2), and ferroportin (FPN1/SLC40A1) proteins, and the clinical features are well described. However, there have been only a few detailed reports of HH in Chinese populations. Thus, there is insufficient patient information for population-based analyses in Chinese populations or comparative studies among different ethical groups. In the current work, we describe eight Chinese cases of hereditary hemochromatosis. Gene sequencing results revealed eight mutations (five novel mutations) in HFE, HFE2, TfR2, and SLC40A1 genes in these Chinese HH patients. In addition, we used Polymorphism Phenotyping v2 (Polyphen), Sorting Intolerant From Tolerant (SIFT), and a sequence alignment program to predict the molecular consequences of missense mutations.

  10. Natural selection on HFE in Asian populations contributes to enhanced non-heme iron absorption.

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    Ye, Kaixiong; Cao, Chang; Lin, Xu; O'Brien, Kimberly O; Gu, Zhenglong

    2015-06-10

    HFE, a major regulator of iron (Fe) homeostasis, has been suggested to be under positive selection in both European and Asian populations. While the genetic variant under selection in Europeans (a non-synonymous mutation, C282Y) has been relatively well-studied, the adaptive variant in Asians and its functional consequences are still unknown. Identifying the adaptive HFE variants in Asians will not only elucidate the evolutionary history and the genetic basis of population difference in Fe status, but also assist the future practice of genome-informed dietary recommendation. Using data from the International HapMap Project, we confirmed the signatures of positive selection on HFE in Asian populations and identified a candidate adaptive haplotype that is common in Asians (52.35-54.71%) but rare in Europeans (5.98%) and Africans (4.35%). The T allele at tag SNP rs9366637 (C/T) captured 95.8% of this Asian-common haplotype. A significantly reduced HFE expression was observed in individuals carrying T/T at rs9366637 compared to C/C and C/T, indicating a possible role of gene regulation in adaptation. We recruited 57 women of Asian descent and measured Fe absorption using stable isotopes in those homozygous at rs9366637. We observed a 22% higher absorption in women homozygous for the Asian-common haplotype (T/T) compared to the control genotype (C/C). Additionally, compared with a group of age-matched Caucasian women, Asian women exhibited significantly elevated Fe absorption. Our results indicate parallel adaptation of HFE gene in Europeans and Asians with different genetic variants. Moreover, natural selection on HFE may have contributed to elevated Fe absorption in Asians. This study regarding population differences in Fe homeostasis has significant medical impact as high Fe level has been linked to an increased disease risk of metabolic syndromes.

  11. Mutations in HFE causing hemochromatosis are associated with primary hypertriglyceridemia.

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    Solanas-Barca, María; Mateo-Gallego, Rocío; Calmarza, Pilar; Jarauta, Estíbaliz; Bea, Ana M; Cenarro, Ana; Civeira, Fernando

    2009-11-01

    Most cases of primary hypertriglyceridemia (HTG) are caused by the interaction of unknown polygenes and environmental factors. Elevated iron storage is associated with metabolic syndrome, diabetes, and obesity, and all of them are associated with HTG. The aim of the study was to analyze whether HFE mutations causing hereditary hemochromatosis (HH) are associated with primary HTG. Genetic predisposition to HH was analyzed in a case-control study. The study was conducted at University Hospital Lipid Clinic. We studied two groups: 1) the HTG group, composed of 208 patients; and 2) the control group, composed of 215 normolipemic subjects and 161 familial hypercholesterolemia patients. Two HFE mutations (C282Y and H63D) were analyzed. We measured HH genetic predisposition difference between groups. HH genetic predisposition was 5.9 and 4.4 times higher in the HTG group than in the normolipemic (P = 0.02) and FH (P = 0.05) subjects, respectively. There were 35 cases (16.8%) of iron overload in the primary HTG group, 14 (6.5%) and nine (5.6%) in the normolipidemic and FH groups, respectively. A higher HH genetic predisposition and a different prevalence of iron overload in subjects with HH genetic predisposition among groups contributed to this higher prevalence. None of the four cases with the HFE genotype associated with high risk of HH in the control groups presented iron overload; however, in eight of 11 subjects (72.7%) with primary HTG and HH genetic predisposition, the iron overload was present. Mutations in HFE gene, favoring iron overload and causing HH, could play an important role in the development of several phenotypes of primary HTG.

  12. Prevalence of HFE and TFR2 gene mutation in 118 Ligurian rheumatic patients.

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    Rovetta, G; Monteforte, P; Buffrini, L; Grignolo, M C; Franchin, F

    2004-12-01

    HFE gene is associated to haemochromatosis, an inherited autosomal recessive disorder responsible of an overload of iron in intestine, liver, pancreas, heart, cutis and joints. Articular and periarticular calcifications may occur. H63D mutation may play a role in the pathogenesis of rheumatoid arthritis. DNA of 118 consecutive patients (28 males, 90 females, mean age 58.5+/-13.44) living in Liguria and affected by different rheumatic diseases was examined to evaluate the presence of HFE mutations. Analysis data showed that in 45% (53/118) of patients almost one mutation of HFE gene was present and the presence of H63D mutation in the rheumatic patients was particularly elevated. Data obtained in this study have permitted to reveal that 25 patients of 53 (47.1%) with 1 of 11 HFE mutations suffered from symptomatic or silent chondrocalcinosis. The conclusion is drawn that this mutation may be correlated to various rheumatic diseases.

  13. HFE MUTATIONS AND IRON OVERLOAD IN PATIENTS WITH ALCOHOLIC LIVER DISEASE

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    Luis COSTA-MATOS

    2013-03-01

    Full Text Available Context Alcoholic liver disease (ALD is generally associated with iron overload, which may contribute to its pathogenesis, through increased oxidative stress and cellular damage. There are conflicting reports in literature about hemochromatosis (HFE gene mutations and the severity of liver disease in alcoholic patients. Objectives To compare the prevalence of mutations in the hemochromatosis (HFE gene between patients with ALD and healthy controls; to assess the relation of HFE mutations with liver iron stores and liver disease severity. Methods Liver biopsy specimens were obtained from 63 ALD patients (during routine treatment and 52 healthy controls (during elective cholecystectomy. All individuals underwent routine liver function tests and HFE genotyping (to detect wild-type sequences and C282Y, H63D, S65C, E168Q, E168X, V59M, H63H, P160delC, Q127H, Q283P, V53M and W164X mutations. Associations between HFE mutations and risk of excessive liver iron stores, abnormal serum ferritin, liver fibrosis, or necroinflammatory activity were assessed by multivariate logistic regression analysis. Results ALD patients had significantly higher serum ferritin and transferrin saturation than controls (both P<0.05, but the distribution of HFE mutations was similar between the two groups. For ALD patients, the odds ratio for having at least one HFE mutation and excessive liver iron stores was 17.23 (95% confidence interval (CI: 2.09-142.34, P = 0.008. However, the presence of at least one HFE mutation was not associated with an increased risk of liver fibrosis or necroinflammatory activity. Active alcohol ingestion showed the strongest association to increased serum ferritin (OR = 8.87, 95% CI: 2.11-34.78, P = 0.003. Conclusions ALD patients do not present with a differential profile of HFE mutations from healthy controls. In ALD patients, however, the presence of at least one HFE mutation increases the risk of having excessive liver iron stores but has no

  14. Non-HFE hemochromatosis

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    Paulo Caleb Júnior de Lima Santos

    2012-01-01

    Full Text Available Hereditary hemochromatosis (HH is an autosomal recessive disorder classically related to HFE mutations. However, since 1996, it is known that HFE mutations explain about 80% of HH cases, with the remaining around 20% denominated non-HFE hemochromatosis. Nowadays, four main genes are implicated in the pathophysiology of clinical syndromes classified as non-HFE hemochromatosis: hemojuvelin (HJV, type 2Ajuvenile HH, hepcidin (HAMP, type 2B juvenile HH, transferrin receptor 2 (TFR2, type 3 HH and ferroportin (SLC40A1, type 4 HH. The aim of this review is to explore molecular, clinical and management aspects of non-HFE hemochromatosis.

  15. A family with hereditary hemochromatosis carrying HFE gene splice site mutation: a case report

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    NING Huibin

    2017-01-01

    Full Text Available ObjectiveTo investigate a new type of HFE gene mutation in a family with hereditary hemochromatosis (HH. MethodsThe analysis of HFE gene was performed for one patient with a confirmed diagnosis of HH and five relatives. Blood genomic DNA was extracted and PCR multiplication was performed for the exon and intron splice sequences of related HFE, HJV, HAMP, transferrin receptor 2 (TfR2, and SLC40A1 genes. After agarose gel electrophoresis and purification, bi-directional direct sequencing was performed to detect mutation sites. ResultsThe proband had abnormal liver function and increases in serum iron, total iron binding capacity, serum ferritin, and transferrin saturation, as well as T→C homozygous mutation in the fourth base of intron 2 in the intervening sequence of the exon EXON2 of HFE gene (IVs 2+4T→C, C/C homozygous, splicing, abnormal. There were no abnormalities in HJV, HAMP, TfR2, and SLC40A1 genes. The proband′s son had the same homozygous mutation, three relatives had heterozygous mutations, and one relative had no abnormal mutations. ConclusionGene detection plays an important role in the diagnosis of hemochromatosis, and IVs 2+4T→C mutation may be a new pathogenic mutation for HH in China.

  16. Associations of iron metabolism genes with blood manganese levels: a population-based study with validation data from animal models

    Science.gov (United States)

    2011-01-01

    Background Given mounting evidence for adverse effects from excess manganese exposure, it is critical to understand host factors, such as genetics, that affect manganese metabolism. Methods Archived blood samples, collected from 332 Mexican women at delivery, were analyzed for manganese. We evaluated associations of manganese with functional variants in three candidate iron metabolism genes: HFE [hemochromatosis], TF [transferrin], and ALAD [δ-aminolevulinic acid dehydratase]. We used a knockout mouse model to parallel our significant results as a novel method of validating the observed associations between genotype and blood manganese in our epidemiologic data. Results Percentage of participants carrying at least one copy of HFE C282Y, HFE H63D, TF P570S, and ALAD K59N variant alleles was 2.4%, 17.7%, 20.1%, and 6.4%, respectively. Percentage carrying at least one copy of either C282Y or H63D allele in HFE gene was 19.6%. Geometric mean (geometric standard deviation) manganese concentrations were 17.0 (1.5) μg/l. Women with any HFE variant allele had 12% lower blood manganese concentrations than women with no variant alleles (β = -0.12 [95% CI = -0.23 to -0.01]). TF and ALAD variants were not significant predictors of blood manganese. In animal models, Hfe-/- mice displayed a significant reduction in blood manganese compared with Hfe+/+ mice, replicating the altered manganese metabolism found in our human research. Conclusions Our study suggests that genetic variants in iron metabolism genes may contribute to variability in manganese exposure by affecting manganese absorption, distribution, or excretion. Genetic background may be critical to consider in studies that rely on environmental manganese measurements. PMID:22074419

  17. Associations of iron metabolism genes with blood manganese levels: a population-based study with validation data from animal models

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    Claus Henn Birgit

    2011-11-01

    Full Text Available Abstract Background Given mounting evidence for adverse effects from excess manganese exposure, it is critical to understand host factors, such as genetics, that affect manganese metabolism. Methods Archived blood samples, collected from 332 Mexican women at delivery, were analyzed for manganese. We evaluated associations of manganese with functional variants in three candidate iron metabolism genes: HFE [hemochromatosis], TF [transferrin], and ALAD [δ-aminolevulinic acid dehydratase]. We used a knockout mouse model to parallel our significant results as a novel method of validating the observed associations between genotype and blood manganese in our epidemiologic data. Results Percentage of participants carrying at least one copy of HFE C282Y, HFE H63D, TF P570S, and ALAD K59N variant alleles was 2.4%, 17.7%, 20.1%, and 6.4%, respectively. Percentage carrying at least one copy of either C282Y or H63D allele in HFE gene was 19.6%. Geometric mean (geometric standard deviation manganese concentrations were 17.0 (1.5 μg/l. Women with any HFE variant allele had 12% lower blood manganese concentrations than women with no variant alleles (β = -0.12 [95% CI = -0.23 to -0.01]. TF and ALAD variants were not significant predictors of blood manganese. In animal models, Hfe-/- mice displayed a significant reduction in blood manganese compared with Hfe+/+ mice, replicating the altered manganese metabolism found in our human research. Conclusions Our study suggests that genetic variants in iron metabolism genes may contribute to variability in manganese exposure by affecting manganese absorption, distribution, or excretion. Genetic background may be critical to consider in studies that rely on environmental manganese measurements.

  18. AVAQ 594-597 deletion of the TfR2 gene in a Japanese family with hemochromatosis.

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    Hattori, Ai; Wakusawa, Shinnya; Hayashi, Hisao; Harashima, Ai; Sanae, Fujiko; Kawanaka, Miwa; Yamada, Gohtaro; Yano, Motoyashi; Yoshioka, Kenntaro

    2003-06-01

    The majority of Caucasian patients with hemochromatosis are homozygous for C282Y mutation of the HFE gene. In contrast to its high prevalence in Caucasians, hemochromatosis is a rare disorder in Japan. This may be due to the low prevalence of the C282Y mutation of the HFE gene in Japanese. Recent reports suggest that the mutations of transferrin receptor 2 (TfR2) gene may be involved in non-HFE hemochromatosis. Therefore, we investigated the TfR2 gene of 6 sporadic and 5 familiar cases of Japanese hemochromatosis. Three siblings in one family were found to be homozygous for an AVAQ 594-597 deletion. All three had severe iron deposits in the hepatocytes and bile ducts, but none was affected by diabetes mellitus. This mutation was not detected in 100 control individuals. Further study was undertaken to investigate whether the large deletion of the TfR2 gene is the mutation responsible for some of the Japanese hemochromatosis cases.

  19. The Correlation of Cardiac and Hepatic Hemosiderosis as Measured by T2*MRI Technique with Ferritin Levels and Hemochromatosis Gene Mutations in Iranian Patients with Beta Thalassemia Major.

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    Soltanpour, Mohammad Soleiman; Davari, Kambiz

    2018-01-01

    Organ-specific hemosiderosis and iron overload complications are more serious and more frequent in some patients with beta thalassemia major (BTM) compared with others. We investigated whether coinheritance of HFE H63D or C282Y gene mutations in patients with BTM contributes to the phenotypic variation of iron overload complications and assessed the correlation of cardiac and hepatic hemosiderosis with plasma ferritin levels. We studied 60 patients with BTM with a mean age of 17.5±9.1 years from the Northwest of Iran. HFE gene mutations were analyzed using the polymerase chain reaction-restriction fragment length polymorphism method. Cardiac and hepatic hemosiderosis was assessed using T2*magnetic resonance imaging (MRI). Ferritin levels were measured using the enzyme immunoassay method. Ferritin levels showed a strong inverse correlation with hepatic T2*MRI values (r = -0.631, p = 0.001) but a poor correlation with cardiac T2*MRI values (r = -0.297, p = 0.044). The correlation between cardiac T2*MRI values and hepatic T2*MRI values was poor and insignificant (r = 0.287, p = 0.058). Genotype and allele distribution of HFE H63D and C282Y mutation did not differ significantly between patients with and without hepatic or cardiac hemosiderosis ( p > 0.050). However, carriers of HFE 63D allele had significantly higher ferritin levels compared with non-carriers (1 903±993 vs. 992±683, p < 0.001). Cardiac T2*MRI values showed a poor correlation with hepatic T2*MRI values and ferritin levels. Accurate assessment of cardiac iron overload in patients with BTM can only be done using the T2*MRI technique. Additionally, HFE H63D is a significant determinant factor for elevated ferritin levels in BTM patients.

  20. The Correlation of Cardiac and Hepatic Hemosiderosis as Measured by T2*MRI Technique with Ferritin Levels and Hemochromatosis Gene Mutations in Iranian Patients with Beta Thalassemia Major

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    Mohammad Soleiman Soltanpour

    2018-01-01

    Full Text Available Objectives: Organ-specific hemosiderosis and iron overload complications are more serious and more frequent in some patients with beta thalassemia major (BTM compared with others. We investigated whether coinheritance of HFE H63D or C282Y gene mutations in patients with BTM contributes to the phenotypic variation of iron overload complications and assessed the correlation of cardiac and hepatic hemosiderosis with plasma ferritin levels. Methods: We studied 60 patients with BTM with a mean age of 17.5±9.1 years from the Northwest of Iran. HFE gene mutations were analyzed using the polymerase chain reaction-restriction fragment length polymorphism method. Cardiac and hepatic hemosiderosis was assessed using T2*magnetic resonance imaging (MRI. Ferritin levels were measured using the enzyme immunoassay method. Results: Ferritin levels showed a strong inverse correlation with hepatic T2*MRI values (r = -0.631, p = 0.001 but a poor correlation with cardiac T2*MRI values (r = -0.297, p = 0.044. The correlation between cardiac T2*MRI values and hepatic T2*MRI values was poor and insignificant (r = 0.287, p = 0.058. Genotype and allele distribution of HFE H63D and C282Y mutation did not differ significantly between patients with and without hepatic or cardiac hemosiderosis (p > 0.050. However, carriers of HFE 63D allele had significantly higher ferritin levels compared with non-carriers (1 903±993 vs. 992±683, p < 0.001. Conclusions: Cardiac T2*MRI values showed a poor correlation with hepatic T2*MRI values and ferritin levels. Accurate assessment of cardiac iron overload in patients with BTM can only be done using the T2*MRI technique. Additionally, HFE H63D is a significant determinant factor for elevated ferritin levels in BTM patients.

  1. Co-localization of the mammalian hemochromatosis gene product (HFE) and a newly identified transferrin receptor (TfR2) in intestinal tissue and cells.

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    Griffiths, William J H; Cox, Timothy M

    2003-05-01

    Mutations in the HFE gene and a newly identified second transferrin receptor gene, TfR2, cause hemochromatosis. The cognate proteins, HFE and TfR2, are therefore of key importance in human iron homeostasis. HFE is expressed in small intestinal crypt cells where transferrin-iron entry may determine subsequent iron absorption by mature enterocytes, but the physiological function of TfR2 is unknown. Using specific peptide antisera, we examined the duodenal localization of HFE and TfR2 in humans and mice, with and without HFE deficiency, by confocal microscopy. We also investigated potential interactions of these proteins in human intestinal cells in situ. Duodenal expression of HFE and TfR2 (but not TfR1) in wild-type mice and humans was restricted to crypt cells, in which they co-localized. HFE deficiency disrupted this interaction, altering the cellular distribution of TfR2 in human crypts. In human Caco-2 cells, HFE and TfR2 co-localized to a distinct CD63-negative vesicular compartment showing marked signal enhancement on exposure to iron-saturated transferrin ligand, indicating that HFE preferentially interacts with TfR2 in a specialized early endosomal transport pathway for transferrin-iron. This interaction occurs specifically in small intestinal crypt cells that differentiate to become iron-absorbing enterocytes. Our immunohistochemical findings provide evidence for a novel mechanism for the regulation of iron balance in mammals.

  2. Mutations in HFE and TFR2 genes in a Spanish patient with hemochromatosis.

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    Rueda, Alejandro del Castillo; Grande, Nuria Cuadrado; Fernández, Emilio Alvarez; Enríquez de Salamanca, Rafael; Sala, Luis Antonio Alvarez; Jiménez, María Josefa Morán

    2011-07-01

    Iron overload disease has a wide variety of genotypes. The genetic study of this disease confirms its hereditary nature and enables us to provide genetic counseling for first-degree relatives. We performed magnetic resonance imaging and liver biopsy in an asymptomatic patient with more than 1,000 µg/L of serum ferritin and studied the genes involved in this condition. The phenotype of iron overload is confirmed by a predominantly periportal pattern of iron deposits in the liver suggestive of genetic disease. In the case we present the molecular study revealed a double heterozygosity for the mutations c.187C>G (p.H63D) and c.840C>G (p.F280L) in the HFE and transferrin receptor 2 (TFR2) genes, respectively.

  3. Hemochromatosis (HFE) gene mutations and risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) study

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    Agudo, A.; Bonet, C.; Sala, N.; Munoz, X.; Aranda, N.; Fonseca-Nunes, A.; Clavel-Chapelon, F.; Boutron-Ruault, M.C.; Vineis, P.; Panico, S; Palli, D.; Tumino, R.; Grioni, S.; Quiros, J.R.; Molina, E.; Navarro, C.; Barricarte, A; Chamosa, S.; Allen, N.E.; Khaw, K.T.; Bueno-de-Mesquita, H.B.; Siersema, P.D.; Numans, M.E.; Trichopoulou, A.; Lagiou, P.; Trichopoulos, D.; Kaaks, R.; Canzian, F.; Boeing, H; Meidtner, K.; Johansson, M.; Sund, M.; Manjer, J.; Overvad, K.; Tjonneland, A.; Lund, E.; Weiderpass, E; Jenab, M.; Fedirko, V.; Offerhaus, G.J.A.; Riboli, E.; Gonzalez, CA; Jakszyn, P.

    2013-01-01

    Hereditary hemochromatosis (HH) is a strong risk factor for hepatocellular cancer, and mutations in the HFE gene associated with HH and iron overload may be related to other tumors, but no studies have been reported for gastric cancer (GC). A nested case- control study was conducted within the

  4. Molecular basis of HFE-hemochromatosis

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    Maja eVujic Spasic

    2014-03-01

    Full Text Available Iron-overload disorders owing to genetic misregulation of iron acquisition are referred to as hereditary hemochromatosis (HH. The most prevalent genetic iron overload disorder in Caucasians is caused by mutations in the HFE gene, an atypical MHC class I molecule. Recent studies classified HFE/Hfe-hemochromatosis as a liver disease with the primarily failure in the production of the liver iron hormone hepcidin in hepatocytes. Inadequate hepcidin expression signals for excessive iron absorption from the diet and iron deposition in tissues causing multiple organ damage and failure. This review focuses on the molecular actions of the HFE/Hfe and hepcidin in maintaining systemic iron homeostasis and approaches undertaken so far to combat iron overload in HFE/Hfe-HH. In the light of the recent investigations, novel roles of extra-hepatocytic Hfe are discussed raising a question to the relevance of the multipurpose functions of Hfe for the understanding of HH associated pathologies.

  5. Prevalence of common HFE and SERPINA1 mutations in patients with hepatocellular carcinoma in a Moroccan population.

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    Ezzikouri, Sayeh; El Feydi, Abdellah Essaid; El Kihal, Latifa; Afifi, Rajae; Benazzouz, Mustapha; Hassar, Mohammed; Chafik, Abdelaziz; Pineau, Pascal; Benjelloun, Soumaya

    2008-02-01

    Hereditary hemochromatosis and SERPINA1 mutation were reported to affect liver functions. Our objective was to estimate the prevalence of HFE and SERPINA1 (formerly known as alpha1-antitrypsin, AAT) mutations and assess their influence on hepatocellular carcinoma development. This study included 222 controls and 96 cases with hepatocellular carcinoma. PCR-RFLP was used to characterize S and Z alleles in SERPINA1, as well as C282Y/H63D alleles of HFE. In healthy subjects and hepatocellular carcinoma patients as well, no homozygotes for the C282Y mutation were found. In controls, heterozygosity and homozygosity for the H63D mutation were 27 and 0.9%, respectively. Among patients, homozygosity for the H63D mutation was 3.1%, whereas heterozygosity for C282Y and H63D was 2.1 and 35.4%, respectively. Interestingly, albeit it does not reach significance (p=0.062), H63D was more prevalent in hepatocellular carcinoma patients than in controls (38.5 vs. 27.9%, respectively). The association was stronger when considering only male patients with hepatocellular carcinoma (47.1 vs. 23.6, p=0.001). Allele frequencies of S and Z in controls were 0.45% (95% CI=0.2-1.07) and 0.22% (95% CI=0.2-0.6), respectively, and 1 for S and 0% for Z in HCC. No significant difference was found between cases and controls. We provide a novel appraisal of HFE and SERPINA1 mutations prevalence in the Moroccan population. Results are consistent with the worldwide spread of the H63D and S mutation and the north European restriction of the C282Y and Z. Our results show that H63D carriage is increased among hepatocellular carcinoma patients, suggesting that it may confer an increased susceptibility to hepatocellular carcinoma even in a heterozygous state. On the contrary, HFE C282Y and SERPINA1 mutations do not contribute to hepatocellular carcinoma development.

  6. Mutation in HFE gene decreases manganese accumulation and oxidative stress in the brain after olfactory manganese exposure.

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    Ye, Qi; Kim, Jonghan

    2016-06-01

    Increased accumulation of manganese (Mn) in the brain is significantly associated with neurobehavioral deficits and impaired brain function. Airborne Mn has a high systemic bioavailability and can be directly taken up into the brain, making it highly neurotoxic. While Mn transport is in part mediated by several iron transporters, the expression of these transporters is altered by the iron regulatory gene, HFE. Mutations in the HFE gene are the major cause of the iron overload disorder, hereditary hemochromatosis, one of the prevalent genetic diseases in humans. However, whether or not HFE mutation modifies Mn-induced neurotoxicity has not been evaluated. Therefore, our goal was to define the role of HFE mutation in Mn deposition in the brain and the resultant neurotoxic effects after olfactory Mn exposure. Mice carrying the H67D HFE mutation, which is homologous to the H63D mutation in humans, and their control, wild-type mice, were intranasally instilled with MnCl2 with different doses (0, 0.2, 1.0 and 5.0 mg kg(-1)) daily for 3 days. Mn levels in the blood, liver and brain were determined using inductively-coupled plasma mass spectrometry (ICP-MS). H67D mutant mice showed significantly lower Mn levels in the blood, liver, and most brain regions, especially in the striatum, while mice fed an iron-overload diet did not. Moreover, mRNA expression of ferroportin, an essential exporter of iron and Mn, was up-regulated in the striatum. In addition, the levels of isoprostane, a marker of lipid peroxidation, were increased in the striatum after Mn exposure in wild-type mice, but were unchanged in H67D mice. Together, our results suggest that the H67D mutation provides decreased susceptibility to Mn accumulation in the brain and neurotoxicity induced by inhaled Mn.

  7. Characteristics of gene mutation in Chinese patients with hereditary hemochromatosis

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    LYU Tingxia

    2016-08-01

    Full Text Available ObjectiveTo investigate the characteristics of gene mutation in Chinese patients with hereditary hemochromatosis (HH. MethodsA total of 9 patients with HH who visited Beijing Friendship Hospital, Capital Medical University from January 2013 to December 2015 were enrolled. The genomic DNA was extracted, and PCR amplification and Sanger sequencing were performed for all the exons of four genotypes of HH, i.e., HFE (type Ⅰ, HJV (type ⅡA, HAMP (type ⅡB, TFR2 (type Ⅲ, and SLC40A1 (type Ⅳ to analyze gene mutations. A total of 50 healthy subjects were enrolled as control group to analyze the prevalence of identified gene mutations in a healthy population. ResultsOf all patients, 2 had H63D mutation of HFE gene in type Ⅰ HH, 1 had E3D mutation of HJV gene in type ⅡA HH, 2 had I238M mutation of TFR2 gene in type Ⅲ HH, and 1 had IVS 3+10 del GTT splice mutation of SLC40A1 gene in type Ⅳ HH. No patients had C282Y mutation of HFE gene in type Ⅰ HH which was commonly seen in European and American populations. Five patients had no missense mutation or splice mutation. In addition, it was found in a family that a HH patient had E3D mutation of HJV gene, H63D mutation of HFE gene, and I238M mutation of TFR2 gene, but the healthy brother and sister carrying two of these mutations did not had the phenotype of HH. ConclusionHH gene mutations vary significantly across patients of different races, and non-HFE-HH is dominant in the Chinese population. There may be HH genes which are different from known genes, and further investigation is needed.

  8. The role of tmprss6 and hfe variants in iron deficiency anemia in celiac disease.

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    De Falco, Luigia; Tortora, Raffaella; Imperatore, Nicola; Bruno, Mariasole; Capasso, Mario; Girelli, Domenico; Castagna, Annalisa; Caporaso, Nicola; Iolascon, Achille; Rispo, Antonio

    2017-12-01

    We investigated the role of HFE C282Y, H63D and TMPRSS6 A736V variants in the pathogenesis of iron deficiency anemia (IDA) in celiac disease (CD) patients, at diagnosis and after 1-year of gluten free diet (GFD). Demographic and clinical features were prospectively recorded for all CD patients between 2013 and 2017. C282Y, H63D and A736V variants were evaluated for CD patients and controls. Finally, 505 consecutive CD patients and 539 age-matched control subjects were enrolled. At diagnosis, 229 CD subjects had IDA (45.3%), with a subgroup of anemic patients (45.4%) presented persistent IDA at follow-up. C282Y allele frequency was significantly increased in CD compared with controls (1.1% vs 0.2%, P=0.001), whereas H63D and A736V allele frequencies were similar among patients and controls (P=0.92 and 0.84, respectively). At diagnosis, C282Y variant in anemic CD patients was significantly increased compared to non-anemic group (2% and 0.5%, P=0.04). At follow-up, A736V was significantly increased in IDA persistent than in IDA not persistent (57.7% vs 35.2%, P<0.0001). CD patients with H63D mutation showed higher Hb, MCV, serum iron and ferritin levels than subjects without HFE mutations. Decreased hepcidin values were observed in anemic compared to non-anemic subjects at follow-up (1.22±1.14 vs 2.08±2.15, P<0.001). This study suggests a protective role of HFE in IDA CD patients and confirms the role of TMPRSS6 in predicting oral iron response modulating hepcidin action on iron absorption. Iron supplementation therapeutic management in CD could depend on TMPRSS6 genotype that could predict persistent IDA despite iron supplementation and GFD. This article is protected by copyright. All rights reserved. © 2017 Wiley Periodicals, Inc.

  9. Mutaciones del gen de la Hemocromatosis en donantes de sangre voluntarios y en pacientes con Porfiria cutánea tarda en Chile Mutations of hemochromatosis gene in volunteer blood donors and Chilean porphyria cutanea tarda patients

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    Carlos Wolff F

    2006-10-01

    Full Text Available La acumulación de hierro hepático asociada a mutaciones en el gen HFE de la hemocromatosis hereditaria (HH en los pacientes con porfiria cutánea tarda (PCT podría tener un papel en la etiología y en la expresión clínica de esta enfermedad. Se estudió la frecuencia de las mutaciones H63D y C282Y en un grupo de pacientes con PCT y se la comparó con la observada en un grupo de donantes voluntarios de sangre. Los pacientes con PCT fueron catalogados como portadores de la forma hereditaria o adquirida de la enfermedad, según presentaran o no mutaciones en el gen uroporfirinógeno decarboxilasa (UROD. El 50% de los pacientes con PCT eran portadores de la forma genética de la enfermedad, porcentaje significativamente mayor que lo informado en otras series. El 23% de los donantes voluntarios de sangre eran portadores de la mutación H63D y 2.4% lo era de la mutación C282Y. Frecuencias similares a lo encontrado por otros autores en población chilena de etnia blanca, en población argentina y española, pero significativamente más alta que lo encontrado en estudios en población aborigen araucana. Esto tiene, probablemente, relación con el predominio de ascendencia española en la población blanca chilena. La frecuencia de mutación en el gen HFE en pacientes con PCT no fue significativamente diferente que la observada en donantes voluntarios de sangre. Tampoco hubo diferencias significativas en la frecuencia de estas mutaciones entre los casos con PCT adquirida respecto de aquellos en que ésta era de origen genético. Los resultados obtenidos no permiten afirmar que exista asociación entre la PCT y la condición de portador de mutaciones del gen HFE de la hemocromatosis hereditaria.In patients with porphyria cutanea tarda (PCT, hepatic iron accumulation associated to hereditary hemochromatosis (HH could play a role in the etiology and in the clinical expression of the disease. The H63D and C282Y mutations of the HFE gene frequency were

  10. Iranian hereditary hemochromatosis patients: Baseline characteristics, laboratory data and gene mutations

    Science.gov (United States)

    Zamani, Farhad; Bagheri, Zohreh; Bayat, Maryam; Fereshtehnejad, Seyed-Mohammad; Basi, Ali; Najmabadi, Hossein; Ajdarkosh, Hossein

    2012-01-01

    Summary Background Hereditary hemochromatosis (HH) is the most common autosomal recessive disorder in white people, characterized by highly abnormal uptake of iron from the gastrointestinal tracts. Recently, mutation studies have focused to detect the genes responsible for HH. Material/Methods In this cross-sectional study, 12 HH patients were recruited, who were referred to Firoozgar Hospital, Tehran, Iran. In addition to the clinical assessments, a complete laboratory evaluation, imaging modalities, histopathologic assessment, atomic absorption spectrophotometry and gene mutation study were performed. The genetic study for HFE gene mutation was examined for all of the patients since 2006, while non-HFE mutation was conducted since December 2010 (only for 1 of them). Results Twelve patients were evaluated consisting of 11 men and 1 woman, with the mean age of 39.58±12.68 yr. The average of atomic iron loads was 13.25±4.83-fold higher than normal standards. Four patients had heterozygotic mutation of H63D (33.3%). There was no significant difference in either the iron load of liver (P=0.927) and heart (P=0.164) or serum concentration of ferritin (P=0.907) and TIBC (P=0.937) between the HFE-mutant and without HFE mutation HH cases. Conclusions In contrast to other studies, C282Y mutation was not detected in any of our Iranian HH patients. Heterozygotic mutations of H63D (HFE) and TFR2 (non-HFE) genes were found to be more common in these patients. Similar to previous reports, these mutations were not found to be significantly associated with severity of presentation in HH patients. PMID:23018356

  11. Association of mutations in the hemochromatosis gene with shorter life expectancy

    DEFF Research Database (Denmark)

    Bathum, L; Christiansen, L; Nybo, H

    2001-01-01

    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....

  12. Haemochromatosis gene mutation H63D is a risk factor for iron ...

    African Journals Online (AJOL)

    Introduction: Iron overload is the main cause of morbidity and mortality in patients with β-thalassemia. The Aim: The aim of this study was to evaluate the prevalence of genetic markers (HFE mutations C282Y and H63D) among Egyptian β-thalassemic. Children and its effect on their iron status. Patients and Methods: 59 ...

  13. A novel (Leu183Pro-)mutation in the HFE-gene co-inherited with the Cys282Tyr mutation in two unrelated Dutch hemochromatosis patients.

    NARCIS (Netherlands)

    Swinkels, D.W.; Venselaar, H.; Wiegerinck, E.T.G.; Bakker, E.; Joosten, I.; Jaspers, C.A.; Vasmel, W.L.; Breuning, M.H.

    2008-01-01

    We describe a novel heterozygous mutation in exon 3 of the HFE-gene that was co-inherited with Cys282Tyr in two unrelated Dutch men both presenting a classical form of hereditary hemochromatosis. Heterozygosity for this mutation was also found in one out of 100 healthy controls of Dutch descent.

  14. Severity of iron overload of proband determines serum ferritin levels in families with HFE-related hemochromatosis: the HEmochromatosis FAmily Study.

    Science.gov (United States)

    Jacobs, Esther M G; Hendriks, Jan C M; van Deursen, Cees Th B M; Kreeftenberg, Herman G; de Vries, Richard A; Marx, Joannes J M; Stalenhoef, Anton F H; Verbeek, André L M; Swinkels, Dorine W

    2009-01-01

    In families of patients with clinically detected hereditary hemochromatosis (HH) early screening has been suggested to prevent morbidity and mortality. Here, we aim to identify determinants for iron overload in first-degree family members of C282Y homozygous probands with clinically detected HH. Data on HFE-genotype, iron parameters, demographics, lifestyle factors and health, were collected from 224 Dutch C282Y homozygous patients with clinically diagnosed HH and 735 of their first-degree family members (FDFM), all participating in the HEmochromatosis FAmily Study (HEFAS). The best predictive multivariable model forecasted 45% of variation of the serum ferritin levels. In this model severity of iron overload in the proband significantly predicted serum ferritin levels in FDFM. Other significant determinants in this model consisted of C282Y homozygosity, compound heterozygosity, age at testing for serum ferritin and supplemental iron intake, whereas a low body mass index showed a protective effect. This study provides a model to assess the risk of development of iron overload for relatives of probands with HH. These results might be instrumental in the development of an optimal strategy for future family screening programs.

  15. Dietary advice in HFE-hemochromatosis

    NARCIS (Netherlands)

    Doorn, van G.M.; Gosselink, I.M.G.

    2012-01-01

    This report aims to provide dietary advice which is based on what is known so far about the effect of a diet, particularly on iron overload in HFE-hemochromatosis. The reason that the recommendations in principle apply only to the group of individuals with HFE-gene mutations and are focused on the

  16. Identification of novel mutations in hemochromatosis genes by targeted next generation sequencing in Italian patients with unexplained iron overload.

    Science.gov (United States)

    Badar, Sadaf; Busti, Fabiana; Ferrarini, Alberto; Xumerle, Luciano; Bozzini, Paolo; Capelli, Paola; Pozzi-Mucelli, Roberto; Campostrini, Natascia; De Matteis, Giovanna; Marin Vargas, Sergio; Giorgetti, Alejandro; Delledonne, Massimo; Olivieri, Oliviero; Girelli, Domenico

    2016-06-01

    Hereditary hemochromatosis, one of the commonest genetic disorder in Caucasians, is mainly associated to homozygosity for the C282Y mutation in the HFE gene, which is highly prevalent (allele frequency up to near 10% in Northern Europe) and easily detectable through a widely available "first level" molecular test. However, in certain geographical regions like the Mediterranean area, up to 30% of patients with a HH phenotype has a negative or non-diagnostic (i.e. simple heterozygosity) test, because of a known heterogeneity involving at least four other genes (HAMP, HJV, TFR2, and SLC40A1). Mutations in such genes are generally rare/private, making the diagnosis of atypical HH essentially a matter of exclusion in clinical practice (from here the term of "non-HFE" HH), unless cumbersome traditional sequencing is applied. We developed a Next Generation Sequencing (NGS)-based test targeting the five HH genes, and applied it to patients with clinically relevant iron overload (IO) and a non-diagnostic first level genetic test. We identified several mutations, some of which were novel (i.e. HFE W163X, HAMP R59X, and TFR2 D555N) and allowed molecular reclassification of "non-HFE" HH clinical diagnosis, particularly in some highly selected IO patients without concurring acquired risk factors. This NGS-based "second level" genetic test may represent a useful tool for molecular diagnosis of HH in patients in whom HH phenotype remains unexplained after the search of common HFE mutations. © 2016 Wiley Periodicals, Inc.

  17. Early onset hereditary hemochromatosis resulting from a novel TFR2 gene nonsense mutation (R105X) in two siblings of north French descent.

    Science.gov (United States)

    Le Gac, G; Mons, F; Jacolot, S; Scotet, V; Férec, C; Frébourg, T

    2004-06-01

    The molecular basis of hereditary hemochromatosis (HH) is more complex than previously expected. More than 80% of hemochromatosis probands of Northern European descent are homozygous for the C282Y HFE gene mutation. However, five novel non-related-HFE HH forms have now been identified. The transferrin receptor(TFR2)-linked form is inherited in an autosomal recessive pattern and is considered to be an adult-onset syndrome. Until now, it has been associated with five mutations that have only been detected in Japanese and southern European patients. Here, we report the identification of a novel TFR2 nonsense mutation in two related French adolescents. We discuss the phenotype of this sibling pair from precedent biological and clinical findings as well as the expected role of TFR2 in iron homeostasis. Finally, we suggest that iron overload phenotypes associated with mutations in TFR2 may be intermediate between those related to mutations in HFE and those related to mutations in juvenile hemochromatosis genes.

  18. A novel (Leu183Pro-)mutation in the HFE-gene co-inherited with the Cys282Tyr mutation in two unrelated Dutch hemochromatosis patients.

    Science.gov (United States)

    Swinkels, Dorine W; Venselaar, Hanka; Wiegerinck, Erwin T; Bakker, Egbert; Joosten, Irma; Jaspers, Christian A J J; Vasmel, Wies L; Breuning, Martijn H

    2008-01-01

    We describe a novel heterozygous mutation in exon 3 of the HFE-gene that was co-inherited with Cys282Tyr in two unrelated Dutch men both presenting a classical form of hereditary hemochromatosis. Heterozygosity for this mutation was also found in one out of 100 healthy controls of Dutch descent. This c.548T>C mutation converts a leucine to a proline residue at position 183 in the alpha2-helix of the HFE-protein (Leu183Pro). Standard bioinformatics analysis shows that the mutation is likely to disturb the HFE interaction with TfR1. This disrupting role of the mutation in the iron regulatory pathway is further corroborated by the familial co-occurrence of the observed compound heterozygosity with increased serum iron parameters. Haplotype analysis strongly suggests that this novel mutation arose from a common ancestor in the distant past. These findings may have implications for HFE-testing of iron overloaded heterozygous Cys282Tyr-patients of Northern European origin and their relatives.

  19. Mutations in HFE and TFR2 genes in a Spanish patient with hemochromatosis Mutaciones en los genes HFE y TFR2 en un paciente español con hemocromatosis

    Directory of Open Access Journals (Sweden)

    Alejandro del-Castillo-Rueda

    2011-07-01

    Full Text Available Iron overload disease has a wide variety of genotypes. The genetic study of this disease confirms its hereditary nature and enables us to provide genetic counseling for first-degree relatives. We performed magnetic resonance imaging and liver biopsy in an asymptomatic patient with more than 1,000 µg/L of serum ferritin and studied the genes involved in this condition. The phenotype of iron overload is confirmed by a predominantly periportal pattern of iron deposits in the liver suggestive of genetic disease. In the case we present the molecular study revealed a double heterozygosity for the mutations c.187C>G (p.H63D and c.840C>G (p.F280L in the HFE and transferrin receptor 2 (TFR2 genes, respectively.La enfermedad por sobrecarga de hierro está originada por diversas anomalías genéticas. El estudio genético de esta enfermedad confirma su carácter hereditario y nos permite ofrecer consejo genético a los familiares en primer grado. Hemos realizado resonancia magnética y biopsia de hígado en un paciente asintomático con más de 1.000 µg/l de ferritina en suero, y hemos analizado los genes implicados en el metabolismo del hierro. El fenotipo de sobrecarga de hierro se confirmó por la presencia de un patrón de depósito de hierro en el hígado con predominio periportal que sugiere la existencia de una enfermedad genética. En el caso que presentamos, el estudio genético reveló que el paciente es doble heterocigoto para las mutaciones c.187C>G (p.H63D y c.840C>G (p.F280L en los genes HFE y receptor 2 de transferrina (TFR2, respectivamente.

  20. Iron-related gene variants and brain iron in multiple sclerosis and healthy individuals.

    Science.gov (United States)

    Hagemeier, Jesper; Ramanathan, Murali; Schweser, Ferdinand; Dwyer, Michael G; Lin, Fuchun; Bergsland, Niels; Weinstock-Guttman, Bianca; Zivadinov, Robert

    2018-01-01

    Brain iron homeostasis is known to be disturbed in multiple sclerosis (MS), yet little is known about the association of common gene variants linked to iron regulation and pathological tissue changes in the brain. In this study, we investigated the association of genetic determinants linked to iron regulation with deep gray matter (GM) magnetic susceptibility in both healthy controls (HC) and MS patients. Four hundred (400) patients with MS and 150 age- and sex-matched HCs were enrolled and obtained 3 T MRI examination. Three (3) single nucleotide polymorphisms (SNPs) associated with iron regulation were genotyped: two SNPs in the human hereditary hemochromatosis protein gene HFE : rs1800562 (C282Y mutation) and rs1799945 (H63D mutation), as well as the rs1049296 SNP in the transferrin gene (C2 mutation). The effects of disease and genetic status were studied using quantitative susceptibility mapping (QSM) voxel-based analysis (VBA) and region-of-interest (ROI) analysis of the deep GM. The general linear model framework was used to compare groups. Analyses were corrected for age and sex, and adjusted for false discovery rate. We found moderate increases in susceptibility in the right putamen of participants with the C282Y (+ 6.1 ppb) and H63D (+ 6.9 ppb) gene variants vs. non-carriers, as well as a decrease in thalamic susceptibility of progressive MS patients with the C282Y mutation (left: - 5.3 ppb, right: - 6.7 ppb, p < 0.05). Female MS patients had lower susceptibility in the caudate (- 6.0 ppb) and putamen (left: - 3.9 ppb, right: - 4.6 ppb) than men, but only when they had a wild-type allele (p < 0.05). Iron-gene linked increases in putamen susceptibility (in HC and relapsing remitting MS) and decreases in thalamus susceptibility (in progressive MS), coupled with apparent sex interactions, indicate that brain iron in healthy and disease states may be influenced by genetic factors.

  1. [Iron in the era of molecular biology].

    Science.gov (United States)

    Deugnier, Y; Moirand, R; Brissot, P; David, V

    1999-11-01

    Identification of the HFE gene and its C282Y and H63D mutations has improved the classification of iron overload disorders. Inherited hemochromatosis is due mainly, or perhaps only, to C282Y homozygosity, whereas nonhemochromatosis forms of iron overload are due to other HFE mutations and are usually responsible for mild overload precipitated by another factor such as cirrhosis or insulin-resistance. In practice, the diagnosis of inherited hemochromatosis rests on demonstration of homozygosity for the C282Y mutation; in this setting, the role of liver biopsy is to evaluate the prognosis by looking for fibrosis. In patients who are not homozygous for the C282Y mutation but have severe iron overload, causes other than hemochromatosis should be looked for before the extremely remote possibility of nonC282Y-related hemochromatosis is considered; here, liver biopsy remains of considerable diagnostic usefulness.

  2. Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice.

    Science.gov (United States)

    Gao, Junwei; Chen, Juxing; De Domenico, Ivana; Koeller, David M; Harding, Cary O; Fleming, Robert E; Koeberl, Dwight D; Enns, Caroline A

    2010-04-22

    Hereditary hemochromatosis is caused by mutations in the hereditary hemochromatosis protein (HFE), transferrin-receptor 2 (TfR2), hemojuvelin, hepcidin, or ferroportin genes. Hepcidin is a key iron regulator, which is secreted by the liver, and decreases serum iron levels by causing the down-regulation of the iron transporter, ferroportin. Mutations in either HFE or TfR2 lower hepcidin levels, implying that both HFE and TfR2 are necessary for regulation of hepcidin expression. In this study, we used a recombinant adeno-associated virus, AAV2/8, for hepatocyte-specific expression of either Hfe or Tfr2 in mice. Expression of Hfe in Hfe-null mice both increased Hfe and hepcidin mRNA and lowered hepatic iron and Tf saturation. Expression of Tfr2 in Tfr2-deficient mice had a similar effect, whereas expression of Hfe in Tfr2-deficient mice or of Tfr2 in Hfe-null mice had no effect on liver or serum iron levels. Expression of Hfe in wild-type mice increased hepcidin mRNA and lowered iron levels. In contrast, expression of Tfr2 had no effect on wild-type mice. These findings suggest that Hfe is limiting in formation of the Hfe/Tfr2 complex that regulates hepcidin expression. In addition, these studies show that the use of recombinant AAV vector to deliver genes is a promising approach for studying physiologic consequences of protein complexes.

  3. Lymphocyte gene expression signatures from patients and mouse models of hereditary hemochromatosis reveal a function of HFE as a negative regulator of CD8+ T-lymphocyte activation and differentiation in vivo.

    Directory of Open Access Journals (Sweden)

    Mónica Costa

    Full Text Available Abnormally low CD8+ T-lymphocyte numbers is characteristic of some patients with hereditary hemochromatosis (HH, a MHC-linked disorder of iron overload. Both environmental and genetic components are known to influence CD8+ T-lymphocyte homeostasis but the role of the HH associated protein HFE is still insufficiently understood. Genome-wide expression profiling was performed in peripheral blood CD8+ T lymphocytes from HH patients selected according to CD8+ T-lymphocyte numbers and from Hfe-/- mice maintained either under normal or high iron diet conditions. In addition, T-lymphocyte apoptosis and cell cycle progression were analyzed by flow cytometry in HH patients. HH patients with low CD8+ T-lymphocyte numbers show a differential expression of genes related to lymphocyte differentiation and maturation namely CCR7, LEF1, ACTN1, NAA50, P2RY8 and FOSL2, whose expression correlates with the relative proportions of naïve, central and effector memory subsets. In addition, expression levels of LEF1 and P2RY8 in memory cells as well as the proportions of CD8+ T cells in G2/M cell cycle phase are significantly different in HH patients compared to controls. Hfe-/- mice do not show alterations in CD8+ T-lymphocyte numbers but differential gene response patterns. We found an increased expression of S100a8 and S100a9 that is most pronounced in high iron diet conditions. Similarly, CD8+ T lymphocytes from HH patients display higher S100a9 expression both at the mRNA and protein level. Altogether, our results support a role for HFE as a negative regulator of CD8+ T-lymphocyte activation. While the activation markers S100a8 and S100a9 are strongly increased in CD8+ T cells from both, Hfe-/- mice and HH patients, a differential profile of genes related to differentiation/maturation of CD8+ T memory cells is evident in HH patients only. This supports the notion that HFE contributes, at least in part, to the generation of low peripheral blood CD8+ T lymphocytes

  4. Novel Method Probe-based Real-Time PCR to Detect 2 Single-Nucleotide Polymorphisms Close to Each Other: HFE Hemochromatosis Gene Model.

    Science.gov (United States)

    Malta, Frederico S V; Reis, Zilma N; Cabral, Antônio C V

    2016-10-01

    Hereditary hemochromatosis is known as the most common genetic disorder among individuals of European genetic background. It is possible to find 2 mutations closely placed in the HFE gene (H63D and S65C) and this proximity can cause errors when genotyped by real-time polymerase chain reaction (PCR) genotyping assay. The aim of this study was to develop a hydrolysis probe-based PCR assay for detection of the H63D and S65C mutations without interference from on each other. Herein the study involved the standardization of an improvement of the real-time PCR 5' nuclease assay to detect the desired mutations close placed using a same probe system. The assay analytical properties performances were tested, including the primers selectivity and detection limits. Also, the interexaminer reproducibility and repeatability of assay were estimated in 30 blood samples. Others 153 results of samples were compared with reference method (PCR_RFLP) and the accordance of the results evaluated by Fleiss' κ method. The results of variation of interexaminer reproducibility and repeatability of assay were not statistically relevant (Pmethods by Fleiss' κ analysis showed that 5' nuclease assay identified the H63D and S65C haplotype as well as the reference method in all 153 tested samples. Our results showed that novel method probe-based real-time PCR were capable to detect 2 adjacent polymorphisms without errors in genotyping.

  5. The mitochondrial nt 16189 polymorphism and hereditary hemochromatosis.

    Science.gov (United States)

    Beutler, Ernest; Beutler, Lisa; Lee, Pauline L; Barton, James C

    2004-01-01

    It has been claimed that a noncoding mitochondrial polymorphism at nt 16189 is correlated with the penetrance of the homozygous state for the C282Y mutation of the HFE gene. We have genotyped homozygotes for the C282Y mutation and find no relationship between the ferritin levels and the inheritance of the mitochondrial polymorphism. Indeed, the small difference found is in the opposite direction of that reported previously.

  6. Mutations in HFE and TFR2 genes in a Spanish patient with hemochromatosis Mutaciones en los genes HFE y TFR2 en un paciente español con hemocromatosis

    National Research Council Canada - National Science Library

    Alejandro del-Castillo-Rueda; Nuria Cuadrado-Grande; Emilio Álvarez-Fernández; Rafael Enríquez-de-Salamanca; Luis Antonio Álvarez-Sala; María Josefa Morán-Jiménez

    2011-01-01

    ... 1,000 µg/L of serum ferritin and studied the genes involved in this condition. The phenotype of iron overload is confirmed by a predominantly periportal pattern of iron deposits in the liver suggestive of genetic disease...

  7. Transgenic HFE-dependent induction of hepcidin in mice does not require transferrin receptor-2.

    Science.gov (United States)

    Schmidt, Paul J; Fleming, Mark D

    2012-06-01

    Hereditary hemochomatosis (HH) is caused by mutations in several genes, including HFE and transferrin receptor-2 (TFR2). Loss of either protein decreases expression of the iron regulatory hormone hepcidin by the liver, leading to inappropriately high iron uptake from the diet, and resulting in systemic iron overload. In tissue culture, overexpressed HFE and TFR2 physically interact. Hepatocellular overexpression of Hfe in vivo increases hepcidin expression, despite an associated decrease in Tfr2. On this basis, we hypothesized that Tfr2 would not be required for Hfe-dependent up-regulation of hepcidin. We show that hepatocellular overexpression of Hfe in Tfr2(Y245X/Y245X) mice leads to hepcidin induction eventuating in iron deficiency and a hypochromic, microcytic anemia. Furthermore, coimmunoprecipitation studies using liver lysates did not provide evidence for physical interaction between Hfe and Tfr2 in vivo. In conclusion, we demonstrate that Tfr2 is not essential for Hfe-mediated induction of hepcidin expression, supporting the possibility that TFR2 may regulate iron metabolism in an HFE-independent manner. Copyright © 2012 Wiley Periodicals, Inc.

  8. Pathophysiological consequences and benefits of HFE mutations: 20 years of research

    Science.gov (United States)

    Hollerer, Ina; Bachmann, André; Muckenthaler, Martina U.

    2017-01-01

    Mutations in the HFE (hemochromatosis) gene cause hereditary hemochromatosis, an iron overload disorder that is hallmarked by excessive accumulation of iron in parenchymal organs. The HFE mutation p.Cys282Tyr is pathologically most relevant and occurs in the Caucasian population with a carrier frequency of up to 1 in 8 in specific European regions. Despite this high prevalence, the mutation causes a clinically relevant phenotype only in a minority of cases. In this review, we summarize historical facts and recent research findings about hereditary hemochromatosis, and outline the pathological consequences of the associated gene defects. In addition, we discuss potential advantages of HFE mutations in asymptomatic carriers. PMID:28280078

  9. HFE and Spherical Cryostats MC Study

    Energy Technology Data Exchange (ETDEWEB)

    Brodsky, Jason P. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2016-09-26

    The copper vessel containing the nEXO TPC is surrounded by a buffer of HFE, a liquid refrigerant with very low levels of radioactive element contamination. The HFE is contained within the cryostat’s inner vessel, which is in turn inside the outer vessel. While some HFE may be necessary for stable cooling of nEXO, it is possible that using substantially more than necessary for thermal reasons will help reduce backgrounds originating in the cryostats. Using a larger amount of HFE is accomplished by making the cryostat vessels larger. By itself, increasing the cryostat size somewhat increases the background rate, as the thickness of the cryostat wall must increase at larger sizes. However, the additional space inside the cryostat will be filled with HFE which can absorb gamma rays headed for the TPC. As a result, increasing the HFE reduces the number of backgrounds reaching the TPC. The aim of this study was to determine the relationship between HFE thickness and background rate. Ultimately, this work should support choosing a cryostat and HFE size that satisfies nEXO’s background budget. I have attempted to account for every consequence of changing the cryostat size, although naturally this remains a work in progress until a final design is achieved. At the moment, the scope of the study includes only the spherical cryostat design. This study concludes that increasing cryostat size reduces backgrounds, reaching neglible backgrounds originating from the cryostat at the largest sizes. It also shows that backgrounds originating from the inherent radioactivity of the HFE plateau quickly, so may be considered essentially fixed at any quantity of HFE.

