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Sample records for hfe mutations associate

  1. An association study of HFE gene mutation with idiopathic male infertility in the Chinese Han population

    Institute of Scientific and Technical Information of China (English)

    Xiao-Ying Yu; Xu Ma; Bin-Bin Wang; Zhong-Cheng Xin; Tao Liu; Ke Ma; Jian Jiang; Xiang Fang; Li-Hua Yu; Yi-Feng Peng

    2012-01-01

    Mutations in the haemochromatosis gene (HFE) influence iron status in the general population of Northern Europe,and excess iron is associated with the impairment of spermatogenesis.The aim of this study is to investigate the association between three mutations (C282Y,H63D and S65C) in the HFE gene with idiopathic male infertility in the Chinese Han population.Two groups of Chinese men were recruited:444 infertile men (including 169 with idiopathic azoospermia) and 423 controls with proven fertility.The HFEgene was detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique.The experimental results demonstrated that no C282Y or S65C mutations were detected.Idiopathic male infertility was not significantly associated with heterozygous H63D mutation (odds ratio=0.801,95% confidence interval=0.452-1.421,X2=0.577,P=0.448).The H63D mutation frequency did not correlate significantly with the serum luteinizing hormone (LH),follicle-stimulating hormone (FSH) and testosterone (T) levels in infertile men (P=0.896,P=0.404 and P=0.05,respectively).Our data suggest that the HFE H63D mutation is not associated with idiopathic male reproductive dysfunction.

  2. Nonalcoholic steatohepatitis in Asian Indians is neither associated with iron overload nor with HFE gene mutations

    Institute of Scientific and Technical Information of China (English)

    Ajay Duseja; Reena Das; Mohit Nanda; Ashim Das; Gurjeewan Garewal; Yogesh Chawla

    2005-01-01

    AIM: The pathogenesis of occurrence of liver inflammation and fibrosis in patients with nonalcoholic steatohepatitis (NASH) is not completely understood. Other than insulin resistance, iron abnormalities have been thought to be one of the triggering factors. Therefore, our aim was to study the role of iron abnormalities and HFE gene mutations in patients with NASH.METHODS: Thirty-one patients of NASH diagnosed on the basis of clinical examination biochemistry, ultrasonography and liver biopsy (n = 14) were included in the study. Serum iron parameters (n = 23) (iron, ferritin, total iron-binding capacity and transferrin saturation), Peris' iron staining on liver biopsies (n = 14) and HFE gene mutations (C282Y and H63D) (n = 16) were studied in these patients. The association between iron staining, necroinflammatory activity and fibrosis stage on liver biopsies was also determined.RESULTS: Elevated serum iron, ferritin and transferrin saturation above 55% were observed in 4.3% of patients.On histology, 71% of the patients had negative iron staining,21.4% had 1+ staining, 7.2% had 2+ staining and none had 3+ or 4+ staining. There was no association between the degree of iron staining and necroinflammatory activity (P = 0.55) and fibrosis stage (P = 0.09) on histology. None of the patients had C282Y HFE gene mutation and four patients (25%) were found to be heterozygotes for H63D gene mutation.CONCLUSION: Our study does not favor iron overload and HFE gene mutations as major factors in the pathogenesis of NASH in Asian Indians.

  3. Association of HFE common mutations with Parkinson's disease, Alzheimer's disease and mild cognitive impairment in a Portuguese cohort

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    Morgadinho Ana S

    2006-07-01

    Full Text Available Abstract Background Pathological brain iron deposition has been implicated as a source of neurotoxic reactive oxygen species in Alzheimer (AD and Parkinson diseases (PD. Iron metabolism is associated with the gene hemochromatosis (HFE Human genome nomenclature committee ID:4886, and mutations in HFE are a cause of the iron mismetabolism disease, hemochromatosis. Several reports have tested the association of HFE variants with neurodegenerative diseases, such as AD and PD with conflicting results. Methods Genotypes were analysed for the two most common variants of HFE in a series of 130 AD, 55 Mild Cognitive Impairment (MCI and 132 PD patients. Additionally, a series of 115 healthy age-matched controls was also screened. Results A statistically significant association was found in the PD group when compared to controls, showing that the presence of the C282Y variant allele may confer higher risk for developing the disease. Conclusion Taken together these results suggest that the common variants in HFE may be a risk factor for PD, but not for AD in the Portuguese population.

  4. Mutations in the hemochromatosis gene (HFE) and stroke

    NARCIS (Netherlands)

    O.T. Njajou (Omer); M. Hollander (Monika); P.J. Koudstaal (Peter Jan); A. Hofman (Albert); C.M. van Duijn (Cock); J.C.M. Witteman (Jacqueline); M.M.B. Breteler (Monique)

    2002-01-01

    textabstractBACKGROUND AND PURPOSE: Increased serum iron is found to be a risk factor for stroke. Carriers of HFE C282Y and H63D mutations have elevated serum iron levels and may have an increased risk for stroke. We studied the association between HFE gene mutations, carotid atherosclerosis, and

  5. 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.

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

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    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.

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

    DEFF Research Database (Denmark)

    Koefoed, P; Dalhoff, K; Dissing, J

    2002-01-01

    Analysis of the common C282Y and H63D mutations in the HFE gene is widely used to diagnose hereditary hemochromatosis (HH). The aim of this study was to evaluate the efficiency with which different hospitals and general practitioners select patients for HH genotype and to determine the distribution...... of HFE mutations in such patients. Nine hundred unrelated patients from Danish hospitals and general practitioners (group A) and 69 consecutive patients from a specialized liver unit (group B) were examined for HFE substitutions using multiplex real-time polymerase chain reaction. In group A we found 13...

  8. 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

  9. HFE H63D mutation frequency shows an increase in Turkish women with breast cancer

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    Guler Emine

    2006-02-01

    Full Text Available Abstract Background The hereditary hemochromatosis gene HFE plays a pivotal role in iron homeostasis. The association between cancer and HFE hetero- or homozygosity has previously been shown including hepatocellular and nonhepatocellular malignancies. This study was performed to compare frequencies of HFE C282Y and H63D variants in Turkish women with breast cancer and healthy controls. Methods Archived DNA samples of Hacettepe University Oncology Institute were used in this study. The HFE gene was investigated by PCR-RFLP. Results All subjects studied were free from C282Y mutation. Thirty-nine patients had H63D mutation and were all heterozygous. H63D allele frequency was 22.2% (39/176 in the breast cancer patients, and 14% (28/200 in the healthy volunteers. Statistical analysis of cases with HFE H63D phenotype showed significant difference between breast cancer and healthy volunteers (P = 0.02. Conclusion Our results suggest that HFE H63D mutation frequencies were increased in the breast cancer patients in comparison to those in the general population. Also, odds ratios (odds ratio = 2.05 computed in this study suggest that H63D has a positive association with breast cancer.

  10. Bone Mineral Density in Postmenopausal Women Heterozygous for the C282Y HFE Mutation

    OpenAIRE

    2016-01-01

    Mutations in the HFE gene may be associated with increased tissue iron stores reflected in an elevated serum ferritin. With homozygous mutation C282Y, the increase in serum ferritin may be associated with tissue damage in the liver, pancreas, and pituitary and with a reduced bone mineral density. With heterozygous mutation C282Y, the degree of iron retention is less but information relating to how a heterozygous C282Y mutation might impact bone mineral density is uncertain. The present study ...

  11. Association between C282Y and H63D mutations of the HFE gene with hepatocellular carcinoma in European populations: a meta-analysis

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    Shen Xi-Zhong

    2010-03-01

    Full Text Available Abstract Background Hereditary hemochromatosis (HH is an autosomal recessive disorder mainly associated with homozygosity for the C282Y and H63D mutations in the hemochromatosis (HFE gene. The reports about the C282Y and H63D mutations and hepatocellular carninoma (HCC were controversial. To clarify the relationship between C282Y and H63D mutations and HCC, a meta-analysis including nine studies (1102 HCC cases and 3766 controls, mainly came from European populations was performed. Methods The association was measured using random-effect (RE or fixed-effect (FE odds ratios (ORs combined with 95% confidence intervals (CIs according to the studies' heterogeneity. Results Meta-analysis of nine studies showed that Y allele of C282Y was associated with HCC risk: RE OR reached 1.50 (95%CI: 1.05-2.14, p for heterogeneity = 0.02, I2 = 0.57. Subgroup analysis of seven studies also showed Y allele was associated with HCC risk in healthy populations: RE OR reached 1.61 (95%CI: 1.08-2.39, p for heterogeneity = 0.04, I2 = 0.55. We further did subgroup analysis in alcoholic liver cirrhosis (LC patients of four studies (224 cases and 380 controls and found that both the dominant model and Y allele of C282Y were associated with HCC risk (FE OR reached 4.06, 95%CI: 2.08-7.92 and 3.41, 95%CI: 1.81-6.41, respectively. There was no distinct heterogeneity among the studies (I2 = 0. Sensitivity analyses showed the results were robust in the subgroup analysis of alcoholic LC patients. Conclusions C282Y mutation was associated with HCC in European alcoholic LC patients.

  12. Hereditary hemochromatosis: HFE mutation analysis in Greeks reveals genetic heterogeneity.

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    Papanikolaou, G; Politou, M; Terpos, E; Fourlemadis, S; Sakellaropoulos, N; Loukopoulos, D

    2000-04-01

    Hereditary hemochromatosis (HH) is common among Caucasians; reported disease frequencies vary from 0.3 to 0.8%. Identification of a candidate HFE gene in 1996 was soon followed by the description of two ancestral mutations, i.e., c.845G-->A (C282Y) and c.187C-->G (H63D). To these was recently added the mutation S65C, which may represent a simple polymorphism. The incidence of HH in Greece is unknown but clinical cases are rare. Also unknown is the carrier frequency of the two mutant alleles. A first estimate of the latter is given in the present report. It is based on data from the genetic analysis of 10 unrelated patients of Greek origin who were referred to our center for genotyping and 158 unselected male blood donors. The allele frequencies for the C282Y and H63D mutations were 0.003 and 0.145, respectively. The C282Y allele was detected in 50% of HH patients. This is considerably lower than the frequencies reported for HH patients in the U.S.A. (82%) and France (91 %) and closer to that reported in Italy (64%). Five patients did not carry any known HFE mutation; three may represent cases of juvenile hemochromatosis, given their early onset with iron overload, hypogonadism, and heart disease. We suggest that genetic heterogeneity is more prominent in Southern Europe. It is also possible that the penetrance of the responsible genes is different across the Mediterranean.

  13. Mutations in the hereditary haemochromatosis gene HFE in professional endurance athletes

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    Chicharro, J; Hoyos, J; Gomez-Gallego, F; Villa, J; Bandres, F; Celaya, P; Jimenez, F; Alonso, J; Cordova, A; Lucia, A

    2004-01-01

    Background: Hereditary haemochromatosis, a disease that affects iron metabolism, progresses with a greater or lesser tendency to induce iron overload, possibly leading to severe organ dysfunction. Most elite endurance athletes take iron supplements during their active sporting life, which could aggravate this condition. Objective: To determine the prevalence and discuss potential clinical implications of mutations of HFE (the gene responsible for hereditary haemochromatosis) in endurance athletes. Methods: Basal concentrations of iron, ferritin, and transferrin and transferrin saturation were determined in the period before competition in 65 highly trained athletes. Possible mutations in the HFE gene were evaluated in each subject by extracting genomic DNA from peripheral blood. The restriction enzymes SnaBI and BclI were used to detect the mutations 845G→A (C282Y) and 187C→G (H63D). Results: Our findings indicate a high prevalence of HFE gene mutations in this population (49.2%) compared with sedentary controls (33.5%). No association was detected in the athletes between mutations and blood iron markers. Conclusions: The findings support the need to assess regularly iron stores in elite endurance athletes. PMID:15273174

  14. Increased duodenal DMT-1 expression and unchanged HFE mRNA levels in HFE-associated hereditary hemochromatosis and iron deficiency.

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    Byrnes, V; Barrett, S; Ryan, E; Kelleher, T; O'Keane, C; Coughlan, B; Crowe, J

    2002-01-01

    HFE-associated hereditary hemochromatosis is characterized by imbalances of iron homeostasis and alterations in intestinal iron absorption. The identification of the HFE gene and the apical iron transporter divalent metal transporter-1, DMT-1, provide a direct method to address the mechanisms of iron overload in this disease. The aim of this study was to evaluate the regulation of duodenal HFE and DMT-1 gene expression in HFE-associated hereditary hemochromatosis. Small bowel biopsies and serum iron indices were obtained from a total of 33 patients. The study population comprised 13 patients with hereditary hemochromatosis (C282Y homozygous), 10 patients with iron deficiency anemia, and 10 apparently healthy controls, all of whom were genotyped for the two common mutations in the HFE gene (C282Y and H63D). Total RNA was isolated from tissue and amplified via RT-PCR for HFE, DMT-1, and the internal control GAPDH. DMT-1 protein expression was additionally assessed by immunohistochemistry. Levels of HFE mRNA did not differ significantly between patient groups (P = 0.09), specifically between C282Y homozygotes and iron deficiency anemic patients, when compared to controls (P = 0.09, P = 0.9, respectively). In contrast, DMT-1 mRNA levels were at least twofold greater in patients with hereditary hemochromatosis and iron deficiency anemia when compared to controls (P = 0.02, P = 0.01, respectively). Heightened DMT-1 protein expression correlated with mRNA levels in all patients. Loss of HFE function in hereditary hemochromatosis is not derived from inhibition of its gene expression. DMT-1 expression in C282Y homozygote subjects is consistent with the hypothesis of a "paradoxical" duodenal iron deficiency in hereditary hemochromatosis. The observed twofold upregulation of the DMT-1 is consistent with the slow but steady increase in body iron stores observed in those presenting with clinical features of hereditary hemochromatosis.

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

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    Luís 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 Contexto A doença hepática alcoólica (DHA está geralmente associada à sobrecarga de ferro, que pode contribuir para a sua patogênese, através do aumento do estresse oxidativo e dano celular. As descrições existentes na literatura sobre a associação entre mutações HFE e a gravidade da DHA nem sempre são concordantes. Objetivos Comparar a prevalência de mutações HFE entre um grupo de pacientes com DHA e uma população de controle. Avaliar a relação entre mutações HFE e os depósitos de ferro hepático. Avaliar se a presença dessas mutações está associada com a gravidade da DHA. Métodos Compararam-se 63 pacientes com DHA que efetuaram biopsia hepática com 52 controles saudáveis. A genotipagem HFE (wild type, C282Y, H63D, S65C, E

  16. 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.

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

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    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.

  18. Nonalcoholic fatty liver disease and HFE gene mutations:A Polish study

    Institute of Scientific and Technical Information of China (English)

    Joanna; Raszeja-Wyszomirska; Grzegorz; Kurzawski; Malg

    2010-01-01

    AIM:To describe a Polish population with nonalcoholic fatty liver disease(NAFLD)with regard to HFE gene mutations,as well as analyzing demographic and clinical data.METHODS:Sixty-two consecutive patients with biopsy-proven NAFLD were included in the study.Demographic,clinical,and laboratory data were summarized in a database.C282Y and H63D mutations of the HFE gene were analyzed using polymerase chain reactionrestriction fragment lenght polymorphism.RESULTS:The analyzed cohort consisted of 62 homo-geneic Ca...

  19. Mutations in the hereditary haemochromatosis gene HFE in professional endurance athletes

    OpenAIRE

    López Chicharro, José; Hoyos, J; Gómez Gallego, Félix; Villa Vicente, José Gerardo; Bandrés Moya, Fernando; Celaya, P; Lucía Mulas, Alejandro

    2004-01-01

    Background: Hereditary haemochromatosis, a disease that affects iron metabolism, progresses with a greater or lesser tendency to induce iron overload, possibly leading to severe organ dysfunction. Most elite endurance athletes take iron supplements during their active sporting life, which could aggravate this condition. Objective: To determine the prevalence and discuss potential clinical implications of mutations of HFE (the gene responsible for hereditary haemochromatosis) in endurance athl...

  20. Non-HFE hemochromatosis

    Science.gov (United States)

    Santos, Paulo Caleb Júnior de Lima; Dinardo, Carla Luana; Cançado, Rodolfo Delfini; Schettert, Isolmar Tadeu; Krieger, José Eduardo; Pereira, Alexandre Costa

    2012-01-01

    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. PMID:23049448

  1. 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.

  2. 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, Antonio; Bonet, Catalina; Sala, Núria; Muñoz, Xavier; Aranda, Núria; Fonseca-Nunes, Ana; Clavel-Chapelon, Françoise; Boutron-Ruault, Marie Christine; Vineis, Paolo; Panico, Salvatore; Palli, Domenico; Tumino, Rosario; Grioni, Sara; Quirós, J Ramón; Molina, Esther; Navarro, Carmen; Barricarte, Aurelio; Chamosa, Saioa; Allen, Naomi E; Khaw, Kay-Tee; Bueno-de-Mesquita, H Bas; Siersema, Peter D; Numans, Mattijs E; Trichopoulou, Antonia; Lagiou, Pagona; Trichopoulos, Dimitrios; Kaaks, Rudof; Canzian, Federico; Boeing, Heiner; Meidtner, Karina; Johansson, Mattias; Sund, Malin; Manjer, Jonas; Overvad, Kim; Tjonneland, Anne; Lund, Eiliv; Weiderpass, Elisabete; Jenab, Mazda; Fedirko, Veronika; Offerhaus, G Johan A; Riboli, Elio; González, Carlos A; Jakszyn, Paula

    2013-06-01

    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 European Prospective Investigation into Cancer and Nutrition (EPIC), including 365 incident gastric adenocarcinoma and 1284 controls matched by center, sex, age and date of blood collection. Genotype analysis was performed for two functional polymorphisms (C282Y/rs1800562 and H63D/rs1799945) and seven tagSNPs of the HFE genomic region. Association with all gastric adenocarcinoma, and according to anatomical localization and histological subtype, was assessed by means of the odds ratio (OR) and 95% confidence interval (CI) estimated by unconditional logistic regression adjusted for the matching variables. We observed a significant association for H63D with OR (per rare allele) of 1.32 (CI = 1.03-1.69). In subgroup analyses, the association was stronger for non-cardia anatomical subsite (OR = 1.60, CI = 1.16-2.21) and intestinal histological subtype (OR = 1.82, CI = 1.27-2.62). Among intestinal cases, two tagSNPs (rs1572982 and rs6918586) also showed a significant association that disappeared after adjustment for H63D. No association with tumors located in the cardia or with diffuse subtype was found for any of the nine SNPs analyzed. Our results suggest that H63D variant in HFE gene seems to be associated with GC risk of the non-cardia region and intestinal type, possibly due to its association with iron overload although a role for other mechanisms cannot be entirely ruled out.

  3. Protective role of calreticulin in HFE hemochromatosis.

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    Pinto, Jorge P; Ramos, Pedro; de Almeida, Sérgio F; Oliveira, Susana; Breda, Laura; Michalak, Marek; Porto, Graça; Rivella, Stefano; de Sousa, Maria

    2008-01-01

    HFE gene mutations are associated with over 80% of cases of hereditary hemochromatosis (HH), an iron-overload disease in which the liver is the most frequently affected organ. Research on HFE has traditionally focused on its interaction with the transferrin receptor. More recent studies have suggested a more complex function for this nonclassical MHC-I protein. The aim of this study was to examine how HFE and its two most common mutations affect the expression of selected genes in a hepatocyte-like cell line. Gene expression was analyzed in HepG2 cells overexpressing wild-type and mutant HFE. The effect of HFE in iron import and oxidative stress levels was assessed. Unfolded protein response (UPR)-activated gene expression was analyzed in peripheral blood mononuclear cells from characterized HH patients. C282Y HFE down-regulated hepcidin and enhanced calreticulin mRNA expression. Calreticulin levels correlated with intracellular iron increase and were associated with protection from oxidative stress. In C282Y(+/+) patients calreticulin levels correlated with the expression of the UPR marker BiP and showed a negative association with the number of hereditary hemochromatosis clinical manifestations. The data show that expression of C282Y HFE triggers a stress-protective response in HepG2 cells and suggest a role for calreticulin as a modifier of the clinical expression of HH.

  4. HFE Gene Mutation Among Turkish Patients with Type 2 Diabetes Mellitus

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    Erdem Akbal

    2013-12-01

    Full Text Available Purpose: Hereditary haemochromatosis (HH is a genetic disease with autosomal recessive trait. Recent studies demonstrated the importance of C282Y gene mutation in the aetiology of HH. Free iron accumulating in pancreas deteriorates insulin secretion and synthesis which can lead to insulin resistance and the development of type 2 diabetes mellitus (T2DM in patients with HH. There has been no study determining the prevalence of haemochromatosis gene (HFE mutations and HH in diabetic patients in Turkey. We planned this study in order to investigate the C282Y and H63D mutation that cause HH in T2DM. Material and Method: In this study, we included185 patients with T2DM. Patients older than thirty-five years, not taking vitamin supplementation, iron preparates and/or oral contraceptives and those without any signs of active bleeding were included while patients with any infectious, systemic or immune disease were excluded from the study. Serum transferrin saturation (TS, ferritin, iron, and total iron binding capacity levels were measured after 12 hours of fasting. Results: Ten (5.4% cases with TS of more than 45% were detected at the first evaluation. The test was repeated in those cases and 6 patients with TS of more than 45% were left according to the second measurement. H63D and C282Y gene polymorphisms were not present in these patients. Discussion: We did not find any correlation between the existence of T2DM and HFE polymorphisms. We assume that screening for HH in T2DM in our population is not needed. Turk Jem 2013; 17: 89-91

  5. HFE p.C282Y gene variant is associated with varicose veins in Russian population.

    Science.gov (United States)

    Sokolova, Ekaterina A; Shadrina, Alexandra S; Sevost'ianova, Kseniya S; Shevela, Andrey I; Soldatsky, Evgenii Yu; Seliverstov, Evgenii I; Demekhova, Marina Yu; Shonov, Oleg A; Ilyukhin, Evgenii A; Smetanina, Mariya A; Voronina, Elena N; Zolotukhin, Igor A; Filipenko, Maxim L

    2016-08-01

    Recently, the association of polymorphism rs1800562 (p.C282Y) in the hemochromatosis (HFE) gene with the increased risk of venous ulceration was shown. We hypothesized that HFE gene polymorphism might be involved not only in ulceration process, but also in susceptibility to primary varicose veins. We genotyped HFE p.C282Y (rs1800562) and p.H63D (rs1799945) variants in patients with primary varicose veins (n = 463) and in the control group (n = 754). In our study, p.282Y variant (rs1800562 A allele) was significantly associated with the risk of varicose veins (OR 1.79, 95 % CI = 1.11-2.89, P = 0.02). A borderline significant reverse association of p.63D variant (rs1799945 G allele) with venous leg ulcer development was revealed in Russians (OR 0.25, 95 % CI = 0.06-1.00, P = 0.05), but not in the meta-analysis (P = 0.56). We conclude that the HFE gene polymorphism can affect the risk of developing primary varicose veins.

  6. 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 ... ly, iron overload is caused by increased iron absorption from the gastrointestinal tract as a ..... of hemoglobin: genetics, pathophysiology and clinical manage- · ment. 2nd ed. .... Spectrum and haplotypes of the HFE hemochro-.