  10. Interaction of Dietary and Genetic Factors Influencing Body Iron Status and Risk of Type 2 Diabetes Within the EPIC-InterAct Study

    DEFF Research Database (Denmark)

    Meidtner, Karina; Podmore, Clara; Kröger, Janine

    2018-01-01

    ferritin levels (β = 0.113 [95% CI 0.082; 0.144]), but not with transferrin (-0.019 [-0.043; 0.006]) or transferrin saturation (0.016 [-0.006; 0.037]). Five SNPs located in four genes (rs1799945 [HFE H63D], rs1800562 [HFE C282Y], rs236918 [PCK7], rs744653 [SLC40A1], and rs855791 [TMPRSS6 V736A]) were...

  11. EMQN best practice guidelines for the molecular genetic diagnosis of hereditary hemochromatosis (HH).

    Science.gov (United States)

    Porto, Graça; Brissot, Pierre; Swinkels, Dorine W; Zoller, Heinz; Kamarainen, Outi; Patton, Simon; Alonso, Isabel; Morris, Michael; Keeney, Steve

    2016-04-01

    Molecular genetic testing for hereditary hemochromatosis (HH) is recognized as a reference test to confirm the diagnosis of suspected HH or to predict its risk. The vast majority (typically >90%) of patients with clinically characterized HH are homozygous for the p.C282Y variant in the HFE gene, referred to as HFE-related HH. Since 1996, HFE genotyping was implemented in diagnostic algorithms for suspected HH, allowing its early diagnosis and prevention. However, the penetrance of disease in p.C282Y homozygotes is incomplete. Hence, homozygosity for p.C282Y is not sufficient to diagnose HH. Neither is p.C282Y homozygosity required for diagnosis as other rare forms of HH exist, generally referred to as non-HFE-related HH. These pose significant challenges when defining criteria for referral, testing protocols, interpretation of test results and reporting practices. We present best practice guidelines for the molecular genetic diagnosis of HH where recommendations are classified, as far as possible, according to the level and strength of evidence. For clarification, the guidelines' recommendations are preceded by a detailed description of the methodology and results obtained with a series of actions taken in order to achieve a wide expert consensus, namely: (i) a survey on the current practices followed by laboratories offering molecular diagnosis of HH; (ii) a systematic literature search focused on some identified controversial topics; (iii) an expert Best Practice Workshop convened to achieve consensus on the practical recommendations included in the guidelines.

  12. EMQN best practice guidelines for the molecular genetic diagnosis of hereditary hemochromatosis (HH)

    Science.gov (United States)

    Porto, Graça; Brissot, Pierre; Swinkels, Dorine W; Zoller, Heinz; Kamarainen, Outi; Patton, Simon; Alonso, Isabel; Morris, Michael; Keeney, Steve

    2016-01-01

    Molecular genetic testing for hereditary hemochromatosis (HH) is recognized as a reference test to confirm the diagnosis of suspected HH or to predict its risk. The vast majority (typically >90%) of patients with clinically characterized HH are homozygous for the p.C282Y variant in the HFE gene, referred to as HFE-related HH. Since 1996, HFE genotyping was implemented in diagnostic algorithms for suspected HH, allowing its early diagnosis and prevention. However, the penetrance of disease in p.C282Y homozygotes is incomplete. Hence, homozygosity for p.C282Y is not sufficient to diagnose HH. Neither is p.C282Y homozygosity required for diagnosis as other rare forms of HH exist, generally referred to as non-HFE-related HH. These pose significant challenges when defining criteria for referral, testing protocols, interpretation of test results and reporting practices. We present best practice guidelines for the molecular genetic diagnosis of HH where recommendations are classified, as far as possible, according to the level and strength of evidence. For clarification, the guidelines' recommendations are preceded by a detailed description of the methodology and results obtained with a series of actions taken in order to achieve a wide expert consensus, namely: (i) a survey on the current practices followed by laboratories offering molecular diagnosis of HH; (ii) a systematic literature search focused on some identified controversial topics; (iii) an expert Best Practice Workshop convened to achieve consensus on the practical recommendations included in the guidelines. PMID:26153218

  13. HFE modulates transferrin receptor 2 levels in hepatoma cells via interactions that differ from transferrin receptor 1-HFE interactions.

    Science.gov (United States)

    Chen, Juxing; Chloupková, Maja; Gao, Junwei; Chapman-Arvedson, Tara L; Enns, Caroline A

    2007-12-21

    Mutations in the transmembrane glycoproteins transferrin receptor 2 (TfR2) and HFE are associated with hereditary hemochromatosis. Interactions between HFE and transferrin receptor 1 (TfR1) have been mapped to the alpha1- and alpha2-helices in HFE and to the helical domain of TfR1. Recently, TfR2 was also reported to interact with HFE in transfected mammalian cells. To test whether similar HFE residues are important for both TfR1 and TfR2 binding, a mutant form of HFE (W81AHFE) that has an approximately 5,000-fold lower affinity for TfR1 than HFE was employed. As expected, W81AHFE does not interact with TfR1. However, we found that the same mutation in HFE does not affect the TfR2/HFE interaction. This finding indicates that the TfR2/HFE and TfR1/HFE interactions are distinct. We further observed that, unlike TfR1/HFE, Tf does not compete with HFE for binding to TfR2 and that binding is independent of pH (pH 6-7.5). TfR2-TfR1 and HFE-HLA-B7 chimeras were generated to map the domains of the TfR2/HFE interaction. TfR1 and HLA-B7 were chosen because of their similar overall structures with TfR2 and HFE, respectively. We mapped the interacting domains to the putative stalk and protease-like domains of TfR2 located between residues 104 and 250 and to the alpha3 domain of HFE, both of which differ from the TfR1/HFE interacting domains. Furthermore, we found that HFE increases TfR2 levels in hepatic cells independent of holo-Tf.

  14. Hereditary hemochromatosis (HFE) genotypes in heart failure: relation to etiology and prognosis

    DEFF Research Database (Denmark)

    Møller, Daniel Vega; Pecini, Redi; Gustafsson, Finn

    2010-01-01

    It is believed that hereditary hemochromatosis (HH) might play a role in cardiac disease (heart failure (HF) and ischemia). Mutations within several genes are HH-associated, the most common being the HFE gene. In a large cohort of HF patients, we sought to determine the etiological role...

  15. Hereditary hemochromatosis (HFE) genotypes in heart failure: relation to etiology and prognosis

    DEFF Research Database (Denmark)

    Møller, Daniel Vega; Pecini, Redi; Gustafsson, Finn

    2010-01-01

    It is believed that hereditary hemochromatosis (HH) might play a role in cardiac disease (heart failure (HF) and ischemia). Mutations within several genes are HH-associated, the most common being the HFE gene. In a large cohort of HF patients, we sought to determine the etiological role and the p...

  16. Frekvensen af haemokromatoseassocierede mutationer i haemokromatosegenet i den danske befolkning. ØsterbroundersØgelsen

    DEFF Research Database (Denmark)

    Larsen, Lisbeth Enggaard; Ellervik, Christina; Appleyard, Merete

    2002-01-01

    INTRODUCTION: Hereditary haemochromatosis is an autosomal recessive condition characterised by systemic iron overload. In Northern Europe, 85-90% of patients with haemochromatosis are homozygous for the C282Y mutation in the HFE gene. In the present study, we determined the prevalence...... hereditary haemochromatosis the potentially most common inherited disorder in Denmark. However, in new studies from USA of the association between genotype and disease in unselected populations the penetrance is very low. On this background, population screening for the presence of these mutations...... of the haemochromatosis-associated mutations, C282Y and H63D, in the Danish general population. MATERIAL AND METHODS: We genotyped 9174 individuals from a random sample of the Danish general population (The Copenhagen City Heart Study), stratified by gender and age in 10-year age groups, for the presence of C282Y and H63...

  17. Combined deletion of Hfe and transferrin receptor 2 in mice leads to marked dysregulation of hepcidin and iron overload.

    Science.gov (United States)

    Wallace, Daniel F; Summerville, Lesa; Crampton, Emily M; Frazer, David M; Anderson, Gregory J; Subramaniam, V Nathan

    2009-12-01

    Hepcidin is a central regulator of iron homeostasis. HFE and transferrin receptor 2 (TFR2) are mutated in adult-onset forms of hereditary hemochromatosis and regulate the expression of hepcidin in response to iron. Whether they act through the same or parallel pathways is unclear. To investigate this, we generated a mouse model with deletion of both Hfe and Tfr2 genes by crossing Hfe and Tfr2 null mice on a genetically identical background. Tissue and serum from wildtype, single-, and double-null mice were analyzed. Serum transferrin saturation and hepatic iron concentrations were determined. The expression of iron-related messenger RNA (mRNA) transcripts was analyzed by real-time polymerase chain reaction (PCR). Levels of the iron-related proteins Tfr1, Tfr2, ferritin, and prohepcidin, and the phosphorylation status of the cell signaling proteins extracellular signal-regulated kinase 1/2 (Erk1/2) and Smad1/5/8, were analyzed by immunoblotting. Double-null mice had more severe iron loading than mice lacking either Hfe or Tfr2; Tfr2 null mice had a greater iron burden than Hfe-null mice. Hepcidin expression relative to iron stores was reduced in the Hfe-null mice, with significantly lower values in the Tfr2-null mice. In the absence of both Hfe and Tfr2, hepcidin expression was reduced even further. A significant decrease in phospho-Erk1/2 in the livers of null mice and a reduction in phospho-Smad1/5/8 suggest that both the mitogen-activated protein kinase (MAPK) and bone morphogenetic protein / mothers against decapentaplegic homolog (BMP/SMAD) signaling pathways may be involved in Hfe- and Tfr2-mediated regulation of hepcidin. These studies demonstrate that iron overload due to deletion of Tfr2 is more severe than that due to Hfe, and that loss of both molecules results in pronounced iron overload. Analysis of Hfe/Tfr2 double-null mice suggests that Hfe and Tfr2 regulate hepcidin through parallel pathways involving Erk1/2 and Smad1/5/8.

  18. Iron regulation of hepcidin despite attenuated Smad1,5,8 signaling in mice without transferrin receptor 2 or Hfe.

    Science.gov (United States)

    Corradini, Elena; Rozier, Molly; Meynard, Delphine; Odhiambo, Adam; Lin, Herbert Y; Feng, Qi; Migas, Mary C; Britton, Robert S; Babitt, Jodie L; Fleming, Robert E

    2011-11-01

    HFE and transferrin receptor 2 (TFR2) are each necessary for the normal relationship between body iron status and liver hepcidin expression. In murine Hfe and Tfr2 knockout models of hereditary hemochromatosis (HH), signal transduction to hepcidin via the bone morphogenetic protein 6 (Bmp6)/Smad1,5,8 pathway is attenuated. We examined the effect of dietary iron on regulation of hepcidin expression via the Bmp6/Smad1,5,8 pathway using mice with targeted disruption of Tfr2, Hfe, or both genes. Hepatic iron concentrations and messenger RNA expression of Bmp6 and hepcidin were compared with wild-type mice in each of the HH models on standard or iron-loading diets. Liver phospho-Smad (P-Smad)1,5,8 and Id1 messenger RNA levels were measured as markers of Bmp/Smad signaling. Whereas Bmp6 expression was increased, liver hepcidin and Id1 expression were decreased in each of the HH models compared with wild-type mice. Each of the HH models also showed attenuated P-Smad1,5,8 levels relative to liver iron status. Mice with combined Hfe/Tfr2 disruption were most affected. Dietary iron loading increased hepcidin and Id1 expression in each of the HH models. Compared with wild-type mice, HH mice demonstrated attenuated (Hfe knockout) or no increases in P-Smad1,5,8 levels in response to dietary iron loading. These observations show that Tfr2 and Hfe are each required for normal signaling of iron status to hepcidin via the Bmp6/Smad1,5,8 pathway. Mice with combined loss of Hfe and Tfr2 up-regulate hepcidin in response to dietary iron loading without increases in liver Bmp6 messenger RNA or steady-state P-Smad1,5,8 levels. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

  19. Reduced white matter MRI transverse relaxation rate in cognitively normal H63D-HFE human carriers and H67D-HFE mice.

    Science.gov (United States)

    Meadowcroft, Mark D; Wang, Jianli; Purnell, Carson J; Peters, Douglas G; Eslinger, Paul J; Neely, Elizabeth B; Gill, David J; Vasavada, Megha; Ali-Rahmani, Fatima; Yang, Qing X; Connor, James R

    2016-12-01

    Mutations within the HFE protein gene sequence have been associated with increased risk of developing a number of neurodegenerative disorders. To this effect, an animal model has been created which incorporates the mouse homologue to the human H63D-HFE mutation: the H67D-HFE knock-in mouse. These mice exhibit alterations in iron management proteins, have increased neuronal oxidative stress, and a disruption in cholesterol regulation. However, it remains undetermined how these differences translate to human H63D carriers in regards to white matter (WM) integrity. To this endeavor, MRI transverse relaxation rate (R2) parametrics were employed to test the hypothesis that WM alterations are present in H63D human carriers and are recapitulated in the H67D mice. H63D carriers exhibit widespread reductions in brain R2 compared to non-carriers within white matter association fibers in the brain. Similar R2 decreases within white matter tracts were observed in the H67D mouse brain. Additionally, an exacerbation of age-related R2 decrease is found in the H67D animal model in white matter regions of interest. The decrease in R2 within white matter tracts of both species is speculated to be multifaceted. The R2 changes are hypothesized to be due to alterations in axonal biochemical tissue composition. The R2 changes observed in both the human-H63D and mouse-H67D data suggest that modified white matter myelination is occurring in subjects with HFE mutations, potentially increasing vulnerability to neurodegenerative disorders.

  20. The hereditary hemochromatosis protein, HFE, specifically regulates transferrin-mediated iron uptake in HeLa cells.

    Science.gov (United States)

    Roy, C N; Penny, D M; Feder, J N; Enns, C A

    1999-03-26

    HFE is the protein product of the gene mutated in the autosomal recessive disease hereditary hemochromatosis (Feder, J. N., Gnirke, A., Thomas, W., Tsuchihashi, Z., Ruddy, D. A., Basava, A., Dormishian, F., Domingo, R. J., Ellis, M. C., Fullan, A., Hinton, L. M., Jones, N. L., Kimmel, B. E., Kronmal, G. S., Lauer, P., Lee, V. K., Loeb, D. B., Mapa, F. A., McClelland, E., Meyer, N. C., Mintier, G. A., Moeller, N., Moore, T., Morikang, E., Prasss, C. E., Quintana, L., Starnes, S. M., Schatzman, R. C., Brunke, K. J., Drayna, D. T., Risch, N. J., Bacon, B. R., and Wolff, R. R. (1996) Nat. Genet. 13, 399-408). At the cell surface, HFE complexes with transferrin receptor (TfR), increasing the dissociation constant of transferrin (Tf) for its receptor 10-fold (Gross, C. N., Irrinki, A., Feder, J. N., and Enns, C. A. (1998) J. Biol. Chem. 273, 22068-22074; Feder, J. N., Penny, D. M., Irrinki, A., Lee, V. K., Lebron, J. A., Watson, N. , Tsuchihashi, Z., Sigal, E., Bjorkman, P. J., and Schatzman, R. C. (1998) Proc. Natl. Acad. Sci. U S A 95, 1472-1477). HFE does not remain at the cell surface, but traffics with TfR to Tf-positive internal compartments (Gross et al., 1998). Using a HeLa cell line in which the expression of HFE is controlled by tetracycline, we show that the expression of HFE reduces 55Fe uptake from Tf by 33% but does not affect the endocytic or exocytic rates of TfR cycling. Therefore, HFE appears to reduce cellular acquisition of iron from Tf within endocytic compartments. HFE specifically reduces iron uptake from Tf, as non-Tf-mediated iron uptake from Fe-nitrilotriacetic acid is not altered. These results explain the decreased ferritin levels seen in our HeLa cell system and demonstrate the specific control of HFE over the Tf-mediated pathway of iron uptake. These results also have implications for the understanding of cellular iron homeostasis in organs such as the liver, pancreas, heart, and spleen that are iron loaded in hereditary hemochromatotic

  1. TFR2-related hereditary hemochromatosis as a frequent cause of primary iron overload in patients from Central-Southern Italy.

    Science.gov (United States)

    Radio, Francesca Clementina; Majore, Silvia; Binni, Francesco; Valiante, Michele; Ricerca, Bianca Maria; De Bernardo, Carmelilia; Morrone, Aldo; Grammatico, Paola

    2014-01-01

    Hereditary hemochromatosis (HH) is a common Mendelian disorder of iron metabolism. Eighty percent of northern Europeans descendant HH patients carry the same mutation (p.C282Y) in the HFE gene. Simultaneously, due to a founder effect, its frequency varies considerably between different populations. In Central-Southern Italy the prevalence of p.C282Y mutation is low and in several patients the disease has different causes. Four additional rarer forms have been described. Type 3 HH has been reported in about 50 families and no more than 30 TFR2 pathogenic mutations have been globally identified. The aim of this study is to assess the TFR2 role in non-HFE HH pathogenesis. TFR2 sequence analysis was performed on 45 Italian patients without HFE mutations. This study revealed TFR2 biallelic pathogenic mutations in 7/45 (15.6%) individuals. Moreover monoallelic TFR2 deleterious defects (18%) or polymorphisms with unclear meaning (36%) were identified. Besides, we recognized 10 novel variants and 9 described changes. We believe this to be the largest series of type 3 HH patients described so far. Present findings support the hypothesis of a main role of the TFR2 gene in HH pathogenesis in those regions, such as Central-Southern Italy, where the p.C282Y frequency is low. © 2013.

  2. Prediction of the Spectroscopic Parameters of New Iron Compounds: Hydride of Iron Cyanide/Isocyanide, HFeCN/HFeNC

    Science.gov (United States)

    Redondo, Pilar; Barrientos, Carmen; Largo, Antonio

    2016-09-01

    Iron is the most abundant transition metal in space. Its abundance is similar to that of magnesium, and until today only, FeO and FeCN have been detected. However, magnesium-bearing compounds such as MgCN, MgNC, and HMgNC are found in IRC+10216. It seems that the hydrides of iron cyanide/isocyanide could be good candidates to be present in space. In the present work we carried out a characterization of the different minima on the quintet and triplet [C, Fe, H, N] potential energy surfaces, employing several theoretical approaches. The most stable isomers are predicted to be hydride of iron cyanide HFeCN, and isocyanide HFeNC, in their 5Δ states. Both isomers are found to be quasi-isoenergetics. The HFeNC isomer is predicted to lie about 0.5 kcal/mol below HFeCN. The barrier for the interconversion process is estimated to be around 6.0 kcal/mol, making this process unfeasible under low temperature conditions, such as those in the interstellar medium. Therefore, both HFeCN and HFeNC could be candidates for their detection. We report geometrical parameters, vibrational frequencies, and rotational constants that could help with their experimental characterization.

  3. A sustainable system of systems approach: a new HFE paradigm.

    Science.gov (United States)

    Thatcher, Andrew; Yeow, Paul H P

    2016-01-01

    Sustainability issues such as natural resource depletion, pollution and poor working conditions have no geographical boundaries in our interconnected world. To address these issues requires a paradigm shift within human factors and ergonomics (HFE), to think beyond a bounded, linear model understanding towards a broader systems framework. For this reason, we introduce a sustainable system of systems model that integrates the current hierarchical conceptualisation of possible interventions (i.e., micro-, meso- and macro-ergonomics) with important concepts from the sustainability literature, including the triple bottom line approach and the notion of time frames. Two practical examples from the HFE literature are presented to illustrate the model. The implications of this paradigm shift for HFE researchers and practitioners are discussed and include the long-term sustainability of the HFE community and comprehensive solutions to problems that consider the emergent issues that arise from this interconnected world. A sustainable world requires a broader systems thinking than that which currently exists in ergonomics. This study proposes a sustainable system of systems model that incorporates ideas from the ecological sciences, notably a nested hierarchy of systems and a hierarchical time dimension. The implications for sustainable design and the sustainability of the HFE community are considered.

  4. Influence of diet, menstruation and genetic factors on iron status: a cross-sectional study in Spanish women of childbearing age.

    Science.gov (United States)

    Blanco-Rojo, Ruth; Toxqui, Laura; López-Parra, Ana M; Baeza-Richer, Carlos; Pérez-Granados, Ana M; Arroyo-Pardo, Eduardo; Vaquero, M Pilar

    2014-03-06

    The aim of this study was to investigate the combined influence of diet, menstruation and genetic factors on iron status in Spanish menstruating women (n = 142). Dietary intake was assessed by a 72-h detailed dietary report and menstrual blood loss by a questionnaire, to determine a Menstrual Blood Loss Coefficient (MBLC). Five selected SNPs were genotyped: rs3811647, rs1799852 (Tf gene); rs1375515 (CACNA2D3 gene); and rs1800562 and rs1799945 (HFE gene, mutations C282Y and H63D, respectively). Iron biomarkers were determined and cluster analysis was performed. Differences among clusters in dietary intake, menstrual blood loss parameters and genotype frequencies distribution were studied. A categorical regression was performed to identify factors associated with cluster belonging. Three clusters were identified: women with poor iron status close to developing iron deficiency anemia (Cluster 1, n = 26); women with mild iron deficiency (Cluster 2, n = 59) and women with normal iron status (Cluster 3, n = 57). Three independent factors, red meat consumption, MBLC and mutation C282Y, were included in the model that better explained cluster belonging (R2 = 0.142, p < 0.001). In conclusion, the combination of high red meat consumption, low menstrual blood loss and the HFE C282Y mutation may protect from iron deficiency in women of childbearing age. These findings could be useful to implement adequate strategies to prevent iron deficiency anemia.

  5. Conducting multistage HFE validations-constructing Systems Usability Case

    Energy Technology Data Exchange (ETDEWEB)

    Laarni, Jari; Savioja, Paula; Norros, Leena; Linasuo, Marja; Karvonen, Hannu; Wahlstorm, Mikael [Human Factors in Complex Systems, Vuorimiehentie 3 (Finland); Salo Leena [Fortum, eilaniementie, Fortum (Finland)

    2014-08-15

    This paper describes how independent stepwise Human Factors Engineering (HFE) validations have been conducted in Fortum Lovisa power plant control room modernization project. We discuss the challenges of HFE verification and validation in a project which is realized in multiple phases, stretches over several years in time, and is in tight coupling with automation modernization. These challenges eventually lead to the need of developing a new approach to control HFE validation; conducting validations in a stepwise manner. In our sub-system validation approach a particular sub-system of the control room are always the main focus of testing but simultaneously we also analyse the overall operational concept and its possible development needs.

  6. Differing impact of the deletion of hemochromatosis-associated molecules HFE and transferrin receptor-2 on the iron phenotype of mice lacking bone morphogenetic protein 6 or hemojuvelin.

    Science.gov (United States)

    Latour, Chloé; Besson-Fournier, Céline; Meynard, Delphine; Silvestri, Laura; Gourbeyre, Ophélie; Aguilar-Martinez, Patricia; Schmidt, Paul J; Fleming, Mark D; Roth, Marie-Paule; Coppin, Hélène

    2016-01-01

    Hereditary hemochromatosis, which is characterized by inappropriately low levels of hepcidin, increased dietary iron uptake, and systemic iron accumulation, has been associated with mutations in the HFE, transferrin receptor-2 (TfR2), and hemojuvelin (HJV) genes. However, it is still not clear whether these molecules intersect in vivo with bone morphogenetic protein 6 (BMP6)/mothers against decapentaplegic (SMAD) homolog signaling, the main pathway up-regulating hepcidin expression in response to elevated hepatic iron. To answer this question, we produced double knockout mice for Bmp6 and β2-microglobulin (a surrogate for the loss of Hfe) and for Bmp6 and Tfr2, and we compared their phenotype (hepcidin expression, Bmp/Smad signaling, hepatic and extrahepatic tissue iron accumulation) with that of single Bmp6-deficient mice and that of mice deficient for Hjv, alone or in combination with Hfe or Tfr2. Whereas the phenotype of Hjv-deficient females was not affected by loss of Hfe or Tfr2, that of Bmp6-deficient females was considerably worsened, with decreased Smad5 phosphorylation, compared with single Bmp6-deficient mice, further repression of hepcidin gene expression, undetectable serum hepcidin, and massive iron accumulation not only in the liver but also in the pancreas, the heart, and the kidneys. These results show that (1) BMP6 does not require HJV to transduce signal to hepcidin in response to intracellular iron, even if the loss of HJV partly reduces this signal, (2) another BMP ligand can replace BMP6 and significantly induce hepcidin expression in response to extracellular iron, and (3) BMP6 alone is as efficient at inducing hepcidin as the other BMPs in association with the HJV/HFE/TfR2 complex; they provide an explanation for the compensatory effect of BMP6 treatment on the molecular defect underlying Hfe hemochromatosis in mice. © 2015 by the American Association for the Study of Liver Diseases.

  7. Intragenic haplotype analysis of common HFE mutations in the ...

    Indian Academy of Sciences (India)

    ... Public Lectures · Lecture Workshops · Refresher Courses · Symposia. Home; Journals; Journal of Genetics; Volume 94; Issue 2. Intragenic haplotype analysis of common HFE mutations in the Portuguese population. Sandra Toste Luís Relvas Catarina Pinto Celeste Bento Augusto Abade M. Letícia Ribeiro Licínio Manco.

  8. Blunted hepcidin response to inflammation in the absence of Hfe and transferrin receptor 2.

    Science.gov (United States)

    Wallace, Daniel F; McDonald, Cameron J; Ostini, Lesa; Subramaniam, V Nathan

    2011-03-10

    The induction of the iron-regulatory peptide hepcidin by proinflammatory cytokines is thought to result in the withholding of iron from invading pathogens. Hfe and transferrin receptor 2 (Tfr2) are involved in the homeostatic regulation of hepcidin and their disruption causes hereditary hemochromatosis (HH). To determine whether either Hfe or Tfr2 is involved in the inflammatory pathway regulating hepcidin, we analyzed the effect of inflammation in 3 mouse models of HH. The inflammatory response and indicators of iron homeostasis were measured in wild-type, Hfe(-/-), Tfr2(-/-), and Hfe(-/-)/Tfr2(-/-) mice injected with lipopolysaccharide (LPS). The administration of LPS significantly reduced serum iron in wild-type and Hfe(-/-) mice, with smaller reductions in Tfr2(-/-) and Hfe(-/-)/Tfr2(-/-) mice. Low basal levels of hepcidin in the Hfe(-/-)/Tfr2(-/-) mice were increased in response to LPS, but remained significantly lower than in the other strains of mice. These results suggest that despite the absence of Hfe and Tfr2, hepcidin is responsive to inflammation; however, the low basal expression and subsequent low levels of circulating hepcidin are insufficient to reduce serum iron effectively. This suggests that in HH, the iron-withholding response to invading pathogens may be inadequate, and this is especially the case in the absence of both Hfe and Tfr2.

  9. Effect of Hfe Deficiency on Memory Capacity and Motor Coordination after Manganese Exposure by Drinking Water in Mice.

    Science.gov (United States)

    Alsulimani, Helal Hussain; Ye, Qi; Kim, Jonghan

    2015-12-01

    Excess manganese (Mn) is neurotoxic. Increased manganese stores in the brain are associated with a number of behavioral problems, including motor dysfunction, memory loss and psychiatric disorders. We previously showed that the transport and neurotoxicity of manganese after intranasal instillation of the metal are altered in Hfe-deficient mice, a mouse model of the iron overload disorder hereditary hemochromatosis (HH). However, it is not fully understood whether loss of Hfe function modifies Mn neurotoxicity after ingestion. To investigate the role of Hfe in oral Mn toxicity, we exposed Hfe-knockout (Hfe (-/-)) and their control wild-type (Hfe (+/+)) mice to MnCl2 in drinking water (5 mg/mL) for 5 weeks. Motor coordination and spatial memory capacity were determined by the rotarod test and the Barnes maze test, respectively. Brain and liver metal levels were analyzed by inductively coupled plasma mass spectrometry. Compared with the water-drinking group, mice drinking Mn significantly increased Mn concentrations in the liver and brain of both genotypes. Mn exposure decreased iron levels in the liver, but not in the brain. Neither Mn nor Hfe deficiency altered tissue concentrations of copper or zinc. The rotarod test showed that Mn exposure decreased motor skills in Hfe (+/+) mice, but not in Hfe (-/-) mice (p = 0.023). In the Barns maze test, latency to find the target hole was not altered in Mn-exposed Hfe (+/+) compared with water-drinking Hfe (+/+) mice. However, Mn-exposed Hfe (-/-) mice spent more time to find the target hole than Mn-drinking Hfe (+/+) mice (p = 0.028). These data indicate that loss of Hfe function impairs spatial memory upon Mn exposure in drinking water. Our results suggest that individuals with hemochromatosis could be more vulnerable to memory deficits induced by Mn ingestion from our environment. The pathophysiological role of HFE in manganese neurotoxicity should be carefully examined in patients with HFE-associated hemochromatosis and

  10. Hepatic iron overload following liver transplantation of a C282y homozygous allograft: a case report and literature review.

    LENUS (Irish Health Repository)

    Dwyer, Jeremy P

    2011-11-01

    Hereditary haemochromatosis is a common genetic disease associated with progressive iron overload and parenchymal organ damage including liver, pancreas and heart. We report a case of inadvertent transplantation of a liver from a haemochromatosis donor to a 56-year-old Asian female. Progressive iron overload occurred over a 2 year follow up as assessed by liver biopsy and iron studies in the absence of a secondary cause of iron overload, supporting a primary role of liver rather than small intestine in the regulation of iron homeostasis in hereditary haemochromatosis.

  11. In-silico Molecular Analysis of Mutated Sequences of HFE1, HFE2, TFR2 and SLC40A1 causing Hemochromatosis Disease

    Directory of Open Access Journals (Sweden)

    Bilal Hussain

    2011-05-01

    Full Text Available Hemochromatosis is a disorder in iron metabolism that is characterized by excess iron absorption. There are two forms of hemochromatosis: primary hemochromatosis is caused by a problem with your genes. Secondary or acquired hemochromatosis can be caused by other diseases. The main objective of this study is to analyze structure of different types of proteins involved in hemochromatosis. As this is the most threatening disease all over the world including Pakistan but unfortunately no data is available about it so it will be a great step to analyze the structure of its different proteins by using different online tools that gave different results according to their potential as each tool must show the same results for the same protein. Protein structure prediction is one of the most important goals persuaded by Bioinformatics for evolutionary studies and drug designing. Other objective of this project is to provide the prevalence of hemochromatosis in Faisalabad and structure prediction of its proteins to find the conserved regions. At the end the creation of a database is done that would contain all necessary information about diseases. Hereditary hemochromatosis is mainly caused by a defect in a gene called HFE. There are several types of genetic hemochromatosis. These include: Type I or Classic (HHC; Type II or Juvenile (JHC; Type III or Transferrin Receptor Mutation; and Type IV or Ferroportin Mutation. Most types of hereditary haemochromatosis have autosomal recessive inheritance, while type IV has autosomal dominant inheritance.

  12. Severe microcytic anemia but increased erythropoiesis in mice lacking Hfe or Tfr2 and Tmprss6.

    Science.gov (United States)

    Lee, Pauline; Hsu, Mei-Hui; Welser-Alves, Jennifer; Peng, Hongfan

    2012-03-15

    Cell surface proteins Hfe, Tfr2, hemojuvelin and Tmprss6 play key roles in iron homeostasis. Hfe and Tfr2 induce transcription of hepcidin, a small peptide that promotes the degradation of the iron transporter ferroportin. Hemojuvelin, a co-receptor for bone morphogenic proteins, induces hepcidin transcription through a Smad signaling pathway. Tmprss6 (also known as matriptase-2), a membrane serine protease that has been found to bind and degrade hemojuvelin in vitro, is a potent suppressor of hepcidin expression. In order to examine if Hfe and Tfr2 are substrates for Tmprss6, we generated mice lacking functional Hfe or Tfr2 and Tmprss6. We found that double mutant mice lacking functional Hfe or Tfr2 and Tmprss6 exhibited a severe iron deficiency microcytic anemia phenotype mimicking the phenotype of single mutant mice lacking functional Tmprss6 (Tmprss6msk/msk mutant) demonstrating that Hfe and Tfr2 are not substrates for Tmprss6. Nevertheless, the phenotype of the mice lacking Hfe or Tfr2 and Tmprss6 differed from Tmprss6 deficient mice alone, in that the double mutant mice exhibited much greater erythropoiesis. Hfe and Tfr2 have been shown to play important roles in the erythron, independent of their role in regulating liver hepcidin transcription. We demonstrate that lack of functional Tfr2 and Hfe allows for increased erythropoiesis even in the presence of high hepcidin expression, but the high levels of hepcidin levels significantly limit the availability of iron to the erythron, resulting in ineffective erythropoiesis. Furthermore, repression of hepcidin expression by hypoxia was unaffected by the loss of functional Hfe, Tfr2 and Tmprss6. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. Transferrin receptor-2 (TFR2) mutation Y250X in Alabama Caucasian and African American subjects with and without primary iron overload.

    Science.gov (United States)

    Barton, E H; West, P A; Rivers, C A; Barton, J C; Acton, R T

    2001-01-01

    Most cases of hemochromatosis are associated with mutations of the HFE gene on Ch6p. In southern Italy and central Alabama, the percentages of patients with hemochromatosis who have "atypical" HFE genotypes (defined as lack of C282Y homozygosity, C282Y/H63D compound heterozygosity, or H63D homozygosity) are relatively great. A mutation of the transferrin receptor-2 gene (TFR2; exon 6, nt 750 C --> G, replaces TAC with stop signal TAG; Y250X) on Ch7q22 was recently identified in two Sicilian families with HFE mutation-negative hemochromatosis. We wanted to estimate the frequency of this mutation in persons from central Alabama. We evaluated Caucasian hemochromatosis probands with atypical HFE genotypes and African Americans with primary iron overload. We also studied control Caucasians, including persons of southern Italian/Sicilian heritage, and control African Americans. Analysis of genomic DNA was performed using a PCR-sequence-specific priming assay and positive control specimens from Sicilian hemochromatosis subjects heterozygous and homozygous for Y250X. Among Alabama subjects, this allele was not detected in 113 Caucasians, including 21 hemochromatosis probands with atypical HFE genotypes and 92 normal control subjects (including 27 of southern Italian/Sicilian descent). In African Americans, Y250X was not detected in 20 index cases with primary iron overload or in 274 unrelated control subjects. We conclude that Y250X is uncommon in Caucasians with hemochromatosis associated with atypical HFE genotypes, in African Americans with primary iron overload, and in the general Caucasian and African American population subgroups in central Alabama. Copyright 2001 Academic Press.

  14. In situ proximity ligation assays indicate that hemochromatosis proteins Hfe and transferrin receptor 2 (Tfr2) do not interact.

    Science.gov (United States)

    Rishi, Gautam; Crampton, Emily M; Wallace, Daniel F; Subramaniam, V Nathan

    2013-01-01

    The hemochromatosis associated proteins HFE and Transferrin Receptor 2 (TFR2) have been shown to be important for the proper regulation of hepcidin. A number of in vitro studies using transient overexpression systems have suggested that an interaction between HFE and TFR2 is required for the regulation of hepcidin. This model of iron sensing which centers upon the requirement for an interaction between HFE and TFR2 has recently been questioned with in vivo studies in mice from our laboratory and others which suggest that Hfe and Tfr2 can regulate hepcidin independently of each other. To re-examine the postulated interaction between Hfe and Tfr2 we developed a novel expression system in which both proteins are stably co-expressed and used the proximity ligation assay to examine the interactions between Hfe, Tfr1 and Tfr2 at a cellular level. We were able to detect the previously described interaction between Hfe and Tfr1, and heterodimers between Tfr1 and Tfr2; however no interaction between Hfe and Tfr2 was observed in our system. The results from this study indicate that Hfe and Tfr2 do not interact with each other when they are stably expressed at similar levels. Furthermore, these results support in vivo studies which suggest that Hfe and Tfr2 can independently regulate hepcidin.

  15. In situ proximity ligation assays indicate that hemochromatosis proteins Hfe and transferrin receptor 2 (Tfr2 do not interact.

    Directory of Open Access Journals (Sweden)

    Gautam Rishi

    Full Text Available The hemochromatosis associated proteins HFE and Transferrin Receptor 2 (TFR2 have been shown to be important for the proper regulation of hepcidin. A number of in vitro studies using transient overexpression systems have suggested that an interaction between HFE and TFR2 is required for the regulation of hepcidin. This model of iron sensing which centers upon the requirement for an interaction between HFE and TFR2 has recently been questioned with in vivo studies in mice from our laboratory and others which suggest that Hfe and Tfr2 can regulate hepcidin independently of each other. To re-examine the postulated interaction between Hfe and Tfr2 we developed a novel expression system in which both proteins are stably co-expressed and used the proximity ligation assay to examine the interactions between Hfe, Tfr1 and Tfr2 at a cellular level. We were able to detect the previously described interaction between Hfe and Tfr1, and heterodimers between Tfr1 and Tfr2; however no interaction between Hfe and Tfr2 was observed in our system. The results from this study indicate that Hfe and Tfr2 do not interact with each other when they are stably expressed at similar levels. Furthermore, these results support in vivo studies which suggest that Hfe and Tfr2 can independently regulate hepcidin.

  16. The effects of okra (Abelmoschus esculentus Linn.) on the cellular events associated with Alzheimer's disease in a stably expressed HFE neuroblastoma SH-SY5Y cell line.

    Science.gov (United States)

    Mairuae, Nootchanat; Connor, James R; Lee, Sang Y; Cheepsunthorn, Poonlarp; Tongjaroenbuangam, Walaiporn

    2015-08-31

    It has been reported that persons carrying the H63D variant in their hemochromatosis (HFE) gene are at increased risk of Alzheimer's disease (AD). We investigated the possibility that okra (Abelmoschus esculentus) and quercetin could mitigate this risk factor by examining its effect on AD-associated cellular events in HFE stably expressing SH-SY5Y cells. Treatment of H63D HFE cells either with okra or quercetin significantly decreased reactive oxygen species (ROS), hydrogen peroxide (H2O2), and protein oxidation compared to untreated cells. The levels of tau phosphorylation at serine-199, serine-202, and serine-396 sites were also significantly decreased when cells were treated with okra. Exposure of the H63D and wild type (WT) cells to iron increased tau phosphorylation, but this response was decreased significantly when cells were treated with okra. The mechanism responsible for these changes appears to be related to decreased glycogen synthase kinase (GSK)-3β activity, an upstream signaling kinase of tau phosphorylation. We also established that okra treatment dramatically decreases intracellular iron levels in H63D cells compared to untreated cells. Our results provide important in vitro data on the effects of okra on various AD-associated cellular processes in H63D variant HFE cells. These results suggest okra may be beneficial in people expressing the H63D variant to reduce the risk of AD and other neurodegenerative diseases related to oxidative stress. Further in vivo studies would help confirm this. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  17. Spent nuclear fuel project, Cold Vacuum Drying Facility human factors engineering (HFE) analysis: Results and findings

    Energy Technology Data Exchange (ETDEWEB)

    Garvin, L.J.

    1998-07-17

    This report presents the background, methodology, and findings of a human factors engineering (HFE) analysis performed in May, 1998, of the Spent Nuclear Fuels (SNF) Project Cold Vacuum Drying Facility (CVDF), to support its Preliminary Safety Analysis Report (PSAR), in responding to the requirements of Department of Energy (DOE) Order 5480.23 (DOE 1992a) and drafted to DOE-STD-3009-94 format. This HFE analysis focused on general environment, physical and computer workstations, and handling devices involved in or directly supporting the technical operations of the facility. This report makes no attempt to interpret or evaluate the safety significance of the HFE analysis findings. The HFE findings presented in this report, along with the results of the CVDF PSAR Chapter 3, Hazards and Accident Analyses, provide the technical basis for preparing the CVDF PSAR Chapter 13, Human Factors Engineering, including interpretation and disposition of findings. The findings presented in this report allow the PSAR Chapter 13 to fully respond to HFE requirements established in DOE Order 5480.23. DOE 5480.23, Nuclear Safety Analysis Reports, Section 8b(3)(n) and Attachment 1, Section-M, require that HFE be analyzed in the PSAR for the adequacy of the current design and planned construction for internal and external communications, operational aids, instrumentation and controls, environmental factors such as heat, light, and noise and that an assessment of human performance under abnormal and emergency conditions be performed (DOE 1992a).

  18. Method for creating gas standards form liquid HFE-7100 and FC-72.

    Energy Technology Data Exchange (ETDEWEB)

    White, Michael K.; Brown, Jason R.; Thornberg, Steven Michael; Hochrein, James Michael; Irwin, Adriane Nadine

    2007-07-01

    HFE-7100 and FC-72 fluorinert are two fluids used during weapon component manufacturing. HFE-7100 is a solvent used in the cleaning of parts, and FC-72 is the blowing agent of a polymeric removable foam. The presence of either FC-72 or HFE-7100 gas in weapon components can provide valuable information as to the stability of the materials. Therefore, gas standards are needed so HFE-7100 and FC-72 gas concentrations can be accurately measured. There is no current established procedure for generating gas standards of either HFE-7100 or FC-72. This report outlines the development of a method to generate gas standards ranging in concentration from 0.1 ppm to 10% by volume. These standards were then run on a Jeol GC-Mate II mass spectrometer and analyzed to produce calibration curves. We present a manifold design that accurately generates gas standards of HFE-7100 and FC-72 and a procedure that allows the amount of each to be determined.

  19. Factors affecting the appreciation generated through applying human factors/ergonomics (HFE) principles to systems of work.

    Science.gov (United States)

    So, R H Y; Lam, S T

    2014-01-01

    This retrospective study examined the levels of appreciation (applause) given by clients to Human Factors/Ergonomic (HFE) specialists after they have modified the systems of work. Thirteen non-academic projects were chosen because the HFE interventions involved changed the way workers work at their workplaces. Companies involved range from multi-national corporations and military organizations with thousands of employees to small trading companies with less than 10 employees. In 5 cases the HFE recommendations were fully adopted and well appreciated. In 4 they were largely ignored and not appreciated, with partial adoption and some appreciation in the other 4 cases. Three factors that predict appreciation were identified: (i) alignment between the benefits HFE can provide and the project's key performance indices; (ii) awareness of HFE among the client's senior management; and (iii) a team organization appropriate for applying HFE recommendations. Having an HFE specialist on the client's side can greatly increase levels of appreciation, but lack of such a specialist will not affect levels of appreciation. A clear contractual requirement for HFE intervention does not promote appreciation significantly, but its absence can greatly reduce levels of appreciation. These relationships are discussed using the Kano's model of quality. Means to generate greater appreciation of the benefits of HFE are discussed. Copyright © 2013 Elsevier Ltd and The Ergonomics Society. All rights reserved.

  20. Development of a HFE program for an operating NPP: Balancing between existing design practices and human factors standards

    Energy Technology Data Exchange (ETDEWEB)

    Salo, Leena [Nuclear and Thermal Power, Fortum (Finland); Savioja, Paula [Human Factors in Complex Systems, VTT Technical Research Centre of Finland, Fortum (Finland)

    2014-08-15

    This paper describes HFE program development project conducted at a Finnish power company Fortum. The aim of developing a formal HFE program was to improve integration of human factors issues in design of technical systems and to systematically document the HFE process of the company. As Fortum has a long tradition of designing control room solutions, the starting point of the HFE program development was the existing own design practices. On the other hand, the aim was to create a program which would comply with international guidelines such as NUREG-0711. The program development was conducted by tracing the HFE design practices in an on-going I and C modernization project. This empirical work was carried out by interviews of designers and other HFE key stake holders. After the explication of the current practices, the gaps, overlaps and differences in relation to the international standards and guidelines were identified. Based on an analysis of current practices and guidelines and standards a new HFE process model was created. The design process model can be followed in modifications which concern systems with human user interfaces of any kind. The model consists of five separate phases which comply with the general engineering design process model utilized at the company. The HFE program is intended to be both a practical guide on how to take human factors issues into consideration in the design of NPP systems and also a tool for the management of HFE activities.

  1. Trends in HFE Methods and Tools and Their Applicability to Safety Reviews

    Energy Technology Data Exchange (ETDEWEB)

    O' Hara, J.M.; Plott, C.; Milanski, J.; Ronan, A.; Scheff, S.; Laux, L.; and Bzostek, J.

    2009-09-30

    The U.S. Nuclear Regulatory Commission's (NRC) conducts human factors engineering (HFE) safety reviews of applicant submittals for new plants and for changes to existing plants. The reviews include the evaluation of the methods and tools (M&T) used by applicants as part of their HFE program. The technology used to perform HFE activities has been rapidly evolving, resulting in a whole new generation of HFE M&Ts. The objectives of this research were to identify the current trends in HFE methods and tools, determine their applicability to NRC safety reviews, and identify topics for which the NRC may need additional guidance to support the NRC's safety reviews. We conducted a survey that identified over 100 new HFE M&Ts. The M&Ts were assessed to identify general trends. Seven trends were identified: Computer Applications for Performing Traditional Analyses, Computer-Aided Design, Integration of HFE Methods and Tools, Rapid Development Engineering, Analysis of Cognitive Tasks, Use of Virtual Environments and Visualizations, and Application of Human Performance Models. We assessed each trend to determine its applicability to the NRC's review by considering (1) whether the nuclear industry is making use of M&Ts for each trend, and (2) whether M&Ts reflecting the trend can be reviewed using the current design review guidance. We concluded that M&T trends that are applicable to the commercial nuclear industry and are expected to impact safety reviews may be considered for review guidance development. Three trends fell into this category: Analysis of Cognitive Tasks, Use of Virtual Environments and Visualizations, and Application of Human Performance Models. The other trends do not need to be addressed at this time.

  2. HFE Process Guidance and Standards for potential application to updating NRC guidance

    Energy Technology Data Exchange (ETDEWEB)

    Jacques Hugo; J. J. Persensky

    2012-07-01

    The U.S. Nuclear Regulatory Commission (NRC) reviews and evaluates the human factors engineering (HFE) programs of applicants for nuclear power plant construction permits, operating licenses, standard design certifications, and combined operating licenses. The purpose of these safety reviews is to help ensure that personnel performance and reliability are appropriately supported. Detailed design review procedures and guidance for the evaluations is provided in three key documents: the Standard Review Plan (NUREG-0800), the HFE Program Review Model (NUREG-0711), and the Human-System Interface Design Review Guidelines (NUREG-0700). These documents were last revised in 2007, 2004 and 2002, respectively. The NRC is committed to the periodic update and improvement of these guidance documents to ensure that they remain state-of-the-art design evaluation tools. Thus, the NRC has initiated a project with BNL to update the NRC guidance to remain current with recent research on human performance, advances in HFE methods and tools, and new technology. INL supported Brookhaven National Lab (BNL) to update the detailed HFE review criteria contained in NUREG-0711 and NUREG-0700 based on (1) feedback obtained from end users, (2) the results of NRC research and development efforts supporting the NRC staff’s HFE safety reviews, and (3) other material the project staff identify as applicable to the update effort. INL submitted comments on development plans and sections of NUREGs 0800, 0711, and 0700. The contractor prepared the report attached here as the deliverable for this work.

  3. Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

    Science.gov (United States)

    Benyamin, Beben; Esko, Tonu; Ried, Janina S; Radhakrishnan, Aparna; Vermeulen, Sita H; Traglia, Michela; Gögele, Martin; Anderson, Denise; Broer, Linda; Podmore, Clara; Luan, Jian’an; Kutalik, Zoltan; Sanna, Serena; van der Meer, Peter; Tanaka, Toshiko; Wang, Fudi; Westra, Harm-Jan; Franke, Lude; Mihailov, Evelin; Milani, Lili; Häldin, Jonas; Winkelmann, Juliane; Meitinger, Thomas; Thiery, Joachim; Peters, Annette; Waldenberger, Melanie; Rendon, Augusto; Jolley, Jennifer; Sambrook, Jennifer; Kiemeney, Lambertus A; Sweep, Fred C; Sala, Cinzia F; Schwienbacher, Christine; Pichler, Irene; Hui, Jennie; Demirkan, Ayse; Isaacs, Aaron; Amin, Najaf; Steri, Maristella; Waeber, Gérard; Verweij, Niek; Powell, Joseph E; Nyholt, Dale R; Heath, Andrew C; Madden, Pamela AF; Visscher, Peter M; Wright, Margaret J; Montgomery, Grant W; Martin, Nicholas G; Hernandez, Dena; Bandinelli, Stefania; van der Harst, Pim; Uda, Manuela; Vollenweider, Peter; Scott, Robert A; Langenberg, Claudia; Wareham, Nicholas J; van Duijn, Cornelia; Beilby, John; Pramstaller, Peter P; Hicks, Andrew A; Ouwehand, Willem H; Oexle, Konrad; Gieger, Christian; Metspalu, Andres; Camaschella, Clara; Toniolo, Daniela; Swinkels, Dorine W; Whitfield, John B

    2014-01-01

    Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here we analyse genetic association data on biochemical markers of iron status from eleven European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find eleven genome-wide-significant (p < 5 × 10−8) loci, some including known iron-related genes (HFE, SLC40A1, TF, TFR2, TFRC, TMPRSS6) and others novel (ABO, ARNTL, FADS2, NAT2, TEX14). SNPs at ARNTL, TF, and TFR2 affect iron markers in HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease. PMID:25352340

  4. Energy and Exergy Analyses of CO2/HFE7000 Cascade Cooling System

    Directory of Open Access Journals (Sweden)

    Fatih YILMAZ

    2017-10-01

    Full Text Available In this study, a new refrigerant HFE7000, has been investigated thermodynamically in the cascade cooling system. Energy (COP and exergy efficiency of cascade cooling system with CO2/HFE7000 refrigerants are performed. In this regard, the impacts of various parameters on the COP and exergy efficiency and exergy destruction rate of CCS are studied. Moreover, the CO2 refrigerant is used in the low-temperature circuit and HFE7000 is used in the high-temperature circuit. The COP and exergy efficiency of cascade cooling system are found as 2.313 and 0.5482, for cooling application. In the last section, comparison with R134a refrigerant is done, which is widely used in cascade cooling system.

  5. HFE Mutations Modulate the Effect of Iron on Serum Hepcidin-25 in Chronic Hemodialysis Patients

    Science.gov (United States)

    Girelli, Domenico; Valenti, Giovanni Francesco; Castagna, Annalisa; Como, Giovanna; Campostrini, Natascia; Rametta, Raffaela; Dongiovanni, Paola; Messa, Piergiorgio

    2009-01-01

    Background and objectives: Increased serum hepcidin has been reported in patients receiving chronic hemodialysis, and hypothesized to contribute to the alterations of iron metabolism of end-stage renal disease. However, no quantitative assessment is available to date; the clinical determinants are still under definition; and the role of genetic factors, namely HFE mutations, has not yet been evaluated. The aim of this study was to quantitatively assess serum hepcidin-25 in hemodialysis patients versus controls, and analyze the relationship between hepcidin, iron indices, HFE genotype, and erythropoietic parameters. Design, setting, participants & measurements: Sixty-five hemodialysis patients and 57 healthy controls were considered. Hepcidin-25 was evaluated by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry, HFE genotype by restriction analysis. Results: Serum hepcidin-25 was higher in hemodialysis patients compared with controls. In patients, hepcidin-25 correlated positively with ferritin and C reactive protein, and negatively with serum iron after adjustment for confounders. Hepcidin/ferritin ratio was lower in patients with (n = 25) than in those without (n = 40) HFE mutations. At multivariate analysis, hepcidin-25 was independently associated with ferritin and HFE status. In a subgroup of 22 “stable” patients, i.e., with Hb levels on target, normal CRP levels, and absence of complications for at least 1 yr, hepcidin-25 was negatively correlated with Hb levels independently of confounders. Conclusions: Serum hepcidin-25 is increased in hemodialysis patients, regulated by iron stores and inflammation, and relatively reduced in subjects carrying frequent HFE mutations. Hepcidin-25 may contribute to the pathogenesis of anemia by decreasing iron availability. PMID:19541813

  6. An Excel Macro to Plot the HFE-Diagram to Identify Sea Water Intrusion Phases.

    Science.gov (United States)

    Giménez-Forcada, Elena; Sánchez San Román, F Javier

    2015-01-01

    A hydrochemical facies evolution diagram (HFE-D) is a multirectangular diagram, which is a useful tool in the interpretation of sea water intrusion processes. This method note describes a simple method for generating an HFE-D plot using the spreadsheet software package, Microsoft Excel. The code was applied to groundwater from the alluvial coastal plain of Grosseto (Tuscany, Italy), which is characterized by a complex salinization process in which sea water mixes with sulfate or bicarbonate recharge water. © 2014, National GroundWater Association.

  7. Condensation of HFE-7100 vapor in a loop heat pipe having a curvilinear fin

    Directory of Open Access Journals (Sweden)

    Lyulin Yuriy

    2017-01-01

    Full Text Available Vapor condensation of the HFE-7100 in loop heat pipe was studied experimentally and theoretically. Numerical calculations of the vapor condensation on the curvilinear fin have been performed. Numerical, theoretical and experimental data are in a good agreement. Minimal condensate film thickness on the top of the fin has been determined and increases monotonously with the increase in the temperature drop.

  8. Experimental study on pool boiling of distilled water and HFE7500 fluid under microgravity

    Science.gov (United States)

    Yang, Yan-jie; Chen, Xiao-qian; Huang, Yi-yong; Li, Guang-yu

    2018-02-01

    The experimental study on bubble behavior and heat transfer of pool boiling for distilled water and HFE7500 fluid under microgravity has been conducted by using drop tower in the National Microgravity Laboratory of China (NMLC). Two MCH ceramic plates of 20 mm(L) × 10 mm(W) × 1.2 mm(H) were used as the heaters. The nucleate boiling evolution under microgravity was observed during the experiment. It has been found that at the same heat flux, the bubbles of HFE7500 (which has smaller contact angle) grew faster and bigger, moved quickly on the heater surface, and were easier to merge into a central big bubble with other bubbles than that of distilled water. The whole process of bubbles coalescence from seven to one was recorded by using video camera. For distilled water (with bigger contact angle), the bubbles tended to keep at the nucleate location on heater surface, and the central big bubble evolved at its nucleate cite by absorbing smaller bubbles nearby. Compared with the bubbles under normal gravity, bubble radius of distilled water under microgravity was about 1.4 times bigger and of HFE7500 was about more than 6 times bigger till the end of experiment. At the beginning, pool boiling heat transfer of distilled water was advanced and then impeded under microgravity. As to HFE7500, the pool boiling impedes the heat transfer from heater to liquid under microgravity throughout the experiment.

  9. high prevalence of the cys282tyr hfe mutation facilitates an improved ...

    African Journals Online (AJOL)

    HIGH PREVALENCE OF THE. CYS282TYR HFE MUTATION. FACILITATES AN IMPROVED. DIAGNOSTIC SERVICE FOR. HEREDITARY HAEMO-. CHROMATOSIS IN SOUTH AFRICA. J Nico P de Villiers, Renate Hillerman, Greetje de Jong. Elzet Langenhoven, Heleen Rossouw, Munro P Marx,. Maritha J Kotze. Objective.

  10. Effects of simulated weightlessness on cellular morphology and biological characteristics of cell lines SGC-7901 and HFE-145

    National Research Council Canada - National Science Library

    Zhu, M; Jin, X W; Wu, B Y; Nie, J L; Li, Y H

    2014-01-01

    We investigated the effects of simulated weightlessness on cellular morphology, proliferation, cell cycle, and apoptosis of the human gastric carcinoma cell line SGC-7901 and the human gastric normal cell line HFE-145...

  11. The hemochromatosis proteins HFE, TfR2, and HJV form a membrane-associated protein complex for hepcidin regulation.

    Science.gov (United States)

    D'Alessio, Flavia; Hentze, Matthias W; Muckenthaler, Martina U

    2012-11-01

    The hereditary hemochromatosis-associated membrane proteins HFE, TfR2, and HJV are required for adequate hepatic expression of the iron hormone hepcidin. While the genetic interactions are clear, it remains elusive how bone morphogenetic protein co-receptor HJV functions together with HFE and TfR2 to activate hepcidin transcription via the BMP-SMAD signaling pathway. Here, we investigate whether HFE, TfR2, and HJV physically interact on the surface of hepatocytes. We explore protein-protein interactions by glycerol gradient sedimentation assays and co-immunoprecipitation analyses in transfected HuH7 hepatoma-derived cells. Our data demonstrate that HFE and TfR2 bind HJV in a non-competitive manner. Co-immunoprecipitation analyses provide direct experimental evidence that HFE, TfR2, and HJV form a multi-protein membrane complex. Our experiments show that like TfR2, HJV competes with TfR1 for binding to HFE, indicating that the expression of TfR2 and HJV may be critical for iron sensing. We identify residues 120-139 of the TfR2 extra-cellular domain as the critical amino acids required for the binding of both HFE and HJV. Interestingly, RGMA, a central nervous system homolog, can substitute for HJV in the complex and promote hepcidin transcription, implicating RGMA in the local control of hepcidin in the CNS. Taken together, our findings provide a biochemical basis for hepcidin control by HFE, TfR2, and HJV. Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  12. Interaction of the Hereditary Hemochromatosis Protein, HFE, with Transferrin Receptor 2 Is Required for Transferrin-Induced Hepcidin Expression

    Science.gov (United States)

    Gao, Junwei; Chen, Juxing; Kramer, Maxwell; Tsukamoto, Hidekazu; Zhang, An-Sheng; Enns, Caroline A.

    2009-01-01

    SUMMARY The mechanisms that allow the body to sense iron levels in order to maintain iron homeostasis are unknown. Patients with the most common form of hereditary iron overload have mutations in the hereditary hemochromatosis protein, HFE. They have lower levels of hepcidin, than unaffected individuals. Hepcidin, a hepatic peptide hormone, negatively regulates iron efflux from the intestines into the blood. We report two hepatic cell lines, WIF-B cells and HepG2 cells transfected with HFE, where hepcidin expression responded to iron-loaded transferrin. The response was abolished when endogenous transferrin receptor 2 (TfR2) was suppressed or in primary hepatocytes lacking either functional TfR2 or HFE. Furthermore, transferrin-treated HepG2 cells transfected with HFE chimeras containing only the α3 and cytoplasmic domains could upregulate hepcidin expression. Since the HFE α3 domain interacts with TfR2, these results supported our finding that TfR2/HFE complex is required for transcriptional regulation of hepcidin by holo-Tf. PMID:19254567

  13. Parenteral vs. oral iron: influence on hepcidin signaling pathways through analysis of Hfe/Tfr2-null mice.

    Science.gov (United States)

    McDonald, Cameron J; Wallace, Daniel F; Ostini, Lesa; Subramaniam, V Nathan

    2014-01-01

    Treatment for iron deficiency anemia can involve iron supplementation via dietary or parenteral routes that result in different cellular iron distributions. The effect of the administered iron on the iron regulatory system and hepcidin in the liver has not been well studied. Hepcidin, the liver-expressed central iron-regulatory peptide, is itself regulated through the bone morphogenetic protein (BMP)/SMAD signaling pathway. Specifically, Bmp6 expression is upregulated in response to iron and induces hepcidin through phosphorylation of Smad1/5/8. The hemochromatosis-associated proteins Hfe and transferrin receptor 2 (Tfr2) are known upstream regulators of hepcidin, although their precise roles are still unclear. To investigate the mechanisms of this regulation and the roles of the Hfe and Tfr2, we subjected wild-type, Hfe(-/-), Tfr2(-/-), and Hfe(-/-)/Tfr2(-/-) mice to iron loading via dietary or parenteral routes. Systematic analysis demonstrated that Tfr2 is required for effective upregulation of Bmp6 in response to hepatocyte iron, but not nonparenchymal iron. Hfe is not required for Bmp6 upregulation, regardless of iron localization, but rather, is required for efficient downstream transmission of the regulatory signal. Our results demonstrate that Hfe and Tfr2 play separate roles in the regulatory responses to iron compartmentalized in different cell types and further elucidates the regulatory mechanisms controlling iron homeostasis.

  14. A systematic review of human factors and ergonomics (HFE)-based healthcare system redesign for quality of care and patient safety.

    Science.gov (United States)

    Xie, Anping; Carayon, Pascale

    2015-01-01

    Healthcare systems need to be redesigned to provide care that is safe, effective and efficient, and meets the multiple needs of patients. This systematic review examines how human factors and ergonomics (HFE) is applied to redesign healthcare work systems and processes and improve quality and safety of care. We identified 12 projects representing 23 studies and addressing different physical, cognitive and organisational HFE issues in a variety of healthcare systems and care settings. Some evidence exists for the effectiveness of HFE-based healthcare system redesign in improving process and outcome measures of quality and safety of care. We assessed risk of bias in 16 studies reporting the impact of HFE-based healthcare system redesign and found varying quality across studies. Future research should further assess the impact of HFE on quality and safety of care, and clearly define the mechanisms by which HFE-based system redesign can improve quality and safety of care.

  15. HFE Mutations Modulate the Effect of Iron on Serum Hepcidin-25 in Chronic Hemodialysis Patients

    OpenAIRE

    Valenti, Luca; Girelli, Domenico; Valenti, Giovanni Francesco; Castagna, Annalisa; Como, Giovanna; Campostrini, Natascia; Rametta, Raffaela; Dongiovanni, Paola; Messa, Piergiorgio; Fargion, Silvia

    2009-01-01

    Background and objectives: Increased serum hepcidin has been reported in patients receiving chronic hemodialysis, and hypothesized to contribute to the alterations of iron metabolism of end-stage renal disease. However, no quantitative assessment is available to date; the clinical determinants are still under definition; and the role of genetic factors, namely HFE mutations, has not yet been evaluated. The aim of this study was to quantitatively assess serum hepcidin-25 in hemodialysis patien...

  16. A systematic review of Human Factors and Ergonomics (HFE)-based healthcare system redesign for quality of care and patient safety

    Science.gov (United States)

    Xie, Anping; Carayon, Pascale

    2014-01-01

    Healthcare systems need to be redesigned to provide care that is safe, effective and efficient, and meets the multiple needs of patients. This systematic review examines how Human Factors and Ergonomics (HFE) is applied to redesign healthcare work systems and processes and improve quality and safety of care. We identified twelve projects representing 23 studies and addressing different physical, cognitive and organizational HFE issues in a variety of healthcare systems and care settings. Some evidence exists for the effectiveness of HFE-based healthcare system redesign in improving process and outcome measures of quality and safety of care. We assessed risk of bias in 16 studies reporting the impact of HFE-based healthcare system redesign and found varying quality across studies. Future research should further assess the impact of HFE on quality and safety of care, and clearly define the mechanisms by which HFE-based system redesign can improve quality and safety of care. Practitioner Summary Existing evidence shows that HFE-based healthcare system redesign has the potential to improve quality of care and patient safety. Healthcare organizations need to recognize the importance of HFE-based healthcare system redesign to quality of care and patient safety, and invest resources to integrate HFE in healthcare improvement activities. PMID:25323570

  17. The 16189 variant of mitochondrial DNA occurs more frequently in C282Y homozygotes with haemochromatosis than those without iron loading

    National Research Council Canada - National Science Library

    Livesey, K J; Wimhurst, V L C; Carter, K; Worwood, M; Cadet, E; Rochette, J; Roberts, A G; Pointon, J J; Merryweather-Clarke, A T; Bassett, M L; Jouanolle, A-M; Mosser, A; David, V; Poulton, J; Robson, K J H

    2004-01-01

    .... The mitochondrial 16189 variant is associated with diabetes, dilated cardiomyopathy, and low body fat at birth, and might contribute to genetic predisposition in further multifactorial disorders...

  18. Gestión de la calidad en paneles de puerta HFE

    OpenAIRE

    Sanz Aceves, Miguel

    2017-01-01

    Este Trabajo Fin de Máster detalla las actividades realizadas en control y seguimiento de la calidad en los proyectos HFE de producción de paneles de puerta, durante el período de prácticas curriculares. En esta estancia he podido colaborar con otros técnicos de calidad responsables de la calidad de estos proyectos. Las tareas principales han sido gestión de proveedores, seguimiento de la calidad en el área de retoque final y muro de calidad Departamento de Construcciones Ar...

  19. Wilson's disease and hemochromatosis.

    Science.gov (United States)

    Neimark, Ezequiel; Schilsky, Michael L; Shneider, Benjamin L

    2004-02-01

    Wilson's disease (WD) and hereditary hemochromatosis (HH) are two inherited disorders with potentially devastating and life-threatening complications. Their eminent treatability makes diagnosis in adolescence or young adulthood critical. WD is the result of abnormal copper homeostasis, causing copper overload and end-organ damage. Chelation therapy can be highly efficacious in preventing manifestations of WD. HH is caused by inappropriate absorption of dietary iron, typically as the result of a specific mutation, C282Y, in the HFE gene. End-organ disease from iron accumulation is protean and includes progressive damage of the liver, pancreas, skin, heart, and pituitary. It is important to permit therapeutic phlebotomy to commence before the onset of complications.

  20. Total and cause-specific mortality by elevated transferrin saturation and hemochromatosis genotype in individuals with diabetes - two general population studies

    DEFF Research Database (Denmark)

    Ellervik, Christina; Mandrup-Poulsen, Thomas; Tybjærg-Hansen, Anne

    2013-01-01

    ObjectiveMortality is increased in patients with hereditary hemochromatosis, in individuals from the general population with increased transferrin saturation(TS), and also in patients with diabetes type 1 and increased TS from a highly specialised diabetes clinic. Thus, we have recommended targeted...... and hemochromatosis genotype(HFE) C282Y/C282Y in individuals with diabetes(type 1,N=118;type 2,N=3228;total,N=3346).ResultsThe cumulative survival was reduced in individuals with diabetes with TS≥50% vs....

  1. H63D mutation in HFE gene is common in Indians and is associated ...

    Indian Academy of Sciences (India)

    Department of Haematology, Postgraduate Institute of Medical Education and Research, Chandigarh 160 012, India; Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research, Uppal Road, Hyderabad 500 007, India; Department of Hepatology, Postgraduate Institute of Medical Education and ...

  2. Associations of common variants in HFE and TMPRSS6 with iron parameters are independent of serum hepcidin in a general population: a replication study.

    Science.gov (United States)

    Galesloot, Tessel E; Geurts-Moespot, Anneke J; den Heijer, Martin; Sweep, Fred C G J; Fleming, Robert E; Kiemeney, Lambertus A L M; Vermeulen, Sita H; Swinkels, Dorine W

    2013-09-01

    Genome-wide association studies have convincingly shown that single nucleotide polymorphisms (SNPs) in HFE and TMPRSS6 are associated with iron parameters. It was commonly thought that these associations could be explained by the intermediate effect on hepcidin concentration. A recent study in an isolated Italian population, however, concluded that these associations were not exclusively dependent on hepcidin values. We report here the second study to investigate the role of hepcidin in the associations between common variants in HFE and TMPRSS6 with iron parameters. We extracted 101 SNPs in HFE and TMPRSS6 from genome-wide imputed SNP data of 1832 individuals from the general population (Nijmegen Biomedical Study). Single locus and haplotype associations with serum iron parameters and hepcidin were studied using linear regression analyses. We found that HFE rs1800562 and TMPRSS6 rs855791 are the main determinants of HFE and TMPRSS6 related variation in serum iron, ferritin, transferrin saturation, and total iron binding capacity. These SNPs are associated with the ratios hepcidin/ferritin (p0.2). Adjustment for hepcidin or the ratio hepcidin/ferritin did not decrease the strength of the SNP-iron parameter associations. Our results do not support an intermediate role for hepcidin in the SNP-iron parameter associations, which confirms previous findings, and indicate a pleiotropic SNP effect on the hepcidin ratios and the iron parameters. Taken together, this suggests that there might be other, yet unknown, serum hepcidin independent mechanisms which play a role in the association of HFE and TMPRSS6 variants with serum iron parameters.

  3. Alterações moleculares associadas à hemocromatose hereditária Molecular changes associated with hereditary hemochromatosis

    Directory of Open Access Journals (Sweden)

    Paulo C. J. L. Santos

    2009-01-01

    Full Text Available A hemocromatose hereditária (HH é a mais comum doença autossômica em caucasianos e caracteriza-se pelo aumento da absorção intestinal de ferro, o qual resulta em acúmulo progressivo de ferro no organismo. A classificação da HH é realizada de acordo com a alteração genética encontrada, sendo os casos divididos em tipos 1, 2A, 2B, 3 e 4, quando a sobrecarga de ferro for associada aos genes HFE, HJV, HAMP, TFR2 e SLC40A1, respectivamente. Não existem estudos brasileiros que avaliaram a presença de mutações em genes relacionados à fisiopatologia da HH (genes HJV, HAMP, TFR2 e SLC40A1, além da pesquisa das três mutações no gene HFE (C282Y, H63D e S65C. Porém, está descrito, nos estudos realizados no Brasil, que alguns pacientes com sobrecarga de ferro primária não são portadores da HH tipo 1 (associada ao gene HFE. Portanto, é de suma importância a identificação das características genéticas dessa população, uma vez que outras mutações nos genes HJV, HAMP, TFR2 e SLC40A1 podem estar associadas à fisiopatologia da doença, podendo haver interações entre os genes alterados, de forma que possa auxiliar no entendimento da fisiopatologia da HH em pacientes brasileiros.Hereditary Hemochromatosis (HH is the most common autosomal disease in Caucasians. It is characterized by an increase in intestinal absorption of iron, which results in a progressive accumulation of iron in the body. The classification of HH is carried out according to the genetic alteration found; thus cases of HH are divided into Types 1, 2A, 2B, 3 and 4, when the iron overload is associated to the HFE, HJV, HAMP, TFR2 and SLC40A1 genes, respectively. There is research on the three HFE gene mutations (C282Y, H63D and S65C in the Brazilian population however there are no Brazilian studies that evaluate the presence of mutations in other genes related to the pathophysiology of HH (HJV, HAMP, TFR2 and SLC40A1 genes. Nevertheless, studies conducted in

  4. A rare cause of osteonecrosis

    Directory of Open Access Journals (Sweden)

    Paolo Agostinis

    2012-01-01

    Full Text Available IntroductionHereditary hemochromatosis (HH is an autosomal recessive disorder caused by mutations in the HFE gene, which increase intestinal iron absorption. The prevalence of C282Y homozygosity, which causes the disorder, is 0.5% in Caucasian populations. The clinical manifestations are related to excess iron in the tissues, especially the liver, heart, pancreas, pituitary, and skin. They include fatigue, loss of libido or impotence in males, liver disease, skin pigmentation, diabetes mellitus, cardiac enlargement—with or without heart failure, and conduction defects. The classic triad of cirrhosis, diabetes mellitus, and skin pigmentation (“bronze diabetes” results from a combination of iron deposits and melanin. It occurs late in the disease, when the total body iron content is more than five times the normal value, about 20 grams. Left untreated, approximately half of all patients with HH eventually develop arthralgia or arthropathy. Chondrocalcinosis, chronic pseudo-osteoarthritis, and osteoporosis are the major rheumatic manifestations of HH. The cause of the arthropathy is still unknown. Iron deposits within joints may trigger a number of pathologic events, such as free radical generation and crystal deposition, which stimulate immune complex formation and inflammation.Materials and methodsWe describe the case of a 48-year-old male suffering from chronic bilateral ankle pain.ResultsThe work-up revealed osteonecrosis of ankle. The patient also presented high plasma ferritin levels and homozygosity for the C282Y mutation. Other than HH, which was confirmed by liver biopsy, the patient had no other risk factors for osteonecrosis.DiscussionHH represents a rare cause of osteonecrosis, and there are no prior reports of aseptic osteonecrosis of the ankle in a patient with this disease. The pathogenetic mechanism remains unknown.

  5. Genetic Aspects of Scurvy and the European Famine of 1845–1848

    Directory of Open Access Journals (Sweden)

    Michel R. Langlois

    2013-09-01

    Full Text Available The view of scurvy being exclusively a nutritional disorder needs to be updated. Genetic polymorphisms of HFE and haptoglobin (Hp may explain the geographic variability of mortality caused by the European famine of the mid-19th century. In this period, potatoes had fallen victim to the potato blight and Ireland was more severely hit than continental Europe. Hereditary hemochromatosis is a genetic disorder with mutations in the HFE gene, characterized by iron overload (with a reduced vitamin C stability and with a predominance of affected men. The Irish have the world’s highest frequency of the C282Y mutation and the particular iron metabolism of the Irish helps to understand the size of the catastrophe and the observed overrepresentation of male skeletons showing scurvy. Hp is a plasma α2-glycoprotein characterized by 3 common phenotypes (Hp 1-1, Hp 2-1 and Hp 2-2. When the antioxidant capacity of Hp is insufficient, its role is taken over by hemopexin and vitamin C. The relative number of scurvy victims corresponds with the Hp 2-2 frequency, which is associated with iron conservation and has an impact on vitamin C stability. As iron is more abundant in males, males are overrepresented in the group of skeletons showing scurvy signs.

  6. Genetic disruption of NRF2 promotes the development of necroinflammation and liver fibrosis in a mouse model of HFE-hereditary hemochromatosis

    Directory of Open Access Journals (Sweden)

    Tiago L. Duarte

    2017-04-01

    Conclusions: The genetic disruption of Nrf2 promotes the transition from iron accumulation (siderosis to liver injury in Hfe-/- mice, representing the first demonstration of spontaneous hepatic fibrosis in the long term in a mouse model of hereditary hemochromatosis displaying mildly elevated liver iron.

  7. Application of human factors engineering (HFE) to the design of a naloxone auto-injector for the treatment of opioid emergencies.

    Science.gov (United States)

    Raffa, Robert B; Taylor, Robert; Pergolizzi, Joseph V; Nalamachu, Srinivas; Edwards, Eric S; Edwards, Evan T

    2017-02-01

    The increased use of opioids for chronic treatment of pain and the resulting epidemic of opioid overdoses have created a major public health challenge. Parenteral naloxone has been used since the 1970's to treat opioid overdose. Recently, a novel naloxone auto-injector device (EVZIO, kaleo, Inc., Richmond, VA) was approved by the Food and Drug Administration. In this article, we review the Human Factors Engineering (HFE) process used in the development and testing of this novel naloxone auto-injector currently used in nonmedical settings for the emergency treatment of known or suspected opioid overdose. HFE methods were employed throughout the product development process for the naloxone auto-injector including formative and summative studies in order to optimize the auto-injector's user interface, mitigate use-related hazards and increase reliability during an opioid emergency use scenario. HFE was also used to optimize the product's design and user interface in order to reduce or prevent user confusion and misuse. The naloxone auto-injector went through a rigorous HFE process that included perceptual, cognitive, and physical action analysis; formative usability evaluations; use error analysis and summative design validation studies. Applying HFE resulted in the development of a product that is safe, fast, easy and predictably reliable to deliver a potentially life-saving dose of naloxone during an opioid overdose emergency. The naloxone auto-injector may be considered as a universal precaution option for at-risk patients prescribed opioids or those who are at increased risk for an opioid overdose emergency.

  8. Expression of iron-related genes in human brain and brain tumors

    Directory of Open Access Journals (Sweden)

    Britton Robert S

    2009-04-01

    Full Text Available Abstract Background Defective iron homeostasis may be involved in the development of some diseases within the central nervous system. Although the expression of genes involved in normal iron balance has been intensively studied in other tissues, little is known about their expression in the brain. We investigated the mRNA levels of hepcidin (HAMP, HFE, neogenin (NEO1, transferrin receptor 1 (TFRC, transferrin receptor 2 (TFR2, and hemojuvelin (HFE2 in normal human brain, brain tumors, and astrocytoma cell lines. The specimens included 5 normal brain tissue samples, 4 meningiomas, one medulloblastoma, 3 oligodendrocytic gliomas, 2 oligoastrocytic gliomas, 8 astrocytic gliomas, and 3 astrocytoma cell lines. Results Except for hemojuvelin, all genes studied had detectable levels of mRNA. In most tumor types, the pattern of gene expression was diverse. Notable findings include high expression of transferrin receptor 1 in the hippocampus and medulla oblongata compared to other brain regions, low expression of HFE in normal brain with elevated HFE expression in meningiomas, and absence of hepcidin mRNA in astrocytoma cell lines despite expression in normal brain and tumor specimens. Conclusion These results indicate that several iron-related genes are expressed in normal brain, and that their expression may be dysregulated in brain tumors.

  9. A Survey on the HFE-related Technologies for the Improvements of Human Performance of Safety Personnel in Rail System

    Energy Technology Data Exchange (ETDEWEB)

    Koo, I. S.; Park, G. O.; Suh, S. M.; Sim, Y. R.; Go, J. H.; Jeong, J. H.; Son, C. H

    2005-08-15

    Many studies have shown that the most cases of rail accidents have occurred because of performing his/her tasks in inappropriate way. It is generally recognised that the rail system without human element could never be happened quite long time. So human element in rail system is going to be the major factor to the next tragic accident. This state-of-the-art report describes three major HFE-related technologies, training simulator, the integrated test facility for human factors engineering, and human performance evaluation system, that are used in the other industries including nuclear power industry for the purpose of increasing rail safety through out the improvement of human task performance. Base on this report, the way of developing those technologies that should be applied to the korean rail system is presented.

  10. No Association between Variation in Longevity Candidate Genes and Aging-related Phenotypes in Oldest-old Danes

    DEFF Research Database (Denmark)

    Sørensen, Mette; Nygaard, Marianne; Debrabant, Birgit

    2016-01-01

    additional genes repeatedly considered as candidates for human longevity: APOE, APOA4, APOC3, ACE, CETP, HFE, IL6, IL6R, MTHFR, TGFB1, SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. Altogether, 1,049 single nucleotide polymorphisms (SNPs) were genotyped in 1,088 oldest-old (age 92-93 years) Danes and analysed...

  11. Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferrin receptor 2 (Tfr2), and IL-6.

    Science.gov (United States)

    Truksa, Jaroslav; Peng, Hongfan; Lee, Pauline; Beutler, Ernest

    2006-07-05

    Recently, it has been suggested that hepcidin, a peptide involved in iron homeostasis, is regulated by bone morphogenetic proteins (BMPs), apparently by binding to hemojuvelin (Hjv) as a coreceptor and signaling through Smad4. We investigate the role of Hfe, Tfr2 (transferrin receptor 2), and IL-6 in BMP2-, BMP4-, and BMP9-stimulated up-regulation of murine hepcidin, because these molecules, like Hjv, are known to be involved in hepcidin signaling. We show that the BMP signaling pathway acts independently of Hfe, Tfr2, and IL-6: The response to BMP2, BMP4, and BMP9 is similar in isolated hepatocytes of wild-type, Hfe(-/-), IL-6(-/-), and Tfr2(m) mutant mice. The potency of different human BMPs in stimulating hepcidin transcription by murine primary hepatocytes is BMP9 > BMP4 > BMP2. However, in human HepG2 cells, BMP4 and BMP9 are equally potent, whereas BMP2 requires a higher dose to become an effective hepcidin activator. Moreover, all of the tested BMPs are more potent regulators of hepcidin than IL-6 and thus are the most potent known stimulators of hepcidin transcription.

  12. Variation in the HFE gene is associated with the development of bleomycin-induced pulmonary toxicity in testicular cancer patients

    NARCIS (Netherlands)

    Schoot, van der Garbiela G.F.; Westerink, Nico-Derk L; Lubberts, Sjoukje; Nuver, Janine; Zwart, Nynke; Walenkamp, Annemiek M E; Wempe, Johan B; Meijer, Coby; Gietema, Jourik A

    BACKGROUND: 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

  13. Association between sex, systemic iron variation and probability of Parkinson's disease.

    Science.gov (United States)

    Mariani, S; Ventriglia, M; Simonelli, I; Bucossi, S; Siotto, M; Donno, S; Vernieri, F; Squitti, R

    2016-01-01

    Iron homeostasis appears altered in Parkinson's disease (PD). Recent genetic studies and meta-analyses have produced heterogeneous and inconclusive results. In order to verify the possible role of iron status in PD, we have screened some of the main metal gene variants, evaluated their effects on iron systemic status, and checked for possible interactions with PD. In 92 PD patients and 112 healthy controls, we screened the D544E and R793H variants of the ceruloplasmin gene (CP), the P589S variant of the transferrin gene (TF), and the H63D and C282Y variants of the HFE gene, encoding for homologous proteins, respectively. Furthermore, we analyzed serum concentrations of iron, copper and their related proteins. The genetic investigation revealed no significant differences in allelic and genotype distributions between patients and controls. Two different multivariable forward stepwise logistic models showed that, when the effect of sex is considered, an increase of the probability of having PD is associated with low iron concentration and Tf-saturation. This study provides new evidence of the involvement of iron metabolism in PD pathogenesis and reveals a biological effect of sex.

  14. Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice

    National Research Council Canada - National Science Library

    Gao, Junwei; Chen, Juxing; De Domenico, Ivana; Koeller, David M; Harding, Cary O; Fleming, Robert E; Koeberl, Dwight D; Enns, Caroline A

    2010-01-01

    ...), transferrin-receptor 2 (TfR2), hemojuvelin, hepcidin, or ferroportin genes. Hepcidin is a key iron regulator, which is secreted by the liver, and decreases serum iron levels by causing the down-regulation of the iron transporter, ferroportin...

  15. Carriers of the Complex Allele HFE c.[187C>G;340+4T>C] Have Increased Risk of Iron Overload in São Miguel Island Population (Azores, Portugal).

    Science.gov (United States)

    Branco, Claudia C; Gomes, Cidália T; De Fez, Laura; Bulhões, Sara; Brilhante, Maria José; Pereirinha, Tânia; Cabral, Rita; Rego, Ana Catarina; Fraga, Cristina; Miguel, António G; Brasil, Gracinda; Macedo, Paula; Mota-Vieira, Luisa

    2015-01-01

    Iron overload is associated with acquired and genetic conditions, the most common being hereditary hemochromatosis (HH) type-I, caused by HFE mutations. Here, we conducted a hospital-based case-control study of 41 patients from the São Miguel Island (Azores, Portugal), six belonging to a family with HH type-I pseudodominant inheritance, and 35 unrelated individuals fulfilling the biochemical criteria of iron overload compatible with HH type-I. For this purpose, we analyzed the most common HFE mutations- c.845G>A [p.Cys282Tyr], c.187C>G [p.His63Asp], and c.193A>T [p.Ser65Cys]. Results revealed that the family's HH pseudodominant pattern is due to consanguineous marriage of HFE-c.845G>A carriers, and to marriage with a genetically unrelated spouse that is a -c.187G carrier. Regarding unrelated patients, six were homozygous for c.845A, and three were c.845A/c.187G compound heterozygous. We then performed sequencing of HFE exons 2, 4, 5 and their intron-flanking regions. No other mutations were observed, but we identified the -c.340+4C [IVS2+4C] splice variant in 26 (74.3%) patients. Functionally, the c.340+4C may generate alternative splicing by HFE exon 2 skipping and consequently, a protein missing the α1-domain essential for HFE/ transferrin receptor-1 interactions. Finally, we investigated HFE mutations configuration with iron overload by determining haplotypes and genotypic profiles. Results evidenced that carriers of HFE-c.187G allele also carry -c.340+4C, suggesting in-cis configuration. This data is corroborated by the association analysis where carriers of the complex allele HFE-c.[187C>G;340+4T>C] have an increased iron overload risk (RR = 2.08, 95% CI = 1.40-2.94, pG;340+4T>C] has a role, as genetic predisposition factor, on iron overload in the São Miguel population. Independent replication studies in other populations are needed to confirm this association.

  16. Maternal hemochromatosis gene H63D single-nucleotide polymorphism and lead levels of placental tissue, maternal and umbilical cord blood

    Energy Technology Data Exchange (ETDEWEB)

    Kayaalti, Zeliha, E-mail: kayaalti@ankara.edu.tr [Ankara University, Institute of Forensic Sciences, Ankara (Turkey); Kaya-Akyüzlü, Dilek [Ankara University, Institute of Forensic Sciences, Ankara (Turkey); Söylemez, Esma [Ankara University, Institute of Forensic Sciences, Ankara (Turkey); Middle Black Sea Passage Generation of Agricultural Research Station Director, Tokat (Turkey); Söylemezoğlu, Tülin [Ankara University, Institute of Forensic Sciences, Ankara (Turkey)

    2015-07-15

    Human hemochromatosis protein (HFE), a major histocompatibility complex class I-like integral membrane protein, participates in the down regulation of intestinal iron absorption by binding to transferrin receptor (TR). HFE competes with transferrin-bound iron for the TR and thus reduces uptake of iron into cells. On the other hand, a lack of HFE increases the intestinal absorption of iron similarly to iron deficiency associated with increasing in absorption and deposition of lead. During pregnancy, placenta cannot prevent transfer lead to the fetus; even low-level lead poisoning causes neurodevelopmental toxicity in children. The aim of this study was to determine the association between the maternal HFE H63D single-nucleotide polymorphism and lead levels in placental tissue, maternal blood and umbilical cord bloods. The study population comprised 93 mother–placenta pairs. Venous blood from mother was collected to investigate lead levels and HFE polymorphism that was detected by standard PCR–RFLP technique. Cord bloods and placentas were collected for lead levels which were analyzed by dual atomic absorption spectrometer system. The HFE H63D genotype frequencies of mothers were found as 75.3% homozygote typical (HH), 23.6% heterozygote (HD) and 1.1% homozygote atypical (DD). Our study results showed that the placental tissue, umbilical cord and maternal blood lead levels of mothers with HD+DD genotypes were significantly higher than those with HH genotype (p<0.05). The present study indicated for the first time that mothers with H63D gene variants have higher lead levels of their newborn's placentas and umbilical cord bloods. - Highlights: • Mothers with H63D gene variants have higher lead levels of their newborn's umbilical cord blood. • Unborn child of women with HD+DD genotypes may be at increased risk of internal exposure to lead. • Maternal HFE status may have an effect on increased placenta, maternal and cord blood lead levels.

  17. Interaction of Dietary and Genetic Factors Influencing Body Iron Status and Risk of Type 2 Diabetes Within the EPIC-InterAct Study.

    Science.gov (United States)

    Meidtner, Karina; Podmore, Clara; Kröger, Janine; van der Schouw, Yvonne T; Bendinelli, Benedetta; Agnoli, Claudia; Arriola, Larraitz; Barricarte, Aurelio; Boeing, Heiner; Cross, Amanda J; Dow, Courtney; Ekblom, Kim; Fagherazzi, Guy; Franks, Paul W; Gunter, Marc J; Huerta, José María; Jakszyn, Paula; Jenab, Mazda; Katzke, Verena A; Key, Timothy J; Khaw, Kay Tee; Kühn, Tilman; Kyrø, Cecilie; Mancini, Francesca Romana; Melander, Olle; Nilsson, Peter M; Overvad, Kim; Palli, Domenico; Panico, Salvatore; Quirós, J Ramón; Rodríguez-Barranco, Miguel; Sacerdote, Carlotta; Sluijs, Ivonne; Stepien, Magdalena; Tjonneland, Anne; Tumino, Rosario; Forouhi, Nita G; Sharp, Stephen J; Langenberg, Claudia; Schulze, Matthias B; Riboli, Elio; Wareham, Nicholas J

    2018-02-01

    Meat intake has been consistently shown to be positively associated with incident type 2 diabetes. Part of that association may be mediated by body iron status, which is influenced by genetic factors. We aimed to test for interactions of genetic and dietary factors influencing body iron status in relation to the risk of incident type 2 diabetes. The case-cohort comprised 9,347 case subjects and 12,301 subcohort participants from eight European countries. Single nucleotide polymorphisms (SNPs) were selected from genome-wide association studies on iron status biomarkers and candidate gene studies. A ferritin-related gene score was constructed. Multiplicative and additive interactions of heme iron and SNPs as well as the gene score were evaluated using Cox proportional hazards regression. Higher heme iron intake (per 1 SD) was associated with higher ferritin levels (β = 0.113 [95% CI 0.082; 0.144]), but not with transferrin (-0.019 [-0.043; 0.006]) or transferrin saturation (0.016 [-0.006; 0.037]). Five SNPs located in four genes (rs1799945 [ HFE H63D], rs1800562 [ HFE C282Y], rs236918 [ PCK7 ], rs744653 [ SLC40A1 ], and rs855791 [ TMPRSS6 V736A]) were associated with ferritin. We did not detect an interaction of heme iron and the gene score on the risk of diabetes in the overall study population ( P add = 0.16, P mult = 0.21) but did detect a trend toward a negative interaction in men ( P add = 0.04, P mult = 0.03). We found no convincing evidence that the interplay of dietary and genetic factors related to body iron status associates with type 2 diabetes risk above the level expected from the sum or product of the two individual exposures. © 2017 by the American Diabetes Association.

  18. A haplotype and linkage disequilibrium analysis of the hereditary hemochromatosis gene region.

    Science.gov (United States)

    Thomas, W; Fullan, A; Loeb, D B; McClelland, E E; Bacon, B R; Wolff, R K

    1998-05-01

    Hereditary hemochromatosis is a recessive disease of iron metabolism widely distributed among people of European descent. Most patients have inherited the causative mutation from a single ancestor. In the course of cloning the hemochromatosis gene, genotypes were generated for these samples at 43 microsatellite repeat markers that span the 6.5-Mb hemochromatosis gene region. The data used to reconstruct the ancestral haplotype across the hemochromatosis gene region are presented in this paper. Portions of the ancestral haplotype were present on 85% of patient chromosomes in this sample and ranged in size from approximately 500 kb to greater than 6.5 Mb. Only one marker, D6S2239, was identical by descent on all of the patient chromosomes containing the ancestral mutation. In contrast, only 3 of the 128 control chromosomes, or 2.3%, carried the ancestral mutation and the surrounding ancestral haplotype. To test new methods for gene finding using linkage disequilibrium we analyzed the genotypic data with a multilocus maximum likelihood method (DISMULT) and a single point method (DISLAMB), both written to analyze data generated from multi-allelic markers. The maximum value from DISLAMB analysis occurred at marker D6S2239, which is less than 20 kb from the hemochromatosis gene HFE, consistent with the haplotype analysis. The peak of the multi-point analysis was 700 kb from HFE, possibly due to the nonuniform recombination rates within this large region. The recombination rate appears to be lower than expected centromeric of the HFE gene.

  19. Theoretical studies on kinetics, mechanism and thermochemistry of gas-phase reactions of HFE-449mec-f with OH radicals and Cl atom.

    Science.gov (United States)

    Deka, Ramesh Chandra; Mishra, Bhupesh Kumar

    2014-09-01

    A theoretical study on the mechanism and kinetics of the gas phase reactions of CF3CHFCF2OCH2CF3 (HFE-449mec-f) with the OH radicals and Cl atom have been performed using meta-hybrid modern density functional M06-2X using 6-31+G(d,p) basis set. Two conformers have been identified for CF3CHFCF2OCH2CF3 and the most stable one is considered for detailed study. Reaction profiles for OH-initiated hydrogen abstraction are modeled including the formation of pre-reactive and post-reactive complexes at entrance and exit channels. Our calculations reveal that hydrogen abstraction from the CH2 group is thermodynamically and kinetically more facile than that from the CHF group. Using group-balanced isodesmic reactions, the standard enthalpies of formation for HFE-449mecf and radicals generated by hydrogen abstraction, are also reported. The calculated bond dissociation energies for CH bonds are in good agreement with experimental results. The rate constants of the two reactions are determined for the first time in a wide temperature range of 250-450K. The calculated rate constant values are found to be 9.10×10(-15) and 4.77×10(-17)cm(3)molecule(-1)s(-1) for reactions with OH radicals and Cl atom, respectively. At 298K, the total calculated rate coefficient for reactions with OH radical is in good agreement with the experimental results. The atmospheric life time of HFE-449mec-f is estimated to be 0.287 years. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. [Diagnosis and therapy of inheritable liver diseases: hemochromatisis, Wilson's disease and alpha-1-antitrypsin deficiency].

    Science.gov (United States)

    Strassburg, Ch P

    2005-01-19

    The recent years have seen significant progress in the area of genetically determined liver diseases. For hereditary hemochromatosis, Wilson's disease and alpha-1 antitrypsin deficiency the underlying genetic defects have been described and well characterized. Although a direct relationship between genetic defect and disease manifestation exists genetic test only have a limited diagnostic usefulness which requires exact knowledge of the underlying molecular pathology. The classical C282Y and H63D mutations of the HFE gene only show a penetrance of 10-20% in hemochromatosis and are not useful for population screening. Genetic screening for ATP7B (Wilson's disease) and alpha-1 antitrypsin deficiency variants is limited by the existence of a plethora of individual mutations. Genetic tests are mainly restricted to the counseling of families in whom these diseases are present. Foremost the diagnosis of the three diseases is reached by clinical, biochemical and in some instances also histological means which are supplemented and confirmed by the use of appropriate genetic tests.

  1. Iron supplementation in athletes--first do no harm.

    Science.gov (United States)

    Zoller, Heinz; Vogel, Wolfgang

    2004-01-01

    Although it generally does not improve performance, iron is often used by elite athletes. The physiologic changes induced by exercise can mimic iron deficiency and decrease hemoglobin and ferritin concentrations. Determination of serum transferrin receptor concentrations may identify true iron deficiency, which occurs particularly in young athletes. In contrast, increased iron stores in the body are a frequent finding in elite athletes who have used long-term iron supplementation. Elite runners have increased intestinal blood loss, but this usually can be compensated by enhanced absorption of dietary iron. The combination of exercise-induced hemolysis with enhanced intestinal blood loss in various endurance sports leads to severe abnormalities of routine tests, and extreme physical activity may be responsible for positive fecal occult blood determinations. Indiscriminate iron supplementation carries the risk of inducing hemochromatosis in individuals homozygous for the widespread C282Y allele of the HFE gene. This polymorphism is common and can be found in about 1% of individuals of Northern European descent; moreover, iron supplementation can modify the presentation of important underlying diseases such as celiac disease or colon carcinoma. In conclusion, iron supplements should be prescribed for athletes with iron-deficiency anemia and carefully monitored if given for prophylaxis; unless a therapeutic response occurs, investigations to establish the cause of iron deficiency should be initiated.

  2. Experimental investigation and numerical simulation of a copper micro-channel heat exchanger with HFE-7200 working fluid

    Science.gov (United States)

    Borquist, Eric

    Ever increasing cost and consumption of global energy resources has inspired the development of energy harvesting techniques which increase system efficiency, sustainability, and environmental impact by using waste energy otherwise lost to the surroundings. As part of a larger effort to produce a multi-energy source prototype, this study focused on the fabrication and testing of a waste heat recovery micro-channel heat exchanger. Reducing cost and facility requirements were a priority for potential industry and commercial adoption of such energy harvesting devices. During development of the micro-channel heat exchanger, a new fabrication process using mature technologies was created that reduced cost, time, and required equipment. Testing involved filling the micro-channel heat exchanger with 3MTM NovecTM HFE-7200 working fluid. The working fluid was chosen for appropriate physical and environmental properties for the prototypes intended application. Using a dry heat exchanger as the baseline, the addition of the working fluid proved advantageous by increasing energy output by 8% while decreasing overall device temperatures. Upon successful experimental testing of the physical device, internal operation was determined based on implementation of the lattice Boltzmann method, a physics-based statistical method that actively tracked the phase change occurring in a simulated micro-channel. The simulation demonstrated three primary areas of phase change occurring, surfaces adjacent to where the heat source and heat sink were located and the bulk vapor-liquid interface, which agreed with initial device design intentions. Condensation film thickness grew to 5microm over the time interval, while the bulk interface tracked from initial 12microm from the lid to 20microm from the lid. Surface tension effects dominating vapor pressure kept the liquid near the heat source; however, the temperature and pressure VLE data suggested vapor interface growth from the heated surface to

  3. Evaluation of a high throughput method for the detection of mutations associated with thrombosis and hereditary hemochromatosis in Brazilian blood donors.

    Directory of Open Access Journals (Sweden)

    Vivian Dionisio Tavares Niewiadonski

    Full Text Available The aim of this study was to evaluate the OpenArray platform for genetic testing of blood donors and to assess the genotype frequencies of nucleotide-polymorphisms (SNPs associated with venous thrombosis (G1691A and G20210A, hyperhomocysteinemia (C677T, A1298C, and hereditary hemochromatosis (C282Y, H63D and S65C in blood donors from Sao Paulo, Brazil.We examined 400 blood donor samples collected from October to November 2011. The SNPs were detected using OpenArray technology. The blood samples were also examined using a real-time PCR-FRET system to compare the results and determine the accuracy of the OpenArray method.We observed 100% agreement in all assays tested, except HFE C282Y, which showed 99.75% agreement. The HFE C282Y assay was further confirmed through direct sequencing, and the results showed that OpenArray analysis was accurate. The calculated frequencies of each SNP were FV G1691A 98.8% (G/G, 1.2% (G/A; FII G2021A 99.5% (G/G, 0.5% (G/A; MTHFR C677T 45.5% (C/C, 44.8% (C/T, 9.8% (T/T; MTHFR A1298C 60.3% (A/A, 33.6% (A/C, 6.1% (C/C; HFE C282Y 96%(G/G, 4%(G/A, HFE H63D 78.1%(C/C, 20.3% (C/G, 1.6% (G/G; and HFE S65C 98.1% (A/A, 1.9% (A/T.Taken together, these results describe the frequencies of SNPs associated with diseases and are important to enhance our current knowledge of the genetic profiles of Brazilian blood donors, although a larger study is needed for a more accurate determination of the frequency of the alleles. Furthermore, the OpenArray platform showed a high concordance rate with standard FRET RT-PCR.

  4. Arvelig hemokromatose - nytten av screening

    Directory of Open Access Journals (Sweden)

    Arne Åsberg

    2009-10-01

    Full Text Available Arvelig hemokromatose fører til jernopphopning i kroppen, men gir sjelden alvorlig helseskade. Nesten alle hemokromatosepasienter i vårt land er homozygote for C282Y-mutasjonen i HFE-genet. Omtrent 7 per 1000 innbyggere har denne genotypen. Alvorlig syke blir bare omkring 5-15% av homozygote menn og nesten ingen kvinner. Likevel er det holdepunkter for at screening for hemokromatose blant friske, yngre menn kan være kostnadseffektivt. Det er relativt lett å påvise om en person er disponert for sykdommen, i god tid før den bryter ut, og forebyggende behandling er billig og effektiv. Imidlertid kan vi ikke forutsi hvilke screeningpositive personer som ubehandlet får alvorlig sykdom. Et kontrollert forsøk med screening bør gjennomføresHereditary hemochromatosis – benefits of screening. Hereditary hemochromatosis leads to iron accumulation in the body; however, serious illness due to hemochromatosis is rare. In Norway, almost all patients with hemochromatosis are homozygous for the C282Ymutation in the HFE-gene, a genotype carried by about 7 per 1000 inhabitants. Serious complications are seen in only about 5-15% of homozygous men and in very few women. Nevertheless, screening young men for hemochromatosis may be cost-effective. Detecting predisposed men is relatively straightforward, and prophylactic treatment is cheap and effective. However, we can not predict, among screen-positive men, the few who untreated will become seriously ill. A controlled screening trial should be conducted.

  5. The Effects of Degraded Digital Instrumentation and Control Systems on Human-system Interfaces and Operator Performance: HFE Review Guidance and Technical Basis

    Energy Technology Data Exchange (ETDEWEB)

    O' Hara, J.M.; W. Gunther, G. Martinez-Guridi

    2010-02-26

    New and advanced reactors will use integrated digital instrumentation and control (I&C) systems to support operators in their monitoring and control functions. Even though digital systems are typically highly reliable, their potential for degradation or failure could significantly affect operator performance and, consequently, impact plant safety. The U.S. Nuclear Regulatory Commission (NRC) supported this research project to investigate the effects of degraded I&C systems on human performance and plant operations. The objective was to develop human factors engineering (HFE) review guidance addressing the detection and management of degraded digital I&C conditions by plant operators. We reviewed pertinent standards and guidelines, empirical studies, and plant operating experience. In addition, we conducted an evaluation of the potential effects of selected failure modes of the digital feedwater system on human-system interfaces (HSIs) and operator performance. The results indicated that I&C degradations are prevalent in plants employing digital systems and the overall effects on plant behavior can be significant, such as causing a reactor trip or causing equipment to operate unexpectedly. I&C degradations can impact the HSIs used by operators to monitor and control the plant. For example, sensor degradations can make displays difficult to interpret and can sometimes mislead operators by making it appear that a process disturbance has occurred. We used the information obtained as the technical basis upon which to develop HFE review guidance. The guidance addresses the treatment of degraded I&C conditions as part of the design process and the HSI features and functions that support operators to monitor I&C performance and manage I&C degradations when they occur. In addition, we identified topics for future research.

  6. Gene

    Data.gov (United States)

    U.S. Department of Health & Human Services — Gene integrates information from a wide range of species. A record may include nomenclature, Reference Sequences (RefSeqs), maps, pathways, variations, phenotypes,...

  7. Hereditary hemochromatosis and risk of ischemic heart disease

    DEFF Research Database (Denmark)

    Ellervik, Christina; Tybjaerg-Hansen, Anne; Grande, Peer

    2005-01-01

    BACKGROUND: We tested the hypothesis that the hereditary hemochromatosis genotypes C282Y/C282Y, C282Y/H63D, or C282Y/wild-type are risk factors for ischemic heart disease (IHD) and myocardial infarction (MI). METHODS AND RESULTS: We performed a prospective study of 9178 individuals from the Danish...

  8. Association between inherited monogenic liver disorders and chronic hepatitis C.

    Science.gov (United States)

    Piekuse, Linda; Kreile, Madara; Zarina, Agnese; Steinberga, Zane; Sondore, Valentina; Keiss, Jazeps; Lace, Baiba; Krumina, Astrida

    2014-02-27

    To determine the frequencies of mutations that cause inherited monogenic liver disorders in patients with chronic hepatitis C. This study included 86 patients with chronic hepatitis C (55 men, 31 women; mean age at diagnosis, 38.36 ± 14.52 years) who had undergone antiviral therapy comprising pegylated interferon and ribavirin. Viral load, biochemical parameter changes, and liver biopsy morphological data were evaluated in all patients. The control group comprised 271 unrelated individuals representing the general population of Latvia for mutation frequency calculations. The most frequent mutations that cause inherited liver disorders [gene (mutation): ATP7B (H1069Q), HFE (C282Y, H63D), UGT1A1 (TA)7, and SERPINA1 (PiZ)] were detected by polymerase chain reaction (PCR), bidirectional PCR allele-specific amplification, restriction fragment length polymorphism analysis, and sequencing. The viral genotype was detected in 80 of the 86 patients. Viral genotypes 1, 2, and 3 were present in 61 (76%), 7 (9%), and 12 (15%) patients, respectively. Among all 86 patients, 50 (58%) reached an early viral response and 70 (81%) reached a sustained viral response. All 16 patients who did not reach a sustained viral response had viral genotype 1. Case-control analysis revealed a statistically significant difference in only the H1069Q mutation between patients and controls (patients, 0.057; controls, 0.012; odds ratio, 5.514; 95%CI: 1.119-29.827, P = 0.022). However, the H1069Q mutation was not associated with antiviral treatment outcomes or biochemical indices. The (TA) 7 mutation of the UGT1A1 gene was associated with decreased ferritin levels (beta regression coefficient = -295.7, P = 0.0087). Genetic mutations that cause inherited liver diseases in patients with hepatitis C should be studied in detail.

  9. Non-coding keratin variants associate with liver fibrosis progression in patients with hemochromatosis.

    Directory of Open Access Journals (Sweden)

    Pavel Strnad

    Full Text Available BACKGROUND: Keratins 8 and 18 (K8/K18 are intermediate filament proteins that protect the liver from various forms of injury. Exonic K8/K18 variants associate with adverse outcome in acute liver failure and with liver fibrosis progression in patients with chronic hepatitis C infection or primary biliary cirrhosis. Given the association of K8/K18 variants with end-stage liver disease and progression in several chronic liver disorders, we studied the importance of keratin variants in patients with hemochromatosis. METHODS: The entire K8/K18 exonic regions were analyzed in 162 hemochromatosis patients carrying homozygous C282Y HFE (hemochromatosis gene mutations. 234 liver-healthy subjects were used as controls. Exonic regions were PCR-amplified and analyzed using denaturing high-performance liquid chromatography and DNA sequencing. Previously-generated transgenic mice overexpressing K8 G62C were studied for their susceptibility to iron overload. Susceptibility to iron toxicity of primary hepatocytes that express K8 wild-type and G62C was also assessed. RESULTS: We identified amino-acid-altering keratin heterozygous variants in 10 of 162 hemochromatosis patients (6.2% and non-coding heterozygous variants in 6 additional patients (3.7%. Two novel K8 variants (Q169E/R275W were found. K8 R341H was the most common amino-acid altering variant (4 patients, and exclusively associated with an intronic KRT8 IVS7+10delC deletion. Intronic, but not amino-acid-altering variants associated with the development of liver fibrosis. In mice, or ex vivo, the K8 G62C variant did not affect iron-accumulation in response to iron-rich diet or the extent of iron-induced hepatocellular injury. CONCLUSION: In patients with hemochromatosis, intronic but not exonic K8/K18 variants associate with liver fibrosis development.

  10. Bovine NR1I3 gene polymorphisms and its association with feed efficiency traits in Nellore cattle.

    Science.gov (United States)

    Alexandre, Pâmela A; Gomes, Rodrigo C; Santana, Miguel H A; Silva, Saulo L; Leme, Paulo R; Mudadu, Maurício A; Regitano, Luciana C A; Meirelles, Flávio V; Ferraz, José B S; Fukumasu, Heidge

    2014-12-01

    The Nuclear receptor 1 family I member 3 (NR1I3), also known as the Constitutive Androstane Receptor (CAR), was initially characterized as a key regulator of xenobiotic metabolism. However, recent biochemical and structural data suggest that NR1I3 is activated in response to metabolic and nutritional stress in a ligand-independent manner. Thus, we prospected the Bovine NR1I3 gene for polymorphisms and studied their association with feed efficiency traits in Nellore cattle. First, 155 purebred Nellore bulls were individually measured for Residual Feed Intake (RFI) and the 25 best (High Feed Efficiency group, HFE) and the 25 worst animals (Low Feed Efficiency group, LFE) were selected for DNA extraction. The entire Bovine NR1I3 gene was amplified and polymorphisms were identified by sequencing. Then, one SNP different between HFE and LFE groups was genotyped in all the 155 animals and in another 288 animals totalizing 443 Nellore bulls genotyped for association of NR1I3 SNPs with feed efficiency traits. We found 24 SNPs in the NR1I3 gene and choose a statistically different SNP between HFE and LFE groups for further analysis. Genotyping of the 155 animals showed a significant association within SNP and RFI (p = 0.04), Residual Intake and BW Gain (p = 0.04) and Dry Matter Intake (p = 0.01). This SNP is located in the 5'flanking promoter region of NR1I3 gene and different alleles alter the binding site for predicted transcriptional factors as HNF4alpha, CREM and c-MYB, leading us to conclude that NR1I3 expression and regulation might be important to feed efficiency.

  11. Bovine NR1I3 gene polymorphisms and its association with feed efficiency traits in Nellore cattle

    Science.gov (United States)

    Alexandre, Pâmela A.; Gomes, Rodrigo C.; Santana, Miguel H.A.; Silva, Saulo L.; Leme, Paulo R.; Mudadu, Maurício A.; Regitano, Luciana C.A.; Meirelles, Flávio V.; Ferraz, José B.S.; Fukumasu, Heidge

    2014-01-01

    Abstract The Nuclear receptor 1 family I member 3 (NR1I3), also known as the Constitutive Androstane Receptor (CAR), was initially characterized as a key regulator of xenobiotic metabolism. However, recent biochemical and structural data suggest that NR1I3 is activated in response to metabolic and nutritional stress in a ligand-independent manner. Thus, we prospected the Bovine NR1I3 gene for polymorphisms and studied their association with feed efficiency traits in Nellore cattle. First, 155 purebred Nellore bulls were individually measured for Residual Feed Intake (RFI) and the 25 best (High Feed Efficiency group, HFE) and the 25 worst animals (Low Feed Efficiency group, LFE) were selected for DNA extraction. The entire Bovine NR1I3 gene was amplified and polymorphisms were identified by sequencing. Then, one SNP different between HFE and LFE groups was genotyped in all the 155 animals and in another 288 animals totalizing 443 Nellore bulls genotyped for association of NR1I3 SNPs with feed efficiency traits. We found 24 SNPs in the NR1I3 gene and choose a statistically different SNP between HFE and LFE groups for further analysis. Genotyping of the 155 animals showed a significant association within SNP and RFI (p = 0.04), Residual Intake and BW Gain (p = 0.04) and Dry Matter Intake (p = 0.01). This SNP is located in the 5′flanking promoter region of NR1I3 gene and different alleles alter the binding site for predicted transcriptional factors as HNF4alpha, CREM and c-MYB, leading us to conclude that NR1I3 expression and regulation might be important to feed efficiency. PMID:25606404

  12. HFE-associated hereditary hemochromatosis

    NARCIS (Netherlands)

    Eijkelkamp, EJ; Yapp, TR; Powell, LW

    Hereditary hemochromatosis is a common inherited disorder of the iron metabolism Screening studies indicate that it has a prevalence of one in 200 to 400, depending on the population studied, and a carrier rate of about one in seven to one in 10. Feder et al identified the hereditary hemochromatosis

  13. Population Screening for Hereditary Haemochromatosis in Australia: Construction and Validation of a State-Transition Cost-Effectiveness Model.