  7. Prevalence of C282Y, H63D, and S65C mutations in hereditary HFE-hemochromatosis gene in Lithuanian population.

    Science.gov (United States)

    Kucinskas, Laimutis; Juzenas, Simonas; Sventoraityte, Jurgita; Cedaviciute, Ruta; Vitkauskiene, Astra; Kalibatas, Vytenis; Kondrackiene, Jurate; Kupcinskas, Limas

    2012-04-01

    HFE-hemochromatosis is a common autosomal recessive disease caused by HFE gene mutations and characterized as iron overload and failure of different organs. The aim of this study was to determine the prevalence of C282Y (c.845 G>A), H63D (c.187 C>G), and S65C (c.193A>T) alleles of HFE gene in the Lithuanian population. One thousand and eleven healthy blood donors of Lithuanian nationality were examined in four different ethnic Lithuanian regions to determine HFE gene alleles and genotype frequencies. The samples of DNA were analyzed for the presence of restriction fragment length polymorphism and validated by DNA sequencing. Among 1,011 blood donors tested, the frequency of C282Y, H63D, and S65C alleles were 2.6%, 15.9%, and 1.9%, respectively. One third of the tested subjects (n = 336) had at least one of the C282Y or H63D HFE gene mutations. The screening of Lithuanian blood donors has detected 13 (1.3%) subjects with a genotype C282Y/C282Y or C282Y/H63D responsible for the development of HFE-hemochromatosis. The prevalence of C282Y mutation was significantly higher among the inhabitants of Zemaitija (Somogitia) at the Baltic Sea area (5.9%) in comparison to the regions of continental part of Lithuania (2.4% in Dzukija, 2.3% in Aukstaitija, and 2% in Suvalkija, p Vikings along the Baltic Sea coast. The first epidemiological investigation of HFE gene mutations in ethnic Lithuanians showed that the frequencies of H63D, C282Y, and S65C of HFE gene alleles are similar to the other North-Eastern Europeans, especially in the Baltic region (Estonia, Latvia), Poland, and part of Russia (Moscow region).

  8. Non-HFE haemochromatosis

    Institute of Scientific and Technical Information of China (English)

    Daniel F Wallace; V Nathan Subramaniam

    2007-01-01

    Non-HFF hereditary haemochromatosis (HH) refers to a genetically heterogeneous group of iron overload disorders that are unlinked to mutations in the HFF gene. The four main types of non-HFE HH are caused by mutations in the hemojuvelin, hepcidin,transferrin receptor 2 and ferroportin genes. Juvenile haemochromatosis is an autosomal recessive disorder and can be caused by mutations in either hemojuvelin or hepcidin. An adult onset form of HH similar to HFE-HH is caused by homozygosity for mutations in transferrin receptor 2. The autosomal dominant iron overload disorder ferroportin disease is caused by mutations in the iron exporter ferroportin. The clinical characteristics and molecular basis of the various types of non-HFE haemochromatosis are reviewed. The study of these disorders and the molecules involved has been invaluable in improving our understanding of the mechanisms involved in the regulation of iron metabolism.

  9. Examination of HFE associations with childhood leukemia risk and extension to other iron regulatory genes.

    Science.gov (United States)

    Kennedy, Amy E; Kamdar, Kala Y; Lupo, Philip J; Okcu, M Fatih; Scheurer, Michael E; Baum, Marianna K; Dorak, M Tevfik

    2014-09-01

    Hereditary hemochromatosis (HFE) variants correlating with body iron levels have shown associations with cancer risk, including childhood acute lymphoblastic leukemia (ALL). Using a multi-ethnic sample of cases and controls from Houston, TX, we examined two HFE variants (rs1800562 and rs1799945), one transferrin receptor gene (TFRC) variant (rs3817672) and three additional iron regulatory gene (IRG) variants (SLC11A2 rs422982; TMPRSS6 rs855791 and rs733655) for their associations with childhood ALL. Being positive for either of the HFE variants yielded a modestly elevated odds ratio (OR) for childhood ALL risk in males (1.40, 95% CI=0.83-2.35), which increased to 2.96 (95% CI=1.29-6.80) in the presence of a particular TFRC genotype for rs3817672 (P interaction=0.04). The TFRC genotype also showed an ethnicity-specific association, with increased risk observed in non-Hispanic Whites (OR=2.54, 95% CI=1.05-6.12; P interaction with ethnicity=0.02). The three additional IRG SNPs all showed individual risk associations with childhood ALL in males (OR=1.52-2.60). A polygenic model based on the number of variant alleles in five IRG SNPs revealed a linear increase in risk among males with the increasing number of variants possessed (OR=2.0 per incremental change, 95% CI=1.29-3.12; P=0.002). Our results replicated previous HFE risk associations with childhood ALL in a US population and demonstrated novel associations for IRG SNPs, thereby strengthening the hypothesis that iron excess mediated by genetic variants contributes to childhood ALL risk.

  10. Diagnostic evaluation of hereditary hemochromatosis (HFE and non-HFE).

    Science.gov (United States)

    Bardou-Jacquet, Edouard; Brissot, Pierre

    2014-08-01

    The management and understanding of hereditary hemochromatosis have evolved with recent advances in iron biology and the associated discovery of numerous genes involved in iron metabolism. HFE-related (type 1) hemochromatosis remains the most frequent form, characterized by C282Y mutation homozygosity. Rare forms of hereditary hemochromatosis include type 2 (A and B, juvenile hemochromatosis caused by HJV and HAMP mutation), type 3 (related to TFR2 mutation), and type 4 (A and B, ferroportin disease). The diagnostic evaluation relies on comprehension of the involved pathophysiologic defect, and careful characterization of the phenotype, which gives clues to guide appropriate genetic testing.

  11. 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

    HFE gene were identified in leucocyte genomic DNA using a polymerase chain reaction (PCR and specific restriction enzymes. Results (cases/controls: 1. Genotype distribution: a C282Y mutation: homozygotes 1/0, heterozygotes 12/23, wild type 183/158 (p = 0.07, non significant; b H63D mutation: homozygotes 9/5, heterozygotes 85/52, wild type 102/124 (0dds ratio 2.00, 95% C.I. 1.29-3.12, p = 0.002. Four cases and 6 controls were carriers of heterozygous mixed genotypes. 2. Allele frequencies: a C282Y mutation: wild type allele 378/339, mutated allele 14/23 (p = 0.11, non significant; b H63D mutation: wild type allele 289/300, mutated allele 103/62 (0dds ratio 1.72, 95% C.I. 1.19-2.50, p = 0.004. Age at diagnosis, gender and etiology of the underlying liver disease do not influence these findings. Conclusion: the C282Y mutation in the HFE gene is not related to the risk of HCC in non-hemochromatosis patients. The H63D mutation is associated with a higher risk of HCC in cirrhotic patients irrespective of their underlying liver disease.

  12. Diabetes in HFE Hemochromatosis

    Directory of Open Access Journals (Sweden)

    James C. Barton

    2017-01-01

    Full Text Available Diabetes in whites of European descent with hemochromatosis was first attributed to pancreatic siderosis. Later observations revealed that the pathogenesis of diabetes in HFE hemochromatosis is multifactorial and its clinical manifestations are heterogeneous. Increased type 2 diabetes risk in HFE hemochromatosis is associated with one or more factors, including abnormal iron homeostasis and iron overload, decreased insulin secretion, cirrhosis, diabetes in first-degree relatives, increased body mass index, insulin resistance, and metabolic syndrome. In p.C282Y homozygotes, serum ferritin, usually elevated at hemochromatosis diagnosis, largely reflects body iron stores but not diabetes risk. In persons with diabetes type 2 without hemochromatosis diagnoses, serum ferritin levels are higher than those of persons without diabetes, but most values are within the reference range. Phlebotomy therapy to achieve iron depletion does not improve diabetes control in all persons with HFE hemochromatosis. The prevalence of type 2 diabetes diagnosed today in whites of European descent with and without HFE hemochromatosis is similar. Routine iron phenotyping or HFE genotyping of patients with type 2 diabetes is not recommended. Herein, we review diabetes in HFE hemochromatosis and the role of iron in diabetes pathogenesis in whites of European descent with and without HFE hemochromatosis.

  13. Liver steatosis correlates with iron overload but not with HFE gene mutations in chronic hepatitis C

    Institute of Scientific and Technical Information of China (English)

    Katarzyna Sikorska; Piotr Stalke; Tomasz Romanowski

    2013-01-01

    BACKGROUND: Liver  steatosis  and  iron  overload,  which are  frequently  observed  in  chronic  hepatitis  C  (CHC),  may contribute to the progression of liver injury. This study aimed to  evaluate  the  correlation  between  liver  steatosis  and  iron overload  in  Polish  patients  with  CHC  compared  to  non-alcoholic  fatty  liver  disease  (NAFLD)  and  HFE-hereditary hemochromatosis (HH) patients. METHODS: A total of 191 CHC patients were compared with 67  NAFLD  and  21  HH  patients.  Liver  function  tests,  serum markers of iron metabolism, cholesterol and triglycerides were assayed. The inflammatory activity, fibrosis, iron deposits and steatosis  stages  were  assessed  in  liver  specimens.  HFE  gene polymorphisms were investigated by PCR-RFLP. RESULTS: Liver  steatosis  was  associated  with  obesity  and diabetes mellitus. This disease was confirmed in 76/174 (44%) CHC  patients,  most  of  whom  were  infected  with  genotype  1. The average grade of  steatosis  was higher  in  NAFLD  patients. CHC  patients  had  significantly  higher  iron  concentrations and  transferrin  saturations  than  NAFLD  patients.  Compared with  CHC  patients,  HH  patients  had  higher  values  of  serum iron  parameters  and  more  intensive  hepatocyte  iron  deposits without  differences  in  the  prevalence  and  intensity  of  liver steatosis. In the CHC group, lipids accumulation in hepatocytes was  significantly  associated  with  the  presence  of  serum markers of iron overload. No correlation between the HFE gene

  14. Prevalence of HFE mutations and relation to serum iron status in patients with chronic hepatitis C and patients with nonalcoholic fatty liver disease in Taiwan

    Institute of Scientific and Technical Information of China (English)

    Tsung-Jung Lin; Chih-Lin Lin; Chaur-Shine Wang; Shu-O Liu; Li-Ying Liao

    2005-01-01

    AIM: To assess the prevalence of the two mutations, C282Y and H63D of HFE gene, in healthy subjects, patients with chronic hepatitis C (CHC), and patients with nonalcoholic fatty liver disease (NAFLD) in Taiwan and to explore the contribution of the HFE mutation on serum iron stores in CHC and NAFLD groups.METHODS: We examined C282Y and H63D mutations of HFE gene in 125 healthy subjects, 29 patients with CHC,and 33 patients with NAFLD. The serum iron markers,including ferritin, iron, and total iron binding capacity (TIBC),were assessed in all patients.RESULTS: All of the healthy subjects and patients were free from C282Y mutation. The prevalence of H63D heterozygosity was 4/125 (3.20%) in healthy subjects, 2/29(6.90%) in CHC group, and 1/33 (3.03%) in NAFLD group.The healthy subjects showed no significant difference in the prevalence of H63D mutation as compared with the CHC or NAFLD group. Increased serum iron store was found in 34.48% of CHC patients and 36.36% of NAFLD patients.In three patients of H63D heterozygosity, only one CHC patient had increased serum iron store. There was no significant difference in the prevalence of HFE mutations between patients with increased serum iron store and those without in CHC or NAFLD group.CONCLUSION: The HFE mutations may not contribute to iron accumulation in the CHC or NAFLD group even when serum iron overload is observed in more than one-third of these patients in Taiwan.

  15. Analysis of HLA-A antigens and C282Y and H63D mutations of the HFE gene in Brazilian patients with hemochromatosis

    Directory of Open Access Journals (Sweden)

    P.L. Bittencourt

    2002-03-01

    Full Text Available The hemochromatosis gene, HFE, is located on chromosome 6 in close proximity to the HLA-A locus. Most Caucasian patients with hereditary hemochromatosis (HH are homozygous for HLA-A3 and for the C282Y mutation of the HFE gene, while a minority are compound heterozygotes for C282Y and H63D. The prevalence of these mutations in non-Caucasian patients with HH is lower than expected. The objective of the present study was to evaluate the frequencies of HLA-A antigens and the C282Y and H63D mutations of the HFE gene in Brazilian patients with HH and to compare clinical and laboratory profiles of C282Y-positive and -negative patients with HH. The frequencies of HLA-A and C282Y and H63D mutations were determined by PCR-based methods in 15 male patients (median age 44 (20-72 years with HH. Eight patients (53% were homozygous and one (7% was heterozygous for the C282Y mutation. None had compound heterozygosity for C282Y and H63D mutations. All but three C282Y homozygotes were positive for HLA-A3 and three other patients without C282Y were shown to be either heterozygous (N = 2 or homozygous (N = 1 for HLA-A3. Patients homozygous for the C282Y mutation had higher ferritin levels and lower age at onset, but the difference was not significant. The presence of C282Y homozygosity in roughly half of the Brazilian patients with HH, together with the findings of HLA-A homozygosity in C282Y-negative subjects, suggest that other mutations in the HFE gene or in other genes involved in iron homeostasis might also be linked to HH in Brazil.

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

    DEFF Research Database (Denmark)

    Bathum, L; Christiansen, L; Nybo, H;

    2001-01-01

    BACKGROUND: To investigate whether the frequency of carriers of mutations in the HFE gene associated with hereditary hemochromatosis diminishes with age as an indication that HFE mutations are associated with increased mortality. It is of value in the debate concerning screening for hereditary...... hemochromatosis to determine the significance of heterozygosity. METHODS: Genotyping for mutations in exons 2 and 4 of the HFE gene using denaturing gradient gel electrophoresis in 1784 participants aged 45 to 100 years from 4 population-based studies: all 183 centenarians from the Danish Centenarian Study, 601...... heterozygotes for the C282Y mutation-the mutation most often associated with hereditary hemochromatosis-was found. This was significant for the whole population (P=.005) and for women (P=.004) but not for men (P=.26). A group of 599 participants was screened for mutations in exon 2, and there was no variation...

  17. HFE mutations in Caucasian participants of the Hemochromatosis and Iron Overload Screening study with serum ferritin level <1000 µg/L.

    Science.gov (United States)

    Adams, Paul C; McLaren, Christine E; Speechley, Mark; McLaren, Gordon D; Barton, James C; Eckfeldt, John H

    2013-07-01

    Many patients referred for an elevated serum ferritin level iron overload and hemochromatosis. To determine the prevalence of HFE mutations in the hemochromatosis gene for 11 serum ferritin concentration intervals from 200 µg⁄L to 1000 µg⁄L in Caucasian participants in a primary care, population-based study. The Hemochromatosis and Iron Overload Screening study screened 99,711 participants for serum ferritin levels, transferrin saturation and genetic testing for the C282Y and H63D mutations of the HFE gene. This analysis was confined to 17,160 male and 27,465 female Caucasian participants because the HFE C282Y mutation is rare in other races. Post-test likelihood was calculated for prediction of C282Y homozygosity from a ferritin interval. A subgroup analysis was performed in participants with both an elevated serum ferritin level and transferrin saturation. There were 3359 male and 2416 female participants with an elevated serum ferritin level (200 µg⁄L to 1000 µg⁄L for women, 300 µg⁄L to 1000 µg⁄L for men). There were 69 male (2.1%) and 87 female (3.6%) C282Y homozygotes, and the probability of being a homozygote increased as the ferritin level increased. Post-test likelihood values were 0.3% to 16% in men and 0.3% to 30.4% in women. Iron loading HFE mutations are unlikely to be the most common cause of an elevated serum ferritin level in patients with mild hyperferritinemia. Patients should be advised that there are many causes of an elevated serum ferritin level including iron overload.

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

    Science.gov (United States)

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

    2016-05-01

    Bleomycin and cisplatin are of key importance in testicular cancer treatment. Known potential serious adverse effects are bleomycin-induced pulmonary toxicity (BIP) and cisplatin-induced renal toxicity. Iron handling may play a role in development of this toxicity. Carriage of allelic variants of the HFE gene induces altered iron metabolism and may contribute to toxicity. We investigated the association between two common allelic variants of the HFE gene, H63D and C282Y, with development of pulmonary and renal toxicity during and after treatment with bleomycin- and cisplatin-containing chemotherapy. In 369 testicular cancer patients treated with bleomycin and cisplatin at the University Medical Center Groningen between 1978 and 2006, H63D and/or C282Y genotypes were determined with an allelic discrimination assay. Data were collected on development of BIP, pulmonary function parameters, renal function, and survival. BIP developed more frequently in patients who were heterozygote (16 in 75, 21%) and homozygote (2 in 4, 50%) for the H63D variant, compared with those who had the HFE wild-type gene (31 in 278, 11%) (p = 0.012). Overall survival, testicular cancer-related survival, and change in renal function were not associated with the H63D variant. We observed an association between presence of one or both H63D alleles and development of BIP in testicular cancer patients treated with bleomycin combination chemotherapy. In patients heterozygote and homozygote for the H63D variant, BIP occurred more frequently compared with wild-type patients. When validated and confirmed, HFE H63D genotyping may be used to identify patients with increased risk for pulmonary bleomycin toxicity. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. 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 m

  20. Frequency of the hemochromatosis HFE mutations C282Y, H63D, and S65C in blood donors in the Faroe Islands

    DEFF Research Database (Denmark)

    Milman, Nils; á Steig, Torkil; Koefoed, Pernille;

    2004-01-01

    The aim of the study was to assess the frequencies of the hereditary hemochromatosis HFE mutations C282Y, H63D, and S65C in the population in the Faroe Islands. The series comprised 200 randomly selected blood donors of Faroese heritage. The frequency of the C282Y, H63D, and S65C mutations...... on the HFE gene was assessed by genotyping using the polymerase chain reaction (PCR) technique and calculated from direct allele counting. We found no C282Y homozygous subjects; 28 (14.0%) subjects were C282Y heterozygous and four subjects were C282Y/H63D compound heterozygous (2.0%). The C282Y allele.......3-2.5%). The frequency of the C282Y mutation is high in Faroese blood donors, being close to and not significantly different from the frequencies reported in other Scandinavian countries: Denmark 5.7%, Norway 6.6%, Iceland 5.1%, and Sweden 6.1%. The frequency of the H63D mutation in Faroese subjects is significantly...

  1. Frequency of primary iron overload and HFE gene mutations (C282Y, H63D and S65C) in chronic liver disease patients in north India

    Institute of Scientific and Technical Information of China (English)

    Barjinderjit Kaur Dhillon; Reena Das; Gurjeewan Garewal; Yogesh Chawla; RK Dhiman; Ashim Das; Ajay Duseja; GR Chandak

    2007-01-01

    AIM: To identify the frequency of iron overload and study the three mutations in the HFE gene (C282Y,H63D, and S65C) in patients with chronic liver disorders (CLD) and controls.METHODS: To identify patients with iron overload (transferrin saturation > 45% in females and > 50% in males and serum ferritin > 1000 ng/mL) we evaluated 236 patients with CLD, including 59 with non-alcoholic steatohepatitis (NASH), 22 with alcoholic liver disease (ALD), 19 of cirrhosis due to viruses (HBV, HCV), and 136 with cryptogenic cirrhosis. Mutations of the HFE gene were analyzed by PCR-RE. hundred controls were screened for iron status and the mutations.RESULTS: Seventeen patients with CLD showed evidence of iron overload. Fifteen cases of iron overload had cryptogenic cirrhosis and two had ALD. None of the controls showed iron overload. We did not find any individual with 282Y or 65C either in the cases or in the controls. The prevalence of H63D heterozygosity was 12% in normal individuals, 14.8% in 236 patients (16.9% in NASH, 13.6% in ALD, 26.3% in viral and 12.5% in cryptogenic cirrhosis) and the overall prevalence was 13.98%. Only two of the 17 patients with primary iron overload were heterozygous for H63D. One patient with NASH and one normal individual who were homozygous for H63D showed no iron overload.CONCLUJSION: Primary iron overload in Indians is nonHFE type, which is different from that in Europeans and further molecular studies are required to determine the defect in various iron regulatory genes.

  2. Function of the hemochromatosis protein HFE: Lessons from animal models

    Institute of Scientific and Technical Information of China (English)

    Kostas Pantopoulos

    2008-01-01

    Hereditary hemochromatosis (HH) is caused by chronic hyperabsorption of dietary iron. Progressive accumulation of excess iron within tissue parenchymal cells may lead to severe organ damage. The most prevalent type of HH is linked to mutations in the HFE gene, encoding an atypical major histocompatibility complex class Ⅰ molecule. Shortly after its discovery in 1996, the hemochromatosis protein HFE was shown to physically interact with transferrin receptor 1 (TfR1)and impair the uptake of transferrin-bound iron in cells. However, these findings provided no clue why /-/FE mutations associate with systemic iron overload.It was later established that all forms of HH result from misregulation of hepcidin expression. This liverderived circulating peptide hormone controls iron efflux from duodenal enterocytes and reticuloendothelial macrophages by promoting the degradation of the iron exporter ferroportin. Recent studies with animal models of HH uncover a crucial role of HFE as a hepatocyte iron sensor and upstream regulator of helpcidin. Thus,hepatocyte HFE is indispensable for signaling to hepcidin, presumably as a constituent of a larger ironsensing complex. A working model postulates that the signaling activity of HFE is silenced when the protein is bound to TfR1. An increase in the iron saturation of plasma transferrin leads to displacement of TfR1 from HFE and assembly of the putative iron-sensing complex.In this way, iron uptake by the hepatocyte is translated into upregulation of hepcidin, reinforcing the concept that the liver is the major regulatory site for systemic iron homeostasis, and not merely an iron storage depot.

  3. 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 (pserum hepcidin (p>0.2). 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.

  4. Fatores precipitantes na porfiria cutânea tardia no Brasil com ênfase nas mutações do gene (HFE) da hemocromatose. Estudo de 60 casos

    OpenAIRE

    2014-01-01

    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 fa...

  5. 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.

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

    NARCIS (Netherlands)

    Galesloot, T.E.; Geurts-Moespot, A.; Heijer, M. den; Sweep, F.C.; Fleming, R.E.; Kiemeney, L.A.L.M.; Vermeulen, S.; Swinkels, D.W.

    2013-01-01

    BACKGROUND: 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

  7. 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......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...

  8. Evidence that the Cys282Tyr mutation of the HFE gene originated from a population in Southern Scandinavia and spread with the Vikings.

    Science.gov (United States)

    Milman, N; Pedersen, P

    2003-07-01

    Hereditary hemochromatosis has been recognized as a clinical disorder for more than 100 years. The common form of the disorder is caused by the Cys282Tyr mutation (C282Y) of the HFE gene. Hereditary hemochromatosis affects predominantly people of Northern European origin. The C282Y mutation probably occurred on a single chromosome carrying the ancestral hemochromatosis haplotype, which subsequently was spread by emigration and the founder effect. It has been estimated that the C282Y mutation appeared 60-70 generations ago. It was initially suggested that the ancestral C282Y mutation occurred within the Celtic group of peoples. However, we hypothesize that the distribution of the C282Y mutation in Europe is more consistent with an origin among the Germanic Iron Age population in Southern Scandinavia. From this area, the mutation could later be spread by the migratory activities of the Vikings. The aim of the present study was to evaluate the validity of these two hypotheses. Several arguments are in favor of the 'Viking hypothesis': first, the highest frequencies (5.1-9.7%) of the C282Y mutation are observed in populations in the Northern part of Europe, i.e. Denmark, Norway, Sweden, Faeroe Islands, Iceland, Eastern part of England (Danelaw) and the Dublin area, all Viking homelands and settlements. Second, the highest allele frequencies are reported among populations living along the coastlines. Third, the frequencies of the C282Y mutation decline from Northern to Southern Europe. Intermediate allele frequencies (3.1-4.8%) are seen in the populations in Central Europe, which is the original Celtic homeland. Low allele frequencies (0-3.1%) are recognized in populations in Southern Europe and the Mediterranean.