    Science.gov (United States)

    de Graaff, Barbara; Si, Lei; Neil, Amanda L; Yee, Kwang Chien; Sanderson, Kristy; Gurrin, Lyle C; Palmer, Andrew J

    2017-03-01

    HFE-associated haemochromatosis, the most common monogenic disorder amongst populations of northern European ancestry, is characterised by iron overload. Excess iron is stored in parenchymal tissues, leading to morbidity and mortality. Population screening programmes are likely to improve early diagnosis, thereby decreasing associated disease. Our aim was to develop and validate a health economics model of screening using utilities and costs from a haemochromatosis cohort. A state-transition model was developed with Markov states based on disease severity. Australian males (aged 30 years) and females (aged 45 years) of northern European ancestry were the target populations. The screening strategy was the status quo approach in Australia; the model was run over a lifetime horizon. Costs were estimated from the government perspective and reported in 2015 Australian dollars ($A); costs and quality-adjusted life-years (QALYs) were discounted at 5% annually. Model validity was assessed using goodness-of-fit analyses. Second-order Monte-Carlo simulation was used to account for uncertainty in multiple parameters. For validity, the model reproduced mortality, life expectancy (LE) and prevalence rates in line with published data. LE for C282Y homozygote males and females were 49.9 and 40.2 years, respectively, slightly lower than population rates. Mean (95% confidence interval) QALYS were 15.7 (7.7-23.7) for males and 14.4 (6.7-22.1) for females. Mean discounted lifetime costs for C282Y homozygotes were $A22,737 (3670-85,793) for males and $A13,840 (1335-67,377) for females. Sensitivity analyses revealed discount rates and prevalence had the greatest impacts on outcomes. We have developed a transparent, validated health economics model of C282Y homozygote haemochromatosis. The model will be useful to decision makers to identify cost-effective screening strategies.

  14. Associations among Behavior-Related Susceptibility Factors in Porphyria Cutanea Tarda

    Science.gov (United States)

    Jalil, Sajid; Grady, James J.; Lee, Chul; Anderson, Karl E.

    2009-01-01

    Background & Aims Porphyria cutanea tarda (PCT) is the most common of the human porphyrias and results from an acquired deficiency of hepatic uroporphyrinogen decarboxylase (UROD). Some susceptibility factors have been identified; we examined associations among multiple factors in a large cohort of patients. Methods Multiple known or suspected susceptibility factors and demographic and clinical features of 143 patients (mean age 52 years, 66% male, 88% Caucasian) with documented PCT (mean onset at 41±8.8 yrs) were tabulated; associations were examined by contingency tables, classification and regression tree (CART) analysis and logistic regression. Results The most common susceptibility factors for PCT were ethanol use (87%), smoking (81%), chronic hepatitis C virus (HCV) infection (69%), and HFE mutations (53%; 6% C282Y/C282Y and 8% C282Y/H63D). Of those who underwent hepatic biopsy or ultrasound, 56% had evidence of hepatic steatosis. Of those with PCT, 66% of females took estrogen, 8% were diabetic, 13% had human immunodeficiency virus (HIV) infection, and 17% had inherited uroporphyrinogen decarboxylase (UROD) deficiency (determined by low erythrocyte UROD activity). HCV infection in patients with PCT was significantly associated with other behavior-related factors such as ethanol use (odds ratio [OR] 6.3) and smoking (OR 11.9). Conclusions Susceptibility factors for PCT were similar to previous studies; most patients had 3 or more. Associations between PCT and HCV, ethanol or smoking could be accounted for by a history of multiple substance abuse; other factors are distributed more randomly amongpatients. PMID:19948245

  15. Highly sensitivity adhesion molecules detection in hereditary haemochromatosis patients reveals altered expression.

    LENUS (Irish Health Repository)

    Norris, S

    2012-02-01

    Several abnormalities in the immune status of patients with hereditary haemochromatosis (HH) have been reported, suggesting an imbalance in their immune function. This may include persistent production of, or exposure to, altered immune signalling contributing to the pathogenesis of this disorder. Adhesion molecules L-, E- and P-Selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) are some of the major regulators of the immune processes and altered levels of these proteins have been found in pathological states including cardiovascular diseases, arthritis and liver cancer. The aim of this study was to assess L-, E- and P-Selectin, ICAM-1 and VCAM-1 expression in patients with HH and correlate these results with HFE mutation status and iron indexes. A total of 139 subjects were diagnosed with HH (C282Y homozygotes = 87, C282Y\\/H63D = 26 heterozygotes, H63D homozygotes = 26), 27 healthy control subjects with no HFE mutation (N\\/N), 18 normal subjects heterozygous for the H63D mutation served as age-sex-matched controls. We observed a significant decrease in L-selectin (P = 0.0002) and increased E-selectin and ICAM-1 (P = 0.0006 and P = 0.0059) expression in HH patients compared with healthy controls. This study observes for the first time that an altered adhesion molecules profile occurs in patients with HH that is associated with specific HFE genetic component for iron overload, suggesting that differential expression of adhesion molecules may play a role in the pathogenesis of HH.

  16. Complex gene-chemical interactions: hepatic uroporphyria as a paradigm.

    Science.gov (United States)

    Smith, Andrew G; Elder, George H

    2010-04-19

    Many toxicological disorders, in common with numerous human diseases, are probably the consequence of multigene interactions with a variety of chemical and physiological factors. The importance of genetic factors may not be obvious initially from association studies because of their complexity and variable penetrance. The human disease, porphyria cutanea tarda (PCT), is a skin disease caused by the photosensitizing action of porphyrins arising secondary to the decreased activity of an enzyme of heme biosynthesis, uroporphyrinogen decarboxylase (UROD), in the liver. It is triggered by idiosyncratic hepatic interaction between genetic factors and chemicals such as alcohol, estrogenic drugs, and polyhalogenated aromatics. PCT and its animal models are known collectively as the hepatic uroporphyrias. There is strong evidence for the participation of iron in the pathogenesis of these conditions. Mouse models have been used to explore the relative importance of a variety of agents such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), alcohol, and iron in the development of uroporphyria and to elucidate the mechanism of the depression of hepatic UROD activity. Mutations of the UROD and hemochromatosis (HFE) genes are genetic factors in some PCT patients which can be mimicked in mice heterozygous for the Hfe and Urod null genes. Association studies of uroporphyria induced by TCDD or hexachlorobenzene with DNA markers in mouse intercrosses have shown the participation of other, unknown, genetic factors in addition to the strong influence of the Ahr gene. The pathogenesis of hepatic uroporphyrias exemplifies the complexity of the interactions between chemical and genetic factors that can contribute to the hepatotoxicity of chemicals.

  17. Blood lead levels, iron metabolism gene polymorphisms and homocysteine: a gene-environment interaction study.

    Science.gov (United States)

    Kim, Kyoung-Nam; Lee, Mee-Ri; Lim, Youn-Hee; Hong, Yun-Chul

    2017-12-01

    Homocysteine has been causally associated with various adverse health outcomes. Evidence supporting the relationship between lead and homocysteine levels has been accumulating, but most prior studies have not focused on the interaction with genetic polymorphisms. From a community-based prospective cohort, we analysed 386 participants (aged 41-71 years) with information regarding blood lead and plasma homocysteine levels. Blood lead levels were measured between 2001 and 2003, and plasma homocysteine levels were measured in 2007. Interactions of lead levels with 42 genotyped single-nucleotide polymorphisms (SNPs) in five genes ( TF , HFE , CBS , BHMT and MTR ) were assessed via a 2-degree of freedom (df) joint test and a 1-df interaction test. In secondary analyses using imputation, we further assessed 58 imputed SNPs in the TF and MTHFR genes. Blood lead concentrations were positively associated with plasma homocysteine levels (p=0.0276). Six SNPs in the TF and MTR genes were screened using the 2-df joint test, and among them, three SNPs in the TF gene showed interactions with lead with respect to homocysteine levels through the 1-df interaction test (plead levels. Blood lead levels were positively associated with plasma homocysteine levels measured 4-6 years later, and three SNPs in the TF gene modified the association. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  18. A rapid PCR-SSP assay for the hemochromatosis-associated Tyr250Stop mutation in the TFR2 gene.

    Science.gov (United States)

    Rivers, C A; Barton, J C; Acton, R T

    2001-01-01

    Several genes associated with hemochromatosis and primary iron overload have been identified. Mutations in the HFE gene have been detected in 60-100% of hemochromatosis patients of northern, central, and western European descent, although the frequencies of these mutations vary among racial and ethnic groups. Recently, a mutation in the gene encoding transferrin receptor-2 (exon 6, nucleotide 750 C --> G; Y250X) was detected by a PCR-restriction fragment length polymorphism (RFLP) method in Sicilians with hemochromatosis. We describe a modification of the original assay in which the sequence-specific priming PCR assay does not require the use of restriction endonuclease. The modified assay is robust and cost-efficient, and may be more useful for large-scale population studies because it can be performed rapidly on DNA extracted from buccal swabs.

  19. Hepcidin is decreased in TFR2 hemochromatosis.

    Science.gov (United States)

    Nemeth, Elizabeta; Roetto, Antonella; Garozzo, Giovanni; Ganz, Tomas; Camaschella, Clara

    2005-02-15

    The hepatic peptide hepcidin is the key regulator of iron metabolism in mammals. Recent evidence indicates that certain forms of hereditary hemochromatosis are caused by hepcidin deficiency. Juvenile hemochromatosis is associated with hepcidin or hemojuvelin mutations, and these patients have low or absent urinary hepcidin. Patients with C282Y HFE hemochromatosis also have inappropriately low hepcidin levels for the degree of iron loading. The relationship between the hemochromatosis due to transferrin receptor 2 (TFR2) mutations and hepcidin was unknown. We measured urinary hepcidin levels in 10 patients homozygous for TFR2 mutations, all with increased transferrin saturation. Urinary hepcidin was low or undetectable in 8 of 10 cases irrespective of the previous phlebotomy treatments. The only 2 cases with normal hepcidin values had concomitant inflammatory conditions. Our data indicate that TFR2 is a modulator of hepcidin production in response to iron.

  20. Genes and Gene Therapy

    Science.gov (United States)

    ... correctly, a child can have a genetic disorder. Gene therapy is an experimental technique that uses genes to ... or prevent disease. The most common form of gene therapy involves inserting a normal gene to replace an ...

  1. Haemochromatosis genotype and iron overload: association with hypertension and left ventricular hypertrophy

    DEFF Research Database (Denmark)

    Ellervik, C; Tybjaerg-Hansen, A; Appleyard, M

    2010-01-01

    We hypothesized that there is an association between haemochromatosis genotype C282Y/C282Y and/or iron overload and risk of hypertension and/or left ventricular hypertrophy (LVH).......We hypothesized that there is an association between haemochromatosis genotype C282Y/C282Y and/or iron overload and risk of hypertension and/or left ventricular hypertrophy (LVH)....

  2. Gender and iron genes may modify associations between brain iron and memory in healthy aging.

    Science.gov (United States)

    Bartzokis, George; Lu, Po H; Tingus, Kathleen; Peters, Douglas G; Amar, Chetan P; Tishler, Todd A; Finn, J Paul; Villablanca, Pablo; Altshuler, Lori L; Mintz, Jim; Neely, Elizabeth; Connor, James R

    2011-06-01

    Brain iron increases with age and is abnormally elevated early in the disease process in several neurodegenerative disorders that impact memory including Alzheimer's disease (AD). Higher brain iron levels are associated with male gender and presence of highly prevalent allelic variants in genes encoding for iron metabolism proteins (hemochromatosis H63D (HFE H63D) and transferrin C2 (TfC2)). In this study, we examined whether in healthy older individuals memory performance is associated with increased brain iron, and whether gender and gene variant carrier (IRON+) vs noncarrier (IRON-) status (for HFE H63D/TfC2) modify the associations. Tissue iron deposited in ferritin molecules can be measured in vivo with magnetic resonance imaging utilizing the field-dependent relaxation rate increase (FDRI) method. FDRI was assessed in hippocampus, basal ganglia, and white matter, and IRON+ vs IRON- status was determined in a cohort of 63 healthy older individuals. Three cognitive domains were assessed: verbal memory (delayed recall), working memory/attention, and processing speed. Independent of gene status, worse verbal-memory performance was associated with higher hippocampal iron in men (r=-0.50, p=0.003) but not in women. Independent of gender, worse verbal working memory performance was associated with higher basal ganglia iron in IRON- group (r=-0.49, p=0.005) but not in the IRON+ group. Between-group interactions (p=0.006) were noted for both of these associations. No significant associations with white matter or processing speed were observed. The results suggest that in specific subgroups of healthy older individuals, higher accumulations of iron in vulnerable gray matter regions may adversely impact memory functions and could represent a risk factor for accelerated cognitive decline. Combining genetic and MRI biomarkers may provide opportunities to design primary prevention clinical trials that target high-risk groups.

  3. Identification of a common variant in the TFR2 gene implicated in the physiological regulation of serum iron levels.

    Science.gov (United States)

    Pichler, Irene; Minelli, Cosetta; Sanna, Serena; Tanaka, Toshiko; Schwienbacher, Christine; Naitza, Silvia; Porcu, Eleonora; Pattaro, Cristian; Busonero, Fabio; Zanon, Alessandra; Maschio, Andrea; Melville, Scott A; Grazia Piras, Maria; Longo, Dan L; Guralnik, Jack; Hernandez, Dena; Bandinelli, Stefania; Aigner, Elmar; Murphy, Anthony T; Wroblewski, Victor; Marroni, Fabio; Theurl, Igor; Gnewuch, Carsten; Schadt, Eric; Mitterer, Manfred; Schlessinger, David; Ferrucci, Luigi; Witcher, Derrick R; Hicks, Andrew A; Weiss, Günter; Uda, Manuela; Pramstaller, Peter P

    2011-03-15

    The genetic determinants of variation in iron status are actively sought, but remain incompletely understood. Meta-analysis of two genome-wide association (GWA) studies and replication in three independent cohorts was performed to identify genetic loci associated in the general population with serum levels of iron and markers of iron status, including transferrin, ferritin, soluble transferrin receptor (sTfR) and sTfR-ferritin index. We identified and replicated a novel association of a common variant in the type-2 transferrin receptor (TFR2) gene with iron levels, with effect sizes highly consistent across samples. In addition, we identified and replicated an association between the HFE locus and ferritin and confirmed previously reported associations with the TF, TMPRSS6 and HFE genes. The five replicated variants were tested for association with expression levels of the corresponding genes in a publicly available data set of human liver samples, and nominally statistically significant expression differences by genotype were observed for all genes, although only rs3811647 in the TF gene survived the Bonferroni correction for multiple testing. In addition, we measured for the first time the effects of the common variant in TMPRSS6, rs4820268, on hepcidin mRNA in peripheral blood (n = 83 individuals) and on hepcidin levels in urine (n = 529) and observed an association in the same direction, though only borderline significant. These functional findings require confirmation in further studies with larger sample sizes, but they suggest that common variants in TMPRSS6 could modify the hepcidin-iron feedback loop in clinically unaffected individuals, thus making them more susceptible to imbalances of iron homeostasis.

  4. Genetics Home Reference: hereditary hemochromatosis

    Science.gov (United States)

    ... several genes, including HAMP , HFE , HFE2 , SLC40A1 , and TFR2 , can cause hereditary hemochromatosis . Type 1 hemochromatosis results ... the HFE2 or HAMP gene. Mutations in the TFR2 gene cause type 3 hemochromatosis, and mutations in ...

  5. Genetic influences on hand osteoarthritis in Finnish women--a replication study of candidate genes.

    Science.gov (United States)

    Hämäläinen, Satu; Solovieva, Svetlana; Vehmas, Tapio; Luoma, Katariina; Leino-Arjas, Päivi; Hirvonen, Ari

    2014-01-01

    Our aims were to replicate some previously reported associations of single nucleotide polymorphisms (SNPs) in five genes (A2BP1, COG5, GDF5, HFE, ESR1) with hand osteoarthritis (OA), and to examine whether genes (BCAP29, DIO2, DUS4L, DVWA, HLA, PTGS2, PARD3B, TGFB1 and TRIB1) associated with OA at other joint sites were associated with hand OA among Finnish women. We examined the bilateral hand radiographs of 542 occupationally active Finnish female dentists and teachers aged 45 to 63 and classified them according to the presence of OA by using reference images. Data regarding finger joint pain and other risk factors were collected using a questionnaire. We defined two hand OA phenotypes: radiographic OA in at least three joints (ROA) and symptomatic DIP OA. The genotypes were determined by PCR-based methods. In statistical analysis, we used SNPStats software, the chi-square test and logistic regression. Of the SNPs, rs716508 in A2BP1 was associated with ROA (OR = 0.7, 95% CI 0.5-0.9) and rs1800470 in TGFB1 with symptomatic DIP OA (1.8, 1.2-2.9). We found an interaction between ESR1 (rs9340799) and occupation: teachers with the minor allele were at an increased risk of symptomatic DIP OA (2.8, 1.3-6.5). We saw no association among the dentists. We also found that the carriage of the COG5 rs3757713 C allele increased the risk of ROA only among women with the BCAP29 rs10953541 CC genotype (2.6; 1.1-6.1). There was also a suggestive interaction between the HFE rs179945 and the ESR1 rs9340799, and the carriage of the minor allele of either of these SNPs was associated with an increased risk of symptomatic DIP OA (2.1, 1.3-2.5). Our results support the earlier findings of A2BP1 and TBGF1 being OA susceptibility genes and provide evidence of a possible gene-gene interaction in the genetic influence on hand OA predisposition.

  6. Genetic influences on hand osteoarthritis in Finnish women--a replication study of candidate genes.

    Directory of Open Access Journals (Sweden)

    Satu Hämäläinen

    Full Text Available OBJECTIVES: Our aims were to replicate some previously reported associations of single nucleotide polymorphisms (SNPs in five genes (A2BP1, COG5, GDF5, HFE, ESR1 with hand osteoarthritis (OA, and to examine whether genes (BCAP29, DIO2, DUS4L, DVWA, HLA, PTGS2, PARD3B, TGFB1 and TRIB1 associated with OA at other joint sites were associated with hand OA among Finnish women. DESIGN: We examined the bilateral hand radiographs of 542 occupationally active Finnish female dentists and teachers aged 45 to 63 and classified them according to the presence of OA by using reference images. Data regarding finger joint pain and other risk factors were collected using a questionnaire. We defined two hand OA phenotypes: radiographic OA in at least three joints (ROA and symptomatic DIP OA. The genotypes were determined by PCR-based methods. In statistical analysis, we used SNPStats software, the chi-square test and logistic regression. RESULTS: Of the SNPs, rs716508 in A2BP1 was associated with ROA (OR = 0.7, 95% CI 0.5-0.9 and rs1800470 in TGFB1 with symptomatic DIP OA (1.8, 1.2-2.9. We found an interaction between ESR1 (rs9340799 and occupation: teachers with the minor allele were at an increased risk of symptomatic DIP OA (2.8, 1.3-6.5. We saw no association among the dentists. We also found that the carriage of the COG5 rs3757713 C allele increased the risk of ROA only among women with the BCAP29 rs10953541 CC genotype (2.6; 1.1-6.1. There was also a suggestive interaction between the HFE rs179945 and the ESR1 rs9340799, and the carriage of the minor allele of either of these SNPs was associated with an increased risk of symptomatic DIP OA (2.1, 1.3-2.5. CONCLUSIONS: Our results support the earlier findings of A2BP1 and TBGF1 being OA susceptibility genes and provide evidence of a possible gene-gene interaction in the genetic influence on hand OA predisposition.

  7. Gene Therapy

    Science.gov (United States)

    Gene therapy Overview Gene therapy involves altering the genes inside your body's cells in an effort to treat or stop disease. Genes contain your ... that don't work properly can cause disease. Gene therapy replaces a faulty gene or adds a new ...

  8. Atmospheric chemistry of HFE-7000 (CF(3)CF (2)CF (2)OCH (3)) and 2,2,3,3,4,4,4-heptafluoro-1-butanol (CF (3)CF (2)CF (2)CH (2)OH): kinetic rate coefficients and temperature dependence of reactions with chlorine atoms.

    Science.gov (United States)

    Díaz-de-Mera, Yolanda; Aranda, Alfonso; Bravo, Iván; Rodríguez, Diana; Rodríguez, Ana; Moreno, Elena

    2008-10-01

    The adverse environmental impacts of chlorinated hydrocarbons on the Earth's ozone layer have focused attention on the effort to replace these compounds by nonchlorinated substitutes with environmental acceptability. Hydrofluoroethers (HFEs) and fluorinated alcohols are currently being introduced in many applications for this purpose. Nevertheless, the presence of a great number of C-F bonds drives to atmospheric long-lived compounds with infrared absorption features. Thus, it is necessary to improve our knowledge about lifetimes and global warming potentials (GWP) for these compounds in order to get a complete evaluation of their environmental impact. Tropospheric degradation is expected to be initiated mainly by OH reactions in the gas phase. Nevertheless, Cl atoms reaction may also be important since rate constants are generally larger than those of OH. In the present work, we report the results obtained in the study of the reactions of Cl radicals with HFE-7000 (CF(3)CF(2)CF(2)OCH(3)) (1) and its isomer CF(3)CF(2)CF(2)CH(2)OH (2). Kinetic rate coefficients with Cl atoms have been measured using the discharge flow tube-mass spectrometric technique at 1 Torr of total pressure. The reactions of these chlorofluorocarbons (CFCs) substitutes have been studied under pseudo-first-order kinetic conditions in excess of the fluorinated compounds over Cl atoms. The temperature ranges were 266-333 and 298-353 K for reactions of HFE-7000 and CF(3)CF(2)CF(2)CH(2)OH, respectively. The measured room temperature rate constants were k(Cl+CF(3)CF(2)CF(2)OCH(3)) = (1.24 +/- 0.28) x 10(-13) cm(3) molecule(-1) s(-1)and k(Cl+CF(3)CF(2)CF(2)CH(2)OH) = (8.35 +/- 1.63) x 10(-13) cm(3) molecule(-1) s(-1) (errors are 2sigma + 10% to cover systematic errors). The Arrhenius expression for reaction 1 was k (1)(266-333 K) = (6.1 +/- 3.8) x 10(-13)exp[-(445 +/- 186)/T] cm(3) molecule(-1) s(-1) and k (2)(298-353 K) = (1.9 +/- 0.7) x 10(-12)exp[-(244 +/- 125)/T] cm(3) molecule(-1) s(-1) (errors

  9. No Association between Variation in Longevity Candidate Genes and Aging-related Phenotypes in Oldest-old Danes

    Science.gov (United States)

    Soerensen, Mette; Nygaard, Marianne; Debrabant, Birgit; Mengel-From, Jonas; Dato, Serena; Thinggaard, Mikael; Christensen, Kaare; Christiansen, Lene

    2016-01-01

    In this study we explored the association between aging-related phenotypes previously reported to predict survival in old age and variation in 77 genes from the DNA repair pathway, 32 genes from the growth hormone 1/insulin-like growth factor 1/insulin (GH/IGF-1/INS) signalling pathway and 16 additional genes repeatedly considered as candidates for human longevity: APOE, APOA4, APOC3, ACE, CETP, HFE, IL6, IL6R, MTHFR, TGFB1, SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. Altogether, 1,049 single nucleotide polymorphisms (SNPs) were genotyped in 1,088 oldest-old (age 92–93 years) Danes and analysed with phenotype data on physical functioning (hand grip strength), cognitive functioning (mini mental state examination and a cognitive composite score), activity of daily living and self-rated health. Five SNPs showed association to one of the phenotypes; however, none of these SNPs were associated with a change in the relevant phenotype over time (7 years of follow-up) and none of the SNPs could be confirmed in a replication sample of 1,281 oldest-old Danes (age 94–100). Hence, our study does not support association between common variation in the investigated longevity candidate genes and aging-related phenotypes consistently shown to predict survival. It is possible that larger sample sizes are needed to robustly reveal associations with small effect sizes. PMID:26946122

  10. gene structure, gene expression

    Indian Academy of Sciences (India)

    Primer 5.0 software. To adjust for RNA quality and diffe- rences in cDNA concentration, we amplified actin as an internal control with the following primers: PtActin-F (5′-TG. AAGGAGAAACTTGCGTAT-3′) and PtActin-R (5′-GCA. CAATGTTACCGTACAGAT-3′). These genes were ampli- fied from first-strand cDNA using ...

  11. Gene Locater

    DEFF Research Database (Denmark)

    Anwar, Muhammad Zohaib; Sehar, Anoosha; Rehman, Inayat-Ur

    2012-01-01

    UNLABELLED: Locating genes on a chromosome is important for understanding the gene function and its linkage and recombination. Knowledge of gene positions on chromosomes is necessary for annotation. The study is essential for disease genetics and genomics, among other aspects. Currently available...... software's for calculating recombination frequency is mostly limited to the range and flexibility of this type of analysis. GENE LOCATER is a fully customizable program for calculating recombination frequency, written in JAVA. Through an easy-to-use interface, GENE LOCATOR allows users a high degree...

  12. Trichoderma genes

    Science.gov (United States)

    Foreman, Pamela [Los Altos, CA; Goedegebuur, Frits [Vlaardingen, NL; Van Solingen, Pieter [Naaldwijk, NL; Ward, Michael [San Francisco, CA

    2012-06-19

    Described herein are novel gene sequences isolated from Trichoderma reesei. Two genes encoding proteins comprising a cellulose binding domain, one encoding an arabionfuranosidase and one encoding an acetylxylanesterase are described. The sequences, CIP1 and CIP2, contain a cellulose binding domain. These proteins are especially useful in the textile and detergent industry and in pulp and paper industry.

  13. Gene Therapy

    Science.gov (United States)

    ... or improve your body's ability to fight disease. Gene therapy holds promise for treating a wide range of diseases, such as cancer, cystic fibrosis, heart disease, diabetes, hemophilia and AIDS. Researchers are still studying how and ...

  14. Absorption of manganese and iron in a mouse model of hemochromatosis.

    Directory of Open Access Journals (Sweden)

    Jonghan Kim

    Full Text Available Hereditary hemochromatosis, an iron overload disease associated with excessive intestinal iron absorption, is commonly caused by loss of HFE gene function. Both iron and manganese absorption are regulated by iron status, but the relationships between the transport pathways of these metals and how they are affected by HFE-associated hemochromatosis remain poorly understood. Loss of HFE function is known to alter the intestinal expression of DMT1 (divalent metal transporter-1 and Fpn (ferroportin, transporters that have been implicated in absorption of both iron and manganese. Although the influence of HFE deficiency on dietary iron absorption has been characterized, potential effects on manganese metabolism have yet to be explored. To investigate the role of HFE in manganese absorption, we characterized the uptake and distribution of the metal in Hfe (-/- knockout mice after intravenous, intragastric, and intranasal administration of (54Mn. These values were compared to intravenous and intragastric administration of (59Fe. Intestinal absorption of (59Fe was increased and clearance of injected (59Fe was also increased in Hfe(-/- mice compared to controls. Hfe (-/- mice displayed greater intestinal absorption of (54Mn compared to wild-type Hfe(+/+ control mice. After intravenous injection, the distribution of (59Fe to heart and liver was greater in Hfe (-/- mice but no remarkable differences were observed for (54Mn. Although olfactory absorption of (54Mn into blood was unchanged in Hfe (-/- mice, higher levels of intranasally-instilled (54Mn were associated with Hfe(-/- brain compared to controls. These results show that manganese transport and metabolism can be modified by HFE deficiency.

  15. Towards A Unified HFE Process For The Nuclear Industry

    Energy Technology Data Exchange (ETDEWEB)

    Jacques Hugo

    2012-07-01

    As nuclear power utilities embark on projects to upgrade and modernize power plants, they are likely to discover that traditional engineering methods do not typically make provision for the integration of human considerations. In addition, human factors professionals will find that traditional human performance methods such as function allocation, task analysis, human reliability analysis and human-machine interface design do not scale well to the complexity of a large-scale nuclear power upgrade project. Up-to-date human factors engineering processes, methods, techniques and tools are required to perform these kinds of analyses. This need is recognized widely in industry and an important part of the Department of Energy’s Light Water Reactor Sustainability Program deals with identifying potential impacts of emerging technologies on human performance and the technical bases needed to address them. However, so far no formal initiative has been launched to deal with the lack of integrated processes. Although human factors integration frameworks do exist in industries such as aviation or defense, no formal integrated human factors process exists in the nuclear industry. As a first step towards creating such a process, a “unified human factors engineering process” is proposed as a framework within which engineering organizations, human factors practitioners and regulatory bodies can ensure that human factors requirements are embedded in engineering activities throughout the upgrade project life cycle.

  16. Intragenic haplotype analysis of common HFE mutations in the ...

    Indian Academy of Sciences (India)

    CHUC), 3000 Coimbra, Portugal. [Toste S., Relvas L., Pinto .... Restriction. Digestion. SNP ID. Ta (◦C) sequence product (bp) enzyme product (bp) Reference rs1800702. 54. 5′-GATCCTTTAACCGAGGAGAT-3′. 567. BbvI. G: 511, 56. Rochette.

  17. Human Factors Evaluation Automated Tool (HFE-AT) Project

    Data.gov (United States)

    National Aeronautics and Space Administration — In this proposal, TiER1 Performance Solutions and Alion Science and Technology offer to identify requirements and specifications, and implement a proof-of-concept...

  18. HFE (Human Factors Engineering) Technology for Navy Weapon System Acquisition.

    Science.gov (United States)

    1979-07-01

    The above techniques are based in part on the manual Linear Programming technique reported by Freud and Sadosky (1967). The manual approach uses...components. The program determines the execution time of each task (visual, motor transitions), ana performance reliability (product of reliabilities for...effectiveness evaluation data * Analyze and revise system - Field job performance data - Instructional system re- vision. 3-99 -. - ANA "" A technique

  19. Association analysis of nine candidate gene polymorphisms in Indian patients with type 2 diabetic retinopathy

    Directory of Open Access Journals (Sweden)

    Govindarajan Gowthaman

    2010-11-01

    Full Text Available Abstract Background Diabetic retinopathy (DR is classically defined as a microvasculopathy that primarily affects the small blood vessels of the inner retina as a complication of diabetes mellitus (DM.It is a multifactorial disease with a strong genetic component. The aim of this study is to investigate the association of a set of nine candidate genes with the development of diabetic retinopathy in a South Indian cohort who have type 2 diabetes mellitus (T2DM. Methods Seven candidate genes (RAGE, PEDF, AKR1B1, EPO, HTRA1, ICAM and HFE were chosen based on reported association with DR in the literature. Two more, CFH and ARMS2, were chosen based on their roles in biological pathways previously implicated in DR. Fourteen single nucleotide polymorphisms (SNPs and one dinucleotide repeat polymorphism, previously reported to show association with DR or other related diseases, were genotyped in 345 DR and 356 diabetic patients without retinopathy (DNR. The genes which showed positive association in this screening set were tested further in additional sets of 100 DR and 90 DNR additional patients from the Aravind Eye Hospital. Those which showed association in the secondary screen were subjected to a combined analysis with the 100 DR and 100 DNR subjects previously recruited and genotyped through the Sankara Nethralaya Hospital, India. Genotypes were evaluated using a combination of direct sequencing, TaqMan SNP genotyping, RFLP analysis, and SNaPshot PCR assays. Chi-square and Fisher exact tests were used to analyze the genotype and allele frequencies. Results Among the nine loci (15 polymorphisms screened, SNP rs2070600 (G82S in the RAGE gene, showed significant association with DR (allelic P = 0.016, dominant model P = 0.012, compared to DNR. SNP rs2070600 further showed significant association with DR in the confirmation cohort (P = 0.035, dominant model P = 0.032. Combining the two cohorts gave an allelic P HTRA1, rs11200638 (G>A, showed marginal

  20. Gene Ontology

    Directory of Open Access Journals (Sweden)

    Gaston K. Mazandu

    2012-01-01

    Full Text Available The wide coverage and biological relevance of the Gene Ontology (GO, confirmed through its successful use in protein function prediction, have led to the growth in its popularity. In order to exploit the extent of biological knowledge that GO offers in describing genes or groups of genes, there is a need for an efficient, scalable similarity measure for GO terms and GO-annotated proteins. While several GO similarity measures exist, none adequately addresses all issues surrounding the design and usage of the ontology. We introduce a new metric for measuring the distance between two GO terms using the intrinsic topology of the GO-DAG, thus enabling the measurement of functional similarities between proteins based on their GO annotations. We assess the performance of this metric using a ROC analysis on human protein-protein interaction datasets and correlation coefficient analysis on the selected set of protein pairs from the CESSM online tool. This metric achieves good performance compared to the existing annotation-based GO measures. We used this new metric to assess functional similarity between orthologues, and show that it is effective at determining whether orthologues are annotated with similar functions and identifying cases where annotation is inconsistent between orthologues.

  1. Sepsis and siderosis, Yersinia enterocolitica and hereditary haemochromatosis.

    Science.gov (United States)

    Thwaites, Phoebe A; Woods, Marion L

    2017-01-04

    A 60-year-old woman was admitted with sepsis, relative bradycardia, CT evidence of numerous small liver abscesses and 'skin bronzing' consistent with hereditary haemochromatosis (HH). Yersinia enterocolitica O:9 infection was confirmed by serology specimens taken 10 days apart. Iron overload was detected, and homozygous C282Y gene mutation confirmed HH. Liver biopsy revealed grade IV siderosis with micronodular cirrhosis. Haemochromatosis is a common, inherited disorder leading to iron overload that can produce end-organ damage from excess iron deposition. Haemochromatosis diagnosis allowed aggressive medical management with phlebotomy achieving normalisation of iron stores. Screening for complications of cirrhosis was started that included hepatoma surveillance. Iron overload states are known to increase patient susceptibility to infections caused by lower virulence bacteria lacking sophisticated iron metabolism pathways, for example, Yersinia enterocolitica Although these serious disseminated infections are rare, they may serve as markers for occult iron overload and should prompt haemochromatosis screening. 2017 BMJ Publishing Group Ltd.

  2. Special Issue: Gene Conversion in Duplicated Genes

    Directory of Open Access Journals (Sweden)

    Hideki Innan

    2011-06-01

    Full Text Available Gene conversion is an outcome of recombination, causing non-reciprocal transfer of a DNA fragment. Several decades later than the discovery of crossing over, gene conversion was first recognized in fungi when non-Mendelian allelic distortion was observed. Gene conversion occurs when a double-strand break is repaired by using homologous sequences in the genome. In meiosis, there is a strong preference to use the orthologous region (allelic gene conversion, which causes non-Mendelian allelic distortion, but paralogous or duplicated regions can also be used for the repair (inter-locus gene conversion, also referred to as non-allelic and ectopic gene conversion. The focus of this special issue is the latter, interlocus gene conversion; the rate is lower than allelic gene conversion but it has more impact on phenotype because more drastic changes in DNA sequence are involved.

  3. Disruption of hemochromatosis protein and transferrin receptor 2 causes iron-induced liver injury in mice.

    Science.gov (United States)

    Delima, Roheeth D; Chua, Anita C G; Tirnitz-Parker, Janina E E; Gan, Eng K; Croft, Kevin D; Graham, Ross M; Olynyk, John K; Trinder, Debbie

    2012-08-01

    Mutations in hemochromatosis protein (HFE) or transferrin receptor 2 (TFR2) cause hereditary hemochromatosis (HH) by impeding production of the liver iron-regulatory hormone, hepcidin (HAMP). This study examined the effects of disruption of Hfe or Tfr2, either alone or together, on liver iron loading and injury in mouse models of HH. Iron status was determined in Hfe knockout (Hfe(-/-)), Tfr2 Y245X mutant (Tfr2(mut)), and double-mutant (Hfe(-/-) ×Tfr2(mut) ) mice by measuring plasma and liver iron levels. Plasma alanine transaminase (ALT) activity, liver histology, and collagen deposition were evaluated to assess liver injury. Hepatic oxidative stress was assessed by measuring superoxide dismutase (SOD) activity and F(2)-isoprostane levels. Gene expression was measured by real-time polymerase chain reaction. Hfe(-/-) ×Tfr2(mut) mice had elevated hepatic iron with a periportal distribution and increased plasma iron, transferrin saturation, and non-transferrin-bound iron, compared with Hfe(-/-), Tfr2(mut), and wild-type (WT) mice. Hamp1 expression was reduced to 40% (Hfe(-/-) and Tfr2(mut) ) and 1% (Hfe(-/-) ×Tfr2(mut)) of WT values. Hfe(-/-) ×Tfr2(mut) mice had elevated plasma ALT activity and mild hepatic inflammation with scattered aggregates of infiltrating inflammatory cluster of differentiation 45 (CD45)-positive cells. Increased hepatic hydoxyproline levels as well as Sirius red and Masson's Trichrome staining demonstrated advanced portal collagen deposition. Hfe(-/-) and Tfr2(mut) mice had less hepatic inflammation and collagen deposition. Liver F(2) -isoprostane levels were elevated, and copper/zinc and manganese SOD activities decreased in Hfe(-/-) ×Tfr2(mut), Tfr2(mut), and Hfe(-/-) mice, compared with WT mice. Disruption of both Hfe and Tfr2 caused more severe hepatic iron overload with more advanced lipid peroxidation, inflammation, and portal fibrosis than was observed with the disruption of either gene alone. The Hfe(-/-) ×Tfr2(mut) mouse model

  4. Essential Bacillus subtilis genes

    DEFF Research Database (Denmark)

    Kobayashi, K.; Ehrlich, S.D.; Albertini, A.

    2003-01-01

    To estimate the minimal gene set required to sustain bacterial life in nutritious conditions, we carried out a systematic inactivation of Bacillus subtilis genes. Among approximate to4,100 genes of the organism, only 192 were shown to be indispensable by this or previous work. Another 79 genes were...

  5. Human Gene Therapy: Genes without Frontiers?

    Science.gov (United States)

    Simon, Eric J.

    2002-01-01

    Describes the latest advancements and setbacks in human gene therapy to provide reference material for biology teachers to use in their science classes. Focuses on basic concepts such as recombinant DNA technology, and provides examples of human gene therapy such as severe combined immunodeficiency syndrome, familial hypercholesterolemia, and…

  6. Apo-Ferritin as a Therapeutic Treatment for Amyotrophic Lateral Sclerosis

    Science.gov (United States)

    2013-12-01

    HFE H67D allelic variant, present in 30% of ALS patients, and the SOD1 G93A mutation , infusion of aCSF with or without H-ferritin is not...associated with the iron-overload disorder hereditary hemochromatosis. In the human population, genetic variations in the 9 HFE gene, particularly H63D...increase the incidence of ALS (21-24); indeed, the reported prevalence of variations in the HFE gene in ALS is higher than that of SOD1 (25) and to date

  7. Genes and Hearing Loss

    Science.gov (United States)

    ... Find an ENT Doctor Near You Genes and Hearing Loss Genes and Hearing Loss Patient Health Information News media interested in ... One of the most common birth defects is hearing loss or deafness (congenital), which can affect as ...

  8. Epigenetics: beyond genes

    CSIR Research Space (South Africa)

    Fossey, A

    2009-06-01

    Full Text Available Gene regulatory processes lead to differential gene expression and are referred to as epigenetic phenomena; these are ubiquitous processes in the biological world. These reversible heritable changes concern DNA and RNA, their interactions...

  9. Polydactyly and genes

    National Research Council Canada - National Science Library

    Phadke, Shubha R; Sankar, V H

    2010-01-01

    .... A lot of information about genes involved in development is available now. Genetics of hand development and genes involved in polydactyly syndromes is discussed in this article as a prototype to know about genetics of malformations...

  10. Evolution of gene expression after gene amplification.

    Science.gov (United States)

    Garcia, Nelson; Zhang, Wei; Wu, Yongrui; Messing, Joachim

    2015-04-24

    We took a rather unique approach to investigate the conservation of gene expression of prolamin storage protein genes across two different subfamilies of the Poaceae. We took advantage of oat plants carrying single maize chromosomes in different cultivars, called oat-maize addition (OMA) lines, which permitted us to determine whether regulation of gene expression was conserved between the two species. We found that γ-zeins are expressed in OMA7.06, which carries maize chromosome 7 even in the absence of the trans-acting maize prolamin-box-binding factor (PBF), which regulates their expression. This is likely because oat PBF can substitute for the function of maize PBF as shown in our transient expression data, using a γ-zein promoter fused to green fluorescent protein (GFP). Despite this conservation, the younger, recently amplified prolamin genes in maize, absent in oat, are not expressed in the corresponding OMAs. However, maize can express the oldest prolamin gene, the wheat high-molecular weight glutenin Dx5 gene, even when maize Pbf is knocked down (through PbfRNAi), and/or another maize transcription factor, Opaque-2 (O2) is knocked out (in maize o2 mutant). Therefore, older genes are conserved in their regulation, whereas younger ones diverged during evolution and eventually acquired a new repertoire of suitable transcriptional activators. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  11. How Genes Evolve

    Indian Academy of Sciences (India)

    evolutionary history of duplicated genes within a given lineage. The timings of gene duplication events can be inferred ... evolutionary history of the creatures in which various globin genes are found, the timings of the ..... But I cannot find heart to give any part of my life for money-making purposes ... : In 1901, one of the large ...

  12. Discovering genes underlying QTL

    Energy Technology Data Exchange (ETDEWEB)

    Vanavichit, Apichart [Kasetsart University, Kamphaengsaen, Nakorn Pathom (Thailand)

    2002-02-01

    A map-based approach has allowed scientists to discover few genes at a time. In addition, the reproductive barrier between cultivated rice and wild relatives has prevented us from utilizing the germ plasm by a map-based approach. Most genetic traits important to agriculture or human diseases are manifested as observable, quantitative phenotypes called Quantitative Trait Loci (QTL). In many instances, the complexity of the phenotype/genotype interaction and the general lack of clearly identifiable gene products render the direct molecular cloning approach ineffective, thus additional strategies like genome mapping are required to identify the QTL in question. Genome mapping requires no prior knowledge of the gene function, but utilizes statistical methods to identify the most likely gene location. To completely characterize genes of interest, the initially mapped region of a gene location will have to be narrowed down to a size that is suitable for cloning and sequencing. Strategies for gene identification within the critical region have to be applied after the sequencing of a potentially large clone or set of clones that contains this gene(s). Tremendous success of positional cloning has been shown for cloning many genes responsible for human diseases, including cystic fibrosis and muscular dystrophy as well as plant disease resistance genes. Genome and QTL mapping, positional cloning: the pre-genomics era, comparative approaches to gene identification, and positional cloning: the genomics era are discussed in the report. (M. Suetake)

  13. Gene therapy in periodontics

    Science.gov (United States)

    Chatterjee, Anirban; Singh, Nidhi; Saluja, Mini

    2013-01-01

    GENES are made of DNA - the code of life. They are made up of two types of base pair from different number of hydrogen bonds AT, GC which can be turned into instruction. Everyone inherits genes from their parents and passes them on in turn to their children. Every person's genes are different, and the changes in sequence determine the inherited differences between each of us. Some changes, usually in a single gene, may cause serious diseases. Gene therapy is ‘the use of genes as medicine’. It involves the transfer of a therapeutic or working gene copy into specific cells of an individual in order to repair a faulty gene copy. Thus it may be used to replace a faulty gene, or to introduce a new gene whose function is to cure or to favorably modify the clinical course of a condition. It has a promising era in the field of periodontics. Gene therapy has been used as a mode of tissue engineering in periodontics. The tissue engineering approach reconstructs the natural target tissue by combining four elements namely: Scaffold, signaling molecules, cells and blood supply and thus can help in the reconstruction of damaged periodontium including cementum, gingival, periodontal ligament and bone. PMID:23869119

  14. Gene therapy: An overview

    Directory of Open Access Journals (Sweden)

    Sudip Indu

    2013-01-01

    Full Text Available Gene therapy "the use of genes as medicine" involves the transfer of a therapeutic or working copy of a gene into specific cells of an individual in order to repair a faulty gene copy. The technique may be used to replace a faulty gene, or to introduce a new gene whose function is to cure or to favorably modify the clinical course of a condition. The objective of gene therapy is to introduce new genetic material into target cells while causing no damage to the surrounding healthy cells and tissues, hence the treatment related morbidity is decreased. The delivery system includes a vector that delivers a therapeutic gene into the patient′s target cell. Functional proteins are created from the therapeutic gene causing the cell to return to a normal stage. The vectors used in gene therapy can be viral and non-viral. Gene therapy, an emerging field of biomedicine, is still at infancy and much research remains to be done before this approach to the treatment of condition will realize its full potential.

  15. Modelling prokaryote gene content

    Directory of Open Access Journals (Sweden)

    Edward Susko

    2006-01-01

    Full Text Available The patchy distribution of genes across the prokaryotes may be caused by multiple gene losses or lateral transfer. Probabilistic models of gene gain and loss are needed to distinguish between these possibilities. Existing models allow only single genes to be gained and lost, despite the empirical evidence for multi-gene events. We compare birth-death models (currently the only widely-used models, in which only one gene can be gained or lost at a time to blocks models (allowing gain and loss of multiple genes within a family. We analyze two pairs of genomes: two E. coli strains, and the distantly-related Archaeoglobus fulgidus (archaea and Bacillus subtilis (gram positive bacteria. Blocks models describe the data much better than birth-death models. Our models suggest that lateral transfers of multiple genes from the same family are rare (although transfers of single genes are probably common. For both pairs, the estimated median time that a gene will remain in the genome is not much greater than the time separating the common ancestors of the archaea and bacteria. Deep phylogenetic reconstruction from sequence data will therefore depend on choosing genes likely to remain in the genome for a long time. Phylogenies based on the blocks model are more biologically plausible than phylogenies based on the birth-death model.

  16. Retrieval with gene queries

    Directory of Open Access Journals (Sweden)

    Srinivasan Padmini

    2006-04-01

    Full Text Available Abstract Background Accuracy of document retrieval from MEDLINE for gene queries is crucially important for many applications in bioinformatics. We explore five information retrieval-based methods to rank documents retrieved by PubMed gene queries for the human genome. The aim is to rank relevant documents higher in the retrieved list. We address the special challenges faced due to ambiguity in gene nomenclature: gene terms that refer to multiple genes, gene terms that are also English words, and gene terms that have other biological meanings. Results Our two baseline ranking strategies are quite similar in performance. Two of our three LocusLink-based strategies offer significant improvements. These methods work very well even when there is ambiguity in the gene terms. Our best ranking strategy offers significant improvements on three different kinds of ambiguities over our two baseline strategies (improvements range from 15.9% to 17.7% and 11.7% to 13.3% depending on the baseline. For most genes the best ranking query is one that is built from the LocusLink (now Entrez Gene summary and product information along with the gene names and aliases. For others, the gene names and aliases suffice. We also present an approach that successfully predicts, for a given gene, which of these two ranking queries is more appropriate. Conclusion We explore the effect of different post-retrieval strategies on the ranking of documents returned by PubMed for human gene queries. We have successfully applied some of these strategies to improve the ranking of relevant documents in the retrieved sets. This holds true even when various kinds of ambiguity are encountered. We feel that it would be very useful to apply strategies like ours on PubMed search results as these are not ordered by relevance in any way. This is especially so for queries that retrieve a large number of documents.

  17. Primetime for Learning Genes.

    Science.gov (United States)

    Keifer, Joyce

    2017-02-11

    Learning genes in mature neurons are uniquely suited to respond rapidly to specific environmental stimuli. Expression of individual learning genes, therefore, requires regulatory mechanisms that have the flexibility to respond with transcriptional activation or repression to select appropriate physiological and behavioral responses. Among the mechanisms that equip genes to respond adaptively are bivalent domains. These are specific histone modifications localized to gene promoters that are characteristic of both gene activation and repression, and have been studied primarily for developmental genes in embryonic stem cells. In this review, studies of the epigenetic regulation of learning genes in neurons, particularly the brain-derived neurotrophic factor gene (BDNF), by methylation/demethylation and chromatin modifications in the context of learning and memory will be highlighted. Because of the unique function of learning genes in the mature brain, it is proposed that bivalent domains are a characteristic feature of the chromatin landscape surrounding their promoters. This allows them to be "poised" for rapid response to activate or repress gene expression depending on environmental stimuli.

  18. Primetime for Learning Genes

    Directory of Open Access Journals (Sweden)

    Joyce Keifer

    2017-02-01

    Full Text Available Learning genes in mature neurons are uniquely suited to respond rapidly to specific environmental stimuli. Expression of individual learning genes, therefore, requires regulatory mechanisms that have the flexibility to respond with transcriptional activation or repression to select appropriate physiological and behavioral responses. Among the mechanisms that equip genes to respond adaptively are bivalent domains. These are specific histone modifications localized to gene promoters that are characteristic of both gene activation and repression, and have been studied primarily for developmental genes in embryonic stem cells. In this review, studies of the epigenetic regulation of learning genes in neurons, particularly the brain-derived neurotrophic factor gene (BDNF, by methylation/demethylation and chromatin modifications in the context of learning and memory will be highlighted. Because of the unique function of learning genes in the mature brain, it is proposed that bivalent domains are a characteristic feature of the chromatin landscape surrounding their promoters. This allows them to be “poised” for rapid response to activate or repress gene expression depending on environmental stimuli.

  19. Viral gene therapy.

    Science.gov (United States)

    Mancheño-Corvo, P; Martín-Duque, P

    2006-12-01

    Cancer is a multigenic disorder involving mutations of both tumor suppressor genes and oncogenes. A large body of preclinical data, however, has suggested that cancer growth can be arrested or reversed by treatment with gene transfer vectors that carry a single growth inhibitory or pro-apoptotic gene or a gene that can recruit immune responses against the tumor. Many of these gene transfer vectors are modified viruses. The ability for the delivery of therapeutic genes, made them desirable for engineering virus vector systems. The viral vectors recently in laboratory and clinical use are based on RNA and DNA viruses processing very different genomic structures and host ranges. Particular viruses have been selected as gene delivery vehicles because of their capacities to carry foreign genes and their ability to efficiently deliver these genes associated with efficient gene expression. These are the major reasons why viral vectors derived from retroviruses, adenovirus, adeno-associated virus, herpesvirus and poxvirus are employed in more than 70% of clinical gene therapy trials worldwide. Because these vector systems have unique advantages and limitations, each has applications for which it is best suited. Retroviral vectors can permanently integrate into the genome of the infected cell, but require mitotic cell division for transduction. Adenoviral vectors can efficiently deliver genes to a wide variety of dividing and nondividing cell types, but immune elimination of infected cells often limits gene expression in vivo. Herpes simplex virus can deliver large amounts of exogenous DNA; however, cytotoxicity and maintenance of transgene expression remain as obstacles. AAV also infects many non-dividing and dividing cell types, but has a limited DNA capacity. This review discusses current and emerging virusbased genetic engineering strategies for the delivery of therapeutic molecules or several approaches for cancer treatment.

  20. Gene manupulations in invertebrates

    OpenAIRE

    Čermáková, Eliška

    2017-01-01

    Gene manipulations in invertebrates are based on the same approches used in vertebrates. The are applied for the development of new genotypes in model species, convenient as model systems of human hereditary diseases etc. Gene manipulations are important as well for practical purposes, which is shown by the example of trangenic mosquitoes. Recently, it has been proved that programmable nucleases can be successfully used in invertebrates. Key words: Gene manipulations, invertebrates, methods, ...

  1. Genes and Social Behavior

    OpenAIRE

    Robinson, Gene E.; Fernald, Russell D.; Clayton, David F.

    2008-01-01

    What specific genes and regulatory sequences contribute to the organization and functioning of brain circuits that support social behavior? How does social experience interact with information in the genome to modulate these brain circuits? Here we address these questions by highlighting progress that has been made in identifying and understanding two key “vectors of influence” that link genes, brain, and social behavior: 1) social information alters gene readout in the brain to influence beh...

  2. History of gene therapy.

    Science.gov (United States)

    Wirth, Thomas; Parker, Nigel; Ylä-Herttuala, Seppo

    2013-08-10

    Two decades after the initial gene therapy trials and more than 1700 approved clinical trials worldwide we not only have gained much new information and knowledge regarding gene therapy in general, but also learned to understand the concern that has persisted in society. Despite the setbacks gene therapy has faced, success stories have increasingly emerged. Examples for these are the positive recommendation for a gene therapy product (Glybera) by the EMA for approval in the European Union and the positive trials for the treatment of ADA deficiency, SCID-X1 and adrenoleukodystrophy. Nevertheless, our knowledge continues to grow and during the course of time more safety data has become available that helps us to develop better gene therapy approaches. Also, with the increased understanding of molecular medicine, we have been able to develop more specific and efficient gene transfer vectors which are now producing clinical results. In this review, we will take a historical view and highlight some of the milestones that had an important impact on the development of gene therapy. We will also discuss briefly the safety and ethical aspects of gene therapy and address some concerns that have been connected with gene therapy as an important therapeutic modality. Copyright © 2013 Elsevier B.V. All rights reserved.

  3. Chromatin loops, gene positioning, and gene expression

    NARCIS (Netherlands)

    Holwerda, S.; de Laat, W.

    2012-01-01

    Technological developments and intense research over the last years have led to a better understanding of the 3D structure of the genome and its influence on genome function inside the cell nucleus. We will summarize topological studies performed on four model gene loci: the alpha- and beta-globin

  4. One gene's shattering effects.

    Science.gov (United States)

    Olsen, Kenneth M

    2012-05-29

    A new study shows that three independent mutations in the Sh1 gene, which encodes a YABBY transcription factor, gave rise to the non-shattering seed phenotype in domesticated sorghum. This same gene may have also had a role in the domestication of other cereals, including maize and rice.

  5. Adenovirus Vectors for Gene Therapy, Vaccination and Cancer Gene Therapy

    OpenAIRE

    Wold, William S. M.; Toth, Karoly

    2013-01-01

    Adenovirus vectors are the most commonly employed vector for cancer gene therapy. They are also used for gene therapy and as vaccines to express foreign antigens. Adenovirus vectors can be replication-defective; certain essential viral genes are deleted and replaced by a cassette that expresses a foreign therapeutic gene. Such vectors are used for gene therapy, as vaccines, and for cancer therapy. Replication-competent (oncolytic) vectors are employed for cancer gene therapy. Oncolytic vector...

  6. Gene therapy flexes muscle.

    Science.gov (United States)

    VandenDriessche, Thierry

    2005-09-01

    This commentary highlights the promising results of recent studies in animal models of Duchenne muscular dystrophy and amyotrophic lateral sclerosis that have clearly demonstrated the potential of gene therapy for tackling these diseases. In the absence of effective drugs or other treatments, these advances in gene therapy technology represent the best hope for those patients and families that are blighted by these diseases. Diseases characterized by progressive muscle degeneration are often incurable and affect a relatively large number of individuals. The progressive deterioration of muscle function is like the sword of Damocles that constantly reminds patients suffering from these diseases of their tragic fate, since most of them will eventually die from cardiac or pulmonary dysfunction. Some of these disorders are due to mutations in genes that directly influence the integrity of muscle fibers, such as in Duchenne muscular dystrophy (DMD), a recessive X-linked genetic disease. Others result from a progressive neurodegeneration of the motoneurons that are essential for maintaining muscle function, such as in amyotrophic lateral sclerosis (ALS), also commonly known as Lou Gehrig's disease. The genetic basis of DMD is relatively well understood as it is due to mutations in the dystrophin gene that encodes the cognate sarcolemmal protein. In contrast, the cause of ALS is poorly defined, with the exception of some dominantly inherited familial cases of ALS that are due to gain-of-function mutations in the gene encoding superoxide dismutase (SODG93A). Gene therapy for these disorders has been hampered by the inability to achieve widespread gene transfer. Moreover, since familial ALS is due to a dominant gain-of-function mutation, inhibition of gene expression (rather than gene augmentation) would be required to correct the phenotype, which is particularly challenging. Copyright (c) 2005 John Wiley & Sons, Ltd.

  7. Antisense gene silencing

    DEFF Research Database (Denmark)

    Nielsen, Troels T; Nielsen, Jørgen E

    2013-01-01

    Since the first reports that double-stranded RNAs can efficiently silence gene expression in C. elegans, the technology of RNA interference (RNAi) has been intensively exploited as an experimental tool to study gene function. With the subsequent discovery that RNAi could also be applied...... to mammalian cells, the technology of RNAi expanded from being a valuable experimental tool to being an applicable method for gene-specific therapeutic regulation, and much effort has been put into further refinement of the technique. This review will focus on how RNAi has developed over the years and how...

  8. Gene Therapy for Hemophilia.

    Science.gov (United States)

    Nathwani, Amit C; Davidoff, Andrew M; Tuddenham, Edward G D

    2017-10-01

    The best currently available treatments for hemophilia A and B (factor VIII or factor IX deficiency, respectively) require frequent intravenous infusion of highly expensive proteins that have short half-lives. Factor levels follow a saw-tooth pattern that is seldom in the normal range and falls so low that breakthrough bleeding occurs. Most hemophiliacs worldwide do not have access to even this level of care. In stark contrast, gene therapy holds out the hope of a cure by inducing continuous endogenous expression of factor VIII or factor IX following transfer of a functional gene to replace the hemophilic patient's own defective gene. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Genes underlying altruism.

    Science.gov (United States)

    Thompson, Graham J; Hurd, Peter L; Crespi, Bernard J

    2013-01-01

    William D. Hamilton postulated the existence of 'genes underlying altruism', under the rubric of inclusive fitness theory, a half-century ago. Such genes are now poised for discovery. In this article, we develop a set of intuitive criteria for the recognition and analysis of genes for altruism and describe the first candidate genes affecting altruism from social insects and humans. We also provide evidence from a human population for genetically based trade-offs, underlain by oxytocin-system polymorphisms, between alleles for altruism and alleles for non-social cognition. Such trade-offs between self-oriented and altruistic behaviour may influence the evolution of phenotypic diversity across all social animals.

  10. Gene Expression Omnibus (GEO)

    Data.gov (United States)

    U.S. Department of Health & Human Services — Gene Expression Omnibus is a public functional genomics data repository supporting MIAME-compliant submissions of array- and sequence-based data. Tools are provided...

  11. Evidence for homosexuality gene

    Energy Technology Data Exchange (ETDEWEB)

    Pool, R.

    1993-07-16

    A genetic analysis of 40 pairs of homosexual brothers has uncovered a region on the X chromosome that appears to contain a gene or genes for homosexuality. When analyzing the pedigrees of homosexual males, the researcheres found evidence that the trait has a higher likelihood of being passed through maternal genes. This led them to search the X chromosome for genes predisposing to homosexuality. The researchers examined the X chromosomes of pairs of homosexual brothers for regions of DNA that most or all had in common. Of the 40 sets of brothers, 33 shared a set of five markers in the q28 region of the long arm of the X chromosome. The linkage has a LOD score of 4.0, which translates into a 99.5% certainty that there is a gene or genes in this area that predispose males to homosexuality. The chief researcher warns, however, that this one site cannot explain all instances of homosexuality, since there were some cases where the trait seemed to be passed paternally. And even among those brothers where there was no evidence that the trait was passed paternally, seven sets of brothers did not share the Xq28 markers. It seems likely that homosexuality arises from a variety of causes.

  12. Gene-Gene and Gene-Environment Interactions in the Etiology of Breast Cancer

    National Research Council Canada - National Science Library

    Adegoke, Olufemi

    2003-01-01

    The objective of this CDA is to evaluate the gene-gene and gene-environment interactions in the etiology of breast cancer in two ongoing case-control studies, the Shanghai Breast Cancer Study (SBCS...

  13. The Mycoplasma hominis vaa gene displays a mosaic gene structure

    DEFF Research Database (Denmark)

    Boesen, Thomas; Emmersen, Jeppe M. G.; Jensen, Lise T.

    1998-01-01

    Mycoplasma hominis contains a variable adherence-associated (vaa) gene. To classify variants of the vaa genes, we examined 42 M. hominis isolated by PCR, DNA sequencing and immunoblotting. This uncovered the existence of five gene categories. Comparison of the gene types revealed a modular...

  14. Ribosomal genes in focus

    Science.gov (United States)

    Koberna, Karel; Malínský, Jan; Pliss, Artem; Mašata, Martin; Večeřová, Jaromíra; Fialová, Markéta; Bednár, Jan; Raška, Ivan

    2002-01-01

    T he organization of transcriptionally active ribosomal genes in animal cell nucleoli is investigated in this study in order to address the long-standing controversy with regard to the intranucleolar localization of these genes. Detailed analyses of HeLa cell nucleoli include direct localization of ribosomal genes by in situ hybridization and their indirect localization via nascent ribosomal transcript mappings. On the light microscopy (LM) level, ribosomal genes map in 10–40 fluorescence foci per nucleus, and transcription activity is associated with most foci. We demonstrate that each nucleolar focus observed by LM corresponds, on the EM level, to an individual fibrillar center (FC) and surrounding dense fibrillar components (DFCs). The EM data identify the DFC as the nucleolar subcompartment in which rRNA synthesis takes place, consistent with detection of rDNA within the DFC. The highly sensitive method for mapping nascent transcripts in permeabilized cells on ultrastructural level provides intense and unambiguous clustered immunogold signal over the DFC, whereas very little to no label is detected over the FC. This signal is strongly indicative of nascent “Christmas trees” of rRNA associated with individual rDNA genes, sampled on the surface of thin sections. Stereological analysis of the clustered transcription signal further suggests that these Christmas trees may be contorted in space and exhibit a DNA compaction ratio on the order of 4–5.5. PMID:12034768

  15. On sports and genes.

    Science.gov (United States)

    Zilberman-Schapira, Gili; Chen, Jieming; Gerstein, Mark

    2012-12-01

    Our genes influence our athletic ability. However, the causal genetic factors and mechanisms, and the extent of their effects, remain largely elusive. Many studies investigate this association between specific genes and athletic performance. Such studies have increased in number over the past few years, as recent developments and patents in DNA sequencing have made large amounts of sequencing data available for such analysis. In this paper, we consider four of the most intensively studied genes in relation to athletic ability: angiotensin I-converting enzyme, alpha-actinin 3, peroxismose proliferator-activator receptor alpha and nitric oxide synthase 3. We investigate the connection between genotype and athletic phenotype in the context of these four genes in various sport fields and across different ethnicities and genders. We do an extensive literature survey on these genes and the polymorphisms (single nucleotide polymorphisms or indels) found to be associated with athletic performance. We also present, for each of these polymorphisms, the allele frequencies in the different ethnicities reported in the pilot phase of the 1000 Genomes Project - arguably the largest human genome-sequencing endeavor to date. We discuss the considerable success, and significant drawbacks, of past research along these lines, and propose interesting directions for future research.

  16. Recombination in immunoglobulin gene loci

    Directory of Open Access Journals (Sweden)

    Komisarenko S. V.

    2009-02-01

    Full Text Available Gene network of the lymphoid cell differentiation coordinates precisely the recombination process in immunoglobulin gene loci. In our opinion, cellular microRNAs can contribute to the allelic exclusion through microRNA-directed DNA methylation and participate in retargeting recombinases activity from the gene loci of heavy immunoglobulin chains to the gene loci of light chains

  17. Gene therapy prospects--intranasal delivery of therapeutic genes.

    Science.gov (United States)

    Podolska, Karolina; Stachurska, Anna; Hajdukiewicz, Karolina; Małecki, Maciej

    2012-01-01

    Gene therapy is recognized to be a novel method for the treatment of various disorders. Gene therapy strategies involve gene manipulation on broad biological processes responsible for the spreading of diseases. Cancer, monogenic diseases, vascular and infectious diseases are the main targets of gene therapy. In order to obtain valuable experimental and clinical results, sufficient gene transfer methods are required. Therapeutic genes can be administered into target tissues via gene carriers commonly defined as vectors. The retroviral, adenoviral and adeno-associated virus based vectors are most frequently used in the clinic. So far, gene preparations may be administered directly into target organs or by intravenous, intramuscular, intratumor or intranasal injections. It is common knowledge that the number of gene therapy clinical trials has rapidly increased. However, some limitations such as transfection efficiency and stable and long-term gene expression are still not resolved. Consequently, great effort is focused on the evaluation of new strategies of gene delivery. There are many expectations associated with intranasal delivery of gene preparations for the treatment of diseases. Intranasal delivery of therapeutic genes is regarded as one of the most promising forms of pulmonary gene therapy research. Gene therapy based on inhalation of gene preparations offers an alternative way for the treatment of patients suffering from such lung diseases as cystic fibrosis, alpha-1-antitrypsin defect, or cancer. Experimental and first clinical trials based on plasmid vectors or recombinant viruses have revealed that gene preparations can effectively deliver therapeutic or marker genes to the cells of the respiratory tract. The noninvasive intranasal delivery of gene preparations or conventional drugs seems to be very encouraging, although basic scientific research still has to continue.

  18. Gene decay in archaea

    Directory of Open Access Journals (Sweden)

    M. W. J. van Passel

    2007-01-01

    Full Text Available The gene-dense chromosomes of archaea and bacteria were long thought to be devoid of pseudogenes, but with the massive increase in available genome sequences, whole genome comparisons between closely related species have identified mutations that have rendered numerous genes inactive. Comparative analyses of sequenced archaeal genomes revealed numerous pseudogenes, which can constitute up to 8.6% of the annotated coding sequences in some genomes. The largest proportion of pseudogenes is created by gene truncations, followed by frameshift mutations. Within archaeal genomes, large numbers of pseudogenes contain more than one inactivating mutation, suggesting that pseudogenes are deleted from the genome more slowly in archaea than in bacteria. Although archaea seem to retain pseudogenes longer than do bacteria, most archaeal genomes have unique repertoires of pseudogenes.

  19. Mechanisms of Horizontal Gene Transfer

    OpenAIRE

    Cafini Barrado, Fabio; Medrano Romero, Verónica; Morikawa, Kazuya

    2017-01-01

    Horizontal gene transfer plays important roles in the evolution of S. aureus, and indeed, a variety of virulence factors and antibiotic resistance genes are embedded in a series of mobile genetic elements. In this chapter, we review the mechanisms of horizontal gene transfer, including recent findings on the natural genetic competence. Then, we consider the transfer of two important antibiotic resistance genes: the methicillin resistance gene, mecA (in Staphylococcal Cassette Chromosome) and ...

  20. Idiomatic (gene) expressions.

    Science.gov (United States)

    Rockman, Matthew V

    2003-05-01

    Hidden among the myriad nucleotide variants that constitute each species' gene pool are a few variants that contribute to phenotypic variation. Many of these differences that make a difference are non-coding cis-regulatory variants, which, unlike coding variants, can only be identified through laborious experimental analysis. Recently, Cowles et al.1 described a screening method that does an end-run around this problem by searching for genes whose cis regulation varies without having to find the polymorphic nucleotides that influence transcription. While we will continue to require a diverse arsenal of experimental methods, this versatile method will speed the identification of functional genetic variation. Copyright 2003 Wiley Periodicals, Inc.

  1. A Bayesian approach to gene-gene and gene-environment interactions in chronic fatigue syndrome.

    Science.gov (United States)

    Lin, Eugene; Hsu, Sen-Yen

    2009-01-01

    In the study of genomics, it is essential to address gene-gene and gene-environment interactions for describing the complex traits that involves disease-related mechanisms. In this work, our goal is to detect gene-gene and gene-environment interactions resulting from the analysis of chronic fatigue syndrome patients' genetic and demographic factors including SNPs, age, gender and BMI. We employed the dataset that was original to the previous study by the Centers for Disease Control and Prevention Chronic Fatigue Syndrome Research Group. To investigate gene-gene and gene-environment interactions, we implemented a Bayesian based method for identifying significant interactions between factors. Here, we employed a two-stage Bayesian variable selection methodology based on Markov Chain Monte Carlo approaches. By applying our Bayesian based approach, NR3C1 was found in the significant two-locus gene-gene effect model, as well as in the significant two-factor gene-environment effect model. Furthermore, a significant gene-environment interaction was identified between NR3C1 and gender. These results support the hypothesis that NR3C1 and gender may play a role in biological mechanisms associated with chronic fatigue syndrome. We demonstrated that our Bayesian based approach is a promising method to assess the gene-gene and gene-environment interactions in chronic fatigue syndrome patients by using genetic factors, such as SNPs, and demographic factors such as age, gender and BMI.

  2. Neighboring Genes Show Correlated Evolution in Gene Expression

    Science.gov (United States)

    Ghanbarian, Avazeh T.; Hurst, Laurence D.

    2015-01-01

    When considering the evolution of a gene’s expression profile, we commonly assume that this is unaffected by its genomic neighborhood. This is, however, in contrast to what we know about the lack of autonomy between neighboring genes in gene expression profiles in extant taxa. Indeed, in all eukaryotic genomes genes of similar expression-profile tend to cluster, reflecting chromatin level dynamics. Does it follow that if a gene increases expression in a particular lineage then the genomic neighbors will also increase in their expression or is gene expression evolution autonomous? To address this here we consider evolution of human gene expression since the human-chimp common ancestor, allowing for both variation in estimation of current expression level and error in Bayesian estimation of the ancestral state. We find that in all tissues and both sexes, the change in gene expression of a focal gene on average predicts the change in gene expression of neighbors. The effect is highly pronounced in the immediate vicinity (genes increasing their expression in humans tend to avoid nuclear lamina domains and be enriched for the gene activator 5-hydroxymethylcytosine, we conclude that, most probably owing to chromatin level control of gene expression, a change in gene expression of one gene likely affects the expression evolution of neighbors, what we term expression piggybacking, an analog of hitchhiking. PMID:25743543

  3. Gene Therapy and Children (For Parents)

    Science.gov (United States)

    ... Needs a Kidney Transplant Vision Facts and Myths Gene Therapy and Children KidsHealth > For Parents > Gene Therapy and ... by a "bad" gene. continue Two Types of Gene Therapy The two forms of gene therapy are: Somatic ...

  4. Ultrasound mediated gene transfection

    Science.gov (United States)

    Williamson, Rene G.; Apfel, Robert E.; Brandsma, Janet L.

    2002-05-01

    Gene therapy is a promising modality for the treatment of a variety of human diseases both inherited and acquired, such as cystic fibrosis and cancer. The lack of an effective, safe method for the delivery of foreign genes into the cells, a process known as transfection, limits this effort. Ultrasound mediated gene transfection is an attractive method for gene delivery since it is a noninvasive technique, does not introduce any viral particles into the host and can offer very good temporal and spatial control. Previous investigators have shown that sonication increases transfection efficiency with and without ultrasound contrast agents. The mechanism is believed to be via a cavitation process where collapsing bubble nuclei permeabilize the cell membrane leading to increased DNA transfer. The research is focused on the use of pulsed wave high frequency focused ultrasound to transfect DNA into mammalian cells in vitro and in vivo. A better understanding of the mechanism behind the transfection process is also sought. A summary of some in vitro results to date will be presented, which includes the design of a sonication chamber that allows us to model the in vivo case more accurately.

  5. What is a Gene?

    Indian Academy of Sciences (India)

    His other interests include reading, photography and listening to classical music. The first part of this general article appeared in April 1997. S C Lakhotia. The first part of this article traced the evolution of the concept of a gene from Mendel's times to the middle of this century: starting from the imaginary factors of Mendel, the.

  6. Genes in mammalian reproduction

    Energy Technology Data Exchange (ETDEWEB)

    Gwatkin, R.B.L. [ed.

    1996-11-01

    This is an informative book which deals mainly with genomic imprinting, the role of steroid hormones in development, the expression of a variety of genes during development and the link to hereditary diseases. It is an up-to-date review in a field that is quickly changing and provides valuable basic information and current research trends.

  7. (FIE) gene from soybean

    African Journals Online (AJOL)

    DR. NJ TONUKARI

    2012-04-17

    Apr 17, 2012 ... Harb. Protoc. doi:10.1101/pdb.prot4666. Xu H, Li Y, Yan Y, Wang K, Gao Y, Hu Y (2010). Genome-scale identification of Soybean BURP domain-containing genes and their expression under stress treatments. BMC Plant Biol. 10: 197. Yadegari R, Kinoshita T, Lotan O, Cohen G, Katz A, Choi Y, Nakashima.

  8. Silence of the Genes

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 12; Issue 4. Silence of the Genes - 2006 Nobel Prize in Physiology or Medicine. Utpal Nath Saumitra Das. General Article Volume 12 Issue 4 April 2007 pp 6-18. Fulltext. Click here to view fulltext PDF. Permanent link:

  9. Silence of the Genes

    Indian Academy of Sciences (India)

    Srimath

    research for several decades (See Resonance, Vol. 12, pp.47–53,. March 2007). RNA interference (RNAi) is a novel mechanism for controlling gene expression. In this mechanism, tiny double-stranded RNA molecules called 'small interfering RNA' (siRNA) degrade cellu- lar mRNA that has sequence similarity with them.

  10. Hemochromatosis enhances tumor progression via upregulation of intracellular iron in head and neck cancer.

    Directory of Open Access Journals (Sweden)

    Michelle Lenarduzzi

    Full Text Available Despite improvements in treatment strategies for head and neck squamous cell carcinoma (HNSCC, outcomes have not significantly improved; highlighting the importance of identifying novel therapeutic approaches to target this disease. To address this challenge, we proceeded to evaluate the role of iron in HNSCC.Expression levels of iron-related genes were evaluated in HNSCC cell lines using quantitative RT-PCR. Cellular phenotypic effects were assessed using viability (MTS, clonogenic survival, BrdU, and tumor formation assays. The prognostic significance of iron-related proteins was determined using immunohistochemistry.In a panel of HNSCC cell lines, hemochromatosis (HFE was one of the most overexpressed genes involved in iron regulation. In vitro knockdown of HFE in HNSCC cell lines significantly decreased hepcidin (HAMP expression and intracellular iron level. This in turn, resulted in a significant decrease in HNSCC cell viability, clonogenicity, DNA synthesis, and Wnt signalling. These cellular changes were reversed by re-introducing iron back into HNSCC cells after HFE knockdown, indicating that iron was mediating this phenotype. Concordantly, treating HNSCC cells with an iron chelator, ciclopirox olamine (CPX, significantly reduced viability and clonogenic survival. Finally, patients with high HFE expression experienced a reduced survival compared to patients with low HFE expression.Our data identify HFE as potentially novel prognostic marker in HNSCC that promotes tumour progression via HAMP and elevated intracellular iron levels, leading to increased cellular proliferation and tumour formation. Hence, these findings suggest that iron chelators might have a therapeutic role in HNSCC management.

  11. Gene therapy in pancreatic cancer

    Science.gov (United States)

    Liu, Si-Xue; Xia, Zhong-Sheng; Zhong, Ying-Qiang

    2014-01-01

    Pancreatic cancer (PC) is a highly lethal disease and notoriously difficult to treat. Only a small proportion of PC patients are eligible for surgical resection, whilst conventional chemoradiotherapy only has a modest effect with substantial toxicity. Gene therapy has become a new widely investigated therapeutic approach for PC. This article reviews the basic rationale, gene delivery methods, therapeutic targets and developments of laboratory research and clinical trials in gene therapy of PC by searching the literature published in English using the PubMed database and analyzing clinical trials registered on the Gene Therapy Clinical Trials Worldwide website (http://www. wiley.co.uk/genmed/ clinical). Viral vectors are main gene delivery tools in gene therapy of cancer, and especially, oncolytic virus shows brighter prospect due to its tumor-targeting property. Efficient therapeutic targets for gene therapy include tumor suppressor gene p53, mutant oncogene K-ras, anti-angiogenesis gene VEGFR, suicide gene HSK-TK, cytosine deaminase and cytochrome p450, multiple cytokine genes and so on. Combining different targets or combination strategies with traditional chemoradiotherapy may be a more effective approach to improve the efficacy of cancer gene therapy. Cancer gene therapy is not yet applied in clinical practice, but basic and clinical studies have demonstrated its safety and clinical benefits. Gene therapy will be a new and promising field for the treatment of PC. PMID:25309069

  12. Genes2FANs: connecting genes through functional association networks

    Directory of Open Access Journals (Sweden)

    Dannenfelser Ruth

    2012-07-01

    Full Text Available Abstract Background Protein-protein, cell signaling, metabolic, and transcriptional interaction networks are useful for identifying connections between lists of experimentally identified genes/proteins. However, besides physical or co-expression interactions there are many ways in which pairs of genes, or their protein products, can be associated. By systematically incorporating knowledge on shared properties of genes from diverse sources to build functional association networks (FANs, researchers may be able to identify additional functional interactions between groups of genes that are not readily apparent. Results Genes2FANs is a web based tool and a database that utilizes 14 carefully constructed FANs and a large-scale protein-protein interaction (PPI network to build subnetworks that connect lists of human and mouse genes. The FANs are created from mammalian gene set libraries where mouse genes are converted to their human orthologs. The tool takes as input a list of human or mouse Entrez gene symbols to produce a subnetwork and a ranked list of intermediate genes that are used to connect the query input list. In addition, users can enter any PubMed search term and then the system automatically converts the returned results to gene lists using GeneRIF. This gene list is then used as input to generate a subnetwork from the user’s PubMed query. As a case study, we applied Genes2FANs to connect disease genes from 90 well-studied disorders. We find an inverse correlation between the counts of links connecting disease genes through PPI and links connecting diseases genes through FANs, separating diseases into two categories. Conclusions Genes2FANs is a useful tool for interpreting the relationships between gene/protein lists in the context of their various functions and networks. Combining functional association interactions with physical PPIs can be useful for revealing new biology and help form hypotheses for further experimentation. Our

  13. Using gene expression noise to understand gene regulation

    NARCIS (Netherlands)

    Munsky, B.; Neuert, G.; van Oudenaarden, A.

    2012-01-01

    Phenotypic variation is ubiquitous in biology and is often traceable to underlying genetic and environmental variation. However, even genetically identical cells in identical environments display variable phenotypes. Stochastic gene expression, or gene expression "noise," has been suggested as a

  14. GenBank blastx search result: AK058436 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  15. GenBank blastx search result: AK062355 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  16. GenBank blastn search result: AK058686 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  17. GenBank blastn search result: AK059019 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  18. GenBank blastn search result: AK241145 [KOME

    Lifescience Database Archive (English)

    Full Text Available chromosome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members

  19. GenBank blastn search result: AK119240 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  20. GenBank blastn search result: AK105816 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  1. GenBank blastx search result: AK059019 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  2. GenBank blastn search result: AK058436 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  3. GenBank blastn search result: AK059098 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  4. GenBank blastn search result: AK059159 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  5. GenBank blastn search result: AK058913 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  6. GenBank blastn search result: AK058741 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  7. GenBank blastx search result: AK059159 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  8. GenBank blastx search result: AK058741 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  9. GenBank blastx search result: AK059098 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  10. GenBank blastx search result: AK058686 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  11. Gene set analysis for longitudinal gene expression data

    Directory of Open Access Journals (Sweden)

    Piepho Hans-Peter

    2011-07-01

    Full Text Available Abstract Background Gene set analysis (GSA has become a successful tool to interpret gene expression profiles in terms of biological functions, molecular pathways, or genomic locations. GSA performs statistical tests for independent microarray samples at the level of gene sets rather than individual genes. Nowadays, an increasing number of microarray studies are conducted to explore the dynamic changes of gene expression in a variety of species and biological scenarios. In these longitudinal studies, gene expression is repeatedly measured over time such that a GSA needs to take into account the within-gene correlations in addition to possible between-gene correlations. Results We provide a robust nonparametric approach to compare the expressions of longitudinally measured sets of genes under multiple treatments or experimental conditions. The limiting distributions of our statistics are derived when the number of genes goes to infinity while the number of replications can be small. When the number of genes in a gene set is small, we recommend permutation tests based on our nonparametric test statistics to achieve reliable type I error and better power while incorporating unknown correlations between and within-genes. Simulation results demonstrate that the proposed method has a greater power than other methods for various data distributions and heteroscedastic correlation structures. This method was used for an IL-2 stimulation study and significantly altered gene sets were identified. Conclusions The simulation study and the real data application showed that the proposed gene set analysis provides a promising tool for longitudinal microarray analysis. R scripts for simulating longitudinal data and calculating the nonparametric statistics are posted on the North Dakota INBRE website http://ndinbre.org/programs/bioinformatics.php. Raw microarray data is available in Gene Expression Omnibus (National Center for Biotechnology Information with

  12. Optimal Reference Genes for Gene Expression Normalization in Trichomonas vaginalis

    Science.gov (United States)

    dos Santos, Odelta; de Vargas Rigo, Graziela; Frasson, Amanda Piccoli; Macedo, Alexandre José; Tasca, Tiana

    2015-01-01

    Trichomonas vaginalis is the etiologic agent of trichomonosis, the most common non-viral sexually transmitted disease worldwide. This infection is associated with several health consequences, including cervical and prostate cancers and HIV acquisition. Gene expression analysis has been facilitated because of available genome sequences and large-scale transcriptomes in T. vaginalis, particularly using quantitative real-time polymerase chain reaction (qRT-PCR), one of the most used methods for molecular studies. Reference genes for normalization are crucial to ensure the accuracy of this method. However, to the best of our knowledge, a systematic validation of reference genes has not been performed for T. vaginalis. In this study, the transcripts of nine candidate reference genes were quantified using qRT-PCR under different cultivation conditions, and the stability of these genes was compared using the geNorm and NormFinder algorithms. The most stable reference genes were α-tubulin, actin and DNATopII, and, conversely, the widely used T. vaginalis reference genes GAPDH and β-tubulin were less stable. The PFOR gene was used to validate the reliability of the use of these candidate reference genes. As expected, the PFOR gene was upregulated when the trophozoites were cultivated with ferrous ammonium sulfate when the DNATopII, α-tubulin and actin genes were used as normalizing gene. By contrast, the PFOR gene was downregulated when the GAPDH gene was used as an internal control, leading to misinterpretation of the data. These results provide an important starting point for reference gene selection and gene expression analysis with qRT-PCR studies of T. vaginalis. PMID:26393928

  13. Influence of lead on repetitive behavior and dopamine metabolism in a mouse model of iron overload.

    Science.gov (United States)

    Chang, JuOae; Kueon, Chojin; Kim, Jonghan

    2014-12-01

    Exposures to lead (Pb) are associated with neurological problems including psychiatric disorders and impaired learning and memory. Pb can be absorbed by iron transporters, which are up-regulated in hereditary hemochromatosis, an iron overload disorder in which increased iron deposition in various parenchymal organs promote metal-induced oxidative damage. While dysfunction in HFE (High Fe) gene is the major cause of hemochromatosis, the transport and toxicity of Pb in Hfe-related hemochromatosis are largely unknown. To elucidate the relationship between HFE gene dysfunction and Pb absorption, H67D knock-in Hfe-mutant and wild-type mice were given drinking water containing Pb 1.6 mg/ml ad libitum for 6 weeks and examined for behavioral phenotypes using the nestlet-shredding and marble-burying tests. Latency to nestlet-shredding in Pb-treated wild-type mice was prolonged compared with non-exposed wild-types (p < 0.001), whereas Pb exposure did not alter shredding latency in Hfe-mutant mice. In the marble-burying test, Hfe-mutant mice showed an increased number of marbles buried compared with wild-type mice (p = 0.002), indicating more repetitive behavior upon Hfe mutation. Importantly, Pb-exposed wild-type mice buried more marbles than non-exposed wild-types, whereas the number of marbles buried by Hfe-mutant mice did not change whether or not exposed to Pb. These results suggest that Hfe mutation could normalize Pb-induced behavioral alteration. To explore the mechanism of repetitive behavior caused by Pb, western blot analysis was conducted for proteins involved in brain dopamine metabolism. The levels of tyrosine hydroxylase and dopamine transporter increased upon Pb exposure in both genotypes, whereas Hfe-mutant mice displayed down-regulation of the dopamine transporter and dopamine D1 receptor with D2 receptor elevated. Taken together, our data support the idea that both Pb exposure and Hfe mutation increase repetitive behavior in mice and further suggest that

  14. Genes, stress, and depression.

    Science.gov (United States)

    Wurtman, Richard J

    2005-05-01

    A relationship between genetic makeup and susceptibility to major depressive disorder (MDD) has long been suspected on the basis of family and twin studies. A metaanalysis of reports on the basis of twin studies has estimated MDD's degree of heritability to be 0.33 (confidence interval, 0.26-0.39). Among families exhibiting an increased prevalence of MDD, risk of developing the illness was enhanced in members exposed to a highly stressful environment. Aberrant genes can predispose to depression in a number of ways, for example, by diminishing production of growth factors that act during brain development. An aberrant gene could also increase or decrease a neurotransmitter's release into synapses, its actions, or its duration of activity. The gene products of greatest interest at present are those involved in the synthesis and actions of serotonin; among them, the serotonin-uptake protein localized within the terminals and dendrites of serotonin-releasing neurons. It has been found that the Vmax of platelet serotonin uptake is low in some patients with MDD; also, Vmax is highly correlated in twins. Antidepressant drugs such as the selective serotonin reuptake inhibitors act on this uptake protein. The specific genetic locus causing serotonin uptake to be lower in some patients with major depression involves a polymorphic region (5-HTTLPR) in the promoter region of the gene for the uptake protein. The gene itself exists as several alleles, the short "S" allele and the long "L" allele. The S variant is associated with less, and the L variant with more, of the uptake protein. The effect of stressful life events on depressive symptoms in young adults was found to be significantly stronger among SS or SL subjects than among LL subjects. Neuroimaging studies showed that people with the SS or SL alleles exhibited a greater activation of the amygdala in response to fearful stimuli than those with LL. It has been reported recently that mutations in the gene that controls

  15. Vertebrate gene predictions and the problem of large genes

    DEFF Research Database (Denmark)

    Wang, Jun; Li, ShengTing; Zhang, Yong

    2003-01-01

    To find unknown protein-coding genes, annotation pipelines use a combination of ab initio gene prediction and similarity to experimentally confirmed genes or proteins. Here, we show that although the ab initio predictions have an intrinsically high false-positive rate, they also have a consistent...

  16. Hemochromatosis and diabetes mellitus: case report and literature review

    Directory of Open Access Journals (Sweden)

    Karina Biavatti

    2008-12-01

    Full Text Available Hemochromatosis is a disorder characterized by iron storage amended. The acquired form of the disease can be caused by iron overload, alcoholism, infection by  C virus hepatitis, non-alcoholic hepatitis and chronic liver disease. The hereditary form can be caused by different mutations, being the C282Y and H63D the most frequent, 83% of cases are homozigotous for C282Y and 4% are compound heterozygous (C282Y/H63D. Hemochromatosis is a condition that can affect several organs, including: heart, joints, liver, hypothalamus, pituitary, pancreas and gonads. The aim of this study was to report a case of hemochromatosis and review the literature, with special attention to the association of hemochromatosis and diabetes mellitus. Patient 53 years, male presented to the doctor with arthralgia metacarpophalangeal, ankles, knees, coxofemoral right, and cervical and lumbar, complaints of fatigue and weight loss. Between 3 brothers, one of them had a diagnosis of hereditary hemochromatosis, with PCR demonstrating homozygous for C282Y. Labs: GOT 128 U/L, ALT 231 U/L, alkaline phosphatase 258 U/L, abdominal ultrasound with hepatomegaly and spleen at the upper limit of normal. Liver biopsy demonstrated portal fibrosis extension with hemosiderosis intense. It also made the diagnosis of diabetes mellitus. The research confirmed the same mutation of the changing family: homozygous for C282Y

  17. Gene Therapy for Lung Cancer.

    Science.gov (United States)

    Lara-Guerra, Humberto; Roth, Jack A

    2016-01-01

    Gene therapy was originally conceived to treat monogenic diseases. The replacement of a defective gene with a functional gene can theoretically cure the disease. In cancer, multiple genetic defects are present and the molecular profile changes during the course of the disease, making the replacement of all defective genes impossible. To overcome these difficulties, various gene therapy strategies have been adopted, including immune stimulation, transfer of suicide genes, inhibition of driver oncogenes, replacement of tumor-suppressor genes that could mediate apoptosis or anti-angiogenesis, and transfer of genes that enhance conventional treatments such as radiotherapy and chemotherapy. Some of these strategies have been tested successfully in non-small-cell lung cancer patients and the results of laboratory studies and clinical trials are reviewed herein.

  18. Gene therapy in keratoconus

    Directory of Open Access Journals (Sweden)

    Mahgol Farjadnia

    2015-01-01

    Full Text Available Keratoconus (KC is the most common ectasia of the cornea and is a common reason for corneal transplant. Therapeutic strategies that can arrest the progression of this disease and modify the underlying pathogenesis are getting more and more popularity among scientists. Cumulating data represent strong evidence of a genetic role in the pathogenesis of KC. Different loci have been identified, and certain mutations have also been mapped for this disease. Moreover, Biophysical properties of the cornea create an appropriate candidate of this tissue for gene therapy. Immune privilege, transparency and ex vivo stability are among these properties. Recent advantage in vectors, besides the ability to modulate the corneal milieu for accepting the target gene for a longer period and fruitful translation, make a big hope for stupendous results reasonable.

  19. The sulfatase gene family.

    Science.gov (United States)

    Parenti, G; Meroni, G; Ballabio, A

    1997-06-01

    During the past few years, molecular analyses have provided important insights into the biochemistry and genetics of the sulfatase family of enzymes, identifying the molecular bases of inherited diseases caused by sulfatase deficiencies. New members of the sulfatase gene family have been identified in man and other species using a genomic approach. These include the gene encoding arylsulfatase E, which is involved in X-linked recessive chondrodysplasia punctata, a disorder of cartilage and bone development. Another important breakthrough has been the discovery of the biochemical basis of multiple sulfatase deficiency, an autosomal recessive disorder characterized by a severe of all sulfatase activities. These discoveries, together with the resolution of the crystallographic structure of sulfatases, have improved our understanding of the function and evolution of this fascinating family of enzymes.

  20. Brains, Genes and Primates

    Science.gov (United States)

    Belmonte, Juan Carlos Izpisua; Callaway, Edward M.; Churchland, Patricia; Caddick, Sarah J.; Feng, Guoping; Homanics, Gregg E.; Lee, Kuo-Fen; Leopold, David A.; Miller, Cory T.; Mitchell, Jude F.; Mitalipov, Shoukhrat; Moutri, Alysson R.; Movshon, J. Anthony; Okano, Hideyuki; Reynolds, John H.; Ringach, Dario; Sejnowski, Terrence J.; Silva, Afonso C.; Strick, Peter L.; Wu, Jun; Zhang, Feng

    2015-01-01

    One of the great strengths of the mouse model is the wide array of genetic tools that have been developed. Striking examples include methods for directed modification of the genome, and for regulated expression or inactivation of genes. Within neuroscience, it is now routine to express reporter genes, neuronal activity indicators and opsins in specific neuronal types in the mouse. However, there are considerable anatomical, physiological, cognitive and behavioral differences between the mouse and the human that, in some areas of inquiry, limit the degree to which insights derived from the mouse can be applied to understanding human neurobiology. Several recent advances have now brought into reach the goal of applying these tools to understanding the primate brain. Here we describe these advances, consider their potential to advance our understanding of the human brain and brain disorders, discuss bioethical considerations, and describe what will be needed to move forward. PMID:25950631

  1. PRRT2 gene mutations

    Science.gov (United States)

    Gardiner, Alice R.; Bhatia, Kailash P.; Stamelou, Maria; Dale, Russell C.; Kurian, Manju A.; Schneider, Susanne A.; Wali, G.M.; Counihan, Tim; Schapira, Anthony H.; Spacey, Sian D.; Valente, Enza-Maria; Silveira-Moriyama, Laura; Teive, Hélio A.G.; Raskin, Salmo; Sander, Josemir W.; Lees, Andrew; Warner, Tom; Kullmann, Dimitri M.; Wood, Nicholas W.; Hanna, Michael

    2012-01-01

    ABSTRACT Objective: The proline-rich transmembrane protein (PRRT2) gene was recently identified using exome sequencing as the cause of autosomal dominant paroxysmal kinesigenic dyskinesia (PKD) with or without infantile convulsions (IC) (PKD/IC syndrome). Episodic neurologic disorders, such as epilepsy, migraine, and paroxysmal movement disorders, often coexist and are thought to have a shared channel-related etiology. To investigate further the frequency, spectrum, and phenotype of PRRT2 mutations, we analyzed this gene in 3 large series of episodic neurologic disorders with PKD/IC, episodic ataxia (EA), and hemiplegic migraine (HM). Methods: The PRRT2 gene was sequenced in 58 family probands/sporadic individuals with PKD/IC, 182 with EA, 128 with HM, and 475 UK and 96 Asian controls. Results: PRRT2 genetic mutations were identified in 28 out of 58 individuals with PKD/IC (48%), 1/182 individuals with EA, and 1/128 individuals with HM. A number of loss-of-function and coding missense mutations were identified; the most common mutation found was the p.R217Pfs*8 insertion. Males were more frequently affected than females (ratio 52:32). There was a high proportion of PRRT2 mutations found in families and sporadic cases with PKD associated with migraine or HM (10 out of 28). One family had EA with HM and another large family had typical HM alone. Conclusions: This work expands the phenotype of mutations in the PRRT2 gene to include the frequent occurrence of migraine and HM with PKD/IC, and the association of mutations with EA and HM and with familial HM alone. We have also extended the PRRT2 mutation type and frequency in PKD and other episodic neurologic disorders. PMID:23077024

  2. Gene Porter Bridwell

    Science.gov (United States)

    1994-01-01

    Gene Porter Bridwell served as the director of the Marshall Space Flight Center from January 6, 1994 until February 3, 1996, when he retired from NASA after thirty-four years service. Bridwell, a Marshall employee since 1962, had been Marshall's Space Shuttle Projects Office Director and Space Station Redesign Team deputy manager. Under Bridwell, Marshall worked to develop its role as a Center of Excellence for propulsion and for providing access to space.

  3. Genealogy and gene trees.

    Science.gov (United States)

    Rasmuson, Marianne

    2008-02-01

    Heredity can be followed in persons or in genes. Persons can be identified only a few generations back, but simplified models indicate that universal ancestors to all now living persons have occurred in the past. Genetic variability can be characterized as variants of DNA sequences. Data are available only from living persons, but from the pattern of variation gene trees can be inferred by means of coalescence models. The merging of lines backwards in time leads to a MRCA (most recent common ancestor). The time and place of living for this inferred person can give insights in human evolutionary history. Demographic processes are incorporated in the model, but since culture and customs are known to influence demography the models used ought to be tested against available genealogy. The Icelandic data base offers a possibility to do so and points to some discrepancies. Mitochondrial DNA and Y chromosome patterns give a rather consistent view of human evolutionary history during the latest 100 000 years but the earlier epochs of human evolution demand gene trees with longer branches. The results of such studies reveal as yet unsolved problems about the sources of our genome.

  4. Gene-gene and gene-environmental interactions of childhood asthma: a multifactor dimension reduction approach.

    Directory of Open Access Journals (Sweden)

    Ming-Wei Su

    Full Text Available BACKGROUND: The importance of gene-gene and gene-environment interactions on asthma is well documented in literature, but a systematic analysis on the interaction between various genetic and environmental factors is still lacking. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a population-based, case-control study comprised of seventh-grade children from 14 Taiwanese communities. A total of 235 asthmatic cases and 1,310 non-asthmatic controls were selected for DNA collection and genotyping. We examined the gene-gene and gene-environment interactions between 17 single-nucleotide polymorphisms in antioxidative, inflammatory and obesity-related genes, and childhood asthma. Environmental exposures and disease status were obtained from parental questionnaires. The model-free and non-parametrical multifactor dimensionality reduction (MDR method was used for the analysis. A three-way gene-gene interaction was elucidated between the gene coding glutathione S-transferase P (GSTP1, the gene coding interleukin-4 receptor alpha chain (IL4Ra and the gene coding insulin induced gene 2 (INSIG2 on the risk of lifetime asthma. The testing-balanced accuracy on asthma was 57.83% with a cross-validation consistency of 10 out of 10. The interaction of preterm birth and indoor dampness had the highest training-balanced accuracy at 59.09%. Indoor dampness also interacted with many genes, including IL13, beta-2 adrenergic receptor (ADRB2, signal transducer and activator of transcription 6 (STAT6. We also used likelihood ratio tests for interaction and chi-square tests to validate our results and all tests showed statistical significance. CONCLUSIONS/SIGNIFICANCE: The results of this study suggest that GSTP1, INSIG2 and IL4Ra may influence the lifetime asthma susceptibility through gene-gene interactions in schoolchildren. Home dampness combined with each one of the genes STAT6, IL13 and ADRB2 could raise the asthma risk.

  5. Gene therapy of cancer and development of therapeutic target gene

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Chang Min; Kwon, Hee Chung

    1998-04-01

    We applied HSV-tk/GCV strategy to orthotopic rat hepatoma model and showed anticancer effects of hepatoma. The increased expression of Lac Z gene after adenovirus-mediated gene delivery throughout hepatic artery was thought that is increased the possibility of gene therapy for curing hepatoma. With the construction of kGLP-laboratory, it is possible to produce a good quantity and quality of adenovirus in lage-scale production and purification of adenovirus vector. Also, the analysis of hepatoma related genes by PCR-LOH could be used for the diagnosis of patients and the development of therapeutic gene.

  6. Independent Gene Discovery and Testing

    Science.gov (United States)

    Palsule, Vrushalee; Coric, Dijana; Delancy, Russell; Dunham, Heather; Melancon, Caleb; Thompson, Dennis; Toms, Jamie; White, Ashley; Shultz, Jeffry

    2010-01-01

    A clear understanding of basic gene structure is critical when teaching molecular genetics, the central dogma and the biological sciences. We sought to create a gene-based teaching project to improve students' understanding of gene structure and to integrate this into a research project that can be implemented by instructors at the secondary level…

  7. Gene probes: principles and protocols

    National Research Council Canada - National Science Library

    Rapley, Ralph; Aquino de Muro, Marilena

    2002-01-01

    ... of labeled DNA has allowed genes to be mapped to single chromosomes and in many cases to a single chromosome band, promoting significant advance in human genome mapping. Gene Probes: Principles and Protocols presents the principles for gene probe design, labeling, detection, target format, and hybridization conditions together with detailed protocols, accom...

  8. Compositional gradients in Gramineae genes

    DEFF Research Database (Denmark)

    Wong, Gane Ka-Shu; Wang, Jun; Tao, Lin

    2002-01-01

    In this study, we describe a property of Gramineae genes, and perhaps all monocot genes, that is not observed in eudicot genes. Along the direction of transcription, beginning at the junction of the 5'-UTR and the coding region, there are gradients in GC content, codon usage, and amino-acid usage...

  9. Optimal gene partition into operons correlates with gene functional order

    Science.gov (United States)

    Zaslaver, Alon; Mayo, Avi; Ronen, Michal; Alon, Uri

    2006-09-01

    Gene arrangement into operons varies between bacterial species. Genes in a given system can be on one operon in some organisms and on several operons in other organisms. Existing theories explain why genes that work together should be on the same operon, since this allows for advantageous lateral gene transfer and accurate stoichiometry. But what causes the frequent separation into multiple operons of co-regulated genes that act together in a pathway? Here we suggest that separation is due to benefits made possible by differential regulation of each operon. We present a simple mathematical model for the optimal distribution of genes into operons based on a balance of the cost of operons and the benefit of regulation that provides 'just-when-needed' temporal order. The analysis predicts that genes are arranged such that genes on the same operon do not skip functional steps in the pathway. This prediction is supported by genomic data from 137 bacterial genomes. Our work suggests that gene arrangement is not only the result of random historical drift, genome re-arrangement and gene transfer, but has elements that are solutions of an evolutionary optimization problem. Thus gene functional order may be inferred by analyzing the operon structure across different genomes.

  10. Somatic gene therapy for dyslipidemias.

    Science.gov (United States)

    Belalcazar, M; Chan, L

    1999-09-01

    Somatic gene transfer is a valuable tool for the in vivo evaluation of lipoprotein metabolism. It has been used to dissect metabolic pathways, to establish structure-function relationships of various gene products, and to evaluate conventional lipid-lowering and novel therapeutic genes for the treatment of lipoprotein disorders. In this article we review some general aspects of somatic gene therapy and the different vehicles used for the delivery of therapeutic genes. We highlight some recent advances in adenoviral vector development that make this vector an attractive system for clinical trials.

  11. Gene electrotransfer in clinical trials

    DEFF Research Database (Denmark)

    Gehl, Julie

    2014-01-01

    Electroporation is increasingly being used for delivery of chemotherapy to tumors. Likewise, gene delivery by electroporation is rapidly gaining momentum for both vaccination purposes and for delivery of genes coding for other therapeutic molecules, such as chronic diseases or cancer. This chapte...... describes how gene therapy may be performed using electric pulses to enhance uptake and expression.......Electroporation is increasingly being used for delivery of chemotherapy to tumors. Likewise, gene delivery by electroporation is rapidly gaining momentum for both vaccination purposes and for delivery of genes coding for other therapeutic molecules, such as chronic diseases or cancer. This chapter...

  12. Tumor-suppressing gene therapy.

    Science.gov (United States)

    Fang, Bingliang; Roth, Jack A

    2003-01-01

    Tumor-suppressor genes play pivotal roles in maintaining genome integrity and in regulating cell proliferation, differentiation, and apoptosis. Their loss-of-function mutations are related directly to tumorigenesis. Thus, use of tumor-suppressor genes as anticancer therapeutics has been investigated rigorously in both experimental and clinical researches. Transfer of various tumor-suppressor genes directly to cancer cells has been demonstrated to suppress tumor growth via induction of apoptosis and cell-cycle arrest and, in some cases, with evidence for bystander effects. Various studies also have shown that combination of tumor-suppressor gene therapy with conventional anticancer therapy can yield synergistic therapeutic benefits. Clinical trials with tumor-suppressor genes, especially the p53 gene, have demonstrated that the treatment is well tolerated, and; favorable clinical responses, including a pathologically complete responses, have been observed in a subset of patients with advanced disease or with cancers resistant to conventional therapy. Yet, current gene replacement approaches in cancer gene therapy must be improved if they are to have a broader clinical impact. Efficient systemic gene delivery systems will be required ultimately for treatment of metastatic disease. In this review, we have recently summarized achievements in tumor-suppressor gene therapy with a focus on the p53 gene.

  13. Horizontal gene transfer in choanoflagellates.

    Science.gov (United States)

    Tucker, Richard P

    2013-01-01

    Horizontal gene transfer (HGT), also known as lateral gene transfer, results in the rapid acquisition of genes from another organism. HGT has long been known to be a driving force in speciation in prokaryotes, and there is evidence for HGT from symbiotic and infectious bacteria to metazoans, as well as from protists to bacteria. Recently, it has become clear that as many as a 1,000 genes in the genome of the choanoflagellate Monosiga brevicollis may have been acquired by HGT. Interestingly, these genes reportedly come from algae, bacteria, and other choanoflagellate prey. Some of these genes appear to have allowed an ancestral choanoflagellate to exploit nutrient-poor environments and were not passed on to metazoan descendents. However, some of these genes are also found in animal genomes, suggesting that HGT into a common ancestor of choanozoans and animals may have contributed to metazoan evolution. Copyright © 2012 Wiley Periodicals, Inc.

  14. Gene finding in novel genomes

    Directory of Open Access Journals (Sweden)

    Korf Ian

    2004-05-01

    Full Text Available Abstract Background Computational gene prediction continues to be an important problem, especially for genomes with little experimental data. Results I introduce the SNAP gene finder which has been designed to be easily adaptable to a variety of genomes. In novel genomes without an appropriate gene finder, I demonstrate that employing a foreign gene finder can produce highly inaccurate results, and that the most compatible parameters may not come from the nearest phylogenetic neighbor. I find that foreign gene finders are more usefully employed to bootstrap parameter estimation and that the resulting parameters can be highly accurate. Conclusion Since gene prediction is sensitive to species-specific parameters, every genome needs a dedicated gene finder.

  15. Progress in gene targeting and gene therapy for retinitis pigmentosa

    Energy Technology Data Exchange (ETDEWEB)

    Farrar, G.J.; Humphries, M.M.; Erven, A. [Trinity College, Dublin (Ireland)] [and others

    1994-09-01

    Previously, we localized disease genes involved in retinitis pigmentosa (RP), an inherited retinal degeneration, close to the rhodopsin and peripherin genes on 3q and 6p. Subsequently, we and others identified mutations in these genes in RP patients. Currently animal models for human retinopathies are being generated using gene targeting by homologous recombination in embryonic stem (ES) cells. Genomic clones for retinal genes including rhodopsin and peripherin have been obtained from a phage library carrying mouse DNA isogenic with the ES cell line (CC1.2). The peripherin clone has been sequenced to establish the genomic structure of the mouse gene. Targeting vectors for rhodopsin and peripherin including a neomycin cassette for positive selection and thymidine kinase genes enabling selection against random intergrants are under construction. Progress in vector construction will be presented. Simultaneously we are developing systems for delivery of gene therapies to retinal tissues utilizing replication-deficient adenovirus (Ad5). Efficacy of infection subsequent to various methods of intraocular injection and with varying viral titers is being assayed using an adenovirus construct containing a CMV promoter LacZ fusion as reporter and the range of tissues infected and the level of duration of LacZ expression monitored. Viral constructs with the LacZ reporter gene under the control of retinal specific promoters such as rhodopsin and IRBP cloned into pXCJL.1 are under construction. An update on developments in photoreceptor cell-directed expression of virally delivered genes will be presented.

  16. From gene expression to gene regulatory networks in Arabidopsis thaliana.

    Science.gov (United States)

    Needham, Chris J; Manfield, Iain W; Bulpitt, Andrew J; Gilmartin, Philip M; Westhead, David R

    2009-09-03

    The elucidation of networks from a compendium of gene expression data is one of the goals of systems biology and can be a valuable source of new hypotheses for experimental researchers. For Arabidopsis, there exist several thousand microarrays which form a valuable resource from which to learn. A novel Bayesian network-based algorithm to infer gene regulatory networks from gene expression data is introduced and applied to learn parts of the transcriptomic network in Arabidopsis thaliana from a large number (thousands) of separate microarray experiments. Starting from an initial set of genes of interest, a network is grown by iterative addition to the model of the gene, from another defined set of genes, which gives the 'best' learned network structure. The gene set for iterative growth can be as large as the entire genome. A number of networks are inferred and analysed; these show (i) an agreement with the current literature on the circadian clock network, (ii) the ability to model other networks, and (iii) that the learned network hypotheses can suggest new roles for poorly characterized genes, through addition of relevant genes from an unconstrained list of over 15,000 possible genes. To demonstrate the latter point, the method is used to suggest that particular GATA transcription factors are regulators of photosynthetic genes. Additionally, the performance in recovering a known network from different amounts of synthetically generated data is evaluated. Our results show that plausible regulatory networks can be learned from such gene expression data alone. This work demonstrates that network hypotheses can be generated from existing gene expression data for use by experimental biologists.

  17. Gene circuit analysis of the terminal gap gene huckebein.

    Directory of Open Access Journals (Sweden)

    Maksat Ashyraliyev

    2009-10-01

    Full Text Available The early embryo of Drosophila melanogaster provides a powerful model system to study the role of genes in pattern formation. The gap gene network constitutes the first zygotic regulatory tier in the hierarchy of the segmentation genes involved in specifying the position of body segments. Here, we use an integrative, systems-level approach to investigate the regulatory effect of the terminal gap gene huckebein (hkb on gap gene expression. We present quantitative expression data for the Hkb protein, which enable us to include hkb in gap gene circuit models. Gap gene circuits are mathematical models of gene networks used as computational tools to extract regulatory information from spatial expression data. This is achieved by fitting the model to gap gene expression patterns, in order to obtain estimates for regulatory parameters which predict a specific network topology. We show how considering variability in the data combined with analysis of parameter determinability significantly improves the biological relevance and consistency of the approach. Our models are in agreement with earlier results, which they extend in two important respects: First, we show that Hkb is involved in the regulation of the posterior hunchback (hb domain, but does not have any other essential function. Specifically, Hkb is required for the anterior shift in the posterior border of this domain, which is now reproduced correctly in our models. Second, gap gene circuits presented here are able to reproduce mutants of terminal gap genes, while previously published models were unable to reproduce any null mutants correctly. As a consequence, our models now capture the expression dynamics of all posterior gap genes and some variational properties of the system correctly. This is an important step towards a better, quantitative understanding of the developmental and evolutionary dynamics of the gap gene network.