  9. 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

  10. Estudo das mutações C282Y, H63D e S65C do gene HFE em doentes brasileiros com sobrecarga de ferro Study of C282Y, H63D and S65C mutations in the HFE gene in Brazilian patients with iron overload

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    Rodolfo D. Cançado

    2007-12-01

    Full Text Available Hemocromatose é uma das doenças genéticas mais freqüentes no ser humano e uma das causas mais importantes de sobrecarga de ferro. Os objetivos deste estudo foram determinar a freqüência das mutações C282Y, H63D e S65C do gene HFE em doentes brasileiros com sobrecarga de ferro, verificar a coexistência de anemia hemolítica hereditária, hepatite C e consumo excessivo de bebida alcoólica nestes doentes e avaliar a influência destas variáveis sobre os depósitos de ferro do organismo. Saturação da transferrina, ferritina sérica e análise das mutações C282Y, H63D e S65C do gene HFE, pelo método da PCR, foram determinadas em cinqüenta doentes com sobrecarga de ferro atendidos no Hemocentro da Santa Casa de São Paulo entre janeiro de 2000 e maio de 2004. A freqüência de mutação do gene HFE nos doentes com sobrecarga de ferro foi de 76,0% (38/50. Saturação da transferrina e ferritina foram significativamente maiores nos doentes homozigotos para a mutação C282Y confirmando a correlação entre genótipo C282Y/C282Y e maior risco de sobrecarga de ferro. A coexistência de hepatite C, consumo excessivo de bebida alcoólica ou anemia hemolítica hereditária estão implicados em aumento dos estoques de ferro e constituem fator de risco adicional em pacientes com mutação do gene HFE para a condição de sobrecarga de ferro.Hemochromatosis is one of the most frequent genetic diseases in humans and one of the most important causes of iron overload. The aims of this study were to determine the frequency of C282Y, H63D and S65C mutations of the HFE gene in Brazilian patients with iron overload, to verify the coexistence of chronic hemolytic anemia, hepatitis C and excessive alcohol consumption and to evaluate the influence of these variables on body iron deposits. Transferrin saturation, serum ferritin and C282Y, H63D and S65C HFE gene mutations (by PCR method were determined in 50 patients with iron overload in the Hemocentro da

  11. Enhanced erythropoiesis in Hfe-KO mice indicates a role for Hfe in the modulation of erythroid iron homeostasis.

    Science.gov (United States)

    Ramos, Pedro; Guy, Ella; Chen, Nan; Proenca, Catia C; Gardenghi, Sara; Casu, Carla; Follenzi, Antonia; Van Rooijen, Nico; Grady, Robert W; de Sousa, Maria; Rivella, Stefano

    2011-01-27

    In hereditary hemochromatosis, mutations in HFE lead to iron overload through abnormally low levels of hepcidin. In addition, HFE potentially modulates cellular iron uptake by interacting with transferrin receptor, a crucial protein during erythropoiesis. However, the role of HFE in this process was never explored. We hypothesize that HFE modulates erythropoiesis by affecting dietary iron absorption and erythroid iron intake. To investigate this, we used Hfe-KO mice in conditions of altered dietary iron and erythropoiesis. We show that Hfe-KO mice can overcome phlebotomy-induced anemia more rapidly than wild-type mice (even when iron loaded). Second, we evaluated mice combining the hemochromatosis and β-thalassemia phenotypes. Our results suggest that lack of Hfe is advantageous in conditions of increased erythropoietic activity because of augmented iron mobilization driven by deficient hepcidin response. Lastly, we demonstrate that Hfe is expressed in erythroid cells and impairs iron uptake, whereas its absence exclusively from the hematopoietic compartment is sufficient to accelerate recovery from phlebotomy. In summary, we demonstrate that Hfe influences erythropoiesis by 2 distinct mechanisms: limiting hepcidin expression under conditions of simultaneous iron overload and stress erythropoiesis, and impairing transferrin-bound iron uptake by erythroid cells. Moreover, our results provide novel suggestions to improve the treatment of hemochromatosis.

  12. Hereditary Hemochromatosis (HFE genotypes in heart failure: Relation to etiology and prognosis

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    Torp-Pedersen Christian

    2010-07-01

    Full Text Available Abstract Background 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 prognostic significance of HFE genotypes. Methods We studied 667 HF patients (72.7% men with depressed systolic function, enrolled in a multicentre trial with a follow-up period of up to 5 years. All were genotyped for the known HFE variants C282Y, H63D and S65C. Results The genotype and allele frequencies in the HF group were similar to the frequencies determined in the general Danish population. In multivariable analysis mortality was not predicted by C282Y-carrier status (HR 1.2, 95% CI: 0.8-1.7; H63D-carrier status (HR 1.0, 95% CI: 0.7-1.3; nor S65C-carrier status (HR 1.2, 95% CI: 0.7-2.0. We identified 27 (4.1% homozygous or compound heterozygous carriers of HFE variants. None of these carriers had a clinical presentation suggesting hemochromatosis, but hemoglobin and ferritin levels were higher than in the rest of the cohort. Furthermore, a trend towards reduced mortality was seen in this group in univariate analyses (HR 0.4, 95% CI: 0.2-0.9, p = 0.03, but not in multivariate (HR 0.5, 95% CI: 0.2-1.2. Conclusion HFE genotypes do not seem to be a significant contributor to the etiology of heart failure in Denmark. HFE variants do not affect mortality in HF.

  13. Evidence for non-HFE linked hemochromatosis in Asian Indians

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    Panigrahi I

    2006-12-01

    Full Text Available BACKGROUND: Hereditary hemochromatosis is commonly due to two HFE1 (Histone Family E1 gene mutations - H63D and C282Y. Mutations in the Asian Indians are less well studied. AIMS: The aim of this preliminary study was to find out the prevalence of HFE gene mutations in nonviral liver cirrhosis patients. SETTINGS AND DESIGN: Unexplained liver cirrhosis cases with transferrin saturation> 45%, attending the gastroenterology clinic in the years 2004 and 2005 were subjects of the prospective study. Asymptomatic individuals with negative family history of hemolytic anemia or liver disease served as controls. MATERIALS AND METHODS: The clinical presentation was recorded in the patients. Transferrin saturation was estimated by standard colorimetric technique. The two common mutations in HFE1 gene and Y250X mutation of TFR (transferrin receptor gene were studied by polymerase chain reaction based methods. RESULTS: A majority of the cases were sporadic, but family history was positive in four patients. In one family with multiple affected members, there was clear evidence of autosomal dominant inheritance. Seven out of 31 (22.6% of unexplained cirrhosis cases were positive for mutations. One was homozygous for H63D. In healthy controls, prevalence was 8.1% (6/74. None of the patients or controls was positive for C282Y mutation of HFE1 or Y250X of TFR gene. CONCLUSIONS: Thus, in a number of cases of hemochromatosis in Indians, a gene with dominant inheritance may be involved in causation of the phenotype. The prevalence of HFE mutations in Indians is comparable to that reported from neighboring countries. It is worth studying other mutations in HFE gene and other iron overload genes in cryptogenic cirrhosis cases.

  14. 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

  15. 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

    2015-01-01

    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 other iron overload

  16. Prevalence of C282Y and H63D mutations in the HFE gene of Brazilian individuals with clinical suspicion of hereditary hemochromatosis Prevalência das mutações C282Y e H63D no gene HFE em indivíduos brasileiros com suspeita clínica de hemocromatose hereditária

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    Alessandro C. S. Ferreira

    2008-10-01

    Full Text Available Classical hereditary hemochromatosis is a recessive autosomal disease related to a systemic iron overload that is frequently related to C282Y and H63D mutations in the HFE gene. In Brazil, reports on HFE gene mutation frequencies are rare, mainly in regards to a representative sample population. This study intended to determine the prevalence of C282Y and H63D mutations among individuals with clinical suspicion of hereditary hemochromatosis. A total of 1955 patients were studied with C282Y and H63D mutations being detected by the polymerase chain reaction technique followed by enzymatic restriction. The sample consisted of 76.6% men and 23.4% women. The highest percentage of analyzed individuals (56.9% was concentrated in the 41 to 60-year-old age group. Although there were no genic or genotypic differences between genders, a higher number of over 60-year-old women was observed. The C282Y mutation was found as homozygous in 2.9% of the cases and as heterozygous in 10.1%, while the H63D was homozygous in 4.3% and heterozygous in 30.6%. The C282Y and H63D mutant allele frequencies were 0.079 and 0.196, respectively. The highest frequency was observed for H63D which was in genetic equilibrium. This work is important to determine the genetic profile of the population with hereditary hemochromatosis in Brazi.A hemocromatose hereditária clássica (HH é uma doença autossômica recessiva caracterizada por uma sobrecarga sistêmica de ferro, a qual está freqüentemente relacionada às mutações C282Y e H63D no gene HFE. No Brasil, registros das freqüências das mutações no gene HFE são raros, principalmente envolvendo uma amostra representativa da população. Este estudo teve como objetivo a determinação da prevalência das mutações C282Y e H63D em indivíduos com suspeita clínica de HH. Para isto, foram estudados 1955 pacientes para os quais as mutações C282Y e H63D foram pesquisadas pela técnica de Reação em Cadeia da Polimerase

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

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    Claudia C Branco

    Full Text Available 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.

  18. 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.

  19. HFE gene in primary and secondary hepatic iron overload

    Institute of Scientific and Technical Information of China (English)

    Giada Sebastiani; Ann P Walker

    2007-01-01

    Distinct from hereditary haemochromatosis, hepatic iron overload is a common finding in several chronic liver diseases. Many studies have investigated the prevalence, distribution and possible contributory role of excess hepatic iron in non-haemochromatotic chronic liver diseases. Indeed, some authors have proposed iron removal in liver diseases other than hereditary haemochromatosis. However, the pathogenesis of secondary iron overload remains unclear. The High Fe (HFE) gene has been implicated, but the reported data are controversial. In this article, we summarise current concepts regarding the cellular role of the HFE protein in iron homeostasis. We review the current status of the literature regarding the prevalence, hepatic distribution and possible therapeutic implications of iron overload in chronic hepatitis C, hepatitis B, alcoholic and nonalcoholic fatty liver diseases and porphyria cutanea tarda.We discuss the evidence regarding the role of HFE gene mutations in these liver diseases. Finally, we summarize the common and specific features of iron overload in liver diseases other than haemochromatosis.

  20. Exome sequencing for molecular characterization of non-HFE hereditary hemochromatosis.

    Science.gov (United States)

    Farrell, Colin P; Parker, Charles J; Phillips, John D

    2015-08-01

    Diagnostic genetic testing for hereditary hemochromatosis is readily available for clinically relevant HFE variants (i.e., those that generate the C282Y, H63D and S65C HFE polymorphisms); however, genetic testing for other known causes of iron overload, including mutations affecting genes encoding hemojuvelin, transferrin receptor 2, HAMP, and ferroportin is not. As an alternative to conventional genetic testing we propose diagnostic use of whole exome sequencing for characterization of non-HFE hemochromatosis. To illustrate the effectiveness of whole exome sequencing as a diagnostic tool, we present the case of an 18-year-old female with a probable case of juvenile hemochromatosis, who was referred for specialty care after testing negative for commonly occurring HFE variants. Whole exome sequencing offered complete coverage of target genes and is a fast, cost effective diagnostic tool for characterization of non-HFE hemochromatosis.

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

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    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.

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

    Science.gov (United States)

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

    2016-12-01

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

  3. HFE, MTHFR, and FGFR4 genes polymorphisms and breast cancer in Brazilian women.

    Science.gov (United States)

    Batschauer, Anna P; Cruz, Nathalia G; Oliveira, Vanessa C; Coelho, Fernanda F; Santos, Izabela R; Alves, Michelle T; Fernandes, Ana P; Carvalho, Maria G; Gomes, Karina B

    2011-11-01

    Genetic factors related to cancer have been extensively studied and several polymorphisms have been associated to breast cancer. The FGFR4, MTHFR, and HFE genes have been associated with neoplastic diseases development. The current report outlines the analysis of the polymorphisms G388A (FGFR4), C677T (MTHFR), C282Y, and H63D (HFE) in Brazilian breast cancer patients. We studied 68 patients with invasive ductal and operable breast carcinoma and 85 women as a control group. The polymorphism frequencies in the breast cancer and control groups were analyzed, but no significant difference was observed by comparing the two groups. The presence of each polymorphism was analyzed according to the clinical features and markers already established as prognostic in the breast cancer group. The C677T, H63D, and G388A polymorphisms were not associated to histological grade, age of diagnosis, expression of HER2 receptor, or estrogen and progesterone receptor. The H63D polymorphism showed a significant association (P = 0.02) with the presence of p53 mutations, and C667T showed association to lymph node involvement (P = 0.05). Lymph node involvement, G388A polymorphism, and histological grade were independently associated to metastasis/death. Our data suggests that the polymorphisms G388A, C677T, and H63D are not useful in breast cancer diagnosis, but they may be significant additional prognostic markers related to breast cancer survival.

  4. 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

  5. 中国河南汉族人HFE C282Y基因突变频率调查%Frequency of the C282Y mutation of the hemochromatosis gene (HFE) in the Henan population with the Han nationality in China

    Institute of Scientific and Technical Information of China (English)

    宋丽丽; 刘玉峰; 黄志恒; 王静

    2007-01-01

    目的 调查中国河南汉族人遗传性血色素沉着症HFE C282Y基因突变情况.方法 利用聚合酶链反应和限制性片段长度多态性分析方法 ,检测518例健康献血的河南汉族人血液标本.结果 C282Y突变未见.结论 中国河南汉族人HFE C282Y等位基因突变频率与美国密歇根州高加索人差异具有统计学意义.

  6. The influence of iron status and genetic polymorphisms in the HFE gene on the risk for postoperative complications after bariatric surgery: a prospective cohort study in 1,064 patients

    Directory of Open Access Journals (Sweden)

    Freedman-Weiss Mollie

    2011-01-01

    Full Text Available Abstract Background Gastric bypass surgery is a highly effective therapy for long-term weight loss in severely obese patients, but carries significant perioperative risks including infection, wound dehiscence, and leaks from staple breakdown. Iron status can affect immune function and wound healing, thus may influence peri-operative complications. Common mutations in the HFE gene, the gene responsible for the iron overload disorder hereditary hemochromatosis, may impact iron status. Methods We analyzed 1064 extremely obese Caucasian individuals who underwent open and laparoscopic Roux-n-Y gastric bypass surgery at the Geisinger Clinic. Serum iron, ferritin, transferrin, and iron binding capacity were measured pre-operatively. All patients had intra-operative liver biopsies and were genotyped for the C282Y and H63D mutations in the HFE gene. Associations between surgical complications and serum iron measures, HFE gene status, and liver iron histology were determined. Results We found that increased serum iron and transferrin saturation were present in patients with any post-operative complication, and that increased serum ferritin was also increased in patients with major complications. Increased serum transferrin saturation was also associated with wound complications in open RYGB, and transferrin saturation and ferritin with prolonged lengths of stay. The presence of 2 or more HFE mutations was associated with overall complications as well as wound complications in open RYGB. No differences were found in complication rates between those with stainable liver iron and those without. Conclusion Serum iron status and HFE genotype may be associated with complications following RYGB surgery in the extremely obese.

  7. HFE-associated hereditary hemochromatosis

    NARCIS (Netherlands)

    Eijkelkamp, EJ; Yapp, TR; Powell, LW

    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

  8. 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.

  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. The Study of HFE Genotypes and Its Expression Effect on Iron Status of Iranian Haemochromatosis, Iron Deficiency Anemia Patients, Iron-Taker and Non Iron-Taker Controls.

    Science.gov (United States)

    Beiranvand, Elham; Abediankenari, Saeid; Rostamian, Mosayeb; Beiranvand, Behnoush; Naazeri, Saeed

    2015-01-01

    The role of HFE gene mutations or its expression in regulation of iron metabolism of hereditary haemochromatosis (HH) patients is remained controversial. Therefore here the correlation between two common HFE genotype (p.C282Y, p.H63D) and HFE gene expression with iron status in HH, iron deficiency anemia (IDA) and healthy Iranian participants was studied. For this purpose genotype determination was done by polymerase chain reaction--restriction fragment length polymorphism (PCR-RFLP). Real-Time PCR was applied for evaluation of HFE gene expression. Biochemical parameters and iron consumption were also assessed. Homozygote p.H63D mutation was seen in all HH patients and p.C282Y was not observed in any member of the population. A significant correlation was observed between serum ferritin (SF) level and gender or age of HH patients. p.H63D homozygote was seen to be able to significantly increase SF and transferrin saturation (TS) level without affecting on liver function. Our results also showed that iron consumption affects on TS level increasing. HFE gene expression level of IDA patients was significantly higher than other groups. Also the HFE gene expression was negatively correlated with TS. Finally, the main result of our study showed that loss of HFE function in HH is not derived from its gene expression inhibition and much higher HFE gene expression might lead to IDA. However we propose repeating of the study for more approval of our finding.

  11. Non-HFE hemochromatosis: pathophysiological and diagnostic aspects.

    Science.gov (United States)

    Bardou-Jacquet, Edouard; Ben Ali, Zeineb; Beaumont-Epinette, Marie-Pascale; Loreal, Olivier; Jouanolle, Anne-Marie; Brissot, Pierre

    2014-04-01

    Rare genetic iron overload diseases are an evolving field due to major advances in genetics and molecular biology. Genetic iron overload has long been confined to the classical type 1 hemochromatosis related to the HFE C282Y mutation. Breakthroughs in the understanding of iron metabolism biology and molecular mechanisms led to the discovery of new genes and subsequently, new types of hemochromatosis. To date, four types of hemochromatosis have been identified: HFE-related or type1 hemochromatosis, the most frequent form in Caucasians, and four rare types, named type 2 (A and B) hemochromatosis (juvenile hemochromatosis due to hemojuvelin and hepcidin mutation), type 3 hemochromatosis (related to transferrin receptor 2 mutation), and type 4 (A and B) hemochromatosis (ferroportin disease). The diagnosis relies on the comprehension of the involved physiological defect that can now be explored by biological and imaging tools, which allow non-invasive assessment of iron metabolism. A multidisciplinary approach is essential to support the physicians in the diagnosis and management of those rare diseases.

  12. HFE safety reviews of advanced nuclear power plant control rooms

    Science.gov (United States)

    Ohara, John

    1994-01-01

    Advanced control rooms (ACR's) will utilize human-system interface (HSI) technologies that may have significant implications for plant safety in that they will affect the operator's overall role and means of interacting with the system. The Nuclear Regulatory Commission (NRC) reviews the human factors engineering (HFE) aspects of HSI's to ensure that they are designed to good HFE principles and support performance and reliability in order to protect public health and safety. However, the only available NRC guidance was developed more than ten years ago, and does not adequately address the human performance issues and technology changes associated with ACR's. Accordingly, a new approach to ACR safety reviews was developed based upon the concept of 'convergent validity'. This approach to ACR safety reviews is described.

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

    Directory of Open Access Journals (Sweden)

    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.

  14. 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.

  15. Mutation analysis of the transferrin receptor-2 gene in patients with iron overload.

    Science.gov (United States)

    Lee, P L; Halloran, C; West, C; Beutler, E

    2001-01-01

    Three mutations in the transferrin receptor-2 gene have recently been identified in four Sicilian families with iron overload who had a normal hemochromatosis gene, HFE (C. Camaschella, personal communication). To determine the extent to which mutations in the transferrin receptor-2 gene occur in other populations with iron overload, we have completely sequenced this gene in 17 whites, 10 Asians, and 8 African Americans with iron overload and a C282C/C282C HFE genotype, as well as 4 subjects without iron overload and homozygous for the mutant HFE C282Y genotype, 5 patients with iron overload and homozygous for the mutant HFE C282Y genotype, and 5 normal individuals. None of the individuals exhibited the Sicilian mutations, Y250X in exon 6, M172K in exon 4, and E60X in exon 2. One iron-overloaded individual of Asian descent exhibited a I238M mutation which was subsequently found to be a polymorphism present in the Asian population at a frequency of 0.0192. The presence of the I238M mutation was not associated with an increase in ferritin or transferrin saturation levels. Three silent polymorphisms were also identified, nt 1770 (D590D) and nt 1851 (A617A) and a polymorphism at nt 2255 in the 3' UTR. Thus, mutations in the transferrin receptor-2 gene were not responsible for the iron overload seen in our subjects.

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

    Science.gov (United States)

    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.

  17. Frequency of the Hemochromatosis Gene (HFE Variants in a Jordanian Arab Population and in Diabetics from the Same Region

    Directory of Open Access Journals (Sweden)

    Asem Alkhateeb

    2009-01-01

    Full Text Available Hereditary HFE-linked hemochromatosis is a frequent recessive disorder among individuals of northern European ancestry. The clinical characteristic of this disease is the gradual accumulation of iron in internal organs, which ultimately may lead to organ damage and death. Three allelic variants of HFE gene have been correlated with hereditary hemochromatosis: C282Y is significantly associated with hereditary hemochromatosis in populations of Celtic origin, H63D and S65C are associated with milder form of iron overload. In this study we performed mutation analysis to identify allele frequency of the three variants of HFE gene in Jordanian Arab population, to assess deviations of these frequencies from those detected elsewhere, and to determine if there is an increased frequency of these variants in a diabetic population (Type 2 diabetes from the same area. DNA was extracted from blood samples of 440 individuals attending King Abdullah University Hospital for ambulatory services. We used polymerase chain reaction (PCR to amplify exons 2 and 4 of the HFE gene then restriction fragment length polymorphism (RFLP method to detect the variants. There were neither homozygous nor heterozygous for C282Y variant. For the H63D variant, 0.68% were homozygous and 21.1% were heterozygous. For the S65C variant, there were no homozygous and 0.23% were heterozygous. Allelic frequencies were, 0%, 11.25%, and 0.11% for C282Y, H63D, and S65C, respectively. Our samples were subdivided into two categories of type 2 diabetic (89 cases and controls (blood donors, 204 cases and compared with regard to the H63D variant. Both groups did not have homozygous H63D variant. H63D heterozygous in diabetics were 23.60% and in blood donor controls 22.55%. Allelic frequency of the mutant H63D allele was 11.80% in diabetics and 11.27% for the blood donor controls. This is the first study to show the frequency of the three hemochromatosis gene variants in Jordan with the interesting

  18. Association between the HFE C282Y, H63D Polymorphisms and the Risks of Non-Alcoholic Fatty Liver Disease, Liver Cirrhosis and Hepatocellular Carcinoma: An Updated Systematic Review and Meta-Analysis of 5,758 Cases and 14,741 Controls

    Science.gov (United States)

    Yin, Wei-Li; Wang, Feng-Mei; Han, Tao

    2016-01-01

    Background Conflicting results have been obtained for the association between two common polymorphisms (C282Y, H63D) of human HFE (hereditary hemochromatosis) gene and the risks of the liver diseases, including non-alcoholic fatty liver disease (NAFLD), liver cirrhosis and hepatocellular carcinoma (HCC). Methods An updated systematic review and meta-analysis was conducted to evaluate the potential role of HFE polymorphisms in the susceptibility to NAFLD, liver cirrhosis and HCC. After retrieving articles from online databases, eligible studies were enrolled according to the selection criteria. Stata/SE 12.0 software was utilized to perform the statistical analysis. Results In total, 43 articles with 5,758 cases and 14,741 controls were selected. Compared with the control group, a significantly increased risk of NAFLD was observed for the C282Y polymorphism in the Caucasian population under all genetic models and for the H63D polymorphism under the allele, heterozygote and dominant models (all OR>1, Passociation0.05). In addition, we found that HFE C282Y was statistically associated with increased HCC susceptibility in the overall population, while H63D increased the odds of developing non-cirrhotic HCC in the African population (all OR>1, Passociation<0.05). Moreover, a positive association between compound heterozygosity for C282Y/H63D and the risk of NAFLD and HCC, but not liver cirrhosis, was observed. Conclusion Our meta-analysis provides evidence that the HFE C282Y and H63D polymorphisms confer increased genetic susceptibility to NAFLD and HCC but not liver cirrhosis. Additional well-powered studies are required to confirm our conclusion. PMID:27657935

  19. Mitochondrial DNA Mutations Associated with Aminoglycoside Ototoxicity

    Institute of Scientific and Technical Information of China (English)

    GUAN Min-Xin

    2006-01-01

    The mitochondrial 12S rRNA has been shown to be the hot spot for mutations associated with both aminoglycoside-induced and non-syndromic hearing loss. Of all the mutations, the homoplasmic A1555G and C1494T mutations at a highly conserved decoding region in the 12S rRNA have been associated with aminoglycoside-induced and non-syndromic hearing loss in many families worldwide. The A1555G or C1494T mutation is expected to form novel 1494C-G1555 or 1494U-A1555 base-pair at the highly conserved A-site of 12S rRNA. These transitions make the secondary structure of this RNA more closely resemble the corresponding region of bacterial 16S rRNA. Thus, the new U - A or G-C pair in 12S rRNA created by the C1494T or A1555G transition facilitates the binding of aminoglycosides, thereby accounting for the fact that the exposure to aminoglycosides can induce or worsen hearing loss in individuals carrying these mutations. Furthermore, the growth defect and impairment of mitochondrial translation were observed in cell lines carrying the A1555G or C1494T mutation in the presence of high concentration of aminoglycosides. In addition, nuclear modifier genes and mitochondrial haplotypes modulate the phenotypic manifestation of the A1555G and C1494T mutations. These observations provide the direct genetic and biochemical evidences that the A1555G or C1494T mutation is a pathogenic mtDNA mutation associated with aminoglycoside-induced and nonsyndromic hearing loss. Therefore, these data have been providing valuable information and technology to predict which individuals are at risk for ototoxicity, to improve the safety of aminoglycoside antibiotic therapy, and eventually to decrease the incidence of deafness.

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

    NARCIS (Netherlands)

    Dijk, B.A.C. van; Laarakkers, C.M.; Klaver, S.M.; Jacobs, E.M.G.; Tits, L.J.H. van; Janssen, M.C.H.; Swinkels, D.W.

    2008-01-01

    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

  1. Concomitant presentation of collagenous sprue and HFE hemochromatosis.

    Science.gov (United States)

    Parisian, Keely R; Plesec, Thomas P; Fairbanks, Kyrsten D; Tavill, Anthony S; Shen, Bo

    2011-08-01

    Collagenous sprue (CS) is a progressive malabsorptive disorder characterized by collagen deposition beneath the basement membrane of small bowel epithelium in refractory celiac sprue. CS is a pathologically distinct entity from celiac disease, despite a similar clinical presentation. The etiology of CS is unclear, although there are speculations that CS and celiac disease may share similar pathogenetic pathways. On the other hand, HFE hemochromatosis (HH) is a distinct disease entity. Celiac disease and HH are common HLA-associated genetic disorders in Northern European populations. There are a few case reports linking celiac disease and HH. We present a patient diagnosed with concurrent CS and HH.

  2. HFE p.H63D polymorphism does not influence ALS phenotype and survival

    Science.gov (United States)

    Chiò, Adriano; Mora, Gabriele; Sabatelli, Mario; Caponnetto, Claudia; Lunetta, Christian; Traynor, Bryan J.; Johnson, Janel O.; Nalls, Mike A.; Calvo, Andrea; Moglia, Cristina; Borghero, Giuseppe; Monsurrò, Maria Rosaria; Bella, Vincenzo La; Volanti, Paolo; Simone, Isabella; Salvi, Fabrizio; Logullo, Francesco O.; Nilo, Riva; Giannini, Fabio; Mandrioli, Jessica; Tanel, Raffaella; Murru, Maria Rita; Mandich, Paola; Zollino, Marcella; Conforti, Francesca L.; Penco, Silvana

    2016-01-01

    It has been recently reported that the p.His63Asp polymorphism of the HFE gene accelerates disease progression both in the SOD1 transgenic mouse and in amyotrophic lateral sclerosis (ALS) patients. We have evaluated the effect of HFE p.His63Asp polymorphism on the phenotype in 1351 Italian ALS patients (232 of Sardinian ancestry). Patients were genotyped for the HFE p.His63Asp polymorphism (CC, GC, and GG). All patients were also assessed for C9ORF72, TARDBP, SOD1, and FUS mutations. Of the 1351 ALS patients, 363 (29.2%) were heterozygous (GC) for the p.His63Asp polymorphism and 30 (2.2%) were homozygous for the minor allele (GG). Patients with CC, GC, and GG polymorphisms did not significantly differ by age at onset, site of onset of symptoms, and survival; however, in SOD1 patients with CG or GG polymorphism had a significantly longer survival than those with a CC polymorphism. Differently from what observed in the mouse model of ALS, the HFE p.His63Asp polymorphism has no effect on ALS phenotype in this large series of Italian ALS patients. PMID:26174855

  3. Correlates of hepcidin and NTBI according to HFE status in patients referred to a liver centre

    NARCIS (Netherlands)

    Ryan, E.; Ryan, J.D.; Russell, J.; Coughlan, B.; Tjalsma, H.; Swinkels, D.W.; Stewart, S.; Crowe, J.P.

    2015-01-01

    BACKGROUND/AIMS: Innately low hepcidin levels lead to iron overload in HFE-associated hereditary haemochromatosis. METHODS: This study compared hepcidin and non-transferrin bound iron (NTBI) levels in untreated iron-loaded and non-iron-loaded C282Y homozygotes to levels in C282Y/H63D compound

  4. Correlates of hepcidin and NTBI according to HFE status in patients referred to a liver centre

    NARCIS (Netherlands)

    Ryan, E.; Ryan, J.D.; Russell, J.; Coughlan, B.; Tjalsma, H.; Swinkels, D.W.; Stewart, S.; Crowe, J.P.

    2015-01-01

    BACKGROUND/AIMS: Innately low hepcidin levels lead to iron overload in HFE-associated hereditary haemochromatosis. METHODS: This study compared hepcidin and non-transferrin bound iron (NTBI) levels in untreated iron-loaded and non-iron-loaded C282Y homozygotes to levels in C282Y/H63D compound hetero

  5. Genetic mutations associated with status epilepticus.

    Science.gov (United States)

    Bhatnagar, M; Shorvon, S

    2015-08-01

    This paper reports the results of a preliminary search of the literature aimed at identifying the genetic mutations reported to be strongly associated with status epilepticus. Genetic mutations were selected for inclusion if status epilepticus was specifically mentioned as a consequence of the mutation in standard genetic databases or in a case report or review article. Mutations in 122 genes were identified. The genetic mutations identified were found in only rare conditions (sometimes vanishingly rare) and mostly in infants and young children with multiple other handicaps. Most of the genetic mutations can be subdivided into those associated with cortical dysplasias, inborn errors of metabolism, mitochondrial disease, or epileptic encephalopathies and childhood syndromes. There are no identified 'pure status epilepticus genes'. The range of genes underpinning status epilepticus differs in many ways from the range of genes underpinning epilepsy, which suggests that the processes underpinning status epilepticus differ from those underpinning epilepsy. It has been frequently postulated that status epilepticus is the result of a failure of 'seizure termination mechanisms', but the wide variety of genes affecting very diverse biochemical pathways identified in this survey makes any unitary cause unlikely. The genetic influences in status epilepticus are likely to involve a wide range of mechanisms, some related to development, some to cerebral energy production, some to diverse altered biochemical pathways, some to transmitter and membrane function, and some to defects in networks or systems. The fact that many of the identified genes are involved with cerebral development suggests that status epilepticus might often be a system or network phenomenon. To date, there are very few genes identified which are associated with adult-onset status epilepticus (except in those with preexisting neurological damage), and this is disappointing as the cause of many adult

  6. Comparison of the interactions of transferrin receptor and transferrin receptor 2 with transferrin and the hereditary hemochromatosis protein HFE.

    Science.gov (United States)

    West, A P; Bennett, M J; Sellers, V M; Andrews, N C; Enns, C A; Bjorkman, P J

    2000-12-08

    The transferrin receptor (TfR) interacts with two proteins important for iron metabolism, transferrin (Tf) and HFE, the protein mutated in hereditary hemochromatosis. A second receptor for Tf, TfR2, was recently identified and found to be functional for iron uptake in transfected cells (Kawabata, H., Germain, R. S., Vuong, P. T., Nakamaki, T., Said, J. W., and Koeffler, H. P. (2000) J. Biol. Chem. 275, 16618-16625). TfR2 has a pattern of expression and regulation that is distinct from TfR, and mutations in TfR2 have been recognized as the cause of a non-HFE linked form of hemochromatosis (Camaschella, C., Roetto, A., Cali, A., De Gobbi, M., Garozzo, G., Carella, M., Majorano, N., Totaro, A., and Gasparini, P. (2000) Nat. Genet. 25, 14-15). To investigate the relationship between TfR, TfR2, Tf, and HFE, we performed a series of binding experiments using soluble forms of these proteins. We find no detectable binding between TfR2 and HFE by co-immunoprecipitation or using a surface plasmon resonance-based assay. The affinity of TfR2 for iron-loaded Tf was determined to be 27 nm, 25-fold lower than the affinity of TfR for Tf. These results imply that HFE regulates Tf-mediated iron uptake only from the classical TfR and that TfR2 does not compete for HFE binding in cells expressing both forms of TfR.

  7. Impact of HFE genetic testing on clinical presentation of hereditary hemochromatosis: new epidemiological data

    Directory of Open Access Journals (Sweden)

    Ka Chandran

    2005-06-01

    Full Text Available Abstract Background Hereditary hemochromatosis (HH is a common inherited disorder of iron metabolism in Northern European populations. The discovery of a candidate gene in 1996 (HFE, and of its main mutation (C282Y, has radically altered the way to diagnose this disease. The aim of this study was to assess the impact of the HFE gene discovery on the clinical presentation and epidemiology of HH. Methods We studied our cohort of 415 patients homozygous for the C282Y allele and included in a phlebotomy program in a blood centre in western Brittany, France. Results In this cohort, 56.9% of the patients were male and 21.9% began their phlebotomy program before the implementation of the genetic test. A significant decrease in the sex ratio was noticed following implementation of this DNA test, from 3.79 to 1.03 (p -5, meaning that the proportion of diagnosed females relatives to males greatly increased. The profile of HH patients at diagnosis changed after the DNA test became available. Serum ferritin and iron values were lower and there was a reduced frequency of clinical signs displayed at diagnosis, particularly skin pigmentation (20.1 vs. 40.4%, OR = 0.37, p Conclusion This study highlights the importance of the HFE gene discovery, which has simplified the diagnosis of HH and modified its clinical presentation and epidemiology. This study precisely measures these changes. Enhanced diagnosis of HFE-related HH at an early stage and implementation of phlebotomy treatment are anticipated to maintain normal life expectancy for these patients.

  8. Combined Immunodeficiency Associated with DOCK8 Mutations

    Science.gov (United States)

    Zhang, Qian; Davis, Jeremiah C.; Lamborn, Ian T.; Freeman, Alexandra F.; Jing, Huie; Favreau, Amanda J.; Matthews, Helen F.; Davis, Joie; Turner, Maria L.; Uzel, Gulbu; Holland, Steven M.; Su, Helen C.

    2010-01-01

    BACKGROUND Recurrent sinopulmonary and cutaneous viral infections with elevated serum levels of IgE are features of some variants of combined immunodeficiency. The genetic causes of these variants are unknown. METHODS We collected longitudinal clinical data on 11 patients from eight families who had recurrent sinopulmonary and cutaneous viral infections. We performed comparative genomic hybridization arrays and targeted gene sequencing. Variants with predicted loss-of-expression mutations were confirmed by means of a quantitative reverse-transcriptase –polymerase-chain-reaction assay and immunoblotting. We evaluated the number and function of lymphocytes with the use of in vitro assays and flow cytometry. RESULTS Patients had recurrent otitis media, sinusitis, and pneumonias; recurrent Staphylococcus aureus skin infections with otitis externa; recurrent, severe herpes simplex virus or herpes zoster infections; extensive and persistent infections with molluscum contagiosum; and human papillomavirus infections. Most patients had severe atopy with anaphylaxis; several had squamous-cell carcinomas, and one had T-cell lymphoma –leukemia. Elevated serum IgE levels, hypereosinophilia, low numbers of T cells and B cells, low serum IgM levels, and variable IgG antibody responses were common. Expansion in vitro of activated CD8 T cells was impaired. Novel homozygous or compound heterozygous deletions and point mutations in the gene encoding the dedicator of cytokinesis 8 protein (DOCK8) led to the absence of DOCK8 protein in lymphocytes. CONCLUSIONS Autosomal recessive DOCK8 deficiency is associated with a novel variant of combined immunodeficiency. PMID:19776401

  9. HFE gene variants, iron, and lipids: a novel connection in Alzheimer’s disease

    OpenAIRE

    Ali-Rahmani, Fatima; Schengrund, Cara-Lynne; Connor, James R.

    2014-01-01

    Iron accumulation and associated oxidative stress in the brain have been consistently found in several neurodegenerative diseases. Multiple genetic studies have been undertaken to try to identify a cause of neurodegenerative diseases but direct connections have been rare. In the iron field, variants in the HFE gene that give rise to a protein involved in cellular iron regulation, are associated with iron accumulation in multiple organs including the brain. There is also substantial epidemiolo...

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

    DEFF Research Database (Denmark)

    Koefoed, P; Dalhoff, K; Dissing, J

    2002-01-01

    .0% (0%) C282Y homozygotes, 5.8% (2.6%) H63D/C282Y compound heterozygotes and 1.9% (3.1%) S65C heterozygotes. The values for 420 Danish blood donors are shown in parentheses. The distribution of genotypes in group B was similar to that of the blood donors. Serum ferritin, transferrin iron saturation...

  11. Spliceosome mutations exhibit specific associations with epigenetic modifiers and proto-oncogenes mutated in myelodysplastic syndrome.

    Science.gov (United States)

    Mian, Syed A; Smith, Alexander E; Kulasekararaj, Austin G; Kizilors, Aytug; Mohamedali, Azim M; Lea, Nicholas C; Mitsopoulos, Konstantinos; Ford, Kevin; Nasser, Erick; Seidl, Thomas; Mufti, Ghulam J

    2013-07-01

    The recent identification of acquired mutations in key components of the spliceosome machinery strongly implicates abnormalities of mRNA splicing in the pathogenesis of myelodysplastic syndromes. However, questions remain as to how these aberrations functionally combine with the growing list of mutations in genes involved in epigenetic modification and cell signaling/transcription regulation identified in these diseases. In this study, amplicon sequencing was used to perform a mutation screen in 154 myelodysplastic syndrome patients using a 22-gene panel, including commonly mutated spliceosome components (SF3B1, SRSF2, U2AF1, ZRSR2), and a further 18 genes known to be mutated in myeloid cancers. Sequencing of the 22-gene panel revealed that 76% (n=117) of the patients had mutations in at least one of the genes, with 38% (n=59) having splicing gene mutations and 49% (n=75) patients harboring more than one gene mutation. Interestingly, single and specific epigenetic modifier mutations tended to coexist with SF3B1 and SRSF2 mutations (P<0.03). Furthermore, mutations in SF3B1 and SRSF2 were mutually exclusive to TP53 mutations both at diagnosis and at the time of disease transformation. Moreover, mutations in FLT3, NRAS, RUNX1, CCBL and C-KIT were more likely to co-occur with splicing factor mutations generally (P<0.02), and SRSF2 mutants in particular (P<0.003) and were significantly associated with disease transformation (P<0.02). SF3B1 and TP53 mutations had varying impacts on overall survival with hazard ratios of 0.2 (P<0.03, 95% CI, 0.1-0.8) and 2.1 (P<0.04, 95% CI, 1.1-4.4), respectively. Moreover, patients with splicing factor mutations alone had a better overall survival than those with epigenetic modifier mutations, or cell signaling/transcription regulator mutations with and without coexisting mutations of splicing factor genes, with worsening prognosis (P<0.001). These findings suggest that splicing factor mutations are maintained throughout disease

  12. Hepcidin and Hfe in iron overload in beta-thalassemia.

    Science.gov (United States)

    Gardenghi, Sara; Ramos, Pedro; Follenzi, Antonia; Rao, Niva; Rachmilewitz, Eliezer A; Giardina, Patricia J; Grady, Robert W; Rivella, Stefano

    2010-08-01

    Hepcidin (HAMP) negatively regulates iron absorption, degrading the iron exporter ferroportin at the level of enterocytes and macrophages. We showed that mice with beta-thalassemia intermedia (th3/+) have increased anemia and iron overload. However, their hepcidin expression is relatively low compared to their iron burden. We also showed that the iron metabolism gene Hfe is down-regulated in concert with hepcidin in th3/+ mice. These observations suggest that low hepcidin levels are responsible for abnormal iron absorption in thalassemic mice and that down-regulation of Hfe might be involved in the pathway that controls hepcidin synthesis in beta-thalassemia. Therefore, these studies suggest that increasing hepcidin and/or Hfe expression could be a strategy to reduces iron overload in these animals. The goal of this paper is to review recent findings that correlate hepcidin, Hfe, and iron metabolism in beta-thalassemia and to discuss potential novel therapeutic approaches based on these recent discoveries.

  13. Hepcidin and Hfe in iron overload in β-thalassemia

    Science.gov (United States)

    Gardenghi, Sara; Ramos, Pedro; Follenzi, Antonia; Rao, Niva; Rachmilewitz, Eliezer A.; Giardina, Patricia J.; Grady, Robert W.; Rivella, Stefano

    2013-01-01

    Hepcidin (HAMP) negatively regulates iron absorption, degrading the iron exporter ferroportin at the level of enterocytes and macrophages. We showed that mice with β-thalassemia intermedia (th3/+) have increased anemia and iron overload. However, their hepcidin expression is relatively low compared to their iron burden. We also showed that the iron metabolism gene Hfe is down-regulated in concert with hepcidin in th3/+ mice. These observations suggest that low hepcidin levels are responsible for abnormal iron absorption in thalassemic mice and that down-regulation of Hfe might be involved in the pathway that controls hepcidin synthesis in β-thalassemia. Therefore, these studies suggest that increasing hepcidin and/or Hfe expression could be a strategy to reduces iron overload in these animals. The goal of this paper is to review recent findings that correlate hepcidin, Hfe, and iron metabolism in β-thalassemia and to discuss potential novel therapeutic approaches based on these recent discoveries. PMID:20712796

  14. Pathogenic mutations of nuclear genes associated with mitochondrial disorders

    Institute of Scientific and Technical Information of China (English)

    Xiaoyu Zhu; Xuerui Peng; Min-Xin Guan; Qingfeng Yan

    2009-01-01

    Mitochondrial disorders are clinical phenotypes associated with mitochondrial dysfunction, which can be caused by mutations in mitochondrial DNA (mtDNA) or nuclear genes. In this review, we summarized the pathogenic mutations of nuclear genes associated with mitochondrial disorders. These nuclear genes encode, components of mitochondrial translational machinery and structural subunits and assembly factors of the oxidative phosphorylation, that complex. The molecular mechanisms, that nuclear modifier genes modulate the phenotypic expression of mtDNA mutations, are discussed in detail.

  15. Hfe deficiency impairs pulmonary neutrophil recruitment in response to inflammation.

    Directory of Open Access Journals (Sweden)

    Karolina Benesova

    Full Text Available Regulation of iron homeostasis and the inflammatory response are tightly linked to protect the host from infection. Here we investigate how imbalanced systemic iron homeostasis in a murine disease model of hereditary hemochromatosis (Hfe(-/- mice affects the inflammatory responses of the lung. We induced acute pulmonary inflammation in Hfe(-/- and wild-type mice by intratracheal instillation of 20 µg of lipopolysaccharide (LPS and analyzed local and systemic inflammatory responses and iron-related parameters. We show that in Hfe(-/- mice neutrophil recruitment to the bronchoalveolar space is attenuated compared to wild-type mice although circulating neutrophil numbers in the bloodstream were elevated to similar levels in Hfe(-/- and wild-type mice. The underlying molecular mechanisms are likely multifactorial and include elevated systemic iron levels, alveolar macrophage iron deficiency and/or hitherto unexplored functions of Hfe in resident pulmonary cell types. As a consequence, pulmonary cytokine expression is out of balance and neutrophils fail to be recruited efficiently to the bronchoalveolar compartment, a process required to protect the host from infections. In conclusion, our findings suggest a novel role for Hfe and/or imbalanced iron homeostasis in the regulation of the inflammatory response in the lung and hereditary hemochromatosis.

  16. 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.

  17. The Mutations Associated with Dilated Cardiomyopathy

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    Ruti Parvari

    2012-01-01

    Full Text Available Cardiomyopathy is an important cause of heart failure and a major indication for heart transplantation in children and adults. This paper describes the state of the genetic knowledge of dilated cardiomyopathy (DCM. The identification of the causing mutation is important since presymptomatic interventions of DCM have proven value in preventing morbidity and mortality. Additionally, as in general in genetic studies, the identification of the mutated genes has a direct clinical impact for the families and population involved. Identifying causative mutations immediately amplifies the possibilities for disease prevention through carrier screening and prenatal testing. This often lifts a burden of social isolation from affected families, since healthy family members can be assured of having healthy children. Identification of the mutated genes holds the potential to lead to the understanding of disease etiology, pathophysiology, and therefore potential therapy. This paper presents the genetic variations, or disease-causing mutations, contributing to the pathogenesis of hereditary DCM, and tries to relate these to the functions of the mutated genes.

  18. Management of human factors engineering-associated hemochromatosis: A 2015 update.

    Science.gov (United States)

    Sivakumar, Menaka; Powell, Lawrie W

    2016-03-18

    This review focuses on the management of iron metabolism and iron overload experienced in the hereditary condition, human factors engineering (HFE)-associated hemochromatosis. Hemochromatosis refers to a group of genetic diseases that result in iron overload; the major one globally is HFE-associated hemochromatosis. The evolution in understanding of the most common form of hereditary hemochromatosis, being the substation of cysteine to a tyrosine at position 282 in the HFE gene, has been extensively studied Novel mutations in both HFE and non-HFE genes have been indicated in this disease which hold significance in its application for the Asia-Pacific region. In conditions with iron overload, the storage of excess iron in various body tissues leads to complications and toxic damage. The most common presenting complaint for this disease is malaise, lethargy and other non-specific symptoms. In order to diagnose hereditary hemochromatosis, there are biochemical, imaging and genetic testing options. Currently, cascade screening of affected families is preferred over population-level screening. The mainstay of treatment is venesection and the appropriate approach to treatment has been consolidated over the years. Recently, the indications for venesection therapy of hemochromatosis have been challenged and are the subject of ongoing research.

  19. Management of human factors engineering-associated hemochromatosis: A 2015 update

    Institute of Scientific and Technical Information of China (English)

    Menaka; Sivakumar; Lawrie; W; Powell

    2016-01-01

    This review focuses on the management of iron metabolism and iron overload experienced in the hereditary condition, human factors engineering(HFE)-associated hemochromatosis. Hemochromatosis refers to a group of genetic diseases that result in iron overload; the major one globally is HFE-associated hemochromatosis. The evolution in understanding of the most common form of hereditary hemochromatosis, being the substation of cysteine to a tyrosine at position 282 in the HFE gene, has been extensively studied Novel mutations in both HFE and non-HFE genes have been indicated in this disease which hold significance in its application for the Asia-Pacific region. In conditions with iron overload, the storage of excess iron in various body tissues leads to complications and toxic damage. The most common presenting complaint for this disease is malaise, lethargy and other non-specific symptoms. In order to diagnose hereditary hemochromatosis, there are biochemical, imaging and genetic testing options. Currently, cascade screening of affected families is preferred over population-level screening. The mainstay of treatment is venesection and the appropriate approach to treatment has been consolidated over the years. Recently, the indications for venesection therapy of hemochromatosis have been challenged and are the subject of ongoing research.