  18. The Caenorhabditis chemoreceptor gene families

    Directory of Open Access Journals (Sweden)

    Robertson Hugh M

    2008-10-01

    Full Text Available Abstract Background Chemoreceptor proteins mediate the first step in the transduction of environmental chemical stimuli, defining the breadth of detection and conferring stimulus specificity. Animal genomes contain families of genes encoding chemoreceptors that mediate taste, olfaction, and pheromone responses. The size and diversity of these families reflect the biology of chemoperception in specific species. Results Based on manual curation and sequence comparisons among putative G-protein-coupled chemoreceptor genes in the nematode Caenorhabditis elegans, we identified approximately 1300 genes and 400 pseudogenes in the 19 largest gene families, most of which fall into larger superfamilies. In the related species C. briggsae and C. remanei, we identified most or all genes in each of the 19 families. For most families, C. elegans has the largest number of genes and C. briggsae the smallest number, suggesting changes in the importance of chemoperception among the species. Protein trees reveal family-specific and species-specific patterns of gene duplication and gene loss. The frequency of strict orthologs varies among the families, from just over 50% in two families to less than 5% in three families. Several families include large species-specific expansions, mostly in C. elegans and C. remanei. Conclusion Chemoreceptor gene families in Caenorhabditis species are large and evolutionarily dynamic as a result of gene duplication and gene loss. These dynamics shape the chemoreceptor gene complements in Caenorhabditis species and define the receptor space available for chemosensory responses. To explain these patterns, we propose the gray pawn hypothesis: individual genes are of little significance, but the aggregate of a large number of diverse genes is required to cover a large phenotype space.

  19. MUTATIONS IN CALMODULIN GENES

    DEFF Research Database (Denmark)

    2013-01-01

    The present invention relates to an isolated polynucleotide encoding at least a part of calmodulin and an isolated polypeptide comprising at least a part of a calmodulin protein, wherein the polynucleotide and the polypeptide comprise at least one mutation associated with a cardiac disorder...... the binding of calmodulin to ryanodine receptor 2 and use of such compound in a treatment of an individual having a cardiac disorder. The invention further provides a kit that can be used to detect specific mutations in calmodulin encoding genes....

  20. LHD 7 (USS Iwo Jima) Human Factors Engineering (HFE)/Safety Ship Design Lessons Learned Report

    Science.gov (United States)

    2007-07-02

    APPENDIX C: Access Aids – Doors and Arches Compartment Name/Number/Type/Equipment(s): Main Galley/Galley - Mess/ Reefer Issue(s)/Hazard(s...Description: Step up into reefer is 11" high. This step height is excessive while moving either in or out of the reefer , especially while material handling... reefer in order to bring the reefer threshold down to the deck height outside of the reefer . If this is not feasible, alternately provide movable

  1. Osteoporosis in HFE2 juvenile hemochromatosis. A case report and review of the literature.

    Science.gov (United States)

    Angelopoulos, Nicholas G; Goula, Anastasia K; Papanikolaou, George; Tolis, George

    2006-01-01

    Juvenile hemochromatosis (JH) is a severe form of hemochromatosis, which involves rapid iron overload and leads to organ damage, typically before the age of 30. We report a single case of a 25-year-old man suffering from juvenile hemochromatosis, with aggressive clinical manifestations, typically characterized by transaminasemia and progressive erectile dysfunction, due to hypogonadotropic hypogonadism. The clinical case appears interesting, as the patient also had secondary osteoporosis accompanied by increased bone resorption, which prevalently affected trabecular bone. Approximately 6 months after normalization of serum ferritin levels was achieved by frequent phlebotomies, he became eugonadal and bone mineral density of the lumbar spine increased. Our observations suggest that osteoporosis might occur in the state of JH even at a young age, mainly due to the deprivation of sex steroids and the direct tissue toxicity of iron.

  2. Gene expression analysis identifies global gene dosage sensitivity in cancer

    DEFF Research Database (Denmark)

    Fehrmann, Rudolf S. N.; Karjalainen, Juha M.; Krajewska, Malgorzata

    2015-01-01

    Many cancer-associated somatic copy number alterations (SCNAs) are known. Currently, one of the challenges is to identify the molecular downstream effects of these variants. Although several SCNAs are known to change gene expression levels, it is not clear whether each individual SCNA affects gene...... expression. We reanalyzed 77,840 expression profiles and observed a limited set of 'transcriptional components' that describe well-known biology, explain the vast majority of variation in gene expression and enable us to predict the biological function of genes. On correcting expression profiles...... for these components, we observed that the residual expression levels (in 'functional genomic mRNA' profiling) correlated strongly with copy number. DNA copy number correlated positively with expression levels for 99% of all abundantly expressed human genes, indicating global gene dosage sensitivity. By applying...

  3. The infinitely many genes model with horizontal gene transfer

    OpenAIRE

    Baumdicker, Franz; Pfaffelhuber, Peter

    2013-01-01

    The genome of bacterial species is much more flexible than that of eukaryotes. Moreover, the distributed genome hypothesis for bacteria states that the total number of genes present in a bacterial population is greater than the genome of every single individual. The pangenome, i.e. the set of all genes of a bacterial species (or a sample), comprises the core genes which are present in all living individuals, and accessory genes, which are carried only by some individuals. In order to use acce...

  4. Are TMEM genes potential candidate genes for panic disorder?

    DEFF Research Database (Denmark)

    NO, Gregersen; Buttenschøn, Henriette Nørmølle; Hedemand, Anne

    2014-01-01

    We analysed single nucleotide polymorphisms in two transmembrane genes (TMEM98 and TMEM132E) in panic disorder (PD) patients and control individuals from the Faroe Islands, Denmark and Germany. The genes encode single-pass membrane proteins and are located within chromosome 17q11.2-q12, a previou......We analysed single nucleotide polymorphisms in two transmembrane genes (TMEM98 and TMEM132E) in panic disorder (PD) patients and control individuals from the Faroe Islands, Denmark and Germany. The genes encode single-pass membrane proteins and are located within chromosome 17q11.2-q12...

  5. Hereditary hemochromatosis: genetic complexity and new diagnostic approaches.

    NARCIS (Netherlands)

    Swinkels, D.W.; Janssen, M.C.H.; Bergmans, J.; Marx, J.J.M.

    2006-01-01

    Since the discovery of the hemochromatosis gene (HFE) in 1996, several novel gene defects have been detected, explaining the mechanism and diversity of iron-overload diseases. At least 4 main types of hereditary hemochromatosis (HH) have been identified. Surprisingly, genes involved in HH encode for

  6. Gene therapy for psychiatric disorders.

    Science.gov (United States)

    Gelfand, Yaroslav; Kaplitt, Michael G

    2013-01-01

    Gene therapy has become of increasing interest in clinical neurosurgery with the completion of numerous clinical trials for Parkinson disease, Alzheimer disease, and pediatric genetic disorders. With improved understanding of the dysfunctional circuitry mediating various psychiatric disorders, deep brain stimulation for refractory psychiatric diseases is being increasingly explored in human patients. These factors are likely to facilitate development of gene therapy for psychiatric diseases. Because delivery of gene therapy agents would require the same surgical techniques currently being employed for deep brain stimulation, neurosurgeons are likely to lead the development of this field, as has occurred in other areas of clinical gene therapy for neurologic disorders. We review the current state of gene therapy for psychiatric disorders and focus specifically on particular areas of promising research that may translate into human trials for depression, drug addiction, obsessive-compulsive disorder, and schizophrenia. Issues that are relatively unique to psychiatric gene therapy are also discussed. Copyright © 2013. Published by Elsevier Inc.

  7. Gene set analysis for GWAS

    DEFF Research Database (Denmark)

    Debrabant, Birgit; Soerensen, Mette

    2014-01-01

    Abstract We discuss the use of modified Kolmogorov-Smirnov (KS) statistics in the context of gene set analysis and review corresponding null and alternative hypotheses. Especially, we show that, when enhancing the impact of highly significant genes in the calculation of the test statistic...... parameter and the genesis and distribution of the gene-level statistics, and illustrate the effects of differential weighting in a real-life example....

  8. A genetic ensemble approach for gene-gene interaction identification

    Directory of Open Access Journals (Sweden)

    Ho Joshua WK

    2010-10-01

    Full Text Available Abstract Background It has now become clear that gene-gene interactions and gene-environment interactions are ubiquitous and fundamental mechanisms for the development of complex diseases. Though a considerable effort has been put into developing statistical models and algorithmic strategies for identifying such interactions, the accurate identification of those genetic interactions has been proven to be very challenging. Methods In this paper, we propose a new approach for identifying such gene-gene and gene-environment interactions underlying complex diseases. This is a hybrid algorithm and it combines genetic algorithm (GA and an ensemble of classifiers (called genetic ensemble. Using this approach, the original problem of SNP interaction identification is converted into a data mining problem of combinatorial feature selection. By collecting various single nucleotide polymorphisms (SNP subsets as well as environmental factors generated in multiple GA runs, patterns of gene-gene and gene-environment interactions can be extracted using a simple combinatorial ranking method. Also considered in this study is the idea of combining identification results obtained from multiple algorithms. A novel formula based on pairwise double fault is designed to quantify the degree of complementarity. Conclusions Our simulation study demonstrates that the proposed genetic ensemble algorithm has comparable identification power to Multifactor Dimensionality Reduction (MDR and is slightly better than Polymorphism Interaction Analysis (PIA, which are the two most popular methods for gene-gene interaction identification. More importantly, the identification results generated by using our genetic ensemble algorithm are highly complementary to those obtained by PIA and MDR. Experimental results from our simulation studies and real world data application also confirm the effectiveness of the proposed genetic ensemble algorithm, as well as the potential benefits of

  9. Gene therapy for hemophilia

    Science.gov (United States)

    Rogers, Geoffrey L.; Herzog, Roland W.

    2015-01-01

    Hemophilia is an X-linked inherited bleeding disorder consisting of two classifications, hemophilia A and hemophilia B, depending on the underlying mutation. Although the disease is currently treatable with intravenous delivery of replacement recombinant clotting factor, this approach represents a significant cost both monetarily and in terms of quality of life. Gene therapy is an attractive alternative approach to the treatment of hemophilia that would ideally provide life-long correction of clotting activity with a single injection. In this review, we will discuss the multitude of approaches that have been explored for the treatment of both hemophilia A and B, including both in vivo and ex vivo approaches with viral and nonviral delivery vectors. PMID:25553466

  10. Introduction: Cancer Gene Networks.

    Science.gov (United States)

    Clarke, Robert

    2017-01-01

    Constructing, evaluating, and interpreting gene networks generally sits within the broader field of systems biology, which continues to emerge rapidly, particular with respect to its application to understanding the complexity of signaling in the context of cancer biology. For the purposes of this volume, we take a broad definition of systems biology. Considering an organism or disease within an organism as a system, systems biology is the study of the integrated and coordinated interactions of the network(s) of genes, their variants both natural and mutated (e.g., polymorphisms, rearrangements, alternate splicing, mutations), their proteins and isoforms, and the organic and inorganic molecules with which they interact, to execute the biochemical reactions (e.g., as enzymes, substrates, products) that reflect the function of that system. Central to systems biology, and perhaps the only approach that can effectively manage the complexity of such systems, is the building of quantitative multiscale predictive models. The predictions of the models can vary substantially depending on the nature of the model and its inputoutput relationships. For example, a model may predict the outcome of a specific molecular reaction(s), a cellular phenotype (e.g., alive, dead, growth arrest, proliferation, and motility), a change in the respective prevalence of cell or subpopulations, a patient or patient subgroup outcome(s). Such models necessarily require computers. Computational modeling can be thought of as using machine learning and related tools to integrate the very high dimensional data generated from modern, high throughput omics technologies including genomics (next generation sequencing), transcriptomics (gene expression microarrays; RNAseq), metabolomics and proteomics (ultra high performance liquid chromatography, mass spectrometry), and "subomic" technologies to study the kinome, methylome, and others. Mathematical modeling can be thought of as the use of ordinary

  11. Pompe disease gene therapy

    Science.gov (United States)

    Byrne, Barry J.; Falk, Darin J.; Pacak, Christina A.; Nayak, Sushrusha; Herzog, Roland W.; Elder, Melissa E.; Collins, Shelley W.; Conlon, Thomas J.; Clement, Nathalie; Cleaver, Brian D.; Cloutier, Denise A.; Porvasnik, Stacy L.; Islam, Saleem; Elmallah, Mai K.; Martin, Anatole; Smith, Barbara K.; Fuller, David D.; Lawson, Lee Ann; Mah, Cathryn S.

    2011-01-01

    Pompe disease is an autosomal recessive metabolic myopathy caused by the deficiency of the lysosomal enzyme acid alpha-glucosidase and results in cellular lysosomal and cytoplasmic glycogen accumulation. A wide spectrum of disease exists from hypotonia and severe cardiac hypertrophy in the first few months of life due to severe mutations to a milder form with the onset of symptoms in adulthood. In either condition, the involvement of several systems leads to progressive weakness and disability. In early-onset severe cases, the natural history is characteristically cardiorespiratory failure and death in the first year of life. Since the advent of enzyme replacement therapy (ERT), the clinical outcomes have improved. However, it has become apparent that a new natural history is being defined in which some patients have substantial improvement following ERT, while others develop chronic disability reminiscent of the late-onset disease. In order to improve on the current clinical outcomes in Pompe patients with diminished clinical response to ERT, we sought to address the cause and potential for the treatment of disease manifestations which are not amenable to ERT. In this review, we will focus on the preclinical studies that are relevant to the development of a gene therapy strategy for Pompe disease, and have led to the first clinical trial of recombinant adeno-associated virus-mediated gene-based therapy for Pompe disease. We will cover the preliminary laboratory studies and rationale for a clinical trial, which is based on the treatment of the high rate of respiratory failure in the early-onset patients receiving ERT. PMID:21518733

  12. Gene therapy for meningioma : improved gene delivery with targeted adenoviruses

    NARCIS (Netherlands)

    Dirven, CMF; Grill, J; Lamfers, MLM; Van der Valk, P; Leonhart, AM; Van Beusechem, VW; Haisma, HJ; Pinedo, HM; Curiel, DT; Vandertop, WP; Gerritsen, WR

    Object. Due to their surgical inaccessibility or aggressive behavior, some meningiomas cannot be cured with current treatment strategies. Gene therapy is an emerging strategy for the treatment of brain tumors, which the authors investigated to determine whether adenoviruses could be used for gene

  13. Gene-gene Interaction Analyses for Atrial Fibrillation

    NARCIS (Netherlands)

    H. Lin (Honghuang); M. Mueller-Nurasyid; A.V. Smith (Albert Vernon); D.E. Arking (Dan); J. Barnard (John); T.M. Bartz (Traci M.); K.L. Lunetta (Kathryn); K. Lohman (Kurt); M.E. Kleber (Marcus); S.A. Lubitz (Steven); Geelhoed, B. (Bastiaan); S. Trompet (Stella); M.N. Niemeijer (Maartje); T. Kacprowski (Tim); D.I. Chasman (Daniel); Klarin, D. (Derek); M.F. Sinner (Moritz); M. Waldenberger (Melanie); T. Meitinger (Thomas); T.B. Harris (Tamara); L.J. Launer (Lenore); E.Z. Soliman (Elsayed Z.); L. Chen (Lin); J.D. Smith (Jonathan); D.R. van Wagoner (David); Rotter, J.I. (Jerome I.); B.M. Psaty (Bruce); Xie, Z. (Zhijun); A.E. Hendricks (Audrey E.); Ding, J. (Jingzhong); G.E. Delgado (Graciela E.); N. Verweij (Niek); P. van der Harst (Pim); P.W. MacFarlane (Peter); I. Ford (Ian); A. Hofman (Albert); A.G. Uitterlinden (André); J. Heeringa (Jan); O.H. Franco (Oscar); J.A. Kors (Jan); Weiss, S. (Stefan); H. Völzke (Henry); L.M. Rose (Lynda); Natarajan, P. (Pradeep); S. Kathiresan (Sekar); S. Kääb (Stefan); V. Gudnason (Vilmundur); A. Alonso (Alvaro); M.K. Chung (Mina); S.R. Heckbert (Susan); E.J. Benjamin (Emelia); Y. Liu (Yongmei); W. März (Winfried); S.A. Rienstra; J.W. Jukema (Jan Wouter); B.H.Ch. Stricker (Bruno); M. Dörr (Marcus); C.M. Albert (Christine); P.T. Ellinor (Patrick)

    2016-01-01

    textabstractAtrial fibrillation (AF) is a heritable disease that affects more than thirty million individuals worldwide. Extensive efforts have been devoted to the study of genetic determinants of AF. The objective of our study is to examine the effect of gene-gene interaction on AF susceptibility.

  14. Gene-gene Interaction Analyses for Atrial Fibrillation

    NARCIS (Netherlands)

    Lin, Honghuang; Mueller-Nurasyid, Martina; Smith, Albert V.; Arking, Dan E.; Barnard, John; Bartz, Traci M.; Lunetta, Kathryn L.; Lohman, Kurt; Kleber, Marcus E.; Lubitz, Steven A.; Geelhoed, Bastiaan; Trompet, Stella; Niemeijer, Maartje N.; Kacprowski, Tim; Chasman, Daniel I.; Klarin, Derek; Sinner, Moritz F.; Waldenberger, Melanie; Meitinger, Thomas; Harris, Tamara B.; Launer, Lenore J.; Soliman, Elsayed Z.; Chen, Lin Y.; Smith, Jonathan D.; Van Wagoner, David R.; Rotter, Jerome I.; Psaty, Bruce M.; Xie, Zhijun; Hendricks, Audrey E.; Ding, Jingzhong; Delgado, Graciela E.; Verweij, Niek; van der Harst, Pim; Macfarlane, Peter W.; Ford, Ian; Hofman, Albert; Uitterlinden, Andre; Heeringa, Jan; Franco, Oscar H.; Kors, Jan A.; Weiss, Stefan; Volzke, Henry; Rose, Lynda M.; Natarajan, Pradeep; Kathiresan, Sekar; Kaab, Stefan; Gudnason, Vilmundur; Alonso, Alvaro; Chung, Mina K.; Heckbert, Susan R.; Benjamin, Emelia J.; Liu, Yongmei; Marz, Winfried; Rienstra, Michiel; Jukema, J. Wouter; Stricker, Bruno H.; Dorr, Marcus; Albert, Christine M.; Ellinor, Patrick T.

    2016-01-01

    Atrial fibrillation (AF) is a heritable disease that affects more than thirty million individuals worldwide. Extensive efforts have been devoted to the study of genetic determinants of AF. The objective of our study is to examine the effect of gene-gene interaction on AF susceptibility. We performed

  15. Classifying genes to the correct Gene Ontology Slim term in Saccharomyces cerevisiae using neighbouring genes with classification learning

    Directory of Open Access Journals (Sweden)

    Tsatsoulis Costas

    2010-05-01

    Full Text Available Abstract Background There is increasing evidence that gene location and surrounding genes influence the functionality of genes in the eukaryotic genome. Knowing the Gene Ontology Slim terms associated with a gene gives us insight into a gene's functionality by informing us how its gene product behaves in a cellular context using three different ontologies: molecular function, biological process, and cellular component. In this study, we analyzed if we could classify a gene in Saccharomyces cerevisiae to its correct Gene Ontology Slim term using information about its location in the genome and information from its nearest-neighbouring genes using classification learning. Results We performed experiments to establish that the MultiBoostAB algorithm using the J48 classifier could correctly classify Gene Ontology Slim terms of a gene given information regarding the gene's location and information from its nearest-neighbouring genes for training. Different neighbourhood sizes were examined to determine how many nearest neighbours should be included around each gene to provide better classification rules. Our results show that by just incorporating neighbour information from each gene's two-nearest neighbours, the percentage of correctly classified genes to their correct Gene Ontology Slim term for each ontology reaches over 80% with high accuracy (reflected in F-measures over 0.80 of the classification rules produced. Conclusions We confirmed that in classifying genes to their correct Gene Ontology Slim term, the inclusion of neighbour information from those genes is beneficial. Knowing the location of a gene and the Gene Ontology Slim information from neighbouring genes gives us insight into that gene's functionality. This benefit is seen by just including information from a gene's two-nearest neighbouring genes.

  16. Electro-acupuncture-mediated gene transfer.

    Science.gov (United States)

    Zhang, J; Qin, Y; Fu, A; Tang, J; Chen, G; Cai, D; Han, J

    1998-10-01

    Gene transfer is one of the key techniques in gene therapy application. Unfortunately, it seems that by now, there still exists no approach with simplicity, easiness, efficiency and safety. A novel method for gene delivery, electro-acupuncture needle-mediated gene transfer which combined the Chinese traditional acupuncture with modem gene introduction, was developed. With acupuncture needle carrying exogenous gene into muscle after direct electronic stimuli, efficient gene delivery was achieved.

  17. Determining Semantically Related Significant Genes.

    Science.gov (United States)

    Taha, Kamal

    2014-01-01

    GO relation embodies some aspects of existence dependency. If GO term xis existence-dependent on GO term y, the presence of y implies the presence of x. Therefore, the genes annotated with the function of the GO term y are usually functionally and semantically related to the genes annotated with the function of the GO term x. A large number of gene set enrichment analysis methods have been developed in recent years for analyzing gene sets enrichment. However, most of these methods overlook the structural dependencies between GO terms in GO graph by not considering the concept of existence dependency. We propose in this paper a biological search engine called RSGSearch that identifies enriched sets of genes annotated with different functions using the concept of existence dependency. We observe that GO term xcannot be existence-dependent on GO term y, if x- and y- have the same specificity (biological characteristics). After encoding into a numeric format the contributions of GO terms annotating target genes to the semantics of their lowest common ancestors (LCAs), RSGSearch uses microarray experiment to identify the most significant LCA that annotates the result genes. We evaluated RSGSearch experimentally and compared it with five gene set enrichment systems. Results showed marked improvement.

  18. Uncovering trends in gene naming

    OpenAIRE

    Seringhaus, Michael R.; Cayting, Philip D; Gerstein, Mark B.

    2008-01-01

    We take stock of current genetic nomenclature and attempt to organize strange and notable gene names. We categorize, for instance, those that involve a naming system transferred from another context (for example, Pavlov’s dogs). We hope this analysis provides clues to better steer gene naming in the future.

  19. Uncovering trends in gene naming.

    Science.gov (United States)

    Seringhaus, Michael R; Cayting, Philip D; Gerstein, Mark B

    2008-01-31

    We take stock of current genetic nomenclature and attempt to organize strange and notable gene names. We categorize, for instance, those that involve a naming system transferred from another context (for example, Pavlov's dogs). We hope this analysis provides clues to better steer gene naming in the future.

  20. Gene Synthesis with HG Khorana

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 17; Issue 12. Gene Synthesis with H G Khorana. Marvin H Caruthers. General Article Volume 17 Issue 12 December 2012 pp ... Keywords. Chemical synthesis of genes for yeast alanine tRNA and E. coli supressor tRNA; Khorana's philosophy on science.

  1. Susceptibility Genes in Thyroid Autoimmunity

    Directory of Open Access Journals (Sweden)

    Yoshiyuki Ban

    2005-01-01

    Full Text Available The autoimmune thyroid diseases (AITD are complex diseases which are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility in combination with external factors (e.g. dietary iodine is believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been employed to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions that are linked with AITD, and in some of these loci, putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD and Hashimoto's thyroiditis (HT and some are common to both the diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g. HLA, CTLA-4 and thyroid specific genes (e.g. TSHR, Tg. Most likely, these loci interact and their interactions may influence disease phenotype and severity.

  2. On meme--gene coevolution.

    Science.gov (United States)

    Bull, L; Holland, O; Blackmore, S

    2000-01-01

    In this article we examine the effects of the emergence of a new replicator, memes, on the evolution of a pre-existing replicator, genes. Using a version of the NKCS model we examine the effects of increasing the rate of meme evolution in relation to the rate of gene evolution, for various degrees of interdependence between the two replicators. That is, the effects of memes' (suggested) more rapid rate of evolution in comparison to that of genes is investigated using a tunable model of coevolution. It is found that, for almost any degree of interdependence between the two replicators, as the rate of meme evolution increases, a phase transition-like dynamic occurs under which memes have a significantly detrimental effect on the evolution of genes, quickly resulting in the cessation of effective gene evolution. Conversely, the memes experience a sharp increase in benefit from increasing their rate of evolution. We then examine the effects of enabling genes to reduce the percentage of gene-detrimental evolutionary steps taken by memes. Here a critical region emerges as the comparative rate of meme evolution increases, such that if genes cannot effectively select memes a high percentage of the time, they suffer from meme evolution as if they had almost no selective capability.

  3. Homeobox gene expression in Brachiopoda

    DEFF Research Database (Denmark)

    Altenburger, Andreas; Martinez, Pedro; Wanninger, Andreas

    2011-01-01

    The molecular control that underlies brachiopod ontogeny is largely unknown. In order to contribute to this issue we analyzed the expression pattern of two homeobox containing genes, Not and Cdx, during development of the rhynchonelliform (i.e., articulate) brachiopod Terebratalia transversa....... Not is a homeobox containing gene that regulates the formation of the notochord in chordates, while Cdx (caudal) is a ParaHox gene involved in the formation of posterior tissues of various animal phyla. The T. transversa homolog, TtrNot, is expressed in the ectoderm from the beginning of gastrulation until...... formation. TtrNot expression is absent in unfertilized eggs, in embryos prior to gastrulation, and in settled individuals during and after metamorphosis. Comparison with the expression patterns of Not genes in other metazoan phyla suggests an ancestral role for this gene in gastrulation and germ layer...

  4. CNS Genes Implicated in Relapse

    Directory of Open Access Journals (Sweden)

    Willard M. Freeman

    2008-01-01

    Full Text Available Drug abuse is a condition that impacts not only the individual drug user, but society as a whole. Although prevention of initial drug use is the most effective way to prevent addiction, avoiding relapse is a crucial component of drug addiction recovery. Recent studies suggest that there is a set of genes whose expression is robustly and stably altered following drug use and ensuing abstinence. Such stable changes in gene expression correlate with ultrastructural changes in brain as well as alterations in behavior. As persistent molecular changes, these genes may provide targets for the development of therapeutics. Developing a list of well-characterized candidate genes and examining the effect of manipulating these genes will contribute to the ultimate goal of developing effective treatments to prevent relapse to drug use.

  5. Gene Discovery Methods from Large-Scale Gene Expression Data

    Science.gov (United States)

    Shimizu, Akifumi; Yano, Kentaro

    2010-01-01

    Microarrays provide genome-wide gene expression changes. In current analyses, the majority of genes on the array are frequently eliminated for further analysis just in order for computational effort to be affordable. This strategy risks failure to discover whole sets of genes related to a quantitative trait of interest, which is generally controlled by several loci that might be eliminated in current approaches. Here, we describe a high-throughput gene discovery method based on correspondence analysis with a new index for expression ratios [arctan (1/ratio)] and three artificial marker genes. This method allows us to quickly analyze the whole microarray dataset without elimination and discover up/down-regulated genes related to a trait of interest. We employed an example dataset to show the theoretical advantage of this method. We then used the method to identify 88 cancer-related genes from a published microarray data from patients with breast cancer. This method can be easily performed and the result is also visible in three-dimensional viewing software that we have developed. Our method is useful for revaluating the wealth of microarray data available from web-sites.

  6. Gene recognition by combination of several gene-finding programs.

    Science.gov (United States)

    Murakami, K; Takagi, T

    1998-01-01

    A number of programs have been developed to predict the eukaryotic gene structures in DNA sequences. However, gene finding is still a challenging problem. We have explored the effectiveness when the results of several gene-finding programs were re-analyzed and combined. We studied several methods with four programs (FEXH, GeneParser3, GEN-SCAN and GRAIL2). By HIGHEST-policy combination method or BOUNDARY method, approximate correlation (AC) improved by 3-5% in comparison with the best single gene-finding program. From another viewpoint, OR-based combination of the four programs is the most reliable to know whether a candidate exon overlaps with the real exon or not, although it is less sensitive than GENSCAN for exon-intron boundaries. Our methods can easily be extended to combine other programs. We have developed a server program (Shirokane System) and a client program (GeneScope) to use the methods. GeneScope is available through a WWW site (http://gf.genome.ad.jp/). (katsu,takagi)@ims.u-tokyo.ac.jp

  7. Reference gene screening for analyzing gene expression across goat tissue.

    Science.gov (United States)

    Zhang, Yu; Zhang, Xiao-Dong; Liu, Xing; Li, Yun-Sheng; Ding, Jian-Ping; Zhang, Xiao-Rong; Zhang, Yun-Hai

    2013-12-01

    Real-time quantitative PCR (qRT-PCR) is one of the important methods for investigating the changes in mRNA expression levels in cells and tissues. Selection of the proper reference genes is very important when calibrating the results of real-time quantitative PCR. Studies on the selection of reference genes in goat tissues are limited, despite the economic importance of their meat and dairy products. We used real-time quantitative PCR to detect the expression levels of eight reference gene candidates (18S, TBP, HMBS, YWHAZ, ACTB, HPRT1, GAPDH and EEF1A2) in ten tissues types sourced from Boer goats. The optimal reference gene combination was selected according to the results determined by geNorm, NormFinder and Bestkeeper software packages. The analyses showed that tissue is an important variability factor in genes expression stability. When all tissues were considered, 18S, TBP and HMBS is the optimal reference combination for calibrating quantitative PCR analysis of gene expression from goat tissues. Dividing data set by tissues, ACTB was the most stable in stomach, small intestine and ovary, 18S in heart and spleen, HMBS in uterus and lung, TBP in liver, HPRT1 in kidney and GAPDH in muscle. Overall, this study provided valuable information about the goat reference genes that can be used in order to perform a proper normalisation when relative quantification by qRT-PCR studies is undertaken.

  8. Reference Gene Screening for Analyzing Gene Expression Across Goat Tissue

    Directory of Open Access Journals (Sweden)

    Yu Zhang

    2013-12-01

    Full Text Available Real-time quantitative PCR (qRT-PCR is one of the important methods for investigating the changes in mRNA expression levels in cells and tissues. Selection of the proper reference genes is very important when calibrating the results of real-time quantitative PCR. Studies on the selection of reference genes in goat tissues are limited, despite the economic importance of their meat and dairy products. We used real-time quantitative PCR to detect the expression levels of eight reference gene candidates (18S, TBP, HMBS, YWHAZ, ACTB, HPRT1, GAPDH and EEF1A2 in ten tissues types sourced from Boer goats. The optimal reference gene combination was selected according to the results determined by geNorm, NormFinder and Bestkeeper software packages. The analyses showed that tissue is an important variability factor in genes expression stability. When all tissues were considered, 18S, TBP and HMBS is the optimal reference combination for calibrating quantitative PCR analysis of gene expression from goat tissues. Dividing data set by tissues, ACTB was the most stable in stomach, small intestine and ovary, 18S in heart and spleen, HMBS in uterus and lung, TBP in liver, HPRT1 in kidney and GAPDH in muscle. Overall, this study provided valuable information about the goat reference genes that can be used in order to perform a proper normalisation when relative quantification by qRT-PCR studies is undertaken.

  9. Phylogenetic analysis of gene expression.

    Science.gov (United States)

    Dunn, Casey W; Luo, Xi; Wu, Zhijin

    2013-11-01

    Phylogenetic analyses of gene expression have great potential for addressing a wide range of questions. These analyses will, for example, identify genes that have evolutionary shifts in expression that are correlated with evolutionary changes in morphological, physiological, and developmental characters of interest. This will provide entirely new opportunities to identify genes related to particular phenotypes. There are, however, 3 key challenges that must be addressed for such studies to realize their potential. First, data on gene expression must be measured from multiple species, some of which may be field-collected, and parameterized in such a way that they can be compared across species. Second, it will be necessary to develop comparative phylogenetic methods suitable for large multidimensional datasets. In most phylogenetic comparative studies to date, the number n of independent observations (independent contrasts) has been greater than the number p of variables (characters). The behavior of comparative methods for these classic problems is now well understood under a wide variety of conditions. In studies of gene expression, and in studies based on other high-throughput tools, the number n of samples is dwarfed by the number p of variables. The estimated covariance matrices will be singular, complicating their analysis and interpretation, and prone to spurious results. Third, new approaches are needed to investigate the expression of the many genes whose phylogenies are not congruent with species phylogenies due to gene loss, gene duplication, and incomplete lineage sorting. Here we outline general considerations of project design for phylogenetic analyses of gene expression and suggest solutions to these three categories of challenges. These topics are relevant to high-throughput phenotypic data well beyond gene expression.

  10. Gene Prediction Using Multinomial Probit Regression with Bayesian Gene Selection

    Science.gov (United States)

    Zhou, Xiaobo; Wang, Xiaodong; Dougherty, Edward R.

    2004-12-01

    A critical issue for the construction of genetic regulatory networks is the identification of network topology from data. In the context of deterministic and probabilistic Boolean networks, as well as their extension to multilevel quantization, this issue is related to the more general problem of expression prediction in which we want to find small subsets of genes to be used as predictors of target genes. Given some maximum number of predictors to be used, a full search of all possible predictor sets is combinatorially prohibitive except for small predictors sets, and even then, may require supercomputing. Hence, suboptimal approaches to finding predictor sets and network topologies are desirable. This paper considers Bayesian variable selection for prediction using a multinomial probit regression model with data augmentation to turn the multinomial problem into a sequence of smoothing problems. There are multiple regression equations and we want to select the same strongest genes for all regression equations to constitute a target predictor set or, in the context of a genetic network, the dependency set for the target. The probit regressor is approximated as a linear combination of the genes and a Gibbs sampler is employed to find the strongest genes. Numerical techniques to speed up the computation are discussed. After finding the strongest genes, we predict the target gene based on the strongest genes, with the coefficient of determination being used to measure predictor accuracy. Using malignant melanoma microarray data, we compare two predictor models, the estimated probit regressors themselves and the optimal full-logic predictor based on the selected strongest genes, and we compare these to optimal prediction without feature selection.

  11. Gene Prediction Using Multinomial Probit Regression with Bayesian Gene Selection

    Directory of Open Access Journals (Sweden)

    Wang Xiaodong

    2004-01-01

    Full Text Available A critical issue for the construction of genetic regulatory networks is the identification of network topology from data. In the context of deterministic and probabilistic Boolean networks, as well as their extension to multilevel quantization, this issue is related to the more general problem of expression prediction in which we want to find small subsets of genes to be used as predictors of target genes. Given some maximum number of predictors to be used, a full search of all possible predictor sets is combinatorially prohibitive except for small predictors sets, and even then, may require supercomputing. Hence, suboptimal approaches to finding predictor sets and network topologies are desirable. This paper considers Bayesian variable selection for prediction using a multinomial probit regression model with data augmentation to turn the multinomial problem into a sequence of smoothing problems. There are multiple regression equations and we want to select the same strongest genes for all regression equations to constitute a target predictor set or, in the context of a genetic network, the dependency set for the target. The probit regressor is approximated as a linear combination of the genes and a Gibbs sampler is employed to find the strongest genes. Numerical techniques to speed up the computation are discussed. After finding the strongest genes, we predict the target gene based on the strongest genes, with the coefficient of determination being used to measure predictor accuracy. Using malignant melanoma microarray data, we compare two predictor models, the estimated probit regressors themselves and the optimal full-logic predictor based on the selected strongest genes, and we compare these to optimal prediction without feature selection.

  12. Therapeutic genes for anti-HIV/AIDS gene therapy.

    Science.gov (United States)

    Bovolenta, Chiara; Porcellini, Simona; Alberici, Luca

    2013-01-01

    The multiple therapeutic approaches developed so far to cope HIV-1 infection, such as anti-retroviral drugs, germicides and several attempts of therapeutic vaccination have provided significant amelioration in terms of life-quality and survival rate of AIDS patients. Nevertheless, no approach has demonstrated efficacy in eradicating this lethal, if untreated, infection. The curative power of gene therapy has been proven for the treatment of monogenic immunodeficiensies, where permanent gene modification of host cells is sufficient to correct the defect for life-time. No doubt, a similar concept is not applicable for gene therapy of infectious immunodeficiensies as AIDS, where there is not a single gene to be corrected; rather engineered cells must gain immunotherapeutic or antiviral features to grant either short- or long-term efficacy mostly by acquisition of antiviral genes or payloads. Anti-HIV/AIDS gene therapy is one of the most promising strategy, although challenging, to eradicate HIV-1 infection. In fact, genetic modification of hematopoietic stem cells with one or multiple therapeutic genes is expected to originate blood cell progenies resistant to viral infection and thereby able to prevail on infected unprotected cells. Ultimately, protected cells will re-establish a functional immune system able to control HIV-1 replication. More than hundred gene therapy clinical trials against AIDS employing different viral vectors and transgenes have been approved or are currently ongoing worldwide. This review will overview anti-HIV-1 infection gene therapy field evaluating strength and weakness of the transgenes and payloads used in the past and of those potentially exploitable in the future.

  13. Evidence based selection of housekeeping genes

    NARCIS (Netherlands)

    de Jonge, Hendrik J. M.; Fehrmann, Rudolf S. N.; de Bont, Eveline S. J. M.; Hofstra, Robert M. W.; Gerbens, Frans; Kamps, Willem A.; de Vries, Elisabeth G. E.; van der Zee, Ate G. J.; te Meerman, Gerard J.; ter Elst, Arja

    2007-01-01

    For accurate and reliable gene expression analysis, normalization of gene expression data against housekeeping genes (reference or internal control genes) is required. It is known that commonly used housekeeping genes (e. g. ACTB, GAPDH, HPRT1, and B2M) vary considerably under different experimental

  14. Human Lacrimal Gland Gene Expression.

    Directory of Open Access Journals (Sweden)

    Vinay Kumar Aakalu

    Full Text Available The study of human lacrimal gland biology and development is limited. Lacrimal gland tissue is damaged or poorly functional in a number of disease states including dry eye disease. Development of cell based therapies for lacrimal gland diseases requires a better understanding of the gene expression and signaling pathways in lacrimal gland. Differential gene expression analysis between lacrimal gland and other embryologically similar tissues may be helpful in furthering our understanding of lacrimal gland development.We performed global gene expression analysis of human lacrimal gland tissue using Affymetrix ® gene expression arrays. Primary data from our laboratory was compared with datasets available in the NLM GEO database for other surface ectodermal tissues including salivary gland, skin, conjunctiva and corneal epithelium.The analysis revealed statistically significant difference in the gene expression of lacrimal gland tissue compared to other ectodermal tissues. The lacrimal gland specific, cell surface secretory protein encoding genes and critical signaling pathways which distinguish lacrimal gland from other ectodermal tissues are described.Differential gene expression in human lacrimal gland compared with other ectodermal tissue types revealed interesting patterns which may serve as the basis for future studies in directed differentiation among other areas.

  15. GENES IN SPORT AND DOPING

    Science.gov (United States)

    Kaliszewski, P.; Majorczyk, E.; Zembroń-Łacny, A.

    2013-01-01

    Genes control biological processes such as muscle production of energy, mitochondria biogenesis, bone formation, erythropoiesis, angiogenesis, vasodilation, neurogenesis, etc. DNA profiling for athletes reveals genetic variations that may be associated with endurance ability, muscle performance and power exercise, tendon susceptibility to injuries and psychological aptitude. Already, over 200 genes relating to physical performance have been identified by several research groups. Athletes’ genotyping is developing as a tool for the formulation of personalized training and nutritional programmes to optimize sport training as well as for the prediction of exercise-related injuries. On the other hand, development of molecular technology and gene therapy creates a risk of non-therapeutic use of cells, genes and genetic elements to improve athletic performance. Therefore, the World Anti-Doping Agency decided to include prohibition of gene doping within their World Anti-Doping Code in 2003. In this review article, we will provide a current overview of genes for use in athletes’ genotyping and gene doping possibilities, including their development and detection techniques. PMID:24744482

  16. GENES IN SPORT AND DOPING

    Directory of Open Access Journals (Sweden)

    Andrzej Pokrywka

    2013-06-01

    Full Text Available Genes control biological processes such as muscle production of energy, mitochondria biogenesis, bone formation erythropoiesis, angiogenesis, vasodilation, neurogenesis, etc. DNA profiling for athletes reveals genetic variations that may be associated with endurance ability, muscle performance and power exercise, tendon susceptibility to injuries and psychological aptitude. Already, over 200 genes relating to physical performance have been identified by several research groups. Athletes’ genotyping is developing as a tool for the formulation of personalized training and nutritional programmes to optimize sport training as well as for the prediction of exercise-related injuries. On the other hand, development of molecular technology and gene therapy creates a risk of non-therapeutic use of cells, genes and genetic elements to improve athletic performance. Therefore, the World Anti-Doping Agency decided to include prohibition of gene doping within their World Anti-Doping Code in 2003. In this review article, we will provide a current overview of genes for use in athletes’ genotyping and gene doping possibilities, including their development and detection techniques.

  17. Gene expression profiles in skeletal muscle after gene electrotransfer

    DEFF Research Database (Denmark)

    Hojman, Pernille; Zibert, John R; Gissel, Hanne

    2007-01-01

    BACKGROUND: Gene transfer by electroporation (DNA electrotransfer) to muscle results in high level long term transgenic expression, showing great promise for treatment of e.g. protein deficiency syndromes. However little is known about the effects of DNA electrotransfer on muscle fibres. We have...... therefore investigated transcriptional changes through gene expression profile analyses, morphological changes by histological analysis, and physiological changes by force generation measurements. DNA electrotransfer was obtained using a combination of a short high voltage pulse (HV, 1000 V/cm, 100 mus......) followed by a long low voltage pulse (LV, 100 V/cm, 400 ms); a pulse combination optimised for efficient and safe gene transfer. Muscles were transfected with green fluorescent protein (GFP) and excised at 4 hours, 48 hours or 3 weeks after treatment. RESULTS: Differentially expressed genes were...

  18. Cloning and selection of reference genes for gene expression ...

    African Journals Online (AJOL)

    Full length mRNA sequences of Ac-β-actin and Ac-gapdh, and partial mRNA sequences of Ac-18SrRNA and Ac-ubiquitin were cloned from pineapple in this study. The four genes were tested as housekeeping genes in three experimental sets. GeNorm and NormFinder analysis revealed that β-actin was the most ...

  19. Gene therapy of cancer by vaccines carrying inserted immunostimulatory genes

    Czech Academy of Sciences Publication Activity Database

    Bubeník, Jan

    2007-01-01

    Roč. 53, č. 3 (2007), s. 71-73 ISSN 0015-5500 Grant - others:EU-FP6 NoE Clinigene(XE) 018933; Liga proti rakovině, Praha(CZ) XX Institutional research plan: CEZ:AV0Z50520514 Keywords : gene therapy * immunostimulatory genes * vaccine Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.596, year: 2007

  20. Correction of gene expression data

    DEFF Research Database (Denmark)

    Darbani Shirvanehdeh, Behrooz; Stewart, C. Neal, Jr.; Noeparvar, Shahin

    2014-01-01

    This report investigates for the first time the potential inter-treatment bias source of cell number for gene expression studies. Cell-number bias can affect gene expression analysis when comparing samples with unequal total cellular RNA content or with different RNA extraction efficiencies....... For maximal reliability of analysis, therefore, comparisons should be performed at the cellular level. This could be accomplished using an appropriate correction method that can detect and remove the inter-treatment bias for cell-number. Based on inter-treatment variations of reference genes, we introduce...

  1. Gene Therapy Approaches to Hemoglobinopathies.

    Science.gov (United States)

    Ferrari, Giuliana; Cavazzana, Marina; Mavilio, Fulvio

    2017-10-01

    Gene therapy for hemoglobinopathies is currently based on transplantation of autologous hematopoietic stem cells genetically modified with a lentiviral vector expressing a globin gene under the control of globin transcriptional regulatory elements. Preclinical and early clinical studies showed the safety and potential efficacy of this therapeutic approach as well as the hurdles still limiting its general application. In addition, for both beta-thalassemia and sickle cell disease, an altered bone marrow microenvironment reduces the efficiency of stem cell harvesting as well as engraftment. These hurdles need be addressed for gene therapy for hemoglobinopathies to become a clinical reality. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Panspermia and horizontal gene transfer

    Science.gov (United States)

    Klyce, Brig

    2009-08-01

    Evidence that extremophiles are hardy and ubiquitous is helping to make panspermia a respectable theory. But even if life on Earth originally came from space, biologists assume that the subsequent evolution of life is still governed by the darwinian paradigm. In this review we show how panspermia could amend darwinism and point to a cosmic source for, not only extremophiles but, all of life. This version of panspermia can be called "strong panspermia." To support this theory we will discuss recent evidence pertaining to horizontal gene transfer, viruses, genes apparently older than the Earthly evolution of the features they encode, and primate-specific genes without identifiable precursors.

  3. Genomics screens for metastasis genes

    Science.gov (United States)

    Yan, Jinchun; Huang, Qihong

    2014-01-01

    Metastasis is responsible for most cancer mortality. The process of metastasis is complex, requiring the coordinated expression and fine regulation of many genes in multiple pathways in both the tumor and host tissues. Identification and characterization of the genetic programs that regulate metastasis is critical to understanding the metastatic process and discovering molecular targets for the prevention and treatment of metastasis. Genomic approaches and functional genomic analyses can systemically discover metastasis genes. In this review, we summarize the genetic tools and methods that have been used to identify and characterize the genes that play critical roles in metastasis. PMID:22684367

  4. American Society of Gene & Cell Therapy

    Science.gov (United States)

    ... Chicago Learn More Close The American Society of Gene & Cell Therapy ASGCT is the primary membership organization for scientists, ... Therapeutics Official Journal of the American Society of Gene & Cell Therapy Molecular Therapy is the leading journal for gene ...

  5. Gene Expression Analysis of Breast Cancer Progression

    National Research Council Canada - National Science Library

    Gerald, Wiliam L

    2004-01-01

    ... to identify genes, gene expression profiles and molecular pathways associated with metastatic BC we have performed genome-wide gene expression analysis of a large number of breast cancer samples...

  6. Novel genes in LDL metabolism

    DEFF Research Database (Denmark)

    Christoffersen, Mette; Tybjærg-Hansen, Anne

    2015-01-01

    PURPOSE OF REVIEW: To summarize recent findings from genome-wide association studies (GWAS), whole-exome sequencing of patients with familial hypercholesterolemia and 'exome chip' studies pointing to novel genes in LDL metabolism. RECENT FINDINGS: The genetic loci for ATP-binding cassette......-exome sequencing and 'exome chip' studies have additionally suggested several novel genes in LDL metabolism including insulin-induced gene 2, signal transducing adaptor family member 1, lysosomal acid lipase A, patatin-like phospholipase domain-containing protein 5 and transmembrane 6 superfamily member 2. Most...... of these findings still require independent replications and/or functional studies to confirm the exact role in LDL metabolism and the clinical implications for human health. SUMMARY: GWAS, exome sequencing studies, and recently 'exome chip' studies have suggested several novel genes with effects on LDL cholesterol...

  7. Candidate genes in panic disorder

    DEFF Research Database (Denmark)

    Howe, A. S.; Buttenschön, Henriette N; Bani-Fatemi, A.

    2016-01-01

    The utilization of molecular genetics approaches in examination of panic disorder (PD) has implicated several variants as potential susceptibility factors for panicogenesis. However, the identification of robust PD susceptibility genes has been complicated by phenotypic diversity, underpowered...

  8. Sleep deprivation and gene expression.

    Science.gov (United States)

    da Costa Souza, Annie; Ribeiro, Sidarta

    2015-01-01

    Sleep occurs in a wide range of animal species as a vital process for the maintenance of homeostasis, metabolic restoration, physiological regulation, and adaptive cognitive functions in the central nervous system. Long-term perturbations induced by the lack of sleep are mostly mediated by changes at the level of transcription and translation. This chapter reviews studies in humans, rodents, and flies to address the various ways by which sleep deprivation affects gene expression in the nervous system, with a focus on genes related to neuronal plasticity, brain function, and cognition. However, the effects of sleep deprivation on gene expression and the functional consequences of sleep loss are clearly not restricted to the cognitive domain but may include increased inflammation, expression of stress-related genes, general impairment of protein translation, metabolic imbalance, and thermal deregulation.

  9. Gene Therapy for Parkinson's Disease

    Directory of Open Access Journals (Sweden)

    Rachel Denyer

    2012-01-01

    Full Text Available Current pharmacological and surgical treatments for Parkinson's disease offer symptomatic improvements to those suffering from this incurable degenerative neurological disorder, but none of these has convincingly shown effects on disease progression. Novel approaches based on gene therapy have several potential advantages over conventional treatment modalities. These could be used to provide more consistent dopamine supplementation, potentially providing superior symptomatic relief with fewer side effects. More radically, gene therapy could be used to correct the imbalances in basal ganglia circuitry associated with the symptoms of Parkinson's disease, or to preserve or restore dopaminergic neurons lost during the disease process itself. The latter neuroprotective approach is the most exciting, as it could theoretically be disease modifying rather than simply symptom alleviating. Gene therapy agents using these approaches are currently making the transition from the laboratory to the bedside. This paper summarises the theoretical approaches to gene therapy for Parkinson's disease and the findings of clinical trials in this rapidly changing field.

  10. Deregulated genes in sporadic vestibular schwannomas

    DEFF Research Database (Denmark)

    Cayé-Thomasen, Per; Helweg-Larsen, Rehannah Holga Andrea; Stangerup, Sven-Eric

    2010-01-01

    In search of genes associated with vestibular schwannoma tumorigenesis, this study examines the gene expression in human vestibular nerve versus vestibular schwannoma tissue samples using microarray technology....

  11. Gene expression based cancer classification

    OpenAIRE

    Sara Tarek; Reda Abd Elwahab; Mahmoud Shoman

    2017-01-01

    Cancer classification based on molecular level investigation has gained the interest of researches as it provides a systematic, accurate and objective diagnosis for different cancer types. Several recent researches have been studying the problem of cancer classification using data mining methods, machine learning algorithms and statistical methods to reach an efficient analysis for gene expression profiles. Studying the characteristics of thousands of genes simultaneously offered a deep in...

  12. Transgenic Arabidopsis Gene Expression System

    Science.gov (United States)

    Ferl, Robert; Paul, Anna-Lisa

    2009-01-01

    The Transgenic Arabidopsis Gene Expression System (TAGES) investigation is one in a pair of investigations that use the Advanced Biological Research System (ABRS) facility. TAGES uses Arabidopsis thaliana, thale cress, with sensor promoter-reporter gene constructs that render the plants as biomonitors (an organism used to determine the quality of the surrounding environment) of their environment using real-time nondestructive Green Fluorescent Protein (GFP) imagery and traditional postflight analyses.

  13. Gene mutations in hepatocellular adenomas

    DEFF Research Database (Denmark)

    Raft, Marie B; Jørgensen, Ernö N; Vainer, Ben

    2015-01-01

    is associated with bi-allelic mutations in the TCF1 gene and morphologically has marked steatosis. β-catenin activating HCA has increased activity of the Wnt/β-catenin pathway and is associated with possible malignant transformation. Inflammatory HCA is characterized by an oncogene-induced inflammation due....... This review offers an overview of the reported gene mutations associated with hepatocellular adenomas together with a discussion of the diagnostic and prognostic value....

  14. Rice Multi-Gene Analysis

    Indian Academy of Sciences (India)

    gdyang

    Maps of all the intronic MIR genes analyzed using MPSS database in rice. Click here for a legend that explains the icons and colors in the image below. Click here to jump in the page below to the specific gene. osa-MIR159f osa-MIR399i osa-MIR418 osa-MIR437 osa-MIR439b osa-MIR439j osa-MIR440 osa-MIR442.

  15. Degradable Polymers for Gene Delivery

    Science.gov (United States)

    Sunshine, Joel; Bhise, Nupura; Green, Jordan J.

    2014-01-01

    Degradable polymers were synthesized that self-assemble with DNA to form particles that are effective for gene delivery. Small changes to polymer synthesis conditions, particle formulation conditions, and polymer structure led to significant changes to efficacy in a cell-type dependent manner. Polymers presented here are more effective than Lipofectamine 2000 or polyethylenimine for gene delivery to cancerous fibroblasts or human primary fibroblasts. These materials may be useful for cancer therapeutics and regenerative medicine. PMID:19964958

  16. Cationic Bolaamphiphiles for Gene Delivery

    Science.gov (United States)

    Tan, Amelia Li Min; Lim, Alisa Xue Ling; Zhu, Yiting; Yang, Yi Yan; Khan, Majad

    2014-05-01

    Advances in medical research have shed light on the genetic cause of many human diseases. Gene therapy is a promising approach which can be used to deliver therapeutic genes to treat genetic diseases at its most fundamental level. In general, nonviral vectors are preferred due to reduced risk of immune response, but they are also commonly associated with low transfection efficiency and high cytotoxicity. In contrast to viral vectors, nonviral vectors do not have a natural mechanism to overcome extra- and intracellular barriers when delivering the therapeutic gene into cell. Hence, its design has been increasingly complex to meet challenges faced in targeting of, penetration of and expression in a specific host cell in achieving more satisfactory transfection efficiency. Flexibility in design of the vector is desirable, to enable a careful and controlled manipulation of its properties and functions. This can be met by the use of bolaamphiphile, a special class of lipid. Unlike conventional lipids, bolaamphiphiles can form asymmetric complexes with the therapeutic gene. The advantage of having an asymmetric complex lies in the different purposes served by the interior and exterior of the complex. More effective gene encapsulation within the interior of the complex can be achieved without triggering greater aggregation of serum proteins with the exterior, potentially overcoming one of the great hurdles faced by conventional single-head cationic lipids. In this review, we will look into the physiochemical considerations as well as the biological aspects of a bolaamphiphile-based gene delivery system.

  17. ASPM gene expression in medulloblastoma.

    Science.gov (United States)

    Vulcani-Freitas, Tânia M; Saba-Silva, Najsla; Cappellano, Andréa; Cavalheiro, Sérgio; Marie, Sueli K N; Oba-Shinjo, Sueli M; Malheiros, Suzana M F; de Toledo, Sílvia Regina Caminada

    2011-01-01

    Medulloblastomas are the most common malignant tumors of the central nervous system in childhood. The incidence is about 19-20% between children younger than 16 years old with peak incidence between 4 and 7 years. Despite its sensibility to no specific therapeutic means like chemotherapy and radiotherapy, the treatment is very aggressive and frequently results in regression, growth deficit, and endocrine dysfunction. From this point of view, new treatment approaches are needed such as molecular targeted therapies. Studies in glioblastoma demonstrated that ASPM gene was overexpressed when compared to normal brain and ASPM inhibition by siRNA-mediated inhibits tumor cell proliferation and neural stem cell proliferation, supporting ASPM gene as a potential molecular target in glioblastoma. The aim of this work was to evaluate ASPM expression in medulloblastoma fragment samples, and to compare the results with the patient clinical features. Analysis of gene expression was performed by quantitative PCR real time using SYBR Green system in tumor samples from 37 children. The t test was used to analyze the gene expression, and Mann-Whitney test was performed to analyze the relationship between gene expressions and clinical characteristics. Kaplan-Meier test evaluated curve survival. All samples overexpressed ASPM gene more than 40-fold. However, we did not find any association between the overexpressed samples and the clinical parameters. ASPM overexpression may modify the ability of stem cells to differentiate during the development of the central nervous system, contributing to the development of medulloblastoma, a tumor of embryonic origin from cerebellar progenitor cells.