  20. The functional importance of disease-associated mutation

    Directory of Open Access Journals (Sweden)

    Klein Teri E

    2002-09-01

    Full Text Available Abstract Background For many years, scientists believed that point mutations in genes are the genetic switches for somatic and inherited diseases such as cystic fibrosis, phenylketonuria and cancer. Some of these mutations likely alter a protein's function in a manner that is deleterious, and they should occur in functionally important regions of the protein products of genes. Here we show that disease-associated mutations occur in regions of genes that are conserved, and can identify likely disease-causing mutations. Results To show this, we have determined conservation patterns for 6185 non-synonymous and heritable disease-associated mutations in 231 genes. We define a parameter, the conservation ratio, as the ratio of average negative entropy of analyzable positions with reported mutations to that of every analyzable position in the gene sequence. We found that 84.0% of the 231 genes have conservation ratios less than one. 139 genes had eleven or more analyzable mutations and 88.0% of those had conservation ratios less than one. Conclusions These results indicate that phylogenetic information is a powerful tool for the study of disease-associated mutations. Our alignments and analysis has been made available as part of the database at http://cancer.stanford.edu/mut-paper/. Within this dataset, each position is annotated with the analysis, so the most likely disease-causing mutations can be identified.

  1. EG-08IDH MUTATIONS IN GLIOMAS ASSOCIATED WITH ENCHONDROMATOSIS

    Science.gov (United States)

    Nicholas, M. Kelly; Joseph, Loren; Venneti, Sriram; Daher, Ahmad; Pytel, Peter

    2014-01-01

    The enchondromatoses, Ollier's disease and Maffucci syndrome, are non-heritable developmental disorders characterized by multiple enchondromas (Olllier's) in association with hemangiomas (Maffucci). Glial neoplasms are reported in both disorders but a pathogenic mechanism underlying this association has not been identified. We report a case of anaplastic astrocytoma in a 23 year old man with Maffucci syndrome whose tumor carried a substitution mutation of arginine for cysteine at position 132 (R132C) of the isocitrate dehydrogenase 1 (IDH1) protein. This mutation, commonly found in Maffucci-associated enchondromas and hemangiomas, was not detected on routine immunohistochemical (IHC) analysis of the astrocytoma using the R132H mutation-specific antibody, commonly applied in clinical laboratories. The R132C mutation was detected by polymerase chain reaction (PCR) and subsequently confirmed using a SNaPshot assay. Because somatic mosaic IDH mutations are associated with enchondromas and hemangiomas in Maffucci syndrome, we looked for the R132C mutation in a hemangioma, peripheral blood mononuclear cells (PBMNC) and histologically normal brain surrounding the tumor from this patient. The mutation was present in the hemangioma, absent in PBMNC, and present in 2% of alleles in ‘normal’ brain. The low level in surrounding brain tissue is consistent with tumor cell infiltration, not mosaicism, as a S173T p53 mutation in the tumor showed similar results. Using IHC, we further demonstrated that the mutant IDH1 protein in this glioma functions as an oncometabolite. Two repressive histone trimethylation marks were strongly positive in the tumor, supporting a role for 2-hydroxyglutarate in the inhibition of histone demethylation. Together, these data demonstrate that an IDH1 mutation common in enchodromatoses underlies the association of glial tumors reported in both Ollier's disease and Maffucci syndrome.

  2. Association of TERT Promoter Mutation, But Not BRAF Mutation, With Increased Mortality in PTC.

    Science.gov (United States)

    George, Jonathan R; Henderson, Ying C; Williams, Michelle D; Roberts, Dianna B; Hei, Hu; Lai, Stephen Y; Clayman, Gary L

    2015-12-01

    Papillary thyroid carcinoma (PTC) carrying the BRAF mutation has been reported to be associated with high recurrence and potentially increased mortality. PTC carrying the TERT promoter mutation has been associated with older age, recurrence, and aggressive disease. The objective of this study was to determine the association of BRAF and TERT promoter gene alterations with recurrence and survival in a high-risk population. Genomic DNA was analyzed for the BRAF mutation from 256 persistent/recurrent PTC (p/rPTC; 202 new, 54 previously reported) and for the TERT promoter mutation and polymorphism (242 p/rPTC). Two-tailed Fisher exact tests or the Pearson χ(2) test were performed for the associations between mutations and other variables. Overall and disease-free survivals were compared by log rank tests on Kaplan-Meier plots and by Cox regression analysis. TERT promoter constructs were tested in PTC cell lines to determine their activities in these cells. BRAF V600E mutation was identified in 235 of 256 (91.8%), TERT promoter mutation at -124 was detected in 77 of 242 (31.8%), and TERT promoter polymorphism at -245 was found in 113 of 242 (46.7%) p/rPTC patients. A significant difference in survival was found in p/rPTC patients with the TERT promoter mutation, which also displayed increased activity in vitro as compared to the nonmutated promoter sequence. No association was noted between the BRAF mutation or TERT promoter polymorphism and recurrence or survival. A drawback of our study could be the limited number of patients with nonmutated BRAF (21 of 256 [8.2%]). Mutation in the TERT promoter, but not in BRAF, was associated with decreased survival in 19 (24.7%) p/rPTC patients who died of disease and in 38 (49.4%) p/rPTC patients who died at last contact. The presence or absence of the BRAF mutation and TERT promoter polymorphism, however, was not significantly correlated with survival.

  3. Livedoid vasculopathy and its association with factor V Leiden mutation.

    Science.gov (United States)

    Yong, Angeline Anning; Tan, Audrey Wei Hsia; Giam, Yoke Chin; Tang, Mark Boon Yang

    2012-12-01

    Livedoid vasculopathy is a rare chronic relapsing disorder characterised by recurrent painful thrombotic and vasculitic ulcers on the legs. We present the cases of two Indian women with livedoid vasculopathy that were found to be associated with an underlying factor V Leiden heterozygous mutation. There were no other thrombotic manifestations, and livedoid vasculopathy was the sole presenting feature of the factor V Leiden mutation, although this could also be coincidental. Initial treatment with high-dose immunosuppressive therapy was suboptimal, and the addition of pentoxifylline and antiplatelet therapy was crucial in achieving disease control and remission. These cases highlight the possible association with an underlying prothrombotic disorder, such as factor V Leiden mutation, in patients with livedoid vasculopathy. Although this association is relatively uncommon, it is more relevant to Indian patients, as the presence of factor V Leiden mutation is highest in this ethnicity as compared to the local Malay and Chinese populations.

  4. Cancer-Associated IDH1 Mutations Produce 2-hydroxyglutarate

    Energy Technology Data Exchange (ETDEWEB)

    Dang, L.; White, D; Gross, S; Bennett, B; Bittinger, M; Driggers, E; Fantin, V; Jang, H; Jin, S; et al.

    2009-01-01

    Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are a common feature of a major subset of primary human brain cancers. These mutations occur at a single amino acid residue of the IDH1 active site, resulting in loss of the enzyme's ability to catalyse conversion of isocitrate to {alpha}-ketoglutarate. However, only a single copy of the gene is mutated in tumours, raising the possibility that the mutations do not result in a simple loss of function. Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of {alpha}-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). Structural studies demonstrate that when arginine 132 is mutated to histidine, residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert {alpha}-ketoglutarate to 2HG. Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumours in patients with inborn errors of 2HG metabolism. Similarly, in human malignant gliomas harbouring IDH1 mutations, we find markedly elevated levels of 2HG. These data demonstrate that the IDH1 mutations result in production of the onco-metabolite 2HG, and indicate that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.

  5. Disease-associated mutations prevent GPR56-collagen III interaction.

    Directory of Open Access Journals (Sweden)

    Rong Luo

    Full Text Available GPR56 is a member of the adhesion G protein-coupled receptor (GPCR family. Mutations in GPR56 cause a devastating human brain malformation called bilateral frontoparietal polymicrogyria (BFPP. Using the N-terminal fragment of GPR56 (GPR56(N as a probe, we have recently demonstrated that collagen III is the ligand of GPR56 in the developing brain. In this report, we discover a new functional domain in GPR56(N, the ligand binding domain. This domain contains four disease-associated mutations and two N-glycosylation sites. Our study reveals that although glycosylation is not required for ligand binding, each of the four disease-associated mutations completely abolish the ligand binding ability of GPR56. Our data indicates that these four single missense mutations cause BFPP mostly by abolishing the ability of GPR56 to bind to its ligand, collagen III, in addition to affecting GPR56 protein surface expression as previously shown.

  6. Germline met mutations in mice reveal mutation- and background-associated differences in tumor profiles.

    Directory of Open Access Journals (Sweden)

    Carrie R Graveel

    Full Text Available BACKGROUND: The receptor tyrosine kinase Met is involved in the progression and metastasis of numerous human cancers. Although overexpression and autocrine activation of the Met signaling pathway are commonly found in human cancers, mutational activation of Met has been observed in small cell and non-small cell lung cancers, lung adenocarcinomas, renal carcinomas, and mesotheliomas. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the influence of mutationally activated Met in tumorigenesis, we utilized a novel mouse model. Previously, we observed that various Met mutations developed unique mutation-specific tumor spectra on a C57BL/6 background. Here, we assessed the effect of genetic background on the tumorigenic potential of mutationally activated Met. For this purpose, we created congenic knock-in lines of the Met mutations D1226N, M1248T, and Y1228C on the FVB/N background. Consistent with the mutation-specific tumor spectra, several of the mutations were associated with the same tumor types as observed on C57BL/6 background. However, on the FVB/N background most developed a high incidence of mammary carcinomas with diverse histopathologies. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that on two distinct mouse backgrounds, Met is able to initiate tumorigenesis in multiple cell types, including epithelial, hematopoietic, and endothelial. Furthermore, these observations emphasize that even a modest increase in Met activation can initiate tumorigenesis with both the Met mutational spectra and host background having profound influence on the type of tumor generated. Greater insight into the interaction of genetic modifiers and Met signaling will significantly enhance our ability to tailor combination therapies for Met-driven cancers.

  7. Foxp2 mutations impair auditory-motor association learning.

    Science.gov (United States)

    Kurt, Simone; Fisher, Simon E; Ehret, Günter

    2012-01-01

    Heterozygous mutations of the human FOXP2 transcription factor gene cause the best-described examples of monogenic speech and language disorders. Acquisition of proficient spoken language involves auditory-guided vocal learning, a specialized form of sensory-motor association learning. The impact of etiological Foxp2 mutations on learning of auditory-motor associations in mammals has not been determined yet. Here, we directly assess this type of learning using a newly developed conditioned avoidance paradigm in a shuttle-box for mice. We show striking deficits in mice heterozygous for either of two different Foxp2 mutations previously implicated in human speech disorders. Both mutations cause delays in acquiring new motor skills. The magnitude of impairments in association learning, however, depends on the nature of the mutation. Mice with a missense mutation in the DNA-binding domain are able to learn, but at a much slower rate than wild type animals, while mice carrying an early nonsense mutation learn very little. These results are consistent with expression of Foxp2 in distributed circuits of the cortex, striatum and cerebellum that are known to play key roles in acquisition of motor skills and sensory-motor association learning, and suggest differing in vivo effects for distinct variants of the Foxp2 protein. Given the importance of such networks for the acquisition of human spoken language, and the fact that similar mutations in human FOXP2 cause problems with speech development, this work opens up a new perspective on the use of mouse models for understanding pathways underlying speech and language disorders.

  8. Foxp2 mutations impair auditory-motor association learning.

    Directory of Open Access Journals (Sweden)

    Simone Kurt

    Full Text Available Heterozygous mutations of the human FOXP2 transcription factor gene cause the best-described examples of monogenic speech and language disorders. Acquisition of proficient spoken language involves auditory-guided vocal learning, a specialized form of sensory-motor association learning. The impact of etiological Foxp2 mutations on learning of auditory-motor associations in mammals has not been determined yet. Here, we directly assess this type of learning using a newly developed conditioned avoidance paradigm in a shuttle-box for mice. We show striking deficits in mice heterozygous for either of two different Foxp2 mutations previously implicated in human speech disorders. Both mutations cause delays in acquiring new motor skills. The magnitude of impairments in association learning, however, depends on the nature of the mutation. Mice with a missense mutation in the DNA-binding domain are able to learn, but at a much slower rate than wild type animals, while mice carrying an early nonsense mutation learn very little. These results are consistent with expression of Foxp2 in distributed circuits of the cortex, striatum and cerebellum that are known to play key roles in acquisition of motor skills and sensory-motor association learning, and suggest differing in vivo effects for distinct variants of the Foxp2 protein. Given the importance of such networks for the acquisition of human spoken language, and the fact that similar mutations in human FOXP2 cause problems with speech development, this work opens up a new perspective on the use of mouse models for understanding pathways underlying speech and language disorders.

  9. Acquired mutations associated with ibrutinib resistance in Waldenstrom Macroglobulinemia.

    Science.gov (United States)

    Xu, Lian; Tsakmaklis, Nicholas; Yang, Guang; Chen, Jiaji G; Liu, Xia; Demos, Maria; Kofides, Amanda; Patterson, Christopher J; Meid, Kirsten; Gustine, Joshua; Dubeau, Toni; Palomba, M Lia; Advani, Ranjana; Castillo, Jorge J; Furman, Richard R; Hunter, Zachary R; Treon, Steven P

    2017-02-24

    Ibrutinib produces high response rates and durable remissions in Waldenstrom's Macroglobulinemia (WM) that are impacted by MYD88 and CXCR4(WHIM) mutations. Disease progression can develop on ibrutinib, though the molecular basis remains to be clarified. We sequenced sorted CD19(+) lymphoplasmacytic cells from 6 WM patients who progressed after achieving major responses on ibrutinib using Sanger, TA cloning and sequencing, and highly sensitive and specific AS-PCR assays that we developed for BTK mutations. AS-PCR assays were used to screen patients with and without progressive disease on ibrutinib, and ibrutinib-naïve disease. Targeted next generation sequencing was used to validate AS-PCR findings, assess for other BTK mutations, and other targets in BCR and MYD88 signaling. Among the 6 progressing patients, 3 had BTK(Cys481) variants that included BTK(Cys481Ser(c.1635G>C and c.1634T>A)) and BTK(Cys481Arg(c.1634T>C)) Two of these patients had multiple BTK mutations. Screening of 38 additional patients on ibrutinib without clinical progression identified BTK(Cys481) mutations in 2 (5.1%) individuals, both of whom subsequently progressed. BTK(Cys481) mutations were not detected in baseline samples or in 100 ibrutinib-naive WM patients. Using mutated MYD88 as a tumor marker, BTK(Cys481) mutations were subclonal, with a highly variable clonal distribution. Targeted deep sequencing confirmed AS-PCR findings, and identified an additional BTK(Cys481Tyr(c.1634G>A)) mutation in the two patients with multiple other BTK(Cys481) mutations, as well as CARD11(Leu878Phe(c.2632C>T)) and PLCγ2(Tyr495His(c.1483T>C)) mutations. Four of the five patients with BTK(C481) variants were CXCR4 mutated. BTK(Cys481) mutations are common in WM patients with clinical progression on ibrutinib, and are associated with mutated CXCR4.

  10. Effect of co-inheritance of β-thalassemia and hemochromatosis mutations on iron overload.

    Science.gov (United States)

    López-Escribano, Herminio; Ferragut, Joana F; Parera, Maria M; Guix, Pilar; Castro, José A; Ramon, M Misericòrdia; Picornell, Antònia

    2012-01-01

    Co-inheritance of mutations in the HFE gene underlying hereditary hemocromatosis (HH) may play a role in the variability of iron status in patients with β-thalassemia (β-thal) minor. Different studies have yielded conflicting results: some suggest iron overload might arise from the interaction of the β-thal trait with homozygosity or even heterozygosity for HFE mutations and others that it was unrelated to the HFE genotype. Because of the high frequency of HFE mutations in the Balearic Islands, where the β-thal trait is also moderately common, it is of interest to evaluate the effect of the co-inheritance of mutations in both genes on the severity of iron loading. A retrospective analysis of 142 individuals heterozygous for β-thal was performed to investigate the effect of HFE mutations on iron status of these patients. No significant differences were detected between β-thal carriers with and without HFE mutations. These results suggest that in the Balearic population the β-thal trait does not tend to be aggravated by the co-inheritance of HFE mutations.

  11. Neuroglobin mutation associated with hypoxia adaptation in Tibet chicken

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Globin protein family plays an important role in storing and transporting oxygen.As a newly reported globin,the revealed function of neuroglobin includes binding and storing oxygen as well as facilitating the utilization of oxygen in neuronal cells.In the Dresent study,mutations in exons of chicken Ngb gene were identified with the method of sequencing and created restriction site PCR in Tibet chicken and other four lowland chicken breeds.The mutations of Lys-2224(E4)-Asn and Ser-2279(E4)-Gly were identified in exon 4 of the gene.The Lys-2224(E4)-Asn mutation existed only in Tibet chicken and the mutation frequencies increased with increasing altitude.Analysis of the haplotype and diplotype of the two mutations in Tibet chicken populations of different altitudes showed that the frequencies of TG haplotype and TTGG diplotype also increased with increasing altitude,while the reverse tendency was found on GGAA diplotype.Under the hypoxic simulation incubation,the main haplotype was TG in living embryos and GA in dead embryos.The results showed that the Lys-2224(E4)-Asn mutation may be a specific mutation associated with hypoxia adaptation in Tibet chicken.

  12. Pressure Drop of HFE7000 and HFE7100 in Flow Condensation in Minichannels With Account of Non-Adiabatic Effects

    Directory of Open Access Journals (Sweden)

    Mikielewicz Dariusz

    2014-01-01

    Full Text Available Flow boiling and flow condensation are often regarded as two opposite or symmetrical phenomena involving the change of phase. There is a temptation to describe both these phenomena with one only correlation. From amongst the structures present in flow boiling and flow condensation at least the annular flow structure seems to be mostly appropriate to the common modeling. However, the shear stress acting between vapor phase and liquid phase is not the same in the respective cases, i.e. flow boiling and flow condensation. Most of modeling of heat transfer in case of condensation inside channels relates the heat transfer coefficient to the friction coefficient. All existing approaches are either the empirical fits to experimental data or form an attempt to combine two major influences to heat transfer, namely the convective flow boiling without bubble generation and nucleate boiling. In the paper the authors present investigations of flow condensation with the use of the HFE7100 and HFE 7000 as a working fluids and their own condensation model inside tubes with account of non-adiabatic effects. The model will be confronted with own data for a new fluid HFE7000 and HFE 7100.

  13. Recent advances in disorders of iron metabolism: mutations, mechanisms and modifiers.

    Science.gov (United States)

    Roy, C N; Andrews, N C

    2001-10-01

    The spectrum of known disorders of iron metabolism has expanded dramatically over the past few years. Identification of HFE, the gene most commonly mutated in patients with hereditary hemochromatosis, has allowed molecular diagnosis and paved the way for identification of other genes, such as TFR2, that are important in non-HFE-associated iron overload. There are clearly several other, unidentified, iron overload disease genes yet to be found. In parallel, our understanding of iron transport has expanded through identification of Fpn1/Ireg1/MTP1, Sfxn1 and DCYTB: Ongoing studies of Friedreich's ataxia, sideroblastic anemia, aceruloplasminemia and neurodegeneration with brain-iron accumulation are clarifying the role for iron in the nervous system. Finally, as the number of known iron metabolic genes increases and their respective functions are ascertained, new opportunities have arisen to identify genetic modifiers of iron homeostasis.

  14. Anonymous marker loci within 400 kb of HLA-A generate haplotypes in linkage disequilibrium with the hemochromatosis gene (HFE)

    Energy Technology Data Exchange (ETDEWEB)

    Yaouanq, J.; Perichon, M.; Treut, A.L.; Kahloun, A.E.; Mauvieux, V.; Blayau, M.; Jouanolle, A.M.; Chauvel, B.; Le Gall, J.Y.; David, V. (Faculte de Medicine, Rennes (France)) (and others)

    1994-02-01

    The hemochromatosis gene (HFE) maps to 6p21.3 and is less than 1 cM from the HLA class I gene; however, the precise physical location of the gene has remained elusive and controversial. The unambiguous identification of a crossover event within hemochromatosis families is very difficult; it is particularly hampered by the variability of the phenotypic expression as well as by the sex- and age-related penetrance of the disease. For these considerations, traditional linkage analysis could prove of limited value in further refining the extrapolated physical position of HFE. The authors therefore embarked upon a linkage-disequilibrium analysis of HFE and normal chromosomes for the Brittany population. In this report, 66 hemochromatosis families yielding 151 hemochromatosis chromosomes and 182 normal chromosomes were RFLP-typed with a battery of probes, including two newly derived polymorphic markers from the 6.7 and HLA-F loci located 150 and 250 kb telomeric to HLA-A, respectively. The results suggest a strong peak of existing linkage disequilibrium focused within the i82-to-6.7 interval (approximately 250 kb). The zone of linkage disequilibrium is flanked by the i97 locus, positioned 30 kb proximal to i82, and the HLA-F gene, found 250 kb distal to HLA-A, markers of which display no significant association with HFE. These data support the possibility that HFE resides within the 400-kb expanse of DNA between i97 and HLA-F. Alternatively, the very tight association of HLA-A3 and allele 1 of the 6.7 locus, both of which are comprised by the major ancestral or founder HFE haplotype in Brittany, supports the possibility that the disease gene may reside immediately telomeric to the 6.7 locus within the linkage-disequilibrium zone. Additionally, hemochromatosis haplotypes possessing HLA-A11 and the low-frequency HLA-F polymorphism (allele 2) are supportive of a separate founder chromosome containing a second, independently arising mutant allele. 69 refs., 1 fig., 5 tabs.

  15. 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 BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

  16. Abnormal retinal development associated with FRMD7 mutations.

    Science.gov (United States)

    Thomas, Mervyn G; Crosier, Moira; Lindsay, Susan; Kumar, Anil; Araki, Masasuke; Leroy, Bart P; McLean, Rebecca J; Sheth, Viral; Maconachie, Gail; Thomas, Shery; Moore, Anthony T; Gottlob, Irene

    2014-08-01

    Idiopathic infantile nystagmus (IIN) is a genetically heterogeneous disorder, often associated with FRMD7 mutations. As the appearance of the retina is reported to be normal based on conventional fundus photography, IIN is postulated to arise from abnormal cortical development. To determine whether the afferent visual system is involved in FRMD7 mutations, we performed in situ hybridization studies in human embryonic and fetal stages (35 days post-ovulation to 9 weeks post-conception). We show a dynamic retinal expression pattern of FRMD7 during development. We observe expression within the outer neuroblastic layer, then in the inner neuroblastic layer and at 9 weeks post-conception a bilaminar expression pattern. Expression was also noted within the developing optic stalk and optic disk. We identified a large cohort of IIN patients (n = 100), and performed sequence analysis which revealed 45 patients with FRMD7 mutations. Patients with FRMD7 mutations underwent detailed retinal imaging studies using ultrahigh-resolution optical coherence tomography. The tomograms were compared with a control cohort (n = 60). The foveal pit was significantly shallower in FRMD7 patients (P < 0.0001). The optic nerve head morphology was abnormal with significantly decreased optic disk area, retinal nerve fiber layer thickness, cup area and cup depth in FRMD7 patients (P < 0.0001). This study shows for the first time that abnormal afferent system development is associated with FRMD7 mutations and could be an important etiological factor in the development of nystagmus.

  17. Genome-Wide Scan Reveals Mutation Associated with Melanoma

    Science.gov (United States)

    ... Q R S T U V W X Y Z We want to hear from you You are here: News & Events 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 2001 2000 1999 Spotlight on Research 2012 July 2012 (historical) Genome-Wide Scan Reveals Mutation Associated with Melanoma A team of ...

  18. Hearing impairment and renal failure associated with RMND1 mutations

    DEFF Research Database (Denmark)

    Ravn, Kirstine; Neland, Mette; Wibrand, Flemming

    2016-01-01

    Recently, two research groups reported that mutations in RMND1 were associated with encephalopathy, elevated lactate, hypotonia, and in some patients seizures or myoclonia in individuals from two consanguineous families. A combined respiratory chain deficiency and a defect in mitochondrial protein...