  18. New Gene Evolution: Little Did We Know

    Science.gov (United States)

    Long, Manyuan; VanKuren, Nicholas W.; Chen, Sidi; Vibranovski, Maria D.

    2014-01-01

    Genes are perpetually added to and deleted from genomes during evolution. Thus, it is important to understand how new genes are formed and evolve as critical components of the genetic systems determining the biological diversity of life. Two decades of effort have shed light on the process of new gene origination, and have contributed to an emerging comprehensive picture of how new genes are added to genomes, ranging from the mechanisms that generate new gene structures to the presence of new genes in different organisms to the rates and patterns of new gene origination and the roles of new genes in phenotypic evolution. We review each of these aspects of new gene evolution, summarizing the main evidence for the origination and importance of new genes in evolution. We highlight findings showing that new genes rapidly change existing genetic systems that govern various molecular, cellular and phenotypic functions. PMID:24050177

  19. Novel gene transfer systems: intelligent gene transfer vectors for gene medicines.

    Science.gov (United States)

    Nakajima, Toshihiro

    2012-01-01

    Drug delivery systems for gene transfer are called 'vectors'. These systems were originally invented as a delivery system for the transfection in vitro or in vivo. Several vectors are then developed for clinical use of gene medicines and currently some of them are approved as animal drugs. Conventional drug delivery system generally consists of approved (existing) materials to avoid additional pre-clinical or clinical studies. However, current vectors contain novel materials to improve an efficacy of gene medicines. Thus, these vectors have functions more than a mere delivery of active ingredients. For example some vectors have immunological functions such as adjuvants in vaccines. These new types of vectors are called 'intelligent' or 'innovative' vector system', since the concept or strategy for the development is completely different from conventional drug delivery systems. In this article, we described a current status of 'intelligent gene transfer vectors and discussed on the potentials of them.

  20. The biology of novel animal genes: Mouse APEX gene knockout

    Energy Technology Data Exchange (ETDEWEB)

    MacInnes, M.; Altherr, M.R.; Ludwig, D. [Los Alamos National Lab., NM (United States); Pedersen, R.; Mold, C. [Univ. of California, San Francisco, CA (United States)

    1997-07-01

    This is the final report of a one-year, Laboratory Directed Research and Development (LDRD) project at the Los Alamos National Laboratory (LANL). The controlled breeding of novel genes into mice, including the gene knockout (KO), or conversely by adding back transgenes provide powerful genetic technologies that together suffice to determine in large part the biological role(s) of novel genes. Inbred mouse remains the best understood and most useful mammalian experimental system available for tackling the biology of novel genes. The major mammalian apurinic/apyrimidinic (AP) endonuclease (APE), is involved in a key step in the repair of spontaneous and induced AP sites in DNA. Efficient repair of these lesions is imperative to prevent the stable incorporation of mutations into the cellular genome which may lead to cell death or transformation. Loss or modulation of base excison repair activity in vivo may elevate the spontaneous mutation rate in cells, and may lead to a substantial increase in the incidence of cancer. Despite extensive biochemical analysis, however, the significance of these individual APE functions in vivo has not been elucidated. Mouse embryonic stem (ES) cells heterozygous for a deletion mutation in APE have been generated and whole animals containing the APE mutation have been derived from these ES cells. Animals homozygous for the APE null mutation die early in gestation, underscoring the biological significance of this DNA repair gene.

  1. Newer Gene Editing Technologies toward HIV Gene Therapy

    Directory of Open Access Journals (Sweden)

    Premlata Shankar

    2013-11-01

    Full Text Available Despite the great success of highly active antiretroviral therapy (HAART in ameliorating the course of HIV infection, alternative therapeutic approaches are being pursued because of practical problems associated with life-long therapy. The eradication of HIV in the so-called “Berlin patient” who received a bone marrow transplant from a CCR5-negative donor has rekindled interest in genome engineering strategies to achieve the same effect. Precise gene editing within the cells is now a realistic possibility with recent advances in understanding the DNA repair mechanisms, DNA interaction with transcription factors and bacterial defense mechanisms. Within the past few years, four novel technologies have emerged that can be engineered for recognition of specific DNA target sequences to enable site-specific gene editing: Homing Endonuclease, ZFN, TALEN, and CRISPR/Cas9 system. The most recent CRISPR/Cas9 system uses a short stretch of complementary RNA bound to Cas9 nuclease to recognize and cleave target DNA, as opposed to the previous technologies that use DNA binding motifs of either zinc finger proteins or transcription activator-like effector molecules fused to an endonuclease to mediate sequence-specific DNA cleavage. Unlike RNA interference, which requires the continued presence of effector moieties to maintain gene silencing, the newer technologies allow permanent disruption of the targeted gene after a single treatment. Here, we review the applications, limitations and future prospects of novel gene-editing strategies for use as HIV therapy.

  2. Reduced rates of gene loss, gene silencing, and gene mutation in Dnmt1-deficient embryonic stem cells

    NARCIS (Netherlands)

    Chan, M.F.; van Amerongen, R.; Nijjar, T.; Cuppen, E.; Jones, P.A.; Laird, P.W.

    2001-01-01

    Tumor suppressor gene inactivation is a crucial event in oncogenesis. Gene inactivation mechanisms include events resulting in loss of heterozygosity (LOH), gene mutation, and transcriptional silencing. The contribution of each of these different pathways varies among tumor suppressor genes and by

  3. PoplarGene: poplar gene network and resource for mining functional information for genes from woody plants.

    Science.gov (United States)

    Liu, Qi; Ding, Changjun; Chu, Yanguang; Chen, Jiafei; Zhang, Weixi; Zhang, Bingyu; Huang, Qinjun; Su, Xiaohua

    2016-08-12

    Poplar is not only an important resource for the production of paper, timber and other wood-based products, but it has also emerged as an ideal model system for studying woody plants. To better understand the biological processes underlying various traits in poplar, e.g., wood development, a comprehensive functional gene interaction network is highly needed. Here, we constructed a genome-wide functional gene network for poplar (covering ~70% of the 41,335 poplar genes) and created the network web service PoplarGene, offering comprehensive functional interactions and extensive poplar gene functional annotations. PoplarGene incorporates two network-based gene prioritization algorithms, neighborhood-based prioritization and context-based prioritization, which can be used to perform gene prioritization in a complementary manner. Furthermore, the co-functional information in PoplarGene can be applied to other woody plant proteomes with high efficiency via orthology transfer. In addition to poplar gene sequences, the webserver also accepts Arabidopsis reference gene as input to guide the search for novel candidate functional genes in PoplarGene. We believe that PoplarGene (http://bioinformatics.caf.ac.cn/PoplarGene and http://124.127.201.25/PoplarGene) will greatly benefit the research community, facilitating studies of poplar and other woody plants.

  4. RNA-Seq Analysis of Abdominal Fat Reveals Differences between Modern Commercial Broiler Chickens with High and Low Feed Efficiencies.

    Directory of Open Access Journals (Sweden)

    Zhu Zhuo

    Full Text Available For economic and environmental reasons, chickens with superior feed efficiency (FE are preferred in the broiler chicken industry. High FE (HFE chickens typically have reduced abdominal fat, the major adipose tissue in chickens. In addition to its function of energy storage, adipose tissue is a metabolically active organ that also possesses endocrine and immune regulatory functions. It plays a central role in maintaining energy homeostasis. Comprehensive understanding of the gene expression in the adipose tissue and the biological basis of FE are of significance to optimize selection and breeding strategies. Through gene expression profiling of abdominal fat from high and low FE (LFE commercial broiler chickens, the present study aimed to characterize the differences of gene expression between HFE and LFE chickens. mRNA-seq analysis was carried out on the total RNA of abdominal fat from 10 HFE and 12 LFE commercial broiler chickens, and 1.48 billion of 75-base sequence reads were generated in total. On average, 11,565 genes were expressed (>5 reads/gene/sample in the abdominal fat tissue, of which 286 genes were differentially expressed (DE at q (False Discover Rate 1.3 between HFE and LFE chickens. Expression levels from RNA-seq were confirmed with the NanoString nCounter analysis system. Functional analysis showed that the DE genes were significantly (p < 0.01 enriched in lipid metabolism, coagulation, and immune regulation pathways. Specifically, the LFE chickens had higher expression of lipid synthesis genes and lower expression of triglyceride hydrolysis and cholesterol transport genes. In conclusion, our study reveals the overall differences of gene expression in the abdominal fat from HFE and LFE chickens, and the results suggest that the divergent expression of lipid metabolism genes represents the major differences.

  5. Combining gene prediction methods to improve metagenomic gene annotation

    Directory of Open Access Journals (Sweden)

    Rosen Gail L

    2011-01-01

    Full Text Available Abstract Background Traditional gene annotation methods rely on characteristics that may not be available in short reads generated from next generation technology, resulting in suboptimal performance for metagenomic (environmental samples. Therefore, in recent years, new programs have been developed that optimize performance on short reads. In this work, we benchmark three metagenomic gene prediction programs and combine their predictions to improve metagenomic read gene annotation. Results We not only analyze the programs' performance at different read-lengths like similar studies, but also separate different types of reads, including intra- and intergenic regions, for analysis. The main deficiencies are in the algorithms' ability to predict non-coding regions and gene edges, resulting in more false-positives and false-negatives than desired. In fact, the specificities of the algorithms are notably worse than the sensitivities. By combining the programs' predictions, we show significant improvement in specificity at minimal cost to sensitivity, resulting in 4% improvement in accuracy for 100 bp reads with ~1% improvement in accuracy for 200 bp reads and above. To correctly annotate the start and stop of the genes, we find that a consensus of all the predictors performs best for shorter read lengths while a unanimous agreement is better for longer read lengths, boosting annotation accuracy by 1-8%. We also demonstrate use of the classifier combinations on a real dataset. Conclusions To optimize the performance for both prediction and annotation accuracies, we conclude that the consensus of all methods (or a majority vote is the best for reads 400 bp and shorter, while using the intersection of GeneMark and Orphelia predictions is the best for reads 500 bp and longer. We demonstrate that most methods predict over 80% coding (including partially coding reads on a real human gut sample sequenced by Illumina technology.

  6. COGNATE: comparative gene annotation characterizer.

    Science.gov (United States)

    Wilbrandt, Jeanne; Misof, Bernhard; Niehuis, Oliver

    2017-07-17

    The comparison of gene and genome structures across species has the potential to reveal major trends of genome evolution. However, such a comparative approach is currently hampered by a lack of standardization (e.g., Elliott TA, Gregory TR, Philos Trans Royal Soc B: Biol Sci 370:20140331, 2015). For example, testing the hypothesis that the total amount of coding sequences is a reliable measure of potential proteome diversity (Wang M, Kurland CG, Caetano-Anollés G, PNAS 108:11954, 2011) requires the application of standardized definitions of coding sequence and genes to create both comparable and comprehensive data sets and corresponding summary statistics. However, such standard definitions either do not exist or are not consistently applied. These circumstances call for a standard at the descriptive level using a minimum of parameters as well as an undeviating use of standardized terms, and for software that infers the required data under these strict definitions. The acquisition of a comprehensive, descriptive, and standardized set of parameters and summary statistics for genome publications and further analyses can thus greatly benefit from the availability of an easy to use standard tool. We developed a new open-source command-line tool, COGNATE (Comparative Gene Annotation Characterizer), which uses a given genome assembly and its annotation of protein-coding genes for a detailed description of the respective gene and genome structure parameters. Additionally, we revised the standard definitions of gene and genome structures and provide the definitions used by COGNATE as a working draft suggestion for further reference. Complete parameter lists and summary statistics are inferred using this set of definitions to allow down-stream analyses and to provide an overview of the genome and gene repertoire characteristics. COGNATE is written in Perl and freely available at the ZFMK homepage ( https://www.zfmk.de/en/COGNATE ) and on github ( https

  7. Technology evaluation: HIV ribozyme gene therapy, Gene Shears Pty Ltd.

    Science.gov (United States)

    de Feyter, R; Li, P

    2000-06-01

    Ribozymes (catalytic RNAs) can be made to specifically cleave target RNAs that are involved in disease conditions and therefore have potential as therapeutic agents. Gene Shears Pty Ltd is developing hammerhead ribozyme technology for therapy against HIV infection, targeting either the tat gene or the RNA packaging sequence (Psi) of HIV. These ribozymes have been expressed from constructs that were introduced into hematopoietic cells in culture, thereby protecting the cells against viral infection. Two phase I clinical trials are underway to test the safety and feasibility of the approach with the anti-tat ribozyme in human subjects.

  8. [Gene therapy for Parkinson's disease].

    Science.gov (United States)

    Muramatsu, Shin-Ichi

    2012-01-01

    The current clinical trials of gene therapy for Parkinson's disease (PD) are based on three strategies. 1. To restore the local production of dopamine by introducing genes associated with dopamine-synthesizing enzymes into the putamen. 2. To protect nigrostriatal projection by delivering the neurturin gene, a trophic factor for dopaminergic neurons, both in the putamen and the substantia nigra. 3. To modulate the neural activity by transducing the subthalamic nucleus with vectors expressing glutamic acid decarboxylase. A phase I clinical study was initiated in 2007 to determine the safety of intra-putaminal infusion of a recombinant adeno-associated virus (AAV) vector encoding aromatic (L)-amino acid decarboxylase (AADC). All six patients enrolled in the trial showed improvements from baseline in the Unified Parkinson's Disease Rating Scale motor scores in the OFF medication state at 36 months after treatment. Although this trial was a small, open-label study and the use of a non-blinded, uncontrolled analysis limits interpretation, the efficacy outcomes are encouraging and indicate that the AAV vector-mediated gene transfer of AADC may benefit advanced PD patients. A similar approach, delivering AAV vector carrying AADC gene into the putamen ameliorated the symptoms in children with AADC deficiency.

  9. Melatonin Receptor Genes in Vertebrates

    Directory of Open Access Journals (Sweden)

    Hua Dong Yin

    2013-05-01

    Full Text Available Melatonin receptors are members of the G protein-coupled receptor (GPCR family. Three genes for melatonin receptors have been cloned. The MT1 (or Mel1a or MTNR1A and MT2 (or Mel1b or MTNR1B receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype, Mel1c (or MTNR1C, has been identified in fish, amphibians and birds. Another melatonin related orphan receptor, GPR50, which does not bind melatonin, is found exclusively in mammals. The hormone melatonin is secreted primarily by the pineal gland, with highest levels occurring during the dark period of a circadian cycle. This hormone acts systemically in numerous organs. In the brain, it is involved in the regulation of various neural and endocrine processes, and it readjusts the circadian pacemaker, the suprachiasmatic nucleus. This article reviews recent studies of gene organization, expression, evolution and mutations of melatonin receptor genes of vertebrates. Gene polymorphisms reveal that numerous mutations are associated with diseases and disorders. The phylogenetic analysis of receptor genes indicates that GPR50 is an outgroup to all other melatonin receptor sequences. GPR50 may have separated from a melatonin receptor ancestor before the split between MTNR1C and the MTNR1A/B ancestor.

  10. Systems Biophysics of Gene Expression

    Science.gov (United States)

    Vilar, Jose M.G.; Saiz, Leonor

    2013-01-01

    Gene expression is a process central to any form of life. It involves multiple temporal and functional scales that extend from specific protein-DNA interactions to the coordinated regulation of multiple genes in response to intracellular and extracellular changes. This diversity in scales poses fundamental challenges to the use of traditional approaches to fully understand even the simplest gene expression systems. Recent advances in computational systems biophysics have provided promising avenues to reliably integrate the molecular detail of biophysical process into the system behavior. Here, we review recent advances in the description of gene regulation as a system of biophysical processes that extend from specific protein-DNA interactions to the combinatorial assembly of nucleoprotein complexes. There is now basic mechanistic understanding on how promoters controlled by multiple, local and distal, DNA binding sites for transcription factors can actively control transcriptional noise, cell-to-cell variability, and other properties of gene regulation, including precision and flexibility of the transcriptional responses. PMID:23790365

  11. Control of Renin Gene Expression

    Science.gov (United States)

    Glenn, Sean T.; Jones, Craig A.; Gross, Kenneth W.; Pan, Li

    2015-01-01

    Renin, as part of the renin-angiotensin system, plays a critical role in the regulation of blood pressure, electrolyte homeostasis, mammalian renal development and progression of fibrotic/hypertrophic diseases. Renin gene transcription is subject to complex developmental and tissue-specific regulation. Initial studies using the mouse As4.1 cell line, which has many characteristics of the renin-expressing juxtaglomerular cells of the kidney, have identified a proximal promoter region (−197 to −50 bp) and an enhancer (−2866 to −2625 bp) upstream of the Ren-1c gene, which are critical for renin gene expression. The proximal promoter region contains several transcription factor-binding sites including a binding site for the products of the developmental control genes Hox. The enhancer consists of at least 11 transcription factor-binding sites and is responsive to various signal transduction pathways including cAMP, retinoic acid, endothelin-1, and cytokines, all of which are known to alter renin mRNA levels. Furthermore, in vivo models have validated several of these key components found within the proximal promoter region and the enhancer as well as other key sites necessary for renin gene transcription. PMID:22576577

  12. Molecular Studies on Preproinsulin Gene

    Directory of Open Access Journals (Sweden)

    Sabir Sarah

    2016-01-01

    Full Text Available Insulin plays an important role in maintaining the blood glucose level of the body. The β-cells of pancreas produce insulin in the form of precursor that is preproinsulin. The gene of preproinsulin provides an interesting system for addressing question related to molecular evolution. Recombinant DNA technology has made it possible to isolate and sequence the chromosomal genes coding for unique protein products. Although preproinsulin of various organism has been isolated and cloned, but there is no report from buffalo (Bubalus bubalis that is our major livestock. The genomic DNA of buffalo was isolated using Laura-Lee-Boodram method. The part of preproinsulin gene (596bp and 520bp using BPPI-UPS and bpiful_F as forward and BC1-C as reverse primer was amplified. Cloning of amplified fragments of gene were performed in pCR 2.1 vector. Positive clones were screened on the basis of blue white selection. The band obtained on 596bp and 520bp after colony PCR confirmed the successful cloning of preproinsulin gene in pCR 2.1 vector.

  13. Gene Therapy Applications in Gastroenterology and Hepatology

    Directory of Open Access Journals (Sweden)

    Catherine H Wu

    2000-01-01

    Full Text Available Advantages and disadvantages of viral vectors and nonviral vectors for gene delivery to digestive organs are reviewed. Advances in systems for the introduction of new gene expression are described, including self-deleting retroviral transfer vectors, chimeric viruses and chimeric oligonucleotides. Systems for inhibition of gene expression are discussed, including antisense oligonucleotides, ribozymes and dominant-negative genes.

  14. Evolving chromosomes and gene regulatory networks

    Indian Academy of Sciences (India)

    Aswin

    Many processes change genomes. Koonin and Wolf. 2008. Page 5 .. including horizontal gene transfer. Koonin and Wolf. 2008. Page 6. Horizontal gene transfer. Drastic modification of genetic material. Rapid exploration of ne niches and phenot pes. Page 7. Horizontal gene transfer regulates. New selective forces for gene ...

  15. A Gene Ontology Tutorial in Python.

    Science.gov (United States)

    Vesztrocy, Alex Warwick; Dessimoz, Christophe

    2017-01-01

    This chapter is a tutorial on using Gene Ontology resources in the Python programming language. This entails querying the Gene Ontology graph, retrieving Gene Ontology annotations, performing gene enrichment analyses, and computing basic semantic similarity between GO terms. An interactive version of the tutorial, including solutions, is available at http://gohandbook.org .

  16. How Gene Patents May Inhibit Scientific Research

    Directory of Open Access Journals (Sweden)

    Campo-Engelstein, Lisa

    2015-02-01

    Full Text Available In this paper, we point out three possible ways gene patents could impede scientific research. First, gene patent laws might exacerbate the culture of secrecy ubiquitous in science. Second, gene patents may limit researchers’ ability to study poly or multigenic diseases without access to all genetic etiologies. Third, gene patents could result in a “patent thicket”.

  17. Synthetic promoter libraries- tuning of gene expression

    DEFF Research Database (Denmark)

    Hammer, Karin; Mijakovic, Ivan; Jensen, Peter Ruhdal

    2006-01-01

    The study of gene function often requires changing the expression of a gene and evaluating the consequences. In principle, the expression of any given gene can be modulated in a quasi-continuum of discrete expression levels but the traditional approaches are usually limited to two extremes: gene ...

  18. Deregulated genes in sporadic vestibular schwannomas

    DEFF Research Database (Denmark)

    Cayé-Thomasen, Per; Helweg-Larsen, Rehannah Holga Andrea; Stangerup, Sven-Eric

    2010-01-01

    In search of genes associated with vestibular schwannoma tumorigenesis, this study examines the gene expression in human vestibular nerve versus vestibular schwannoma tissue samples using microarray technology.......In search of genes associated with vestibular schwannoma tumorigenesis, this study examines the gene expression in human vestibular nerve versus vestibular schwannoma tissue samples using microarray technology....

  19. A hybrid approach of gene sets and single genes for the prediction of survival risks with gene expression data.

    Science.gov (United States)

    Seok, Junhee; Davis, Ronald W; Xiao, Wenzhong

    2015-01-01

    Accumulated biological knowledge is often encoded as gene sets, collections of genes associated with similar biological functions or pathways. The use of gene sets in the analyses of high-throughput gene expression data has been intensively studied and applied in clinical research. However, the main interest remains in finding modules of biological knowledge, or corresponding gene sets, significantly associated with disease conditions. Risk prediction from censored survival times using gene sets hasn't been well studied. In this work, we propose a hybrid method that uses both single gene and gene set information together to predict patient survival risks from gene expression profiles. In the proposed method, gene sets provide context-level information that is poorly reflected by single genes. Complementarily, single genes help to supplement incomplete information of gene sets due to our imperfect biomedical knowledge. Through the tests over multiple data sets of cancer and trauma injury, the proposed method showed robust and improved performance compared with the conventional approaches with only single genes or gene sets solely. Additionally, we examined the prediction result in the trauma injury data, and showed that the modules of biological knowledge used in the prediction by the proposed method were highly interpretable in biology. A wide range of survival prediction problems in clinical genomics is expected to benefit from the use of biological knowledge.

  20. Gene conversion in the rice genome

    DEFF Research Database (Denmark)

    Xu, Shuqing; Clark, Terry; Zheng, Hongkun

    2008-01-01

    than ten percent. Pseudogenes in the rice genome with low similarity to Arabidopsis genes showed greater likelihood for gene conversion than those with high similarity to Arabidopsis genes. Functional annotations suggest that at least 14 multigene families related to disease or bacteria resistance were......BACKGROUND: Gene conversion causes a non-reciprocal transfer of genetic information between similar sequences. Gene conversion can both homogenize genes and recruit point mutations thereby shaping the evolution of multigene families. In the rice genome, the large number of duplicated genes......-chromosomal conversions distributed between chromosome 1 and 5, 2 and 6, and 3 and 5 are more frequent than genome average (Z-test, P

  1. Evolution of Hemoglobin and Its Genes

    Science.gov (United States)

    Hardison, Ross C.

    2012-01-01

    Insights into the evolution of hemoglobins and their genes are an abundant source of ideas regarding hemoglobin function and regulation of globin gene expression. This article presents the multiple genes and gene families encoding human globins, summarizes major events in the evolution of the hemoglobin gene clusters, and discusses how these studies provide insights into regulation of globin genes. Although the genes in and around the α-like globin gene complex are relatively stable, the β-like globin gene clusters are more dynamic, showing evidence of transposition to a new locus and frequent lineage-specific expansions and deletions. The cis-regulatory modules controlling levels and timing of gene expression are a mix of conserved and lineage-specific DNA, perhaps reflecting evolutionary constraint on core regulatory functions shared broadly in mammals and adaptive fine-tuning in different orders of mammals. PMID:23209182

  2. Metagenomics and novel gene discovery

    Science.gov (United States)

    Culligan, Eamonn P; Sleator, Roy D; Marchesi, Julian R; Hill, Colin

    2014-01-01

    Metagenomics provides a means of assessing the total genetic pool of all the microbes in a particular environment, in a culture-independent manner. It has revealed unprecedented diversity in microbial community composition, which is further reflected in the encoded functional diversity of the genomes, a large proportion of which consists of novel genes. Herein, we review both sequence-based and functional metagenomic methods to uncover novel genes and outline some of the associated problems of each type of approach, as well as potential solutions. Furthermore, we discuss the potential for metagenomic biotherapeutic discovery, with a particular focus on the human gut microbiome and finally, we outline how the discovery of novel genes may be used to create bioengineered probiotics. PMID:24317337

  3. Gene Therapy in Cardiac Arrhythmias

    Directory of Open Access Journals (Sweden)

    Praveen S.V

    2006-04-01

    Full Text Available Gene therapy has progressed from a dream to a bedside reality in quite a few human diseases. From its first application in adenosine deaminase deficiency, through the years, its application has evolved to vascular angiogenesis and cardiac arrhythmias. Gene based biological pacemakers using viral vectors or mesenchymal cells tested in animal models hold much promise. Induction of pacemaker activity within the left bundle branch can provide stable heart rates. Genetic modification of the AV node mimicking beta blockade can be therapeutic in the management of atrial fibrillation. G protein overexpression to modify the AV node also is experimental. Modification and expression of potassium channel genes altering the delayed rectifier potassium currents may permit better management of congenital long QT syndromes. Arrhythmias in a failing heart are due to abnormal calcium cycling. Potential targets for genetic modulation include the sarcoplasmic reticulum calcium pump, calsequestrin and sodium calcium exchanger.Lastly the ethical concerns need to be addressed.

  4. The KCNE genes in hypertrophic cardiomyopathy: a candidate gene study

    DEFF Research Database (Denmark)

    Hedley, Paula L; Haundrup, Ole; Andersen, Paal S

    2011-01-01

    as well as the T-tubules of the sarcolemma. It has been suggested that minK forms part of an "electro-mechanical feed-back" which links cardiomyocyte stretching to changes in ion channel function. We examined whether mutations in KCNE genes were associated with hypertrophic cardiomyopathy (HCM), a genetic...... disease associated with an improper hypertrophic response....

  5. Candidate Gene Identification of Flowering Time Genes in Cotton

    Directory of Open Access Journals (Sweden)

    Corrinne E. Grover

    2015-07-01

    Full Text Available Flowering time control is critically important to all sexually reproducing angiosperms in both natural ecological and agronomic settings. Accordingly, there is much interest in defining the genes involved in the complex flowering-time network and how these respond to natural and artificial selection, the latter often entailing transitions in day-length responses. Here we describe a candidate gene analysis in the cotton genus , which uses homologs from the well-described flowering network to bioinformatically and phylogenetically identify orthologs in the published genome sequence from Ulbr., one of the two model diploid progenitors of the commercially important allopolyploid cottons, L. and L. Presence and patterns of expression were evaluated from 13 aboveground tissues related to flowering for each of the candidate genes using allopolyploid as a model. Furthermore, we use a comparative context to determine copy number variability of each key gene family across 10 published angiosperm genomes. Data suggest a pattern of repeated loss of duplicates following ancient whole-genome doubling events in diverse lineages. The data presented here provide a foundation for understanding both the parallel evolution of day-length neutrality in domesticated cottons and the flowering-time network, in general, in this important crop plant.

  6. Effect Alpha Globlin Gene Deletion And Gamma Globin Gene -158 ...

    African Journals Online (AJOL)

    We studied the Xmn1 polymorphism (C/T) in γ- globin gene position -158 of β- thalassemia as a modulating factor of the disease severity. Presence of the polymorphism was found in two patients and this was not sufficient to explain the diversity of the phenotype encountered. Co-inheritance of alpha thalassaemia as a ...

  7. FunGeneClusterS

    DEFF Research Database (Denmark)

    Vesth, Tammi Camilla; Brandl, Julian; Andersen, Mikael Rørdam

    2016-01-01

    and industrial biotechnology applications. We have previously published a method for accurate prediction of clusters from genome and transcriptome data, which could also suggest cross-chemistry, however, this method was limited both in the number of parameters which could be adjusted as well as in user......Secondary metabolites of fungi are receiving an increasing amount of interest due to their prolific bioactivities and the fact that fungal biosynthesis of secondary metabolites often occurs from co-regulated and co-located gene clusters. This makes the gene clusters attractive for synthetic biology...

  8. Gene expression in colorectal cancer

    DEFF Research Database (Denmark)

    Birkenkamp-Demtroder, Karin; Christensen, Lise Lotte; Olesen, Sanne Harder

    2002-01-01

    Understanding molecular alterations in colorectal cancer (CRC) is needed to define new biomarkers and treatment targets. We used oligonucleotide microarrays to monitor gene expression of about 6,800 known genes and 35,000 expressed sequence tags (ESTs) on five pools (four to six samples in each......%). Fifteen nuclear encoded mitochondrial proteins were all down-regulated in CRC. We identified several chromosomal locations with clusters of either potential oncogenes or potential tumor suppressors. Some of these, such as aminopeptidase N/CD13 and sigma B3 protein on chromosome 15q25, coincided...

  9. Does inbreeding affect gene expression in birds?

    Science.gov (United States)

    Hansson, Bengt; Naurin, Sara; Hasselquist, Dennis

    2014-09-01

    Inbreeding increases homozygosity, exposes genome-wide recessive deleterious alleles and often reduces fitness. The physiological and reproductive consequences of inbreeding may be manifested already during gene regulation, but the degree to which inbreeding influences gene expression is unknown in most organisms, including in birds. To evaluate the pattern of inbreeding-affected gene expression over the genome and in relation to sex, we performed a transcriptome-wide gene expression (10 695 genes) study of brain tissue of 10-day-old inbred and outbred, male and female zebra finches. We found significantly lower gene expression in females compared with males at Z-linked genes, confirming that dosage compensation is incomplete in female birds. However, inbreeding did not affect gene expression at autosomal or sex-linked genes, neither in males nor in females. Analyses of single genes again found a clear sex-biased expression at Z-linked genes, whereas only a single gene was significantly affected by inbreeding. The weak effect of inbreeding on gene expression in zebra finches contrasts to the situation, for example, in Drosophila where inbreeding has been found to influence gene expression more generally and at stress-related genes in particular. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

  10. Integrones: los coleccionistas de genes Integrons: gene collectors

    Directory of Open Access Journals (Sweden)

    J. A. Di Conza

    2010-02-01

    Full Text Available Los integrones son estructuras genéticas que han despertado gran interés, debido a que algunos de ellos vehiculizan genes de resistencia a los antimicrobianos. Están formados por un fragmento que codifica una integrasa (intI y, a continuación, una secuencia attI a la que se unen los genes en casetes que codifican diferentes mecanismos de resistencia. Dentro de intI, en su extremo 3´, hay una secuencia promotora Pc a partir de la cual se transcriben los casetes de resistencia integrados, ya que estos genes carecen de promotor. Sin embargo, estos casetes presentan una secuencia específica denominada attC, la cual es reconocida por la integrasa que se une, por recombinación, a la secuencia attI del integrón en la orientación adecuada para su expresión. Los integrones se han clasificado según la secuencia de su integrasa, pero en la actualidad se prefiere clasificarlos según su localización. Se habla, en general, de "integrones móviles" para referirse a aquellos asociados a secuencias de inserción, transposones y/o plásmidos conjugativos, los que en su mayoría median mecanismos de resistencia, y de "superintegrones", de localización cromosómica y con grandes arreglos de genes en casetes. Los integrones móviles de clase 1 son los más abundantes en aislamientos clínicos y suelen estar asociados a transposones del subgrupo Tn21, seguidos por los de clase 2, derivados principalmente de Tn7. Estos elementos no son móviles por sí mismos, pero su asociación con elementos que sí lo son facilita su transferencia horizontal, lo que explica su amplia difusión entre las bacterias. Esta revisión intenta recopilar la información disponible acerca de los integrones móviles descritos en Argentina hasta la fecha.Integrons gained great interest due to their participation in resistance gene recruitment and expression. Their basic structure includes a fragment that encodes an integrase (intI followed by a recognition sequence (attI into

  11. Detecting Sequence Homology at the Gene Cluster Level with MultiGeneBlast

    NARCIS (Netherlands)

    Medema, Marnix H.; Takano, Eriko; Breitling, Rainer; Nowick, Katja

    The genes encoding many biomolecular systems and pathways are genomically organized in operons or gene clusters. With MultiGeneBlast, we provide a user-friendly and effective tool to perform homology searches with operons or gene clusters as basic units, instead of single genes. The

  12. Machine Learning-Based Gene Prioritization Identifies Novel Candidate Risk Genes for Inflammatory Bowel Disease.

    Science.gov (United States)

    Isakov, Ofer; Dotan, Iris; Ben-Shachar, Shay

    2017-09-01

    The inflammatory bowel diseases (IBDs) are chronic inflammatory disorders, associated with genetic, immunologic, and environmental factors. Although hundreds of genes are implicated in IBD etiology, it is likely that additional genes play a role in the disease process. We developed a machine learning-based gene prioritization method to identify novel IBD-risk genes. Known IBD genes were collected from genome-wide association studies and annotated with expression and pathway information. Using these genes, a model was trained to identify IBD-risk genes. A comprehensive list of 16,390 genes was then scored and classified. Immune and inflammatory responses, as well as pathways such as cell adhesion, cytokine-cytokine receptor interaction, and sulfur metabolism were identified to be related to IBD. Scores predicted for IBD genes were significantly higher than those for non-IBD genes (P genes had a high prediction score (>0.8). A literature review of the genes, excluding those used to train the model, identified 67 genes without any publication concerning IBD. These genes represent novel candidate IBD-risk genes, which can be targeted in future studies. Our method successfully differentiated IBD-risk genes from non-IBD genes by using information from expression data and a multitude of gene annotations. Crucial features were defined, and we were able to detect novel candidate risk genes for IBD. These findings may help detect new IBD-risk genes and improve the understanding of IBD pathogenesis.

  13. Interactive visualization of gene regulatory networks with associated gene expression time series data

    NARCIS (Netherlands)

    Westenberg, Michel A.; Hijum, Sacha A.F.T. van; Lulko, Andrzej T.; Kuipers, Oscar P.; Roerdink, Jos B.T.M.; Linsen, L; Hagen, H; Hamann, B

    2008-01-01

    We present GENeVis, an application to visualize gene expression time series data in a gene regulatory network context. This is a network of regulator proteins that regulate the expression of their respective target genes. The networks are represented as graphs, in which the nodes represent genes,

  14. A gene-based information gain method for detecting gene-gene interactions in case-control studies.

    Science.gov (United States)

    Li, Jin; Huang, Dongli; Guo, Maozu; Liu, Xiaoyan; Wang, Chunyu; Teng, Zhixia; Zhang, Ruijie; Jiang, Yongshuai; Lv, Hongchao; Wang, Limei

    2015-11-01

    Currently, most methods for detecting gene-gene interactions (GGIs) in genome-wide association studies are divided into SNP-based methods and gene-based methods. Generally, the gene-based methods can be more powerful than SNP-based methods. Some gene-based entropy methods can only capture the linear relationship between genes. We therefore proposed a nonparametric gene-based information gain method (GBIGM) that can capture both linear relationship and nonlinear correlation between genes. Through simulation with different odds ratio, sample size and prevalence rate, GBIGM was shown to be valid and more powerful than classic KCCU method and SNP-based entropy method. In the analysis of data from 17 genes on rheumatoid arthritis, GBIGM was more effective than the other two methods as it obtains fewer significant results, which was important for biological verification. Therefore, GBIGM is a suitable and powerful tool for detecting GGIs in case-control studies.

  15. Gene therapy on demand: site specific regulation of gene therapy.

    Science.gov (United States)

    Jazwa, Agnieszka; Florczyk, Urszula; Jozkowicz, Alicja; Dulak, Jozef

    2013-08-10

    Since 1990 when the first clinical gene therapy trial was conducted, much attention and considerable promise have been given to this form of treatment. Gene therapy has been used with success in patients suffering from severe combined immunodeficiency syndromes (X-SCID and ADA-deficiency), Leber's congenital amaurosis, hemophilia, β-thalassemia and adrenoleukodystrophy. Last year, the first therapeutic vector (Glybera) for treatment of lipoprotein lipase deficiency has been registered in the European Union. Nevertheless, there are still several numerous issues that need to be improved to make this technique more safe, effective and easily accessible for patients. Introduction of the therapeutic gene to the given cells should provide the level of expression which will restore the production of therapeutic protein to normal values or will provide therapeutic efficacy despite not fully physiological expression. However, in numerous diseases the expression of therapeutic genes has to be kept at certain level for some time, and then might be required to be switched off to be activated again when worsening of the symptoms may aggravate the risk of disease relapse. In such cases the promoters which are regulated by local conditions may be more required. In this article the special emphasis is to discuss the strategies of regulation of gene expression by endogenous stimuli. Particularly, the hypoxia- or miRNA-regulated vectors offer the possibilities of tight but, at the same time, condition-dependent and cell-specific expression. Such means have been already tested in certain pathophysiological conditions. This creates the chance for the translational approaches required for development of effective treatments of so far incurable diseases. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. Persistence drives gene clustering in bacterial genomes

    Directory of Open Access Journals (Sweden)

    Rocha Eduardo PC

    2008-01-01

    Full Text Available Abstract Background Gene clustering plays an important role in the organization of the bacterial chromosome and several mechanisms have been proposed to explain its extent. However, the controversies raised about the validity of each of these mechanisms remind us that the cause of this gene organization remains an open question. Models proposed to explain clustering did not take into account the function of the gene products nor the likely presence or absence of a given gene in a genome. However, genomes harbor two very different categories of genes: those genes present in a majority of organisms – persistent genes – and those present in very few organisms – rare genes. Results We show that two classes of genes are significantly clustered in bacterial genomes: the highly persistent and the rare genes. The clustering of rare genes is readily explained by the selfish operon theory. Yet, genes persistently present in bacterial genomes are also clustered and we try to understand why. We propose a model accounting specifically for such clustering, and show that indispensability in a genome with frequent gene deletion and insertion leads to the transient clustering of these genes. The model describes how clusters are created via the gene flux that continuously introduces new genes while deleting others. We then test if known selective processes, such as co-transcription, physical interaction or functional neighborhood, account for the stabilization of these clusters. Conclusion We show that the strong selective pressure acting on the function of persistent genes, in a permanent state of flux of genes in bacterial genomes, maintaining their size fairly constant, that drives persistent genes clustering. A further selective stabilization process might contribute to maintaining the clustering.

  17. Gene-gene and gene-environment interaction on the risk of Parkinson's disease.

    Science.gov (United States)

    Singh, Neeraj Kumar; Banerjee, Basu Dev; Bala, Kiran; Chhillar, Mitrabasu; Chhillar, Neelam

    2014-01-01

    Even with numerous studies the cause of Parkinson's disease (PD) remains elusive. It has been hypothesized that interactions between genetic and environmental factors may play an important role in the pathogenesis of PD. To examine the gene-gene and gene-environment interaction on PD risk with respect to gene polymorphism of cytochrome P450 2D6 (CYP2D6) and glutathione S-transferases pi 1 (GSTP1), organochlorine pesticides (OCPs) and metals. This study included 70 patients of PD and 100 age-matched controls. The restriction fragment length polymorphism was used for analysis of genetic polymorphism. OCPs and serum metal levels were estimated by using gas chromatography and an autoanalyser respectively. The CYP2D6*4 mt and GSTP1 *B allelic variants were significantly associated with increase in PD risk. We found a statistically significant difference in β -hexachlorocyclohexane (β-HCH), dieldrin, 1,1-dichloro-2,2-bis(pchlorophenyl) ethylene (pp'-DDE) and copper levels between the patients and controls. We found significantly high levels of β-HCH, dieldrin and pp'-DDE in the CYP2D6*4 mt allelic variants, β-HCH and pp'-DDE in the GSTP1*B allelic variants and dieldrin in the GSTP1*C allelic variants when comparing CYP2D6*4 non-mt, GSTP1 non-*B and GSTP1 non-*C allelic variants in patients of PD respectively. This study demonstrates that the CYP2D6*4 and GSTP1 genes may be considered as candidate genes for PD and they may also interact with β- HCH, dieldrin and pp'-DDE to influence the risk for PD.

  18. Genome position and gene amplification

    Czech Academy of Sciences Publication Activity Database

    Jirsová, Pavla; Snijders, A.M.; Kwek, S.; Roydasgupta, R.; Fridlyand, J.; Tokuyasu, T.; Pinkel, D.; Albertson, D. G.

    2007-01-01

    Roč. 8, č. 6 (2007), r120 ISSN 1474-760X Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : gene amplification * array comparative genomic hybridization * oncogene Subject RIV: BO - Biophysics Impact factor: 6.589, year: 2007

  19. Positional cloning of deafness genes

    NARCIS (Netherlands)

    Kremer, H.; Cremers, F.P.M.

    2009-01-01

    The identification of the majority of the known causative genes involved in nonsyndromic sensorineural hearing loss (NSHL) started with linkage analysis as part of a positional cloning procedure. The human and mouse genome projects in combination with technical developments on genotyping,

  20. Methylenetetrahydrofolate reductase (MTHFR) gene polymorphism ...

    African Journals Online (AJOL)

    Polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene are associated with abortion, early embryo loss and recurrent spontaneous abortion in human. However, information on the association between MTHFR polymorphism and cow abortion is scarce. In the present study, the effects of MTHFR ...

  1. (TNNC1) gene in goat

    African Journals Online (AJOL)

    Yomi

    2012-02-23

    Feb 23, 2012 ... that TNNC1 was a 161-amino acid polypeptide that had been highly conserved during evolution. Its ... patterns and evolution of TNNC1 gene in animal. .... Dog. 93.00. 98.76. EM. XM533799.2. Genbank. Oryctolagus cuniculus. Rabbit. 90.74. 99.38. EM. XM002713240.1 Genbank. Mus musculus. Mouse.

  2. Sculpting the Barnyard Gene Pool

    Science.gov (United States)

    Childers, Gina; Wolfe, Kim; Dupree, Alan; Young, Sheila; Caver, Jessica; Quintanilla, Ruby; Thornton, Laura

    2016-01-01

    Project-based learning (PBL) takes student engagement to a higher level through reflective collaboration, inquiry, critical thinking, problem solving, and personal relevance. This article explains how six high school teachers developed an interconnected, interdisciplinary STEM-focused PBL called "Sculpting the Barnyard Gene Pool." The…

  3. Gene expression profile of pulpitis

    Science.gov (United States)

    Galicia, Johnah C.; Henson, Brett R.; Parker, Joel S.; Khan, Asma A.

    2016-01-01

    The cost, prevalence and pain associated with endodontic disease necessitate an understanding of the fundamental molecular aspects of its pathogenesis. This study was aimed to identify the genetic contributors to pulpal pain and inflammation. Inflamed pulps were collected from patients diagnosed with irreversible pulpitis (n=20). Normal pulps from teeth extracted for various reasons served as controls (n=20). Pain level was assessed using a visual analog scale (VAS). Genome-wide microarray analysis was performed using Affymetrix GeneTitan Multichannel Instrument. The difference in gene expression levels were determined by the Significance Analysis of Microarray program using a false discovery rate (q-value) of 5%. Genes involved in immune response, cytokine-cytokine receptor interaction and signaling, integrin cell surface interactions, and others were expressed at relatively higher levels in the in the pulpitis group. Moreover, several genes known to modulate pain and inflammation showed differential expression in asymptomatic and mild pain patients (≥30mm on VAS) compared to those with moderate to severe pain. This exploratory study provides a molecular basis for the clinical diagnosis of pulpitis. With an enhanced understanding of pulpal inflammation, future studies on treatment and management of pulpitis and on pain associated with it can have a biological reference to bridge treatment strategies with pulpal biology. PMID:27052691

  4. Gene Expression in Trypanosomatid Parasites

    Directory of Open Access Journals (Sweden)

    Santiago Martínez-Calvillo

    2010-01-01

    Full Text Available The parasites Leishmania spp., Trypanosoma brucei, and Trypanosoma cruzi are the trypanosomatid protozoa that cause the deadly human diseases leishmaniasis, African sleeping sickness, and Chagas disease, respectively. These organisms possess unique mechanisms for gene expression such as constitutive polycistronic transcription of protein-coding genes and trans-splicing. Little is known about either the DNA sequences or the proteins that are involved in the initiation and termination of transcription in trypanosomatids. In silico analyses of the genome databases of these parasites led to the identification of a small number of proteins involved in gene expression. However, functional studies have revealed that trypanosomatids have more general transcription factors than originally estimated. Many posttranslational histone modifications, histone variants, and chromatin modifying enzymes have been identified in trypanosomatids, and recent genome-wide studies showed that epigenetic regulation might play a very important role in gene expression in this group of parasites. Here, we review and comment on the most recent findings related to transcription initiation and termination in trypanosomatid protozoa.

  5. 06 Silence of the Genes

    Indian Academy of Sciences (India)

    Srimath

    April 2007 Volume 12 Number 4. GENERAL ARTICLES. 06 Silence of the Genes. 2006 Nobel Prize in Physiology or Medicine. Utpal Nath and Saumitra Das. 19 Euclid and 'The Elements'. C R Pranesachar. 26 Euclid's Fifth Postulate. Renuka Ravindran. 37 Decoding Reed–Solomon Codes Using Euclid's. Algorithm.

  6. Gene expression profile of pulpitis.

    Science.gov (United States)

    Galicia, J C; Henson, B R; Parker, J S; Khan, A A

    2016-06-01

    The cost, prevalence and pain associated with endodontic disease necessitate an understanding of the fundamental molecular aspects of its pathogenesis. This study was aimed to identify the genetic contributors to pulpal pain and inflammation. Inflamed pulps were collected from patients diagnosed with irreversible pulpitis (n=20). Normal pulps from teeth extracted for various reasons served as controls (n=20). Pain level was assessed using a visual analog scale (VAS). Genome-wide microarray analysis was performed using Affymetrix GeneTitan Multichannel Instrument. The difference in gene expression levels were determined by the significance analysis of microarray program using a false discovery rate (q-value) of 5%. Genes involved in immune response, cytokine-cytokine receptor interaction and signaling, integrin cell surface interactions, and others were expressed at relatively higher levels in the pulpitis group. Moreover, several genes known to modulate pain and inflammation showed differential expression in asymptomatic and mild pain patients (⩾30 mm on VAS) compared with those with moderate to severe pain. This exploratory study provides a molecular basis for the clinical diagnosis of pulpitis. With an enhanced understanding of pulpal inflammation, future studies on treatment and management of pulpitis and on pain associated with it can have a biological reference to bridge treatment strategies with pulpal biology.

  7. Ethics of Gene Therapy Debated.

    Science.gov (United States)

    Borman, Stu

    1991-01-01

    Presented are the highlights of a press conference featuring biomedical ethicist LeRoy Walters of Georgetown University and attorney Andrew Kimbrell of the Foundation on Economic Trends. The opposing points of view of these two speakers serve to outline the pros and cons of the gene therapy issue. (CW)

  8. Embryos, genes, and birth defects

    National Research Council Canada - National Science Library

    Ferretti, Patrizia

    2006-01-01

    ... Structural anomalies The genesis of chromosome abnormalities Embryo survival The cause of high levels of chromosome abnormality in human embryos Relative parental risks - age, translocations, inversions, gonadal and germinal mosaics 33 33 34 35 36 44 44 45 4 Identification and Analysis of Genes Involved in Congenital Malformation Syndromes Peter J. Scambler Ge...

  9. Patching genes to fight disease

    Energy Technology Data Exchange (ETDEWEB)

    Holzman, D.

    1990-09-03

    The National Institutes of Health has approved the first gene therapy experiments, one of which will try to cure cancer by bolstering the immune system. The applications of such therapy are limited, but the potential aid to people with genetic diseases is great.

  10. The Language of the Genes

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 2; Issue 3. The Language of the Genes Linking the Past and the Future. Amitabh Joshi ... Author Affiliations. Amitabh Joshi1. Animal Behaviour Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O., Bangalore 560 064, India.

  11. Homeobox genes and melatonin synthesis

    DEFF Research Database (Denmark)

    Rohde, Kristian; Møller, Morten; Rath, Martin Fredensborg

    2014-01-01

    Nocturnal synthesis of melatonin in the pineal gland is controlled by a circadian rhythm in arylalkylamine N-acetyltransferase (AANAT) enzyme activity. In the rodent, Aanat gene expression displays a marked circadian rhythm; release of norepinephrine in the gland at night causes a cAMP-based indu......Nocturnal synthesis of melatonin in the pineal gland is controlled by a circadian rhythm in arylalkylamine N-acetyltransferase (AANAT) enzyme activity. In the rodent, Aanat gene expression displays a marked circadian rhythm; release of norepinephrine in the gland at night causes a c......AMP-based induction of Aanat transcription. However, additional transcriptional control mechanisms exist. Homeobox genes, which are generally known to encode transcription factors controlling developmental processes, are also expressed in the mature rodent pineal gland. Among these, the cone-rod homeobox (CRX......) transcription factor is believed to control pineal-specific Aanat expression. Based on recent advances in our understanding of Crx in the rodent pineal gland, we here suggest that homeobox genes play a role in adult pineal physiology both by ensuring pineal-specific Aanat expression and by facilitating c...

  12. [Chromosomal rearrangements and fusion genes in carcinoma].

    Science.gov (United States)

    Massard, Christophe; Auger, Nathalie; Lacroix, Ludovic; Bénard, Jean

    2011-12-01

    In the last decades, rarity of chromosomal rearrangements and fusion genes detected in epithelial cancers in using classical karyotyping led to consider these genomic events as specifically restricted to haematological neoplasia and mesenchymal tumors. Today, gene positioning as well as bio-informatics approaches has enabled identifying in carcinoma various fusion genes subsequent to chromosomal translocations, inversions, or deletions. Thus, gene fusion formation appears as a common mechanism in oncology that concerns most of human cancers, independent of original tissue lineage. At a clinical point of view, applications of fusion genes in terms of diagnosis, prognosis and therapeutics can be envisioned. This review will present current knowledge about fusion genes in common carcinoma (prostate, breast, colon). Following a structural and functional description of various fusion genes so far found in human malignant solid tumors, as well as techniques used for their detection, the review will integrate fusion genes in epithelia oncogenesis general scheme. Finally, promising clinical issues of fusion genes will be surveyed.

  13. The combinatorics of overlapping genes.

    Science.gov (United States)

    Lèbre, Sophie; Gascuel, Olivier

    2017-02-21

    Overlapping genes exist in all domains of life and are much more abundant than expected upon their first discovery in the late 1970s. Assuming that the reference gene is read in frame +0, an overlapping gene can be encoded in two reading frames in the sense strand, denoted by +1 and +2, and in three reading frames in the opposite strand, denoted by -0, -1, and -2. This motivated numerous researchers to study the constraints induced by the genetic code on the various overlapping frames, mostly based on information theory. Our focus in this paper is on the constraints induced on two overlapping genes in terms of amino acids, as well as polypeptides. We show that simple linear constraints bind the amino-acid composition of two proteins encoded by overlapping genes. Novel constraints are revealed when polypeptides are considered, and not just single amino acids. For example, in double-coding sequences with an overlapping reading frame -2, each Tyrosine (denoted as Tyr or Y) in the overlapping frame overlaps a Tyrosine in the reference frame +0 (and reciprocally), whereas specific words (e.g. YY) never occur. We thus distinguish between null constraints (YY = 0 in frame -2) and non-null constraints (Y in frame +0 ⇔ Y in frame -2). Our equivalence-based constraints are symmetrical and thus enable the characterization of the joint composition of overlapping proteins. We describe several formal frameworks and a graph algorithm to characterize and compute these constraints. As expected, the degrees of freedom left by these constraints vary drastically among the different overlapping frames. Interestingly, the biological meaning of constraints induced on two overlapping proteins (hydropathy, forbidden di-peptides, expected overlap length …) is also specific to the reading frame. We study the combinatorics of these constraints for overlapping polypeptides of length n, pointing out that, (i) except for frame -2, non-null constraints are deduced from the amino-acid (length

  14. Identification of context-specific gene regulatory networks with GEMULA--Gene Expression Modeling Using LAsso

    NARCIS (Netherlands)

    Geeven, G.; van Kesteren, R.E.; Smit, A.B.; de Gunst, M.C.M.

    2012-01-01

    Motivation: Gene regulatory networks, in which edges between nodes describe interactions between transcriptional regulators and their target genes, determine the coordinated spatiotemporal expression of genes. Especially in higher organisms, context-specific combinatorial regulation by transcription

  15. Gene losses during human origins.

    Directory of Open Access Journals (Sweden)

    Xiaoxia Wang

    2006-03-01

    Full Text Available Pseudogenization is a widespread phenomenon in genome evolution, and it has been proposed to serve as an engine of evolutionary change, especially during human origins (the "less-is-more" hypothesis. However, there has been no comprehensive analysis of human-specific pseudogenes. Furthermore, it is unclear whether pseudogenization itself can be selectively favored and thus play an active role in human evolution. Here we conduct a comparative genomic analysis and a literature survey to identify 80 nonprocessed pseudogenes that were inactivated in the human lineage after its separation from the chimpanzee lineage. Many functions are involved among these genes, with chemoreception and immune response being outstandingly overrepresented, suggesting potential species-specific features in these aspects of human physiology. To explore the possibility of adaptive pseudogenization, we focus on CASPASE12, a cysteinyl aspartate proteinase participating in inflammatory and innate immune response to endotoxins. We provide population genetic evidence that the nearly complete fixation of a null allele at CASPASE12 has been driven by positive selection, probably because the null allele confers protection from severe sepsis. We estimate that the selective advantage of the null allele is about 0.9% and the pseudogenization started shortly before the out-of-Africa migration of modern humans. Interestingly, two other genes related to sepsis were also pseudogenized in humans, possibly by selection. These adaptive gene losses might have occurred because of changes in our environment or genetic background that altered the threat from or response to sepsis. The identification and analysis of human-specific pseudogenes open the door for understanding the roles of gene losses in human origins, and the demonstration that gene loss itself can be adaptive supports and extends the "less-is-more" hypothesis.

  16. Vascular Gene Expression: A Hypothesis

    Directory of Open Access Journals (Sweden)

    Angélica Concepción eMartínez-Navarro

    2013-07-01

    Full Text Available The phloem is the conduit through which photoassimilates are distributed from autotrophic to heterotrophic tissues and is involved in the distribution of signaling molecules that coordinate plant growth and responses to the environment. Phloem function depends on the coordinate expression of a large array of genes. We have previously identified conserved motifs in upstream regions of the Arabidopsis genes, encoding the homologs of pumpkin phloem sap mRNAs, displaying expression in vascular tissues. This tissue-specific expression in Arabidopsis is predicted by the overrepresentation of GA/CT-rich motifs in gene promoters. In this work we have searched for common motifs in upstream regions of the homologous genes from plants considered to possess a primitive vascular tissue (a lycophyte, as well as from others that lack a true vascular tissue (a bryophyte, and finally from chlorophytes. Both lycophyte and bryophyte display motifs similar to those found in Arabidopsis with a significantly low E-value, while the chlorophytes showed either a different conserved motif or no conserved motif at all. These results suggest that these same genes are expressed coordinately in non- vascular plants; this coordinate expression may have been one of the prerequisites for the development of conducting tissues in plants. We have also analyzed the phylogeny of conserved proteins that may be involved in phloem function and development. The presence of CmPP16, APL, FT and YDA in chlorophytes suggests the recruitment of ancient regulatory networks for the development of the vascular tissue during evolution while OPS is a novel protein specific to vascular plants.