  19. Boiling of HFE-7100 on a Straight Pin Fin

    Institute of Scientific and Technical Information of China (English)

    Z. W. Liu; W.W. Lin; D.J. Lee; J.P. Hsu

    2001-01-01

    This paper deals with an experimental investigation of pin fin boiling of saturated and subcooled HFE-7100 under atmospheric pressure. Fin base temperature and heat flux data are measured along with the fin tip temperature. The basic features of boiling stability of HFE-7100 boiling on pin fin had been reported for the first time. For a given liquid/heating surface combination there exist upper steady-state (USS) branch and lower steady-state (LSS)branch, and a large, unstable regime located in between. Zones with different stability characteristics are mapped according to boiling on fins with different aspect ratios. Liquid subcooling can largely enhance heat transfer performance. A longer fin can provide a safer operation.

  20. A myomesin mutation associated with hypertrophic cardiomyopathy deteriorates dimerisation properties.

    Science.gov (United States)

    Siegert, Romy; Perrot, Andreas; Keller, Sandro; Behlke, Joachim; Michalewska-Włudarczyk, Aleksandra; Wycisk, Anna; Tendera, Michal; Morano, Ingo; Ozcelik, Cemil

    2011-02-18

    Myomesin plays an important structural and functional role in the M-band of striated muscles. The C-terminal domain 13 of myomesin dimerises and forms antiparallel strands which cross-link neighboring Myosin filaments and titin in the M-line of the sarcomeres. These interactions stabilise the contractile apparatus during striated muscle contraction. Since myomesin is an important component of the M-band we screened the myomesin gene for genetic variants in patients with hypertrophic cardiomyopathy (HCM). We identified the missense mutation V1490I in domain 12 of myomesin in a family with inherited HCM. Analytical ultracentrifugation experiments, circular dichroism spectra, and surface plasmon resonance spectroscopy of myomesin fragments were carried out to investigate the effects of the mutation V1490I on structure and function of myomesin domains 11-13 and 12-13. Both the wild type and mutated myomesin domains My11-13 revealed similar secondary structures and formed stable dimers. Mutated myomesin domains My11-13 and My12-13 dimers revealed a reduced thermal stability and a significantly decreased dimerisation affinity, showing disturbed functional properties of V1490I mutated myomesin. However, monomeric myomesin domains My11-12, i.e. without dimerisation domain 13 showed no difference in thermal stability between wild type and V1490I mutated myomesin. In conclusion, the V1490I mutation associated with HCM lead to myomesin proteins with abnormal functional properties which affect dimerisation properties of myomesin domain 13. These effects may contribute to the pathogenesis of HCM. Copyright © 2011 Elsevier Inc. All rights reserved.

  1. Chromosomal mutagen sensitivity associated with mutations in BRCA genes.

    Science.gov (United States)

    Speit, G; Trenz, K

    2004-01-01

    Chromosomal mutagen sensitivity is a common feature of cells from patients with different kinds of cancer. A portion of breast cancer patients also shows an elevated sensitivity to the induction of chromosome damage in cells exposed to ionizing radiation or chemical mutagens. Segregation analysis in families of patients with breast cancer indicated heritability of mutagen sensitivity. It has therefore been suggested that mutations in low-penetrance genes which are possibly involved in DNA repair predispose a substantial portion of breast cancer patients. Chromosomal mutagen sensitivity has been determined with the G2 chromosome aberration test and the G(0) micronucleus test (MNT). However, there seems to be no clear correlation between the results from the two tests, indicating that the inherited defect leading to enhanced G(0) sensitivity is different from that causing G2 sensitivity. Less than 5% of breast cancer patients have a familial form of the disease due to inherited mutations in the breast cancer susceptibility genes BRCA1 or BRCA2. Heterozygous mutations in BRCA1 or BRCA2 in lymphocytes from women with familial breast cancer are also associated with mutagen sensitivity. Differentiation between mutation carriers and controls seems to be much better with the MNT than with the G2 assay. Mutagen sensitivity was detected with the MNT not only after irradiation but also after treatment with chemical mutagens including various cytostatics. The enhanced formation of micronuclei after exposure of lymphocytes to these substances suggests that different DNA repair pathways are affected by a BRCA1 mutation in accordance with the proposed central role of BRCA1 in maintaining genomic integrity. Mutations in BRCA1 and BRCA2 seem to predispose cells to an increased risk of mutagenesis and transformation after exposure to radiation or cytostatics. This raises a question about potentially increased risks by mammography and cancer therapy in women carrying a mutation in

  2. [Gliomas and BRCA genes mutations: fortuitous association or imputability?].

    Science.gov (United States)

    Girardstein-Boccara, Laura; Mari, Véronique; Met-Domestici, Marie; Burel-Vandenbos, Fanny; Berthet, Pascaline; Paquis, Philippe; Frenay, Marc Paul; Lebrun-Frenay, Christine

    2014-09-01

    BRCA is a tumor suppressor gene implicated in the major mechanisms of cellular stability in every type of cell. Its mutations are described in numerous cancers, mainly breast and ovarian in women. It was also found an increase of lifetime risk of pancreas, colon, prostate cancer or lymphoma in men carriers. We report the cases of two female patients aged 40 and 58-years-old female patients and one 35-years-old male patient, with brain or medullar gliomas, carriers of a germline mutation of BRCA gene. Those gliomas were particularly aggressive and were not responding to the standard treatment, with chemo and radiotherapy. The very unusual characteristics in location and evolutive profile of these central nervous system tumors raise the question of a genetical underlying mechanism, maybe linked to the BRCA gene mutation that carry these patients. In addition, a non-fortuitous association between germline mutation of BRCA and occurrence of a glioma can be evoked according to the embryological, epidemiological and biomolecular findings noted in the literature. Other clinical and experimental studies are necessary to precise the physiopathological link existing between BRCA mutations and the occurrence of a glioma; this could have therapeutical and clinical implications in the future.

  3. Clinical outcomes in pancreatic adenocarcinoma associated with BRCA-2 mutation.

    Science.gov (United States)

    Vyas, Ojas; Leung, Keith; Ledbetter, Leslie; Kaley, Kristin; Rodriguez, Teresa; Garcon, Marie C; Saif, Muhammad W

    2015-02-01

    Patients with BRCA-1 and BRCA-2 germ line mutations are at an increased risk of developing pancreatic adenocarcinoma (PAC). In particular, the BRCA-2 mutation has been associated with a relative risk of developing PAC of 3.51. The BRCA-2 protein is involved in repair of double-stranded DNA breaks. Recent reports have suggested that in the setting of impaired DNA repair, chemotherapeutic agents that induce DNA damage, such as platinum-based antineoplastic drugs (platins) and poly(ADP-ribose) polymerase inhibitors (PARP inhibitors), have improved efficacy. However, because of the relative rarity of BRCA-related PAC, studies evaluating such agents in this setting are scarce. Patients with a known BRCA-2 mutation and PAC were retrospectively reviewed. Ten patients with PAC and BRCA-2 mutation were identified. Four patients (40%) were of Ashkenazi Jewish descent. Seven patients (70%) received platinum agents, two (20%) received mitomycin-C, one (10%) received a PARP inhibitor, and seven (70%) received a topoisomerase-I inhibitor. Overall, chemotherapy was well tolerated with expected side effects. Patients with a BRCA-2 mutation and PAC represent a group with a unique biology underlying their cancer. Chemotherapies such as platinum derivatives, mitomycin-C, topoisomerase-I inhibitors, and PARP inhibitors targeting DNA require further investigation in this population. Genetic testing may guide therapy in the future.

  4. Frequency of common HFE variants in the Saudi population: a high throughput molecular beacon-based study

    Directory of Open Access Journals (Sweden)

    Al-Hamed Mohamed

    2006-05-01

    Full Text Available Abstract Background Hereditary Hemochromatosis (HH is an autosomal recessive disorder highlighted byiron-overload. Two popular mutations in HFE, p.C282Y and p.H63D, have been discovered and found to associate with HH in different ethnic backgrounds. p.C282Y and p.H63D diagnosis is usually made byrestriction enzyme analysis. However, the use of this technique is largelylimited to research laboratories because they are relativelyexpensive, time-consuming, and difficult to transform into a high throughput format. Methods Single nucleotide variations in target DNA sequences can be readily identified using molecular beacon fluorescent probes. These are quenched probes with loop and hairpin structure, and they become fluorescent upon specific target recognition. We developed high throughput homogeneous real-time PCR assays using molecular beacon technology, to genotype p.C282Y and p.H63D variants. Representative samples of different genotypes for these variants were assayed by restriction enzyme analysis and direct sequencing as bench mark methods for comparison with the newly developed molecular beacon-based real-time PCR assay. Results Complete concordance was achieved by all three assay formats. Homozygotes (mutant and wildtype and heterozygotes were readily differentiated by the allele specific molecular beacons as reported by the associated fluorophore in the real-time assay developed in this study. Additionally, these assays were used in a high throughput format to establish the allele frequency of C282Y and H63D in Saudis for the first time. Conclusion These assays may be reliably applied as a diagnostic test or large scale method for population screening.

  5. Disease-associated mutations that alter the RNA structural ensemble.

    Directory of Open Access Journals (Sweden)

    Matthew Halvorsen

    2010-08-01

    Full Text Available Genome-wide association studies (GWAS often identify disease-associated mutations in intergenic and non-coding regions of the genome. Given the high percentage of the human genome that is transcribed, we postulate that for some observed associations the disease phenotype is caused by a structural rearrangement in a regulatory region of the RNA transcript. To identify such mutations, we have performed a genome-wide analysis of all known disease-associated Single Nucleotide Polymorphisms (SNPs from the Human Gene Mutation Database (HGMD that map to the untranslated regions (UTRs of a gene. Rather than using minimum free energy approaches (e.g. mFold, we use a partition function calculation that takes into consideration the ensemble of possible RNA conformations for a given sequence. We identified in the human genome disease-associated SNPs that significantly alter the global conformation of the UTR to which they map. For six disease-states (Hyperferritinemia Cataract Syndrome, beta-Thalassemia, Cartilage-Hair Hypoplasia, Retinoblastoma, Chronic Obstructive Pulmonary Disease (COPD, and Hypertension, we identified multiple SNPs in UTRs that alter the mRNA structural ensemble of the associated genes. Using a Boltzmann sampling procedure for sub-optimal RNA structures, we are able to characterize and visualize the nature of the conformational changes induced by the disease-associated mutations in the structural ensemble. We observe in several cases (specifically the 5' UTRs of FTL and RB1 SNP-induced conformational changes analogous to those observed in bacterial regulatory Riboswitches when specific ligands bind. We propose that the UTR and SNP combinations we identify constitute a "RiboSNitch," that is a regulatory RNA in which a specific SNP has a structural consequence that results in a disease phenotype. Our SNPfold algorithm can help identify RiboSNitches by leveraging GWAS data and an analysis of the mRNA structural ensemble.

  6. Distinguishing Hypertrophic Cardiomyopathy-Associated Mutations from Background Genetic Noise

    Science.gov (United States)

    Kapplinger, Jamie D.; Landstrom, Andrew P.; Bos, J. Martijn; Salisbury, Benjamin A.; Callis, Thomas E.; Ackerman, Michael J.

    2014-01-01

    Despite the significant progress that has been made in identifying disease-associated mutations, the utility of the Hypertrophic Cardiomyopathy (HCM) genetic test is limited by a lack of understanding of the background genetic variation inherent to these sarcomeric genes in seemingly healthy subjects. This study represents the first comprehensive analysis of genetic variation in 427 ostensibly healthy individuals for the HCM genetic test using the “Gold Standard” Sanger sequencing method validating the background rate identified in the publically available exomes. While mutations are clearly over-represented in disease, a background rate as high as ~5% among healthy individuals prevents diagnostic certainty. To this end, we have identified a number of estimated predictive value-based associations including gene-specific, topology, and conservation methods generating an algorithm aiding in the probabilistic interpretation of an HCM genetic test. PMID:24510615

  7. Common Membrane Trafficking Defects of Disease Associated Dynamin 2 Mutations

    OpenAIRE

    Liu, Ya-Wen; Lukiyanchuk, Vasyl; Schmid, Sandra L.

    2011-01-01

    Dynamin (Dyn) is a multidomain and multifunctional GTPase best known for its essential role in clathrin-mediated endocytosis (CME). Dyn2 mutations have been linked to two human diseases, Centronuclear Myopathy (CNM) and Charcot-Marie-Tooth (CMT) disease. Paradoxically, although Dyn2 is ubiquitously expressed and essential for embryonic development, the disease-associated Dyn2 mutants are autosomal dominant, but result in slowly progressing and tissue-specific diseases. Thus, although the cell...

  8. Biomedical Mutation Analysis (BMA): A software tool for analyzing mutations associated with antiviral resistance.

    Science.gov (United States)

    Salvatierra, Karina; Florez, Hector

    2016-01-01

    Hepatitis C virus (HCV) is considered a major public health problem, with 200 million people infected worldwide. The treatment for HCV chronic infection with pegylated interferon alpha plus ribavirin inhibitors is unspecific; consequently, the treatment is effective in only 50% of patients infected. This has prompted the development of direct-acting antivirals (DAA) that target virus proteins. These DAA have demonstrated a potent effect in vitro and in vivo; however, virus mutations associated with the development of resistance have been described. To design and develop an online information system for detecting mutations in amino acids known to be implicated in resistance to DAA.    We have used computer applications, technological tools, standard languages, infrastructure systems and algorithms, to analyze positions associated with resistance to DAA for the NS3, NS5A, and NS5B genes of HCV. We have designed and developed an online information system named Biomedical Mutation Analysis (BMA), which allows users to calculate changes in nucleotide and amino acid sequences for each selected sequence from conventional Sanger and cloning sequencing using a graphical interface. BMA quickly, easily and effectively analyzes mutations, including complete documentation and examples. Furthermore, the development of different visualization techniques allows proper interpretation and understanding of the results. The data obtained using BMA will be useful for the assessment and surveillance of HCV resistance to new antivirals, and for the treatment regimens by selecting those DAA to which the virus is not resistant, avoiding unnecessary treatment failures. The software is available at: http://bma.itiud.org.

  9. Cryptogenetic liver cirrhosis and prothrombotic mutations: a mere association?

    Directory of Open Access Journals (Sweden)

    María Monereo-Muñoz

    Full Text Available Thrombin activation and microthrombosis of intrahepatic portal venules is a common feature in liver cirrhosis, due in part to relative protein C deficiency and altered coagulation-anticoagulation-fibrinolysis balance. Extension of this microthrombotic process to larger portal vessels explains the increased incidence of portal vein thrombosis in liver cirrhosis. Thrombin not only leads to thrombosis, but also activates liver stellate cells and promotes fibrogenesis. Also, ischemia associated with thrombosis up-regulates the expression and secretion of growth factors involved in fibrogenesis. The coincidence in a given patient of prothrombotic mutations, such as factor V Leiden or PAI-1 polymorphisms, can accelerate the fibrogenetic process. We hereby present two cases of liver cirrhosis in which etiologic evaluation was negative except for the finding of a factor V Leiden mutation in one case and the 4G/5G PAI polymorphism in the second case. These observations support the hypothesis that these mutations may be involved in the etiology of some cases of cirrhosis, or, at least, accelerate the evolution of the disease. It is therefore convenient to search for the presence of prothrombotic mutations in patients with cryptogenetic cirrhosis.

  10. HF-hash : Hash Functions Using Restricted HFE Challenge-1

    CERN Document Server

    Dey, Dhananjoy; Gupta, Indranath Sen

    2009-01-01

    Vulnerability of dedicated hash functions to various attacks has made the task of designing hash function much more challenging. This provides us a strong motivation to design a new cryptographic hash function viz. HF-hash. This is a hash function, whose compression function is designed by using first 32 polynomials of HFE Challenge-1 with 64 variables by forcing remaining 16 variables as zero. HF-hash gives 256 bits message digest and is as efficient as SHA-256. It is secure against the differential attack proposed by Chabaud and Joux as well as by Wang et. al. applied to SHA-0 and SHA-1.

  11. Aminoglycoside induced ototoxicity associated with mitochondrial DNA mutations

    Directory of Open Access Journals (Sweden)

    Joseph Foster II

    2016-07-01

    Full Text Available Despite the risk of permanent ototoxic effects, aminoglycosides remain commonly utilized antibiotics worldwide due to low cost and efficiency in treating severe infections. Over the last two decades, mitochondrial mutations have been shown to enhance the likelihood of ototoxic injury. In particular the 1555A>G mutation in the mitochondrial gene MTRNR1 has been strongly associated with the onset of aminoglycoside-induced deafness; though pinning down the exact mechanism of action has thus far been elusive. Clinically aminoglycoside-induced deafness has been characterized by variation in the degree of hearing loss, which has prompted an investigation into genetic modifiers. To date, several putative mutations have been categorized as contributing factors to the onset of deafness with no single variation being sufficient to bring about hearing loss. Meanwhile current methods to mitigate the risk of ototoxic injury are in various stages of development. Efforts to alter the molecular structure of aminoglycosides have shown a potential path to reducing ototoxicity while preserving antibacterial properties, but these drugs are not clinically available. On the other hand, application of preemptive audiometry provides the most readily available method to both monitor and reduce the extent of aminoglycoside-induced deafness.

  12. BSE case associated with prion protein gene mutation.

    Directory of Open Access Journals (Sweden)

    Jürgen A Richt

    Full Text Available Bovine spongiform encephalopathy (BSE is a transmissible spongiform encephalopathy (TSE of cattle and was first detected in 1986 in the United Kingdom. It is the most likely cause of variant Creutzfeldt-Jakob disease (CJD in humans. The origin of BSE remains an enigma. Here we report an H-type BSE case associated with the novel mutation E211K within the prion protein gene (Prnp. Sequence analysis revealed that the animal with H-type BSE was heterozygous at Prnp nucleotides 631 through 633. An identical pathogenic mutation at the homologous codon position (E200K in the human Prnp has been described as the most common cause of genetic CJD. This finding represents the first report of a confirmed case of BSE with a potential pathogenic mutation within the bovine Prnp gene. A recent epidemiological study revealed that the K211 allele was not detected in 6062 cattle from commercial beef processing plants and 42 cattle breeds, indicating an extremely low prevalence of the E211K variant (less than 1 in 2000 in cattle.

  13. DNAJC6 Mutations Associated With Early-Onset Parkinson's Disease.

    Science.gov (United States)

    Olgiati, Simone; Quadri, Marialuisa; Fang, Mingyan; Rood, Janneke P M A; Saute, Jonas A; Chien, Hsin Fen; Bouwkamp, Christian G; Graafland, Josja; Minneboo, Michelle; Breedveld, Guido J; Zhang, Jianguo; Verheijen, Frans W; Boon, Agnita J W; Kievit, Anneke J A; Jardim, Laura Bannach; Mandemakers, Wim; Barbosa, Egberto Reis; Rieder, Carlos R M; Leenders, Klaus L; Wang, Jun; Bonifati, Vincenzo

    2016-02-01

    DNAJC6 mutations were recently described in two families with autosomal recessive juvenile parkinsonism (onset age < 11), prominent atypical signs, poor or absent response to levodopa, and rapid progression (wheelchair-bound within ∼10 years from onset). Here, for the first time, we report DNAJC6 mutations in early-onset Parkinson's disease (PD). The DNAJC6 open reading frame was analyzed in 274 patients with early-onset sporadic or familial PD. Selected variants were followed up by cosegregation, homozygosity mapping, linkage analysis, whole-exome sequencing, and protein studies. We identified two families with different novel homozygous DNAJC6 mutations segregating with PD. In each family, the DNAJC6 mutation was flanked by long runs of homozygosity within highest linkage peaks. Exome sequencing did not detect additional pathogenic variants within the linkage regions. In both families, patients showed severely decreased steady-state levels of the auxilin protein in fibroblasts. We also identified a sporadic patient carrying two rare noncoding DNAJC6 variants possibly effecting RNA splicing. All these cases fulfilled the criteria for a clinical diagnosis of early-onset PD, had symptoms onset in the third-to-fifth decade, and slow disease progression. Response to dopaminergic therapies was prominent, but, in some patients, limited by psychiatric side effects. The phenotype overlaps that of other monogenic forms of early-onset PD. Our findings delineate a novel form of hereditary early-onset PD. Screening of DNAJC6 is warranted in all patients with early-onset PD compatible with autosomal recessive inheritance. Our data provide further evidence for the involvement of synaptic vesicles endocytosis and trafficking in PD pathogenesis. © 2016 American Neurological Association.

  14. A novel distinctive cerebrovascular phenotype is associated with heterozygous Arg179 ACTA2 mutations

    NARCIS (Netherlands)

    Munot, Pinki; Saunders, Dawn E.; Milewicz, Dianna M.; Regalado, Ellen S.; Ostergaard, John R.; Braun, Kees P.; Kerr, Timothy; Lichtenbelt, Klaske D.; Philip, Sunny; Rittey, Christopher; Jacques, Thomas S.; Cox, Timothy C.; Ganesan, Vijeya

    2012-01-01

    Mutations in the ACTA2 gene lead to diffuse and diverse vascular diseases; the Arg179His mutation is associated with an early onset severe phenotype due to global smooth muscle dysfunction. Cerebrovascular disease associated with ACTA2 mutations has been likened to moyamoya disease, but appears to h

  15. Genetic Mutations Associated with Pesticide Resistance in Rhipicephalus microplus and Haematobia irritans

    Science.gov (United States)

    A number of gene mutation in various arthropods have been found to be associated with pesticide resistance. Some of these mutations have been found in the two cattle pests, Rhipicephalus microplus and Haematobia irritans. Sodium channel gene mutations have been associated with pyrethroid resistance ...

  16. A common mutation associated with the Duarte galactosemia allele

    Energy Technology Data Exchange (ETDEWEB)

    Elsas, L.J.; Dembure, P.P.; Langley, S.; Paulk, E.M.; Hjelm, L.N.; Fridovich-Keil, J. (Emory Univ. School of Medicine, Atlanta, GA (United States))

    1994-06-01

    The human cDNA and gene for galactose-1-phosphate uridyl transferase (GALT) have been cloned and sequenced. A prevalant mutation (Q188R) is known to cause classic galactosemia (G/G). G/G galactosemia has an incidence of 1/38,886 in 1,396,766 Georgia live-born infants, but a more common variant of galactosemia, Duarte, has an unknown incidence. The proposed Duarte biochemical phenotypes of GALT are as follows: D/N, D/D, and D/G, which have [approximately]75%, 50%, and 25% of normal GALT activity, respectively. In addition, the D allele has isoforms of its enzyme that have more acidic pI than normal. Here the authors systematically determine (a) the prevalence of an A-to-G transition at base pair 2744 of exon 10 in the GALT gene, a transition that produces a codon change converting asparagine to aspartic acid at position 314 (N314D), and (b) the association of this mutation with the Duarte biochemical phenotype. The 2744G nucleotide change adds an AvaII (SinI) cut site, which was identified in PCR-amplified DNA. In 111 biochemically unphenotyped controls with no history of galactosemia, 13 N314D alleles were identified (prevalence 5.9%). In a prospective study, 40 D alleles were biochemically phenotyped, and 40 N314D alleles were found. By contrast, in 36 individuals known not to have the Duarte biochemical phenotype, no N314D alleles were found. The authors conclude that the N314D mutation is a common allele that probably causes the Duarte GALT biochemical phenotype and occurs in a predominantly Caucasian, nongalactosemic population, with a prevalence of 5.9%. 36 refs., 3 figs., 2 tabs.

  17. Association of PRPS1 Mutations with Disease Phenotypes

    Directory of Open Access Journals (Sweden)

    Rahul Mittal

    2015-01-01

    Full Text Available Phosphoribosylpyrophosphate synthetase 1 (PRPS1 codes for PRS-I enzyme that catalyzes the first step of nucleotide synthesis. PRPS1 gene mutations have been implicated in a number of human diseases. Recently, new mutations in PRPS1 have been identified that have been associated with novel phenotypes like diabetes insipidus expanding the spectrum of PRPS1-related diseases. The purpose of this review is to evaluate current literature on PRPS1-related syndromes and summarize potential therapies. The overexpression of PRPS1 results in PRS-I superactivity resulting in purine overproduction. Patients with PRS-I superactivity demonstrate uric acid overproduction, hypotonia, ataxia, neurodevelopment abnormalities, and postlingual hearing impairment. On the other hand, decreased activity leads to X-linked nonsyndromic sensorineural deafness (DFNX-2, Charcot-Marie-Tooth disease-5 (CMTX5, and Arts syndrome depending on the residual activity of PRS-I. Mild PRS-I deficiency (DFNX-2 results in non-syndromic progressive hearing loss whereas moderate PRS-I deficiency (CMTX5 and severe PRS-I deficiency (Arts syndrome present with peripheral or optic neuropathy, prelingual progressive sensorineural hearing loss, and central nervous system impairment. Currently, purine replacement via S-adenosylmethionine (SAM supplementation in patients with Arts syndrome appears to improve their condition. This suggests that SAM supplementation can alleviate symptoms of PRPS1 deficient patients and open new avenues of therapeutic intervention.

  18. Fundus albipunctatus associated with compound heterozygous mutations in RPE65

    DEFF Research Database (Denmark)

    Schatz, Patrik; Preising, Markus; Lorenz, Birgit

    2011-01-01

    To describe a family with an 18-year-old woman with fundus albipunctatus and compound heterozygous mutations in RPE65 whose unaffected parents and 1 female sibling harbored single heterozygous RPE65 mutations.......To describe a family with an 18-year-old woman with fundus albipunctatus and compound heterozygous mutations in RPE65 whose unaffected parents and 1 female sibling harbored single heterozygous RPE65 mutations....

  19. SMAD2 Mutations Are Associated with Arterial Aneurysms and Dissections.

    Science.gov (United States)

    Micha, Dimitra; Guo, Dong-Chuan; Hilhorst-Hofstee, Yvonne; van Kooten, Fop; Atmaja, Dian; Overwater, Eline; Cayami, Ferdy K; Regalado, Ellen S; van Uffelen, René; Venselaar, Hanka; Faradz, Sultana M H; Vriend, Gerrit; Weiss, Marjan M; Sistermans, Erik A; Maugeri, Alessandra; Milewicz, Dianna M; Pals, Gerard; van Dijk, Fleur S

    2015-12-01

    We report three families with arterial aneurysms and dissections in which variants predicted to be pathogenic were identified in SMAD2. Moreover, one variant occurred de novo in a proband with unaffected parents. SMAD2 is a strong candidate gene for arterial aneurysms and dissections given its role in the TGF-β signaling pathway. Furthermore, although SMAD2 and SMAD3 probably have functionally distinct roles in cell signaling, they are structurally very similar. Our findings indicate that SMAD2 mutations are associated with arterial aneurysms and dissections and are in accordance with the observation that patients with pathogenic variants in genes encoding proteins involved in the TGF-β signaling pathway exhibit arterial aneurysms and dissections as key features.

  20. Mutation-Periodic Quivers, Integrable Maps and Associated Poisson Algebras

    CERN Document Server

    Fordy, Allan P

    2010-01-01

    We consider a class of map, recently derived in the context of cluster mutation. In this paper we start with a brief review of the quiver context, but then move onto a discussion of a related Poisson bracket, along with the Poisson algebra of a special family of functions associated with these maps. A bi-Hamiltonian structure is derived and used to construct a sequence of Poisson commuting functions and hence show complete integrability. Canonical coordinates are derived, with the map now being a canonical transformation with a sequence of commuting invariant functions. Compatibility of a pair of these functions gives rise to Liouville's equation and the map plays the role of a B\\"acklund transformation.

  1. Three new BLM gene mutations associated with Bloom syndrome.

    Science.gov (United States)

    Amor-Guéret, Mounira; Dubois-d'Enghien, Catherine; Laugé, Anthony; Onclercq-Delic, Rosine; Barakat, Abdelhamid; Chadli, Elbekkay; Bousfiha, Ahmed Aziz; Benjelloun, Meriem; Flori, Elisabeth; Doray, Bérénice; Laugel, Vincent; Lourenço, Maria Teresa; Gonçalves, Rui; Sousa, Silvia; Couturier, Jérôme; Stoppa-Lyonnet, Dominique

    2008-06-01

    Bloom's syndrome (BS) is a rare autosomal recessive disease predisposing patients to all types of cancers affecting the general population. BS cells display a high level of genetic instability, including a 10-fold increase in the rate of sister chromatid exchanges, currently the only objective criterion for BS diagnosis. We have developed a method for screening the BLM gene for mutations based on direct genomic DNA sequencing. A questionnaire based on clinical information, cytogenetic features, and family history was addressed to physicians prescribing BS genetic screening, with the aim of confirming or guiding diagnosis. We report here four BLM gene mutations, three of which have not been described before. Three of the mutations are frameshift mutations, and the fourth is a nonsense mutation. All these mutations introduce a stop codon, and may therefore be considered to have deleterious biological effect. This approach should make it possible to identify new mutations and to correlate them with clinical information.

  2. Alzheimer's Disease Phenotypes and Genotypes Associated with Mutations in Presenilin 2

    Science.gov (United States)

    Jayadev, Suman; Leverenz, James B.; Steinbart, Ellen; Stahl, Justin; Klunk, William; Yu, Cheng-En; Bird, Thomas D.

    2010-01-01

    Mutations in presenilin 2 are rare causes of early onset familial Alzheimer's disease. Eighteen presenilin 2 mutations have been reported, although not all have been confirmed pathogenic. Much remains to be learned about the range of phenotypes associated with these mutations. We have analysed our unique collection of 146 affected cases in 11…

  3. Alzheimer's Disease Phenotypes and Genotypes Associated with Mutations in Presenilin 2

    Science.gov (United States)

    Jayadev, Suman; Leverenz, James B.; Steinbart, Ellen; Stahl, Justin; Klunk, William; Yu, Cheng-En; Bird, Thomas D.

    2010-01-01

    Mutations in presenilin 2 are rare causes of early onset familial Alzheimer's disease. Eighteen presenilin 2 mutations have been reported, although not all have been confirmed pathogenic. Much remains to be learned about the range of phenotypes associated with these mutations. We have analysed our unique collection of 146 affected cases in 11…

  4. HFE H63D, C282Y and AGTR1 A1166C polymorphisms and brain white matter lesions in the aging brain.

    Science.gov (United States)

    Gebril, Ola H; Kirby, Janine; Savva, George; Brayne, Carol; Ince, Paul G

    2011-03-01

    Incidental white matter lesions (WML) are a common neuroradiological finding in elderly people and have been linked to dementia and depression. Various mechanisms including hypoxia and increased production of reactive oxygen species (ROS) are implicated in the etiology of WML. The hemochromatosis (HFE) gene p.H63D and p.C282Y polymorphisms have been linked to dysregulation of iron metabolism and increased levels of ROS, whereas Angiotensin II receptor 1 (AGTR1) c.1166A → C polymorphism is known as a vascular risk factor. These genetic polymorphisms were characterized in brains donated to the UK MRC Cognitive Function and Ageing Study (CFAS) to assess their potential role in the risk for development of age-related WML. The study cohort comprised 258 brain donated to CFAS. WML severity was assessed in the postmortem brain donations using magnetic resonance imaging (MRI) scans and scored using the Scheltens' scale. Polymerase chain reaction (PCR) amplification of extracted DNA followed by restriction enzyme digestion was used to genotype the samples. Genotypes were validated using direct sequencing in a smaller sample. The results show that HFE p.H63D polymorphism is not associated with WML severity in the whole cohort. However, there is a significant association of the D allele with severity of WML in noncarriers of the APOE ε4 allele. No association is demonstrated between the HFE p.C282Y nor the AGTR1 c.1166A → C polymorphisms and WML severity. The HFE gene appears to be a genetic risk factor for severe aging WML independently of the APOE ε4 genotype. This would support the role of iron-related oxidative stress, in addition to previously studied factors, e.g., hypoxia as potential risk factors for developing prominent aging WML.

  5. 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.

  6. Mutations in inhibin and activin genes associated with human disease.

    Science.gov (United States)

    Shelling, Andrew N

    2012-08-15

    Inhibins and activins are members of the transforming growth factor (TGFβ) superfamily, that includes the TGFβs, inhibins and activins, bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs). The family members are expressed throughout the human body, and are involved in the regulation of a range of important functions. The precise regulation of the TGFβ pathways is critical, and mutations of individual molecules or even minor alterations of signalling will have a significant affect on function, that may lead to development of disease or predisposition to the development of disease. The inhibins and activins regulate aspects of the male and female reproductive system, therefore, it is not surprising that most of the diseases associated with abnormalities of the inhibin and activin genes are focused on reproductive disorders and reproductive cancers. In this review, I highlight the role of genetic variants in the development of conditions such as premature ovarian failure, pre-eclampsia, and various reproductive cancers. Given the recent advances in human genetic research, such as genome wide association studies and next generation sequencing, it is likely that inhibins and activins will be shown to play more important roles in a range of human genetic diseases in the future.

  7. Mutation Update: The Spectra of Nebulin Variants and Associated Myopathies

    Science.gov (United States)

    Lehtokari, Vilma-Lotta; Kiiski, Kirsi; Sandaradura, Sarah A.; Laporte, Jocelyn; Repo, Pauliina; Frey, Jennifer A.; Donner, Kati; Marttila, Minttu; Saunders, Carol; Barth, Peter G.; den Dunnen, Johan T.; Beggs, Alan H.; Clarke, Nigel F.; North, Kathryn N.; Laing, Nigel G.; Romero, Norma B.; Winder, Thomas L.; Pelin, Katarina; Wallgren-Pettersson, Carina

    2015-01-01

    A mutation update on the nebulin gene (NEB) is necessary because of recent developments in analysis methodology, the identification of increasing numbers and novel types of variants, and a widening in the spectrum of clinical and histological phenotypes associated with this gigantic, 183 exons containing gene. Recessive pathogenic variants in NEB are the major cause of nemaline myopathy (NM), one of the most common congenital myopathies. Moreover, pathogenic NEB variants have been identified in core-rod myopathy and in distal myopathies. In this update, we present the disease-causing variants in NEB in 159 families, 143 families with NM, and 16 families with NM-related myopathies. Eighty-eight families are presented here for the first time. We summarize 86 previously published and 126 unpublished variants identified in NEB. Furthermore, we have analyzed the NEB variants deposited in the Exome Variant Server (http://evs.gs.washington.edu/EVS/), identifying that pathogenic variants are a minor fraction of all coding variants (~7%). This indicates that nebulin tolerates substantial changes in its amino acid sequence, providing an explanation as to why variants in such a large gene result in relatively rare disorders. Lastly, we discuss the difficulties of drawing reliable genotype–phenotype correlations in NEB-associated disease. PMID:25205138

  8. 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.

  9. 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.

  10. 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.

  11. Human Factors Engineering (HFE) insights for advanced reactors based upon operating experience

    Energy Technology Data Exchange (ETDEWEB)

    Higgins, J.; Nasta, K.

    1997-01-01

    The NRC Human Factors Engineering Program Review Model (HFE PRM, NUREG-0711) was developed to support a design process review for advanced reactor design certification under 10CFR52. The HFE PRM defines ten fundamental elements of a human factors engineering program. An Operating Experience Review (OER) is one of these elements. The main purpose of an OER is to identify potential safety issues from operating plant experience and ensure that they are addressed in a new design. Broad-based experience reviews have typically been performed in the past by reactor designers. For the HFE PRM the intent is to have a more focussed OER that concentrates on HFE issues or experience that would be relevant to the human-system interface (HSI) design process for new advanced reactors. This document provides a detailed list of HFE-relevant operating experience pertinent to the HSI design process for advanced nuclear power plants. This document is intended to be used by NRC reviewers as part of the HFE PRM review process in determining the completeness of an OER performed by an applicant for advanced reactor design certification. 49 refs.

  12. Clinical characteristics and prognosis of acute myeloid leukemia associated with DNA-methylation regulatory gene mutations.

    Science.gov (United States)

    Ryotokuji, Takeshi; Yamaguchi, Hiroki; Ueki, Toshimitsu; Usuki, Kensuke; Kurosawa, Saiko; Kobayashi, Yutaka; Kawata, Eri; Tajika, Kenji; Gomi, Seiji; Kanda, Junya; Kobayashi, Anna; Omori, Ikuko; Marumo, Atsushi; Fujiwara, Yusuke; Yui, Shunsuke; Terada, Kazuki; Fukunaga, Keiko; Hirakawa, Tsuneaki; Arai, Kunihito; Kitano, Tomoaki; Kosaka, Fumiko; Tamai, Hayato; Nakayama, Kazutaka; Wakita, Satoshi; Fukuda, Takahiro; Inokuchi, Koiti

    2016-09-01

    In recent years, it has been reported that the frequency of DNA-methylation regulatory gene mutations - mutations of the genes that regulate gene expression through DNA methylation - is high in acute myeloid leukemia. The objective of the present study was to elucidate the clinical characteristics and prognosis of acute myeloid leukemia with associated DNA-methylation regulatory gene mutation. We studied 308 patients with acute myeloid leukemia. DNA-methylation regulatory gene mutations were observed in 135 of the 308 cases (43.8%). Acute myeloid leukemia associated with a DNA-methylation regulatory gene mutation was more frequent in older patients (Pgene mutation was an unfavorable prognostic factor for overall survival in the whole cohort (P=0.0018), in patients aged ≤70 years, in patients with intermediate cytogenetic risk, and in FLT3-ITD-negative patients (P=0.0409). Among the patients with DNA-methylation regulatory gene mutations, 26.7% were found to have two or more such mutations and prognosis worsened with increasing number of mutations. In multivariate analysis DNA-methylation regulatory gene mutation was an independent unfavorable prognostic factor for overall survival (P=0.0424). However, patients with a DNA-methylation regulatory gene mutation who underwent allogeneic stem cell transplantation in first remission had a significantly better prognosis than those who did not undergo such transplantation (P=0.0254). Our study establishes that DNA-methylation regulatory gene mutation is an important unfavorable prognostic factor in acute myeloid leukemia.

  13. High rate of BRAF and RET/PTC dual mutations associated with recurrent papillary thyroid carcinoma.

    Science.gov (United States)

    Henderson, Ying C; Shellenberger, Thomas D; Williams, Michelle D; El-Naggar, Adel K; Fredrick, Mitchell J; Cieply, Kathleen M; Clayman, Gary L

    2009-01-15

    Papillary thyroid carcinoma (PTC), the most common thyroid malignancy, usually possesses BRAF mutation or rearranged in translation (RET)/PTC rearrangements. PTC usually possesses BRAF mutation or RET/PTC rearrangements. The mutation status of patients with recurrent PTC has never been characterized in a large population. Mutation status was determined in a cohort of 54 patients with recurrent PTC and analyzed for clinicopathologic relationships. BRAF and ras mutations were determined by PCR and sequencing of genomic DNA. RET/PTC rearrangements were analyzed by reverse transcription-PCR. BRAF mutation in exon 15 (V600E) was found in 42/54 (77.8%) recurrent PTC patients. The RET/PTC rearrangements were detected in 9 of 54 (16.7%) patients. In addition, 5 of 54 (9.3%) recurrent PTC patients had both a BRAF mutation and a RET/PTC rearrangement. The prevalence of tumors with dual mutations found in the recurrent population far exceeds the frequency historically reported for patients with primary PTC. Patients with dual mutations were significantly older (80% older than 45 years) than patients with a BRAF mutation alone (38% older than 45 years). Recurrent PTC is significantly associated with a predominant BRAF mutation. RET/PTC rearrangements, although commonly associated with primary PTCs in younger patients, are uncommonly found in recurrent PTC patients. In addition, the incidence of dual mutations was higher in patients with recurrent PTC than in those primary PTC, as reported by others.

  14. Telomerase reverse transcriptase promoter mutations in hepatitis B virus-associated hepatocellular carcinoma

    Science.gov (United States)

    Yang, Xunjun; Guo, Xiuchan; Chen, Yao; Chen, Guorong; Ma, Yin; Huang, Kate; Zhang, Yuning; Zhao, Qiongya; Winkler, Cheryl A.; An, Ping; Lyu, Jianxin

    2016-01-01

    Telomerase reverse transcriptase (TERT) promoter mutations are among the most frequent noncoding somatic mutations in multiple cancers, including hepatocellular carcinoma (HCC). The clinical and pathological implications of TERT promoter mutations in hepatitis B virus (HBV)-associated HCC have not been resolved. To investigate TERT promoter mutations, protein expression, and their clinical-pathological implications, we sequenced the TERT promoter region for hotspot mutations in HCC tissues and performed immunostaining for TERT protein expression from HBV-associated HCC in Chinese patients. Of 276 HCC tumor DNA samples sequenced, 85 (31%) carried TERT promoter mutations. TERT promoter mutations were more frequent in those with low α-fetoprotein (AFP) serum levels (p = 0.03), advanced age (p = 0.04), and in those lacking HCC family history (p = 0.02), but were not correlated with HCC stages and grades. TERT protein levels were higher in HCC (n = 28) compared to normal liver tissues (n = 8) (p =0.001), but did not differ between mutated and non-mutated tumor tissues. In conclusion, TERT promoter mutations are common somatic mutations in HCC of Han Chinese with HBV infection. Detection of TERT promoter mutations in those with low levels of AFP may aid diagnosis of HCC with atypical presentation. PMID:27056898

  15. Mutations in TBL1X are associated with central hypothyroidism

    NARCIS (Netherlands)

    Heinen, C.A. (Charlotte A.); M. Losekoot (Monique); Sun, Y. (Yu); Watson, P.J. (Peter J.); Fairall, L. (Louise); S.D. Joustra (Sjoerd); N. Zwaveling-Soonawala (Nitash); W. Oostdijk (Wilma); E.L.T. van den Akker (Erica); M. Alders (Mariëlle); G.W.E. Santen (Gijs); R.R. van Rijn (Rick); W.A. Dreschler (Wouter); Surovtseva, O.V. (Olga V.); N.R. Biermasz; R.C.M. Hennekam (Raoul); J.M. Wit (Jan); Schwabe, J.W.R. (John W.R.); A. Boelen (Anita); E. Fliers (Eric); A.S.P. van Trotsenburg (Paul)

    2016-01-01

    textabstractContext: Isolated congenital central hypothyroidism (CeH) can result from mutations in TRHR, TSHB, and IGSF1, but its etiology often remains unexplained. We identified a missense mutation in the transducin X-like protein 1, X-linked (TBL1X) gene in three relatives diagnosed with isolated

  16. Household income is associated with the p53 mutation frequency in human breast tumors.

    Directory of Open Access Journals (Sweden)

    Adrienne M Starks

    Full Text Available BACKGROUND: A study from Scotland reported that the p53 mutation frequency in breast tumors is associated with socio-economic deprivation. METHODS: We analyzed the association of the tumor p53 mutational status with tumor characteristics, education, and self-reported annual household income (HI among 173 breast cancer patients from the greater Baltimore area, United States. RESULTS: p53 mutational frequency was significantly associated with HI. Patients with < $15,000 HI had the highest p53 mutation frequency (21%, followed by the income group between $15,000 and $60,000 (18%, while those above $60,000 HI had the fewest mutations (5%. When dichotomized at $60,000, 26 out of 135 patients in the low income category had acquired a p53 mutation, while only 2 out of 38 with a high income carried a mutation (P < 0.05. In the adjusted logistic regression analysis with 3 income categories (trend test, the association between HI and p53 mutational status was independent of tumor characteristics, age, race/ethnicity, tobacco smoking and body mass. Further analyses revealed that HI may impact the p53 mutational frequency preferentially in patients who develop an estrogen receptor (ER-negative disease. Within this group, 42% of the low income patients (< $15,000 HI carried a mutation, followed by the middle income group (21%, while those above $60,000 HI did not carry mutations (Ptrend < 0.05. CONCLUSIONS: HI is associated with the p53 mutational frequency in patients who develop an ER-negative disease. Furthermore, high income patients may acquire fewer p53 mutations than other patients, suggesting that lifetime exposures associated with socio-economic status may impact breast cancer biology.

  17. Prevalence of Mitochondrial 12S rRNA Mutations Associated with Aminoglycoside Ototoxicity

    Science.gov (United States)

    Guan, Min-Xin

    2005-01-01

    The mitochondrial DNA (mtDNA) 12S rRNA is a hot spot for mutations associated with both aminoglycoside-induced and nonsyndromic hearing loss. Of those, the homoplasmic A1555G and C1494T mutations at a highly conserved decoding region of the 12S rRNA have been associated with hearing loss. These two mutations account for a significant number of…

  18. 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.

  19. 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.

  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.

    Directory of Open Access Journals (Sweden)

    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. Glucocerebrosidase gene mutations associated with Parkinson's disease: a meta-analysis in a Chinese population.

    Directory of Open Access Journals (Sweden)

    Jia Chen

    Full Text Available Mutations of glucocerebrosidase (GBA confer susceptibility to Parkinson's disease in several ethnical populations, with a high incidence especially in the Ashkenazi Jewish population. Although there are several studies that have investigated a similar association in a Chinese population, small sample sizes and few positive outcomes have made it difficult to obtain conclusive results from these individual studies. Therefore, the present study used a meta-analysis approach, pooling the appropriate data from published studies to investigate the association of GBA mutations and Parkinson's disease in a Chinese population. Nine studies containing 6536 Chinese subjects (3438 cases and 3098 healthy controls and examining the GBA mutations of L444P, N370S and several other mutations were included. Review Manager 5.2 software was applied to analyze the pooled odds ratios (ORs and 95% confidence intervals (CIs. The results showed a significant association of Parkinson's disease risk with overall GBA mutations (OR = 6.34, 95% CI = 3.77-10.68, p<0.00001, and with the subgroup of L444P mutation (OR = 11.68, 95% CI = 5.23-26.06, p<0.00001. No such association was observed for the subgroup with N370S mutation or other mutations, in part because of the small sample size or rare events. Thus, for the rare occurrence of GBA mutations, studies with larger sample size are necessary to minimize the sampling error and to obtain convincing results.

  2. Glucocerebrosidase gene mutations associated with Parkinson's disease: a meta-analysis in a Chinese population.

    Science.gov (United States)

    Chen, Jia; Li, Wei; Zhang, Tao; Wang, Yan-jiang; Jiang, Xiao-jiang; Xu, Zhi-qiang

    2014-01-01

    Mutations of glucocerebrosidase (GBA) confer susceptibility to Parkinson's disease in several ethnical populations, with a high incidence especially in the Ashkenazi Jewish population. Although there are several studies that have investigated a similar association in a Chinese population, small sample sizes and few positive outcomes have made it difficult to obtain conclusive results from these individual studies. Therefore, the present study used a meta-analysis approach, pooling the appropriate data from published studies to investigate the association of GBA mutations and Parkinson's disease in a Chinese population. Nine studies containing 6536 Chinese subjects (3438 cases and 3098 healthy controls) and examining the GBA mutations of L444P, N370S and several other mutations were included. Review Manager 5.2 software was applied to analyze the pooled odds ratios (ORs) and 95% confidence intervals (CIs). The results showed a significant association of Parkinson's disease risk with overall GBA mutations (OR = 6.34, 95% CI = 3.77-10.68, p<0.00001), and with the subgroup of L444P mutation (OR = 11.68, 95% CI = 5.23-26.06, p<0.00001). No such association was observed for the subgroup with N370S mutation or other mutations, in part because of the small sample size or rare events. Thus, for the rare occurrence of GBA mutations, studies with larger sample size are necessary to minimize the sampling error and to obtain convincing results.