  17. Empirical study of supervised gene screening

    Directory of Open Access Journals (Sweden)

    Ma Shuangge

    2006-12-01

    Full Text Available Abstract Background Microarray studies provide a way of linking variations of phenotypes with their genetic causations. Constructing predictive models using high dimensional microarray measurements usually consists of three steps: (1 unsupervised gene screening; (2 supervised gene screening; and (3 statistical model building. Supervised gene screening based on marginal gene ranking is commonly used to reduce the number of genes in the model building. Various simple statistics, such as t-statistic or signal to noise ratio, have been used to rank genes in the supervised screening. Despite of its extensive usage, statistical study of supervised gene screening remains scarce. Our study is partly motivated by the differences in gene discovery results caused by using different supervised gene screening methods. Results We investigate concordance and reproducibility of supervised gene screening based on eight commonly used marginal statistics. Concordance is assessed by the relative fractions of overlaps between top ranked genes screened using different marginal statistics. We propose a Bootstrap Reproducibility Index, which measures reproducibility of individual genes under the supervised screening. Empirical studies are based on four public microarray data. We consider the cases where the top 20%, 40% and 60% genes are screened. Conclusion From a gene discovery point of view, the effect of supervised gene screening based on different marginal statistics cannot be ignored. Empirical studies show that (1 genes passed different supervised screenings may be considerably different; (2 concordance may vary, depending on the underlying data structure and percentage of selected genes; (3 evaluated with the Bootstrap Reproducibility Index, genes passed supervised screenings are only moderately reproducible; and (4 concordance cannot be improved by supervised screening based on reproducibility.

  18. Homozygous p.M172K mutation of the TFR2 gene in an Italian family with type 3 hereditary hemochromatosis and early onset iron overload.

    Science.gov (United States)

    Majore, S; Milano, F; Binni, F; Stuppia, L; Cerrone, A; Tafuri, A; De Bernardo, C; Palka, G; Grammatico, P

    2006-08-01

    The p.M172K TFR2 mutation was identified in two Italian siblings aged 32 and 40 years old with primary iron overload. The two patients showed a severe increase in serum iron indices. From the age of 25, the male sib also revealed abnormal levels of hepatic enzymes, presumably in relation to iron induced liver damage. Clinical findings seem to evidence that type 3 hemochromatosis can be more serious than classic hemochromatosis. This report adds two more type 3 hereditary hemochromatosis cases which suggest that TFR2 mutations could be more frequently involved in non-HFE hemochromatosis than has been actually thought.

  19. Gene therapy and its implications in Periodontics

    Science.gov (United States)

    Mahale, Swapna; Dani, Nitin; Ansari, Shumaila S.; Kale, Triveni

    2009-01-01

    Gene therapy is a field of Biomedicine. With the advent of gene therapy in dentistry, significant progress has been made in the control of periodontal diseases and reconstruction of dento-alveolar apparatus. Implementation in periodontics include: -As a mode of tissue engineering with three approaches: cell, protein-based and gene delivery approach. -Genetic approach to Biofilm Antibiotic Resistance. Future strategies of gene therapy in preventing periodontal diseases: -Enhances host defense mechanism against infection by transfecting host cells with an antimicrobial peptide protein-encoding gene. -Periodontal vaccination. Gene therapy is one of the recent entrants and its applications in the field of periodontics are reviewed in general here. PMID:20376232

  20. Modulation of gene expression made easy

    DEFF Research Database (Denmark)

    Solem, Christian; Jensen, Peter Ruhdal

    2002-01-01

    A new approach for modulating gene expression, based on randomization of promoter (spacer) sequences, was developed. The method was applied to chromosomal genes in Lactococcus lactis and shown to generate libraries of clones with broad ranges of expression levels of target genes. In one example...... that the method can be applied to modulating the expression of native genes on the chromosome. We constructed a series of strains in which the expression of the las operon, containing the genes pfk, pyk, and ldh, was modulated by integrating a truncated copy of the pfk gene. Importantly, the modulation affected...

  1. Hemochromatosis mutations in the general population

    DEFF Research Database (Denmark)

    Andersen, Rolf Vaern; Tybjaerg-Hansen, Anne; Appleyard, Merete

    2004-01-01

    The progression rate of iron overload in hereditary hemochromatosis in individuals in the general population is unknown. We therefore examined in the general population iron overload progression rate in C282Y homozygotes. Using a cohort study of the Danish general population, The Copenhagen City ...

  2. Genes from scratch – the evolutionary fate of de novo genes

    Science.gov (United States)

    Schlötterer, Christian

    2015-01-01

    Although considered an extremely unlikely event, many genes emerge from previously noncoding genomic regions. This review covers the entire life cycle of such de novo genes. Two competing hypotheses about the process of de novo gene birth are discussed as well as the high death rate of de novo genes. Despite the high death rate, some de novo genes are retained and remain functional, even in distantly related species, through their integration into gene networks. Further studies combining gene expression with ribosome profiling in multiple populations across different species will be instrumental for an improved understanding of the evolutionary processes operating on de novo genes. PMID:25773713

  3. Identification and functional analysis of light-responsive unique genes and gene family members in rice.

    Directory of Open Access Journals (Sweden)

    Ki-Hong Jung

    2008-08-01

    Full Text Available Functional redundancy limits detailed analysis of genes in many organisms. Here, we report a method to efficiently overcome this obstacle by combining gene expression data with analysis of gene-indexed mutants. Using a rice NSF45K oligo-microarray to compare 2-week-old light- and dark-grown rice leaf tissue, we identified 365 genes that showed significant 8-fold or greater induction in the light relative to dark conditions. We then screened collections of rice T-DNA insertional mutants to identify rice lines with mutations in the strongly light-induced genes. From this analysis, we identified 74 different lines comprising two independent mutant lines for each of 37 light-induced genes. This list was further refined by mining gene expression data to exclude genes that had potential functional redundancy due to co-expressed family members (12 genes and genes that had inconsistent light responses across other publicly available microarray datasets (five genes. We next characterized the phenotypes of rice lines carrying mutations in ten of the remaining candidate genes and then carried out co-expression analysis associated with these genes. This analysis effectively provided candidate functions for two genes of previously unknown function and for one gene not directly linked to the tested biochemical pathways. These data demonstrate the efficiency of combining gene family-based expression profiles with analyses of insertional mutants to identify novel genes and their functions, even among members of multi-gene families.

  4. GenePRIMP: A GENE PRediction IMprovement Pipeline for Prokaryotic genomes

    Energy Technology Data Exchange (ETDEWEB)

    Pati, Amrita; Ivanova, Natalia N.; Mikhailova, Natalia; Ovchinnikova, Galina; Hooper, Sean D.; Lykidis, Athanasios; Kyrpides, Nikos C.

    2010-04-01

    We present 'gene prediction improvement pipeline' (GenePRIMP; http://geneprimp.jgi-psf.org/), a computational process that performs evidence-based evaluation of gene models in prokaryotic genomes and reports anomalies including inconsistent start sites, missed genes and split genes. We found that manual curation of gene models using the anomaly reports generated by GenePRIMP improved their quality, and demonstrate the applicability of GenePRIMP in improving finishing quality and comparing different genome-sequencing and annotation technologies.

  5. Thesaurus-based disambiguation of gene symbols.

    Science.gov (United States)

    Schijvenaars, Bob J A; Mons, Barend; Weeber, Marc; Schuemie, Martijn J; van Mulligen, Erik M; Wain, Hester M; Kors, Jan A

    2005-06-16

    Massive text mining of the biological literature holds great promise of relating disparate information and discovering new knowledge. However, disambiguation of gene symbols is a major bottleneck. We developed a simple thesaurus-based disambiguation algorithm that can operate with very little training data. The thesaurus comprises the information from five human genetic databases and MeSH. The extent of the homonym problem for human gene symbols is shown to be substantial (33% of the genes in our combined thesaurus had one or more ambiguous symbols), not only because one symbol can refer to multiple genes, but also because a gene symbol can have many non-gene meanings. A test set of 52,529 Medline abstracts, containing 690 ambiguous human gene symbols taken from OMIM, was automatically generated. Overall accuracy of the disambiguation algorithm was up to 92.7% on the test set. The ambiguity of human gene symbols is substantial, not only because one symbol may denote multiple genes but particularly because many symbols have other, non-gene meanings. The proposed disambiguation approach resolves most ambiguities in our test set with high accuracy, including the important gene/not a gene decisions. The algorithm is fast and scalable, enabling gene-symbol disambiguation in massive text mining applications.

  6. Thesaurus-based disambiguation of gene symbols

    Directory of Open Access Journals (Sweden)

    Wain Hester M

    2005-06-01

    Full Text Available Abstract Background Massive text mining of the biological literature holds great promise of relating disparate information and discovering new knowledge. However, disambiguation of gene symbols is a major bottleneck. Results We developed a simple thesaurus-based disambiguation algorithm that can operate with very little training data. The thesaurus comprises the information from five human genetic databases and MeSH. The extent of the homonym problem for human gene symbols is shown to be substantial (33% of the genes in our combined thesaurus had one or more ambiguous symbols, not only because one symbol can refer to multiple genes, but also because a gene symbol can have many non-gene meanings. A test set of 52,529 Medline abstracts, containing 690 ambiguous human gene symbols taken from OMIM, was automatically generated. Overall accuracy of the disambiguation algorithm was up to 92.7% on the test set. Conclusion The ambiguity of human gene symbols is substantial, not only because one symbol may denote multiple genes but particularly because many symbols have other, non-gene meanings. The proposed disambiguation approach resolves most ambiguities in our test set with high accuracy, including the important gene/not a gene decisions. The algorithm is fast and scalable, enabling gene-symbol disambiguation in massive text mining applications.

  7. [Bt gene flow of transgeic cotton].

    Science.gov (United States)

    Shen, F F; Yu, Y J; Zhang, X K; Bi, J J; Yin, C Y

    2001-01-01

    This study was carried out to determine the gene flow of transgenic cotton under Chinese ecological environment. Transgenic cotton GK-12 containing the marker gene NPTII and Bt gene was planted in the 6 x 6 m2 plot, non-transgenic cotton CCRC 12 and Xinmian 13 were planted respectively around them. At varying distances from transgenic cotton, seeds produced by the non-transgenic cotton were collected and screened for marker gene and Bt gene using kanamycine sulphate and Dot-ELISA method. PCR technique was also used in some seeds to screen Bt gene. The result indicated that gene flow was found to be high at 0-6 m, and to decrease with distances; however gene flow occurred up to distance of 36 m from the transgenic cotton plot. Bt gene flow at 3-6 m increased with increasing the diversity of transgenic cotton in the plot, but gene flow increased little at long distance. The gene flow between species was lower than between cultivars at 0-6 m, and occurred at the distance of 72 m from transgenic plot. 72 m buffer zones would serve to limit gene flow of transgenic cotton from small-scale field test. The possibility of escapes of engineered gene to wild relatives of cotton species was also discussed.

  8. Somatic gene therapy for hypertension

    Directory of Open Access Journals (Sweden)

    Phillips M.I.

    2000-01-01

    Full Text Available Gene therapy for hypertension is needed for the next generation of antihypertensive drugs. Current drugs, although effective, have poor compliance, are expensive and short-lasting (hours or one day. Gene therapy offers a way to produce long-lasting antihypertensive effects (weeks, months or years. We are currently using two strategies: a antisense oligodeoxynucleotides (AS-ODN and b antisense DNA delivered in viral vectors to inhibit genes associated with vasoconstrictive properties. It is not necessary to know all the genes involved in hypertension, since many years of experience with drugs show which genes need to be controlled. AS-ODN are short, single-stranded DNA that can be injected in naked form or in liposomes. AS-ODN, targeted to angiotensin type 1 receptors (AT1-R, angiotensinogen (AGT, angiotensin converting enzyme, and ß1-adrenergic receptors effectively reduce hypertension in rat models (SHR, 2K-1C and cold-induced hypertension. A single dose is effective up to one month when delivered with liposomes. No side effects or toxic effects have been detected, and repeated injections can be given. For the vector, adeno-associated virus (AAV is used with a construct to include a CMV promoter, antisense DNA to AGT or AT1-R and a reporter gene. Results in SHR demonstrate reduction and slowing of development of hypertension, with a single dose administration. Left ventricular hypertrophy is also reduced by AAV-AGT-AS treatment. Double transgenic mice (human renin plus human AGT with high angiotensin II causing high blood pressure, treated with AAV-AT1-R-AS, show a normalization of blood pressure for over six months with a single injection of vector. We conclude that ODNs will probably be developed first because they can be treated like drugs for the treatment of hypertension with long-term effects. Viral vector delivery needs more engineering to be certain of its safety, but one day may be used for a very prolonged control of blood pressure.

  9. New Cholesterol Fighting Meds Target Key Gene

    Science.gov (United States)

    ... https://medlineplus.gov/news/fullstory_165942.html New Cholesterol Fighting Meds Target Key Gene Two trials show ... New gene-based therapies appear to significantly decrease cholesterol levels in people, and could even cut down ...

  10. Biodegradable nanoparticles for gene therapy technology

    Energy Technology Data Exchange (ETDEWEB)

    Hosseinkhani, Hossein, E-mail: hosseinkhani@mail.ntust.edu.tw; He, Wen-Jie [National Taiwan University of Science and Technology (Taiwan Tech), Graduate Institute of Biomedical Engineering (China); Chiang, Chiao-Hsi [School of Pharmacy, National Defense Medical Center (China); Hong, Po-Da [National Taiwan University of Science and Technology (Taiwan Tech), Graduate Institute of Biomedical Engineering (China); Yu, Dah-Shyong [Nanomedicine Research Center, National Defense Medical Center (China); Domb, Abraham J. [The Hebrew University of Jerusalem, Institute of Drug Research, School of Pharmacy, Faculty of Medicine, Center for Nanoscience and Nanotechnology and The Alex Grass Center for Drug Design and Synthesis (Israel); Ou, Keng-Liang [College of Oral Medicine, Taipei Medical University, Research Center for Biomedical Devices and Prototyping Production (China)

    2013-07-15

    Rapid propagations in materials technology together with biology have initiated great hopes in the possibility of treating many diseases by gene therapy technology. Viral and non-viral gene carriers are currently applied for gene delivery. Non-viral technology is safe and effective for the delivery of genetic materials to cells and tissues. Non-viral systems are based on plasmid expression containing a gene encoding a therapeutic protein and synthetic biodegradable nanoparticles as a safe carrier of gene. Biodegradable nanoparticles have shown great interest in drug and gene delivery systems as they are easy to be synthesized and have no side effect in cells and tissues. This review provides a critical view of applications of biodegradable nanoparticles on gene therapy technology to enhance the localization of in vitro and in vivo and improve the function of administered genes.

  11. Scientists Spot Genes Behind Crohn's, Ulcerative Colitis

    Science.gov (United States)

    ... medlineplus.gov/news/fullstory_166957.html Scientists Spot Genes Behind Crohn's, Ulcerative Colitis Large study finds key ... Researchers say they've come closer to pinpointing genes linked with inflammatory bowel diseases such as Crohn's ...

  12. NIH Researchers Identify OCD Risk Gene

    Science.gov (United States)

    ... News From NIH NIH Researchers Identify OCD Risk Gene Past Issues / Summer 2006 Table of Contents For ... and Alcoholism (NIAAA) have identified a previously unknown gene variant that doubles an individual's risk for obsessive- ...

  13. Biodegradable nanoparticles for gene therapy technology

    Science.gov (United States)

    Hosseinkhani, Hossein; He, Wen-Jie; Chiang, Chiao-Hsi; Hong, Po-Da; Yu, Dah-Shyong; Domb, Abraham J.; Ou, Keng-Liang

    2013-07-01

    Rapid propagations in materials technology together with biology have initiated great hopes in the possibility of treating many diseases by gene therapy technology. Viral and non-viral gene carriers are currently applied for gene delivery. Non-viral technology is safe and effective for the delivery of genetic materials to cells and tissues. Non-viral systems are based on plasmid expression containing a gene encoding a therapeutic protein and synthetic biodegradable nanoparticles as a safe carrier of gene. Biodegradable nanoparticles have shown great interest in drug and gene delivery systems as they are easy to be synthesized and have no side effect in cells and tissues. This review provides a critical view of applications of biodegradable nanoparticles on gene therapy technology to enhance the localization of in vitro and in vivo and improve the function of administered genes.

  14. Rounding up sickle cells with gene therapy.

    Science.gov (United States)

    Byrne, Leah

    2017-03-15

    A report of a patient treated with ex vivo lentiviral gene transfer to hematopoietic stem cells shows the promise of gene therapy for sickle cell anemia. Copyright © 2017, American Association for the Advancement of Science.

  15. What Is a Gene? (For Kids)

    Science.gov (United States)

    ... tested is replacing sick genes with healthy ones. Gene therapy trials — where the research is tested on people — and ... THIS TOPIC How to Deal With Hemophilia What's the Right Weight for Me? Do You ...

  16. Genomewide survey and characterization of metacaspase gene ...

    Indian Academy of Sciences (India)

    Oryza sativa). Likai Wang ... Keywords. metacaspases; OsMC gene family; expression profiles; domestication; rice; Oryza sativa. ... The expression profiles of eight OsMC genes were analysed in 27 tissues covering the whole life cycle of rice.

  17. Drugs to awaken a paternal gene

    OpenAIRE

    Beaudet, Arthur L.

    2011-01-01

    Mutations in the maternal copy of the UBE3A gene cause a neurodevelopmental disorder known as Angelman syndrome. Drugs that activate the normally silenced paternal copy of this gene may be of therapeutic value.

  18. RESISTANCE-RELATED GENE TRANSCRIPTION AND ...

    African Journals Online (AJOL)

    jdx

    2014-02-05

    related gene, antioxidant enzyme activity. INTRODUCTION ... oxygen and nitrogen species, through changes in ion flux across the plasma ... A better understanding of the gene network underlying anthracnose resistance in ...

  19. Influence of thiopurine methyltransferase gene polymorphism on ...

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Genetics; Volume 96; Issue 6. Influence of thiopurine methyltransferase gene polymorphism on Egyptian children with acute lymphoblastic leukaemia. AZZA A. G. ... thiopurine methyltransferase gene polymorphism; acute lymphoblastic leukaemia; Egyptian children; thiopurine methyltransferase.

  20. Rogue Genes May Cause Some ALS Cases

    Science.gov (United States)

    ... discover other possible genetic triggers and to further define possible non-genetic factors that may play a ... Services. More Health News on Amyotrophic Lateral Sclerosis Genes and Gene Therapy Recent Health News Related MedlinePlus ...

  1. Nickel and Epigenetic Gene Silencing

    Directory of Open Access Journals (Sweden)

    Hong Sun

    2013-10-01

    Full Text Available Insoluble nickel compounds are well-established human carcinogens. Occupational exposure to these compounds leads to increased incidence of lung and nasal cancer in nickel refinery workers. Apart from its weak mutagenic activity and hypoxia mimicking effect there is mounting experimental evidence indicating that epigenetic alteration plays an important role in nickel-induced carcinogenesis. Multiple epigenetic mechanisms have been identified to mediate nickel-induced gene silencing. Nickel ion is able to induce heterochromatinization by binding to DNA-histone complexes and initiating chromatin condensation. The enzymes required for establishing or removing epigenetic marks can be targeted by nickel, leading to altered DNA methylation and histone modification landscapes. The current review will focus on the epigenetic changes that contribute to nickel-induced gene silencing.

  2. Nickel and epigenetic gene silencing.

    Science.gov (United States)

    Sun, Hong; Shamy, Magdy; Costa, Max

    2013-10-25

    Insoluble nickel compounds are well-established human carcinogens. Occupational exposure to these compounds leads to increased incidence of lung and nasal cancer in nickel refinery workers. Apart from its weak mutagenic activity and hypoxia mimicking effect there is mounting experimental evidence indicating that epigenetic alteration plays an important role in nickel-induced carcinogenesis. Multiple epigenetic mechanisms have been identified to mediate nickel-induced gene silencing. Nickel ion is able to induce heterochromatinization by binding to DNA-histone complexes and initiating chromatin condensation. The enzymes required for establishing or removing epigenetic marks can be targeted by nickel, leading to altered DNA methylation and histone modification landscapes. The current review will focus on the epigenetic changes that contribute to nickel-induced gene silencing.

  3. Function analysis of unknown genes

    DEFF Research Database (Denmark)

    Rogowska-Wrzesinska, A.

    2002-01-01

      This thesis entitled "Function analysis of unknown genes" presents the use of proteome analysis for the characterisation of yeast (Saccharomyces cerevisiae) genes and their products (proteins especially those of unknown function). This study illustrates that proteome analysis can be used...... be obtained using proteome analysis. Chapter 1 and 2 provide the basic theoretical aspects of proteome analysis, its principles, the main techniques involved and their use in the studies of the molecular biology of yeast cells. Chapter 3 presents the methods and tools involved in proteome analysis and used...... to multiple drug resistance in yeast. It analyses the cellular response to the overexpression of the Pdr5p - an ABC transporter protein that is responsible for resistance of yeast cells to several drugs and chemical compounds. It shows that the overexpression of Pdr5p triggers a strong cell stress response...

  4. Gene therapy for lipid disorders

    OpenAIRE

    Rader Daniel J; Kawashiri Masa-aki

    2000-01-01

    Abstract Lipid disorders are associated with atherosclerotic vascular disease, and therapy is associated with a substantial reduction in cardiovascular events. Current approaches to the treatment of lipid disorders are ineffective in a substantial number of patients. New therapies for refractory hypercholesterolemia, severe hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol are needed: somatic gene therapy is one viable approach. The molecular etiology and pathophysi...

  5. Nickel and Epigenetic Gene Silencing

    OpenAIRE

    Hong Sun; Magdy Shamy; Max Costa

    2013-01-01

    Insoluble nickel compounds are well-established human carcinogens. Occupational exposure to these compounds leads to increased incidence of lung and nasal cancer in nickel refinery workers. Apart from its weak mutagenic activity and hypoxia mimicking effect there is mounting experimental evidence indicating that epigenetic alteration plays an important role in nickel-induced carcinogenesis. Multiple epigenetic mechanisms have been identified to mediate nickel-induced gene silencing. Nickel io...

  6. The Insect SNMP Gene Family

    Science.gov (United States)

    2009-01-01

    chemosensory neurons in insects ; in Drosophila melanogaster, SNMP1 has been shown to be essential for the detection of the pheromone cis- vaccenyl...Elsevier Ltd. All rights reserved. 1. Introduction SNMPs are insect membrane proteins which associate with pheromone sensitive neurons in Lepidoptera and...melanogaster, SNMP1 has been shown to be essential for the detection of the pheromone cisvaccenyl acetate (CVA). SNMPs are one of three insect gene clades

  7. Gene Therapy for Fracture Repair

    Science.gov (United States)

    2007-05-01

    forma - tion and finally remodeling [8]. Fracture callus formation eventually results in the bridging of the fracture and the restoration of skeletal...analysis was performed using ImaGene software (BioDiscovery, El Segundo, CA), that used an internal statistical analysis of the signal intensity of...expression during the normal repair of a simple femur fracture with the elimination of scar tissue from the healing bone. This model does not address

  8. Gene Therapy for Childhood Neurofibromatosis

    Science.gov (United States)

    2014-05-01

    Neurofibromatosis PRINCIPAL INVESTIGATOR: Segal, David J. CONTRACTING ORGANIZATION: University of California, Davis Davis, California...May 2014 4. TITLE AND SUBTITLE Gene Therapy for Childhood Neurofibromatosis 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-13-1-0101 5c...project was to develop an innovative therapy for neurofibromatosis . Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders (1

  9. Expression of evolutionarily novel genes in tumors

    OpenAIRE

    A. P. Kozlov

    2016-01-01

    The evolutionarily novel genes originated through different molecular mechanisms are expressed in tumors. Sometimes the expression of evolutionarily novel genes in tumors is highly specific. Moreover positive selection of many human tumor-related genes in primate lineage suggests their involvement in the origin of new functions beneficial to organisms. It is suggested to consider the expression of evolutionarily young or novel genes in tumors as a new biological phenomenon, a phenomenon of TS...

  10. The gene expression signatures of melanoma progression

    OpenAIRE

    Haqq, Christopher; Nosrati, Mehdi; Sudilovsky, Daniel; Crothers, Julia; Khodabakhsh, Daniel; Pulliam, Brian L.; Federman, Scot; Miller, James R.; Allen, Robert E.; Singer, Mark I.; Leong, Stanley P L; Ljung, Britt-Marie; Sagebiel, Richard W.; Kashani-Sabet, Mohammed

    2005-01-01

    Because of the paucity of available tissue, little information has previously been available regarding the gene expression profiles of primary melanomas. To understand the molecular basis of melanoma progression, we compared the gene expression profiles of a series of nevi, primary melanomas, and melanoma metastases. We found that metastatic melanomas exhibit two dichotomous patterns of gene expression, which unexpectedly reflect gene expression differences already apparent in comparing laser...

  11. Ethics of Cancer Gene Transfer Clinical Research.

    Science.gov (United States)

    Kimmelman, Jonathan

    2015-01-01

    Translation of cancer gene transfer confronts many familiar-and some distinctive-ethical challenges. In what follows, I survey three major ethical dimensions of cancer gene transfer development. Subheading 1 centers on the ethics of planning, designing, and reporting animal studies. Subheading 2 describes basic elements of human subjects protection as pertaining to cancer gene transfer. In Subheading 3, I describe how cancer gene transfer researchers have obligations to downstream consumers of the evidence they produce.

  12. Gene Coexpression Network Analysis as a Source of Functional Annotation for Rice Genes

    Science.gov (United States)

    Childs, Kevin L.; Davidson, Rebecca M.; Buell, C. Robin

    2011-01-01

    With the existence of large publicly available plant gene expression data sets, many groups have undertaken data analyses to construct gene coexpression networks and functionally annotate genes. Often, a large compendium of unrelated or condition-independent expression data is used to construct gene networks. Condition-dependent expression experiments consisting of well-defined conditions/treatments have also been used to create coexpression networks to help examine particular biological processes. Gene networks derived from either condition-dependent or condition-independent data can be difficult to interpret if a large number of genes and connections are present. However, algorithms exist to identify modules of highly connected and biologically relevant genes within coexpression networks. In this study, we have used publicly available rice (Oryza sativa) gene expression data to create gene coexpression networks using both condition-dependent and condition-independent data and have identified gene modules within these networks using the Weighted Gene Coexpression Network Analysis method. We compared the number of genes assigned to modules and the biological interpretability of gene coexpression modules to assess the utility of condition-dependent and condition-independent gene coexpression networks. For the purpose of providing functional annotation to rice genes, we found that gene modules identified by coexpression analysis of condition-dependent gene expression experiments to be more useful than gene modules identified by analysis of a condition-independent data set. We have incorporated our results into the MSU Rice Genome Annotation Project database as additional expression-based annotation for 13,537 genes, 2,980 of which lack a functional annotation description. These results provide two new types of functional annotation for our database. Genes in modules are now associated with groups of genes that constitute a collective functional annotation of those

  13. Gene coexpression network analysis as a source of functional annotation for rice genes.

    Directory of Open Access Journals (Sweden)

    Kevin L Childs

    Full Text Available With the existence of large publicly available plant gene expression data sets, many groups have undertaken data analyses to construct gene coexpression networks and functionally annotate genes. Often, a large compendium of unrelated or condition-independent expression data is used to construct gene networks. Condition-dependent expression experiments consisting of well-defined conditions/treatments have also been used to create coexpression networks to help examine particular biological processes. Gene networks derived from either condition-dependent or condition-independent data can be difficult to interpret if a large number of genes and connections are present. However, algorithms exist to identify modules of highly connected and biologically relevant genes within coexpression networks. In this study, we have used publicly available rice (Oryza sativa gene expression data to create gene coexpression networks using both condition-dependent and condition-independent data and have identified gene modules within these networks using the Weighted Gene Coexpression Network Analysis method. We compared the number of genes assigned to modules and the biological interpretability of gene coexpression modules to assess the utility of condition-dependent and condition-independent gene coexpression networks. For the purpose of providing functional annotation to rice genes, we found that gene modules identified by coexpression analysis of condition-dependent gene expression experiments to be more useful than gene modules identified by analysis of a condition-independent data set. We have incorporated our results into the MSU Rice Genome Annotation Project database as additional expression-based annotation for 13,537 genes, 2,980 of which lack a functional annotation description. These results provide two new types of functional annotation for our database. Genes in modules are now associated with groups of genes that constitute a collective functional

  14. Suicide gene therapy of rhabdomyosarcoma.

    Science.gov (United States)

    Konieczny, Paweł; Sułkowski, Maciej; Badyra, Bogna; Kijowski, Jacek; Majka, Marcin

    2017-02-01

    Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood and young adulthood. Conventional treatment consisting of surgery, chemotherapy and radiotherapy can be insufficient, as long-term survival chances decrease dramatically when cancer recurrence occurs. Due to this fact, efficient treatment of this cancer is still a demanding issue, thus, novel and innovative therapies have to be considered as a part of combined treatment. In the present study, we present effective suicide gene therapy of rhabdomyosarcoma cell line Rh30 involving herpes simplex thymidine kinase (HSV-TK) and ganciclovir (GCV). Transduction of rhabdomyosarcoma cells using lentiviral vectors allowed efficient introduction of HSV-TK gene. In this study we proved high susceptibility of modified cells to ganciclovir resulting in eradication of cancer cells both in vitro and in vivo. Our data revealed strong gap junctional intercellular communication in examined cell line responsible for elimination of unmodified cells by bystander effect, even if HSV-TK-expressing cells comprise only 20% of cultured cells. Moreover, investigated approach is also efficient in vivo, where complete remission of tumors upon only 14 days of systemic administration of GCV can be observed. Obtained results suggest that HSV-TK suicide gene therapy is very promising concept in future clinical studies concerning rhabdomyosarcoma.

  15. Nongenomic regulation of gene expression.

    Science.gov (United States)

    Iglesias-Platas, Isabel; Monk, David

    2016-08-01

    The purpose of this review is to highlight the recent advances in epigenetic regulation and chromatin biology for a better understanding of gene regulation related to human disease. Alterations to chromatin influence genomic function, including gene transcription. At its most simple level, this involves DNA methylation and posttranscriptional histone modifications. However, recent developments in biochemical and molecular techniques have revealed that transcriptional regulation is far more complex, involving combinations of histone modifications and discriminating transcription factor binding, and long-range chromatin loops with enhancers, to generate a multifaceted code. Here, we describe the most recent advances, culminating in the example of genomic imprinting, the parent-of-origin monoallelic expression that utilizes the majority of these mechanisms to attain one active and one repressed allele. It is becoming increasingly evident that epigenetic mechanisms work in unison to maintain tight control of gene expression and genome function. With the wealth of knowledge gained from recent molecular studies, future goals should focus on the application of this information in deciphering their role in developmental diseases.

  16. Horizontal gene transfer in chromalveolates

    Directory of Open Access Journals (Sweden)

    Bhattacharya Debashish

    2007-09-01

    Full Text Available Abstract Background Horizontal gene transfer (HGT, the non-genealogical transfer of genetic material between different organisms, is considered a potentially important mechanism of genome evolution in eukaryotes. Using phylogenomic analyses of expressed sequence tag (EST data generated from a clonal cell line of a free living dinoflagellate alga Karenia brevis, we investigated the impact of HGT on genome evolution in unicellular chromalveolate protists. Results We identified 16 proteins that have originated in chromalveolates through ancient HGTs before the divergence of the genera Karenia and Karlodinium and one protein that was derived through a more recent HGT. Detailed analysis of the phylogeny and distribution of identified proteins demonstrates that eight have resulted from independent HGTs in several eukaryotic lineages. Conclusion Recurring intra- and interdomain gene exchange provides an important source of genetic novelty not only in parasitic taxa as previously demonstrated but as we show here, also in free-living protists. Investigating the tempo and mode of evolution of horizontally transferred genes in protists will therefore advance our understanding of mechanisms of adaptation in eukaryotes.

  17. Targeted gene flow for conservation.

    Science.gov (United States)

    Kelly, Ella; Phillips, Ben L

    2016-04-01

    Anthropogenic threats often impose strong selection on affected populations, causing rapid evolutionary responses. Unfortunately, these adaptive responses are rarely harnessed for conservation. We suggest that conservation managers pay close attention to adaptive processes and geographic variation, with an eye to using them for conservation goals. Translocating pre-adapted individuals into recipient populations is currently considered a potentially important management tool in the face of climate change. Targeted gene flow, which involves moving individuals with favorable traits to areas where these traits would have a conservation benefit, could have a much broader application in conservation. Across a species' range there may be long-standing geographic variation in traits or variation may have rapidly developed in response to a threatening process. Targeted gene flow could be used to promote natural resistance to threats to increase species resilience. We suggest that targeted gene flow is a currently underappreciated strategy in conservation that has applications ranging from the management of invasive species and their impacts to controlling the impact and virulence of pathogens. © 2015 Society for Conservation Biology.

  18. DMRT genes in vertebrate gametogenesis.

    Science.gov (United States)

    Zarkower, David

    2013-01-01

    Genes containing the DM domain DNA-binding motif regulate sex determination and sexual differentiation in a broad variety of metazoans, including nematodes, insects, and vertebrates. They can function in primary sex determination or downstream in sexual differentiation, and they can act either throughout the body or in highly restricted cell types. In vertebrates, several DM domain genes--DMRT genes--play critical roles in gonadal differentiation or gametogenesis. DMRT1 has the most prominent role and likely regulates testicular differentiation in all vertebrates. In the mammalian gonad, DMRT1 exerts both intrinsic and extrinsic control of gametogenesis; it is required for germ cell differentiation in males and regulates meiosis in both sexes, and it is required in supporting cells for the establishment and maintenance of male fate in the testis. These varied functions of DMRT1 serve to coordinate gonadal development and function. In other vertebrates, DMRT1 regulates gonadal differentiation, and it also appears to have played a central role in the evolution of new sex-determining mechanisms in at least three vertebrate clades. This chapter focuses on the regulation of vertebrate gametogenesis by DMRT1. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. Gene transfer to the cerebellum.

    Science.gov (United States)

    Louboutin, Jean-Pierre; Reyes, Beverly A S; Van Bockstaele, Elisabeth J; Strayer, David S

    2010-12-01

    There are several diseases for which gene transfer therapy to the cerebellum might be practicable. In these studies, we used recombinant Tag-deleted SV40-derived vectors (rSV40s) to study gene delivery targeting the cerebellum. These vectors transduce neurons and microglia very effectively in vitro and in vivo, and so we tested them to evaluate gene transfer to the cerebellum in vivo. Using a rSV40 vector carrying human immunodeficiency virus (HIV)-Nef with a C-terminal FLAG epitope, we characterized the distribution, duration, and cell types transduced. Rats received test and control vectors by stereotaxic injection into the cerebellum. Transgene expression was assessed 1, 2, and 4 weeks later by immunostaining of serial brain sections. FLAG epitope-expressing cells were seen, at all times after vector administration, principally detected in the Purkinje cells of the cerebellum, identified as immunopositive for calbindin. Occasional microglial cells were tranduced; transgene expression was not detected in astrocytes or oligodendrocytes. No inflammatory or other reaction was detected at any time. Thus, SV40-derived vectors can deliver effective, safe, and durable transgene expression to the cerebellum.

  20. Scintigraphic imaging of HSVtk gene therapy

    NARCIS (Netherlands)

    de Vries, EFJ; Buursma, AR; Hospers, GAP; Mulder, NH; Vaalburg, W

    2002-01-01

    The evolution of molecular biology has enabled the exploration of novel sophisticated gene-directed treating modalities for cancer. Suicide gene therapy - i.e. transfection of a so-called suicide gene that sensitizes target cells towards a prodrug - may offer an attractive approach to treat

  1. Uses of antimicrobial genes from microbial genome

    Science.gov (United States)

    Sorek, Rotem; Rubin, Edward M.

    2013-08-20

    We describe a method for mining microbial genomes to discover antimicrobial genes and proteins having broad spectrum of activity. Also described are antimicrobial genes and their expression products from various microbial genomes that were found using this method. The products of such genes can be used as antimicrobial agents or as tools for molecular biology.

  2. Structure of the murine Thy-1 gene

    NARCIS (Netherlands)

    V. Giguere; K-I. Isobe; F.G. Grosveld (Frank)

    1985-01-01

    textabstractWe have cloned the murine Thy-1.1 (AKR) and Thy-1.2 (Balb/c) genes. The complete exon/intron structure and the nucleotide sequence of the Thy-1.2 gene was determined. The gene contains four exons and three intervening sequences. The complete transcriptional unit gives rise to a tissue

  3. Network topology reveals key cardiovascular disease genes.

    Directory of Open Access Journals (Sweden)

    Anida Sarajlić

    Full Text Available The structure of protein-protein interaction (PPI networks has already been successfully used as a source of new biological information. Even though cardiovascular diseases (CVDs are a major global cause of death, many CVD genes still await discovery. We explore ways to utilize the structure of the human PPI network to find important genes for CVDs that should be targeted by drugs. The hope is to use the properties of such important genes to predict new ones, which would in turn improve a choice of therapy. We propose a methodology that examines the PPI network wiring around genes involved in CVDs. We use the methodology to identify a subset of CVD-related genes that are statistically significantly enriched in drug targets and "driver genes." We seek such genes, since driver genes have been proposed to drive onset and progression of a disease. Our identified subset of CVD genes has a large overlap with the Core Diseasome, which has been postulated to be the key to disease formation and hence should be the primary object of therapeutic intervention. This indicates that our methodology identifies "key" genes responsible for CVDs. Thus, we use it to predict new CVD genes and we validate over 70% of our predictions in the literature. Finally, we show that our predicted genes are functionally similar to currently known CVD drug targets, which confirms a potential utility of our methodology towards improving therapy for CVDs.

  4. Transposon based functional characterization of soybean genes

    Science.gov (United States)

    Type II transposable elements that use cut and paste mechanism for jumping from one genomic region to another is ideal in tagging and cloning genes. Precise excision from an insertion site in a mutant gene leads to regaining the wild-type function. Thus, function of a gene can be established based o...

  5. Study of obesity associated proopiomelanocortin gene polymorphism

    African Journals Online (AJOL)

    Study of obesity associated proopiomelanocortin gene polymorphism: Relation to metabolic profile and eating habits in a sample of obese Egyptian children and ... Polymorphisms in the POMC gene locus are associated with obesity phenotypes. Aim: To ... Keywords: Childhood obesity; POMC gene; Metabolic syndrome ...

  6. Mining disease genes using integrated protein-protein interaction and gene-gene co-regulation information.

    Science.gov (United States)

    Li, Jin; Wang, Limei; Guo, Maozu; Zhang, Ruijie; Dai, Qiguo; Liu, Xiaoyan; Wang, Chunyu; Teng, Zhixia; Xuan, Ping; Zhang, Mingming

    2015-01-01

    In humans, despite the rapid increase in disease-associated gene discovery, a large proportion of disease-associated genes are still unknown. Many network-based approaches have been used to prioritize disease genes. Many networks, such as the protein-protein interaction (PPI), KEGG, and gene co-expression networks, have been used. Expression quantitative trait loci (eQTLs) have been successfully applied for the determination of genes associated with several diseases. In this study, we constructed an eQTL-based gene-gene co-regulation network (GGCRN) and used it to mine for disease genes. We adopted the random walk with restart (RWR) algorithm to mine for genes associated with Alzheimer disease. Compared to the Human Protein Reference Database (HPRD) PPI network alone, the integrated HPRD PPI and GGCRN networks provided faster convergence and revealed new disease-related genes. Therefore, using the RWR algorithm for integrated PPI and GGCRN is an effective method for disease-associated gene mining.

  7. Author Details

    African Journals Online (AJOL)

    Wilson, MM. Vol 16, No 2 (2015) - Articles Study of the effect of HFE gene mutations on iron overload in Egyptian thalassemia patients. Abstract PDF. ISSN: 1110-8630. AJOL African Journals Online. HOW TO USE AJOL... for Researchers · for Librarians · for Authors · FAQ's · More about AJOL · AJOL's Partners · Terms and ...

  8. Egyptian Journal of Medical Human Genetics - Vol 16, No 2 (2015)

    African Journals Online (AJOL)

    Study of the effect of HFE gene mutations on iron overload in Egyptian thalassemia patients · EMAIL FREE FULL TEXT EMAIL FREE FULL TEXT DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT. MM Wilson, H Al-Wakeel, F Said, M El-Ghamrawy, M Assaad, A El-Beshlawy, 129-133.

  9. Recent advance in the molecular genetics of Wilson disease and hereditary hemochromatosis.

    Science.gov (United States)

    Lv, Tingxia; Li, Xiaojin; Zhang, Wei; Zhao, Xinyan; Ou, Xiaojuan; Huang, Jian

    2016-10-01

    Metabolic liver diseases such as Wilson disease (WD) and hereditary hemochromatosis (HH) possess complicated pathogenesis and typical hereditary characteristics with the hallmarks of a deficiency in metal metabolism. Mutations in genes encoding ATPase, Cu + transporting, beta polypeptide (ATP7B) and hemochromatosis (HFE) or several non-HFE genes are considered to be causative for WD and HH, respectively. Although the identification of novel mutations in ATP7B for WD and HFE or the non-HFE genes for HH has increased, especially with the application of whole genome sequencing technology in recent years, the biological function of the identified mutations, as well as genotype-phenotype correlations remain to be explored. Further analysis of the causative gene mutation would be critical to clarify the mechanisms underlying specific disease phenotypes. In this review, we therefore summarize the recent advances in the molecular genetics of WD and HH including the updated mutation spectrums and the correlation between genotype and phenotype, with an emphasis on biological functional studies of the individual mutations identified in WD and HH. The weakness of the current functional studies and analysis for the clinical association of the individual mutation was also discussed. These works are essential for the understanding of the association between genotypes and phenotypes of these inherited metabolic liver diseases. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  10. High diversity of polyketide synthase genes and the melanin biosynthesis gene cluster in Penicillium marneffei.

    Science.gov (United States)

    Woo, Patrick C Y; Tam, Emily W T; Chong, Ken T K; Cai, James J; Tung, Edward T K; Ngan, Antonio H Y; Lau, Susanna K P; Yuen, Kwok-Yung

    2010-09-01

    Despite the unique phenotypic properties and clinical importance of Penicillium marneffei, the polyketide synthase genes in its genome have never been characterized. Twenty-three putative polyketide synthase genes and two putative polyketide synthase nonribosomal peptide-synthase hybrid genes were identified in the P. marneffei genome, a diversity much higher than found in other pathogenic thermal dimorphic fungi, such as Histoplasma capsulatum (one polyketide synthase gene) and Coccidioides immitis (10 polyketide synthase genes). These genes were evenly distributed on the phylogenetic tree with polyketide synthase genes of Aspergillus and other fungi, indicating that the high diversity was not a result of lineage-specific gene expansion through recent gene duplication. The melanin-biosynthesis gene cluster had gene order and orientations identical to those in the Talaromyces stipitatus (a teleomorph of Penicillium emmonsii) genome. Phylogenetically, all six genes of the melanin-biosynthesis gene cluster in P. marneffei were also most closely related to those in T. stipitatus, with high bootstrap supports. The polyketide synthase gene of the melanin-biosynthesis gene cluster (alb1) in P. marneffei was knocked down, which was accompanied by loss of melanin pigment production and reduced ornamentation in conidia. The survival of mice challenged with the alb1 knockdown mutant was significantly better than those challenged with wild-type P. marneffei (P melanin-biosynthesis gene cluster contributed to virulence through decreased susceptibility to killing by hydrogen peroxide. © 2010 The Authors Journal compilation © 2010 FEBS.

  11. Evolutionary and Topological Properties of Genes and Community Structures in Human Gene Regulatory Networks.

    Science.gov (United States)

    Szedlak, Anthony; Smith, Nicholas; Liu, Li; Paternostro, Giovanni; Piermarocchi, Carlo

    2016-06-01

    The diverse, specialized genes present in today's lifeforms evolved from a common core of ancient, elementary genes. However, these genes did not evolve individually: gene expression is controlled by a complex network of interactions, and alterations in one gene may drive reciprocal changes in its proteins' binding partners. Like many complex networks, these gene regulatory networks (GRNs) are composed of communities, or clusters of genes with relatively high connectivity. A deep understanding of the relationship between the evolutionary history of single genes and the topological properties of the underlying GRN is integral to evolutionary genetics. Here, we show that the topological properties of an acute myeloid leukemia GRN and a general human GRN are strongly coupled with its genes' evolutionary properties. Slowly evolving ("cold"), old genes tend to interact with each other, as do rapidly evolving ("hot"), young genes. This naturally causes genes to segregate into community structures with relatively homogeneous evolutionary histories. We argue that gene duplication placed old, cold genes and communities at the center of the networks, and young, hot genes and communities at the periphery. We demonstrate this with single-node centrality measures and two new measures of efficiency, the set efficiency and the interset efficiency. We conclude that these methods for studying the relationships between a GRN's community structures and its genes' evolutionary properties provide new perspectives for understanding evolutionary genetics.

  12. Reranking candidate gene models with cross-species comparison for improved gene prediction

    Directory of Open Access Journals (Sweden)

    Pereira Fernando CN

    2008-10-01

    Full Text Available Abstract Background Most gene finders score candidate gene models with state-based methods, typically HMMs, by combining local properties (coding potential, splice donor and acceptor patterns, etc. Competing models with similar state-based scores may be distinguishable with additional information. In particular, functional and comparative genomics datasets may help to select among competing models of comparable probability by exploiting features likely to be associated with the correct gene models, such as conserved exon/intron structure or protein sequence features. Results We have investigated the utility of a simple post-processing step for selecting among a set of alternative gene models, using global scoring rules to rerank competing models for more accurate prediction. For each gene locus, we first generate the K best candidate gene models using the gene finder Evigan, and then rerank these models using comparisons with putative orthologous genes from closely-related species. Candidate gene models with lower scores in the original gene finder may be selected if they exhibit strong similarity to probable orthologs in coding sequence, splice site location, or signal peptide occurrence. Experiments on Drosophila melanogaster demonstrate that reranking based on cross-species comparison outperforms the best gene models identified by Evigan alone, and also outperforms the comparative gene finders GeneWise and Augustus+. Conclusion Reranking gene models with cross-species comparison improves gene prediction accuracy. This straightforward method can be readily adapted to incorporate additional lines of evidence, as it requires only a ranked source of candidate gene models.

  13. Integrating Ontological Knowledge and Textual Evidence in Estimating Gene and Gene Product Similarity

    Energy Technology Data Exchange (ETDEWEB)

    Sanfilippo, Antonio P.; Posse, Christian; Gopalan, Banu; Tratz, Stephen C.; Gregory, Michelle L.

    2006-06-08

    With the rising influence of the Gene On-tology, new approaches have emerged where the similarity between genes or gene products is obtained by comparing Gene Ontology code annotations associ-ated with them. So far, these approaches have solely relied on the knowledge en-coded in the Gene Ontology and the gene annotations associated with the Gene On-tology database. The goal of this paper is to demonstrate that improvements to these approaches can be obtained by integrating textual evidence extracted from relevant biomedical literature.

  14. Liposomes as a gene delivery system

    Directory of Open Access Journals (Sweden)

    C. Ropert

    1999-02-01

    Full Text Available Gene therapy is an active field that has progressed rapidly into clinical trials in a relatively short time. The key to success for any gene therapy strategy is to design a vector able to serve as a safe and efficient gene delivery vehicle. This has encouraged the development of nonviral DNA-mediated gene transfer techniques such as liposomes. Many liposome-based DNA delivery systems have been described, including molecular components for targeting given cell surface receptors or for escaping from the lysosomal compartment. Another recent technology using cationic lipids has been evaluated and has generated substantial interest in this approach to gene transfer.

  15. Validation of reference genes for quantifying changes in gene expression in virus-infected tobacco.

    Science.gov (United States)

    Baek, Eseul; Yoon, Ju-Yeon; Palukaitis, Peter

    2017-10-01

    To facilitate quantification of gene expression changes in virus-infected tobacco plants, eight housekeeping genes were evaluated for their stability of expression during infection by one of three systemically-infecting viruses (cucumber mosaic virus, potato virus X, potato virus Y) or a hypersensitive-response-inducing virus (tobacco mosaic virus; TMV) limited to the inoculated leaf. Five reference-gene validation programs were used to establish the order of the most stable genes for the systemically-infecting viruses as ribosomal protein L25 > β-Tubulin > Actin, and the least stable genes Ubiquitin-conjugating enzyme (UCE) genes were EF1α > Cysteine protease > Actin, and the least stable genes were GAPDH genes, three defense responsive genes were examined to compare their relative changes in gene expression caused by each virus. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Review: the dominant flocculation genes of Saccharomyces cerevisiae constitute a new subtelomeric gene family.

    Science.gov (United States)

    Teunissen, A W; Steensma, H Y

    1995-09-15

    The quality of brewing strains is, in large part, determined by their flocculation properties. By classical genetics, several dominant, semidominant and recessive flocculation genes have been recognized. Recent results of experiments to localize the flocculation genes FLO5 and FLO8, combined with the in silicio analysis of the available sequence data of the yeast genome, have revealed that the flocculation genes belong to a family which comprises at least four genes and three pseudogenes. All members of this gene family are located near the end of chromosomes, just like the SUC, MEL and MAL genes, which are also important for good quality baking or brewing strains. Transcription of the flocculation genes is repressed by several regulatory genes. In addition, a number of genes have been found which cause cell aggregation upon disruption or overexpression in an as yet unknown manner. In total, 33 genes have been reported that are involved in flocculation or cell aggregation.

  17. Mining Association Rules among Gene Functions in Clusters of Similar Gene Expression Maps.

    Science.gov (United States)

    An, Li; Obradovic, Zoran; Smith, Desmond; Bodenreider, Olivier; Megalooikonomou, Vasileios

    2009-11-01

    Association rules mining methods have been recently applied to gene expression data analysis to reveal relationships between genes and different conditions and features. However, not much effort has focused on detecting the relation between gene expression maps and related gene functions. Here we describe such an approach to mine association rules among gene functions in clusters of similar gene expression maps on mouse brain. The experimental results show that the detected association rules make sense biologically. By inspecting the obtained clusters and the genes having the gene functions of frequent itemsets, interesting clues were discovered that provide valuable insight to biological scientists. Moreover, discovered association rules can be potentially used to predict gene functions based on similarity of gene expression maps.

  18. Biological cluster evaluation for gene function prediction.

    Science.gov (United States)

    Klie, Sebastian; Nikoloski, Zoran; Selbig, Joachim

    2014-06-01

    Recent advances in high-throughput omics techniques render it possible to decode the function of genes by using the "guilt-by-association" principle on biologically meaningful clusters of gene expression data. However, the existing frameworks for biological evaluation of gene clusters are hindered by two bottleneck issues: (1) the choice for the number of clusters, and (2) the external measures which do not take in consideration the structure of the analyzed data and the ontology of the existing biological knowledge. Here, we address the identified bottlenecks by developing a novel framework that allows not only for biological evaluation of gene expression clusters based on existing structured knowledge, but also for prediction of putative gene functions. The proposed framework facilitates propagation of statistical significance at each of the following steps: (1) estimating the number of clusters, (2) evaluating the clusters in terms of novel external structural measures, (3) selecting an optimal clustering algorithm, and (4) predicting gene functions. The framework also includes a method for evaluation of gene clusters based on the structure of the employed ontology. Moreover, our method for obtaining a probabilistic range for the number of clusters is demonstrated valid on synthetic data and available gene expression profiles from Saccharomyces cerevisiae. Finally, we propose a network-based approach for gene function prediction which relies on the clustering of optimal score and the employed ontology. Our approach effectively predicts gene function on the Saccharomyces cerevisiae data set and is also employed to obtain putative gene functions for an Arabidopsis thaliana data set.

  19. Integrating various resources for gene name normalization.

    Science.gov (United States)

    Hu, Yuncui; Li, Yanpeng; Lin, Hongfei; Yang, Zhihao; Cheng, Liangxi

    2012-01-01

    The recognition and normalization of gene mentions in biomedical literature are crucial steps in biomedical text mining. We present a system for extracting gene names from biomedical literature and normalizing them to gene identifiers in databases. The system consists of four major components: gene name recognition, entity mapping, disambiguation and filtering. The first component is a gene name recognizer based on dictionary matching and semi-supervised learning, which utilizes the co-occurrence information of a large amount of unlabeled MEDLINE abstracts to enhance feature representation of gene named entities. In the stage of entity mapping, we combine the strategies of exact match and approximate match to establish linkage between gene names in the context and the EntrezGene database. For the gene names that map to more than one database identifiers, we develop a disambiguation method based on semantic similarity derived from the Gene Ontology and MEDLINE abstracts. To remove the noise produced in the previous steps, we design a filtering method based on the confidence scores in the dictionary used for NER. The system is able to adjust the trade-off between precision and recall based on the result of filtering. It achieves an F-measure of 83% (precision: 82.5% recall: 83.5%) on BioCreative II Gene Normalization (GN) dataset, which is comparable to the current state-of-the-art.

  20. Integrating various resources for gene name normalization.

    Directory of Open Access Journals (Sweden)

    Yuncui Hu

    Full Text Available The recognition and normalization of gene mentions in biomedical literature are crucial steps in biomedical text mining. We present a system for extracting gene names from biomedical literature and normalizing them to gene identifiers in databases. The system consists of four major components: gene name recognition, entity mapping, disambiguation and filtering. The first component is a gene name recognizer based on dictionary matching and semi-supervised learning, which utilizes the co-occurrence information of a large amount of unlabeled MEDLINE abstracts to enhance feature representation of gene named entities. In the stage of entity mapping, we combine the strategies of exact match and approximate match to establish linkage between gene names in the context and the EntrezGene database. For the gene names that map to more than one database identifiers, we develop a disambiguation method based on semantic similarity derived from the Gene Ontology and MEDLINE abstracts. To remove the noise produced in the previous steps, we design a filtering method based on the confidence scores in the dictionary used for NER. The system is able to adjust the trade-off between precision and recall based on the result of filtering. It achieves an F-measure of 83% (precision: 82.5% recall: 83.5% on BioCreative II Gene Normalization (GN dataset, which is comparable to the current state-of-the-art.