  3. Leber's hereditary optic neuropathy mutations associated with infantile-onset myoclonic epilepsy.

    Science.gov (United States)

    Frye, Richard E

    2011-06-01

    Epilepsy syndromes with onset in the first year of life, especially when they include myoclonic features, have special significance since they are associated with long-term developmental and neurological abnormalities. Dravet's severe myoclonic epilepsy in infancy is especially interesting as it is associated with fever-provoked seizures and mutations in the alpha subunit of the sodium channel (SCN1A) in about one-third of the cases. Here, we report 2 children who had clinical features of severe myoclonic epilepsy of infancy without mutations in the SCN1A gene who were found to have mitochondrial DNA mutations associated with Leber's hereditary optic neuropathy. These 2 children demonstrated markers of mitochondrial dysfunction, drug-resistant epilepsy, and dysfunction of nonneurological systems. These cases demonstrate that mitochondrial DNA mutations, especially those associated with Leber's hereditary optic neuropathy, should be considered in cases of myclonic epilepsy starting in infancy, especially when mutations in the SCN1A gene are not found.

  4. 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.

  5. High frequency of additional gene mutations in acute myeloid leukemia with MLL partial tandem duplication: DNMT3A mutation is associated with poor prognosis.

    Science.gov (United States)

    Kao, Hsiao-Wen; Liang, D Cherng; Kuo, Ming-Chung; Wu, Jin-Hou; Dunn, Po; Wang, Po-Nan; Lin, Tung-Liang; Shih, Yu-Shu; Liang, Sung-Tzu; Lin, Tung-Huei; Lai, Chen-Yu; Lin, Chun-Hui; Shih, Lee-Yung

    2015-10-20

    The mutational profiles of acute myeloid leukemia (AML) with partial tandem duplication of mixed-lineage leukemia gene (MLL-PTD) have not been comprehensively studied. We studied 19 gene mutations for 98 patients with MLL-PTD AML to determine the mutation frequency and clinical correlations. MLL-PTD was screened by reverse-transcriptase PCR and confirmed by real-time quantitative PCR. The mutational analyses were performed with PCR-based assays followed by direct sequencing. Gene mutations of signaling pathways occurred in 63.3% of patients, with FLT3-ITD (44.9%) and FLT3-TKD (13.3%) being the most frequent. 66% of patients had gene mutations involving epigenetic regulation, and DNMT3A (32.7%), IDH2 (18.4%), TET2 (18.4%), and IDH1 (10.2%) mutations were most common. Genes of transcription pathways and tumor suppressors accounted for 23.5% and 10.2% of patients. RUNX1 mutation occurred in 23.5% of patients, while none had NPM1 or double CEBPA mutation. 90.8% of MLL-PTD AML patients had at least one additional gene mutation. Of 55 MLL-PTD AML patients who received standard chemotherapy, age older than 50 years and DNMT3A mutation were associated with inferior outcome. In conclusion, gene mutations involving DNA methylation and activated signaling pathway were common co-existed gene mutations. DNMT3A mutation was a poor prognostic factor in MLL-PTD AML.

  6. Isocitrate dehydrogenase 1 Gene Mutation Is Associated with Prognosis in Clinical Low-Grade Gliomas.

    Directory of Open Access Journals (Sweden)

    Ming-Yang Li

    Full Text Available Isocitrate dehydrogenase 1 gene mutations are found in most World Health Organization grade II and III gliomas and secondary glioblastomas. Isocitrate dehydrogenase 1 mutations are known to have prognostic value in high-grade gliomas. However, their prognostic significance in low-grade gliomas remains controversial. We determined the predictive and prognostic value of isocitrate dehydrogenase 1 status in low-grade gliomas. The association of isocitrate dehydrogenase 1 status with clinicopathological and genetic factors was also evaluated. Clinical information and genetic data including isocitrate dehydrogenase 1 mutation, O 6-methylguanine DNA methyltransferase promoter methylation, 1p/19q chromosome loss, and TP53 mutation of 417 low-grade gliomas were collected from the Chinese Glioma Genome Atlas database. Kaplan-Meier and Cox proportional hazards regression analyses were performed to evaluate the prognostic effect of clinical characteristics and molecular biomarkers. Isocitrate dehydrogenase 1 mutation was identified as an independent prognostic factor for overall, but not progression-free, survival. Notably, isocitrate dehydrogenase 1 mutation was found to be a significant prognostic factor in patients with oligodendrogliomas, but not in patients with astrocytomas. Furthermore, O 6-methylguanine DNA methyltransferase promoter methylation (p = 0.017 and TP53 mutation (p < 0.001, but not 1p/19q loss (p = 0.834, occurred at a higher frequency in isocitrate dehydrogenase 1-mutated tumors than in isocitrate dehydrogenase 1 wild-type tumors. Younger patient age (p = 0.041 and frontal lobe location (p = 0.010 were significantly correlated with isocitrate dehydrogenase 1 mutation. Chemotherapy did not provide a survival benefit in patients with isocitrate dehydrogenase 1-mutated tumors. Isocitrate dehydrogenase 1 mutation was an independent prognostic factor in low-grade gliomas, whereas it showed no predictive value for chemotherapy response

  7. Isocitrate dehydrogenase 1 Gene Mutation Is Associated with Prognosis in Clinical Low-Grade Gliomas.

    Science.gov (United States)

    Li, Ming-Yang; Wang, Yin-Yan; Cai, Jin-Quan; Zhang, Chuan-Bao; Wang, Kuan-Yu; Cheng, Wen; Liu, Yan-Wei; Zhang, Wei; Jiang, Tao

    2015-01-01

    Isocitrate dehydrogenase 1 gene mutations are found in most World Health Organization grade II and III gliomas and secondary glioblastomas. Isocitrate dehydrogenase 1 mutations are known to have prognostic value in high-grade gliomas. However, their prognostic significance in low-grade gliomas remains controversial. We determined the predictive and prognostic value of isocitrate dehydrogenase 1 status in low-grade gliomas. The association of isocitrate dehydrogenase 1 status with clinicopathological and genetic factors was also evaluated. Clinical information and genetic data including isocitrate dehydrogenase 1 mutation, O 6-methylguanine DNA methyltransferase promoter methylation, 1p/19q chromosome loss, and TP53 mutation of 417 low-grade gliomas were collected from the Chinese Glioma Genome Atlas database. Kaplan-Meier and Cox proportional hazards regression analyses were performed to evaluate the prognostic effect of clinical characteristics and molecular biomarkers. Isocitrate dehydrogenase 1 mutation was identified as an independent prognostic factor for overall, but not progression-free, survival. Notably, isocitrate dehydrogenase 1 mutation was found to be a significant prognostic factor in patients with oligodendrogliomas, but not in patients with astrocytomas. Furthermore, O 6-methylguanine DNA methyltransferase promoter methylation (p = 0.017) and TP53 mutation (p isocitrate dehydrogenase 1-mutated tumors than in isocitrate dehydrogenase 1 wild-type tumors. Younger patient age (p = 0.041) and frontal lobe location (p = 0.010) were significantly correlated with isocitrate dehydrogenase 1 mutation. Chemotherapy did not provide a survival benefit in patients with isocitrate dehydrogenase 1-mutated tumors. Isocitrate dehydrogenase 1 mutation was an independent prognostic factor in low-grade gliomas, whereas it showed no predictive value for chemotherapy response. Isocitrate dehydrogenase 1 mutation was highly associated with O 6-methylguanine DNA

  8. Adiposity is associated with p53 gene mutations in breast cancer.

    Science.gov (United States)

    Ochs-Balcom, Heather M; Marian, Catalin; Nie, Jing; Brasky, Theodore M; Goerlitz, David S; Trevisan, Maurizio; Edge, Stephen B; Winston, Janet; Berry, Deborah L; Kallakury, Bhaskar V; Freudenheim, Jo L; Shields, Peter G

    2015-10-01

    Mutations in the p53 gene are among the most frequent genetic events in human cancer and may be triggered by environmental and occupational exposures. We examined the association of clinical and pathological characteristics of breast tumors and breast cancer risk factors according to the prevalence and type of p53 mutations. Using tumor blocks from incident cases from a case-control study in western New York, we screened for p53 mutations in exons 2-11 using the Affymetrix p53 Gene Chip array and analyzed case-case comparisons using logistic regression. The p53 mutation frequency among cases was 28.1 %; 95 % were point mutations (13 % of which were silent) and the remainder were single base pair deletions. Sixty seven percent of all point mutations were transitions; 24 % of them are G:C>A:T at CpG sites. Positive p53 mutation status was associated with poorer differentiation (OR, 95 % CI 2.29, 1.21-4.32), higher nuclear grade (OR, 95 % CI 1.99, 1.22-3.25), and increased Ki-67 status (OR, 95 % CI 1.81, 1.10-2.98). Cases with P53 mutations were more likely to have a combined ER-positive and PR-negative status (OR, 95 % CI 1.65, 1.01-2.71), and a combined ER-negative and PR-negative status (OR, 95 % CI 2.18, 1.47-3.23). Body mass index >30 kg/m(2), waist circumference >79 cm, and waist-to-hip ratio >0.86 were also associated with p53 status; obese breast cancer cases are more likely to have p53 mutations (OR, 95 % CI 1.78, 1.19-2.68). We confirmed that p53 mutations are associated with less favorable tumor characteristics and identified an association of p53 mutation status and adiposity.

  9. Mitochondrial DNA Mutation Associated with Leber's Hereditary Optic Neuropathy

    Science.gov (United States)

    Wallace, Douglas C.; Singh, Gurparkash; Lott, Marie T.; Hodge, Judy A.; Schurr, Theodore G.; Lezza, Angela M. S.; Elsas, Louis J.; Nikoskelainen, Eeva K.

    1988-12-01

    Leber's hereditary optic neuropathy is a maternally inherited disease resulting in optic nerve degeneration and cardiac dysrhythmia. A mitochondrial DNA replacement mutation was identified that correlated with this disease in multiple families. This mutation converted a highly conserved arginine to a histidine at codon 340 in the NADH dehydrogenase subunit 4 gene and eliminated an Sfa NI site, thus providing a simple diagnostic test. This finding demonstrated that a nucleotide change in a mitochondrial DNA energy production gene can result in a neurological disease.

  10. Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy

    NARCIS (Netherlands)

    Ostergaard, P.; Simpson, M.A.; Mendola, A.; Vasudevan, P.; Connell, F.C.; Impel, A. van; Moore, A.T.; Loeys, B.L.; Ghalamkarpour, A.; Onoufriadis, A.; Martinez-Corral, I.; Devery, S.; Leroy, J.G.; Laer, L. van; Singer, A.; Bialer, M.G.; McEntagart, M.; Quarrell, O.; Brice, G.; Trembath, R.C.; Schulte-Merker, S.; Makinen, T.; Vikkula, M.; Mortimer, P.S.; Mansour, S.; Jeffery, S.

    2012-01-01

    We have identified KIF11 mutations in individuals with syndromic autosomal-dominant microcephaly associated with lymphedema and/or chorioretinopathy. Initial whole-exome sequencing revealed heterozygous KIF11 mutations in three individuals with a combination of microcephaly and lymphedema from a mic

  11. Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy

    NARCIS (Netherlands)

    Ostergaard, P.; Simpson, M.A.; Mendola, A.; Vasudevan, P.; Connell, F.C.; van Impel, A.; Moore, A.T.; Loeys, B.L.; Ghalamkarpour, A.; Onoufriadis, A.; Martinez-Corral, I.; Devery, S.; Leroy, J.G.; van Laer, L.; Singer, A.; Bialer, M.G.; McEntagart, M.; Quarrell, O.; Brice, G.; Trembath, R.C.; Schulte-Merker, S.; Makinen, T.; Vikkula, M.; Mortimer, P.S.; Mansour, S.; Jeffery, S.

    2012-01-01

    We have identified KIF11 mutations in individuals with syndromic autosomal-dominant microcephaly associated with lymphedema and/or chorioretinopathy. Initial whole-exome sequencing revealed heterozygous KIF11 mutations in three individuals with a combination of microcephaly and lymphedema from a

  12. Gain of function in IKs secondary to a mutation in KCNE5 associated with atrial fibrillation

    DEFF Research Database (Denmark)

    Ravn, Lasse S; Aizawa, Yoshiyasu; Pollevick, Guido D;

    2008-01-01

    to mutations in KCNQ1. Coexpression of KCNE5, the gene encoding the MiRP4 beta-subunit, has been shown to reduce IKs. OBJECTIVE: The purpose of this study was to test the hypothesis that mutations in KCNE5 are associated with AF in a large cohort of patients with AF. METHODS: One-hundred fifty-eight patients...

  13. Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers

    NARCIS (Netherlands)

    Bhonsale, Aditya; Groeneweg, Judith A.; James, Cynthia A.; Dooijes, Dennis; Tichnell, Crystal; Jongbloed, Jan D. H.; Murray, Brittney; Riele, Anneline S. J. M. te; van den Berg, Maarten P.; Bikker, Hennie; Atsma, Douwe E.; de Groot, Natasja M.; Houweling, Arjan C.; van der Heijden, Jeroen F.; Russell, Stuart D.; Doevendans, Pieter A.; van Veen, Toon A.; Tandri, Harikrishna; Wilde, Arthur A.; Judge, Daniel P.; van Tintelen, J. Peter; Calkins, Hugh; Hauer, Richard N.

    2015-01-01

    AIMS: We sought to determine the influence of genotype on clinical course and arrhythmic outcome among arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)-associated mutation carriers. METHODS AND RESULTS: Pathogenic mutations in desmosomal and non-desmosomal genes were identified in

  14. Mutations in XPR1 cause primary familial brain calcification associated with altered phosphate export

    NARCIS (Netherlands)

    A. Legati (Andrea); D. Giovannini (Donatella); G. Nicolas (Gaël); U. López-Sánchez (Uriel); B. Quintáns (Beatriz); J.R. Oliveira (Joao); R.L. Sears (Renee L); E.M. Ramos (Eliana Marisa); E. Spiteri (Elizabeth); M.J. Sobrido (Maria); A. Carracedo (Angel); C. Castro-Fernández (Cristina); S. Cubizolle (Stéphanie); B.L. Fogel (Brent L); C. Goizet (Cyril); J.C. Jen (Joanna C); S. Kirdlarp (Suppachok); A.E. Lang (Anthony E); Z. Miedzybrodzka (Zosia); W. Mitarnun (Witoon); M. Paucar (Martin); H.L. Paulson (Henry); J. Pariente (Jérémie); A.-C. Richard (Anne-Claire); N.S. Salins (Naomi S); S.A. Simpson (Sheila A); P. Striano (Pasquale); P. Svenningsson (Per); F. Tison (François); V.K. Unni (Vivek K); O. Vanakker (Olivier); M.W. Wessels (Marja); S. Wetchaphanphesat (Suppachok); M. Yang (Michele); F. Boller (Francois); D. Campion (Dominique); D. Hannequin (Didier); M. Sitbon (Marc); H. Geschwind; J.-L. Battini (Jean-Luc); D. Coppola (Domenico)

    2015-01-01

    textabstractPrimary familial brain calcification (PFBC) is a neurological disease characterized by calcium phosphate deposits in the basal ganglia and other brain regions and has thus far been associated with SLC20A2, PDGFB or PDGFRB mutations. We identified in multiple families with PFBC mutations

  15. Isolated renal vein thrombosis associated with MTHFR-1298 and PAI-1 4G gene mutations.

    Science.gov (United States)

    Cinemre, Hakan; Bilir, Cemil; Akdemir, Nermin

    2010-12-01

    Isolated renal vein thrombosis is very rare without the presence of nephrotic syndrome. It is more common in the newborns and infants. Whereas major risk factors in adults are the procoagulant states such as protein C or S deficiency, factor V Leiden mutation, primary or secondary antiphospholipid syndrome, severe hypothyroidism, and trauma. Here, we report a case of isolated renal vein thrombosis associated with MTHFR-1298 and PAI-1 4G gene mutations. It should be noted that the presence of MTHFR-1298 and PAI-1 4G gene mutations together might be one of the examples of genetic mutation combinations that increase the likelihood of a thrombotic event.

  16. Immunodeficiency associated with FCN3 mutation and ficolin-3 deficiency

    DEFF Research Database (Denmark)

    Munthe-Fog, Lea; Hummelshøj, Tina; Honoré, Christian

    2009-01-01

    Ficolin-3, encoded by the FCN3 gene and expressed in the lung and liver, is a recognition molecule in the lectin pathway of the complement system. Heterozygosity for an FCN3 frameshift mutation (rs28357092), leading to a distortion of the C-terminal end of the molecule, occurs in people without d...

  17. DNAJC6 Mutations Associated with Early-Onset Parkinson's Disease

    NARCIS (Netherlands)

    S. Olgiati (Simone); M. Quadri (Marialuisa); M. Fang (Mingyan); J.P.M.A. Rood (Janneke P.M.A.); J.A. Saute (Jonas A.); H.F. Chien (Hsin Fen); C.G. Bouwkamp (Christian); J. Graafland (Josja); M. Minneboo (Michelle); G.J. Breedveld (Guido J.); J. Zhang (Jianguo); F.W. Verheijen (Frans W.); A.J.W. Boon (Agnita J.W.); A.J.A. Kievit (Anneke J.A.); L.B. Jardim (L.); W.J. Mandemakers (Wim); E.R. Barbosa (Egberto Reis); C.R.M. Rieder (Carlos); K.L. Leenders (Klaus L.); J. Wang (Jinxia); V. Bonifati (Vincenzo)

    2016-01-01

    markdownabstract_Objective_ DNAJC6 mutations were recently described in two families with autosomal recessive juvenile parkinsonism (onset age < 11), prominent atypical signs, poor or absent response to levodopa, and rapid progression (wheelchair-bound within ∼10 years from onset). Here, for the

  18. DNAJC6 Mutations Associated With Early-Onset Parkinson's Disease

    NARCIS (Netherlands)

    Olgiati, Simone; Quadri, Marialuisa; Fang, Mingyan; Rood, Janneke P. M. A.; Saute, Jonas A.; Chien, Hsin Fen; Bouwkamp, Christian G.; Graafland, Josja; Minneboo, Michelle; Breedveld, Guido J.; Zhang, Jianguo; Verheijen, Frans W.; Boon, Agnita J. W.; Kievit, Anneke J. A.; Jardim, Laura Bannach; Mandemakers, Wim; Barbosa, Egberto Reis; Rieder, Carlos R. M.; Leenders, Klaus L.; Wang, Jun; Bonifati, Vincenzo

    ObjectiveDNAJC6 mutations were recently described in two families with autosomal recessive juvenile parkinsonism (onset age MethodsThe DNAJC6 open reading frame was analyzed in 274 patients with early-onset sporadic or familial PD. Selected variants were followed up by cosegregation, homozygosity

  19. Mutations associated with succinate dehydrogenase D-related malignant paragangliomas.

    NARCIS (Netherlands)

    Timmers, H.J.L.M.; Pacak, K.; Bertherat, J.; Lenders, J.W.M.; Duet, M.; Eisenhofer, G.; Stratakis, C.A.; Niccoli-Sire, P.; Tran, B.H.; Burnichon, N.; Gimenez-Roqueplo, A.P.

    2008-01-01

    OBJECTIVE: Hereditary paraganglioma (PGL) syndromes result from germline mutations in genes encoding subunits B, C and D of the mitochondrial enzyme succinate dehydrogenase (SDHB, SDHC and SDHD). SDHB-related PGLs are known in particular for their high malignant potential. Recently, however, maligna

  20. Serum ferritin concentration predicts hepatic fibrosis better than hepatic iron concentration in human HFE-Haemochromatosis.

    Science.gov (United States)

    Wood, Marnie J; Crawford, Darrell H G; Wockner, Leesa F; Powell, Lawrie W; Ramm, Grant A

    2017-09-01

    Ferritin is purported to have proinflammatory and profibrogenic effects on hepatic stellate cells. Thus, rather than acting as a passive indicator of hepatic iron concentration (HIC) in haemochromatosis, ferritin may directly influence fibrosis. This study evaluated whether serum ferritin is a better predictor of hepatic fibrosis compared to variables previously associated with increased fibrosis risk in haemochromatosis. We identified 291 C282Y HFE-homozygous patients who had undergone liver biopsy for histological fibrosis staging and measurement of HIC. Ordinal logistic regression determined the best model for fibrosis stage not including serum ferritin. Then, serum ferritin was introduced into this model to assess whether the predictive power of the model was significantly increased and to evaluate the effect on other predictors of fibrosis. Ordinal logistic regression analyses without serum ferritin demonstrated that log HIC (OR 2.89; P serum ferritin in multivariate analysis substantially improved the predictive power of the model (χ(2 ) = 37.15; P serum ferritin in this model rendered the effects of HIC, gender, alcohol and steatosis to non-significance. In haemochromatosis, serum ferritin is a better predictor of fibrosis stage than HIC, gender, steatosis and alcohol. These data support a hypothesis that ferritin may play a role in fibrosis rather than simply acting as a passive indicator of iron storage. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Functional analysis of 'a' determinant mutations associated with occult HBV in HIV-positive South Africans.

    Science.gov (United States)

    Powell, Eleanor A; Boyce, Ceejay L; Gededzha, Maemu P; Selabe, Selokela G; Mphahlele, M Jeffrey; Blackard, Jason T

    2016-07-01

    Occult hepatitis B is defined by the presence of hepatitis B virus (HBV) DNA in the absence of hepatitis B surface antigen (HBsAg). Occult HBV is associated with the development of hepatocellular carcinoma, reactivation during immune suppression, and virus transmission. Viral mutations contribute significantly to the occult HBV phenotype. Mutations in the 'a' determinant of HBsAg are of particular interest, as these mutations are associated with immune escape, vaccine escape and diagnostic failure. We examined the effects of selected occult HBV-associated mutations identified in a population of HIV-positive South Africans on HBsAg production in vitro. Mutations were inserted into two different chronic HBV backbones and transfected into a hepatocyte-derived cell line. HBsAg levels were quantified by enzyme-linked immunosorbent assay (ELISA), while the detectability of mutant HBsAg was determined using an HA-tagged HBsAg expression system. Of the seven mutations analysed, four (S132P, C138Y, N146D and C147Y) resulted in decreased HBsAg expression in one viral background but not in the second viral background. One mutation (N146D) led to a decrease in HBsAg detected as compared to HA-tag, indicating that this mutation compromises the ability of the ELISA to detect HBsAg. The contribution of occult-associated mutations to the HBsAg-negative phenotype of occult HBV cannot be determined adequately by testing the effect of the mutation in a single viral background, and rigorous analysis of these mutations is required.

  2. LHON/MELAS overlap syndrome associated with a mitochondrial MTND1 gene mutation.

    Science.gov (United States)

    Blakely, Emma L; de Silva, Rajith; King, Andrew; Schwarzer, Verena; Harrower, Tim; Dawidek, Gervase; Turnbull, Douglass M; Taylor, Robert W

    2005-05-01

    Pathogenic point mutations in the mitochondrial MTND1 gene have previously been described in association with two distinct clinical phenotypes -- Leber hereditary optic neuropathy (LHON) and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Here we report the first heteroplasmic mitochondrial DNA (mtDNA) point mutation (3376G>A) in the MTND1 gene associated with an overlap syndrome comprising the clinical features of both LHON and MELAS. Muscle histochemistry revealed subtle mitochondrial abnormalities, while biochemical analysis showed an isolated complex I deficiency. Our findings serve to highlight the growing importance of mutations in mitochondrial complex I structural genes in MELAS and its associated overlap syndromes.

  3. A Novel AXIN2 Missense Mutation Is Associated with Non-Syndromic Oligodontia.

    Directory of Open Access Journals (Sweden)

    Haochen Liu

    Full Text Available Oligodontia is defined as the congenital absence of six or more permanent teeth, excluding the third molars. Oligodontia may contribute to masticatory dysfunction, speech alteration, aesthetic problems and malocclusion. Numerous gene mutations have been association with oligodontia. In the present study, we identified a de novo AXIN2 missense mutation (c.314T>G in a Chinese individual with non-syndromic oligodontia. This mutation results in the substitution of Val at residue 105 for Gly (p.Val105Gly; residue 105 is located in the highly conserved regulator of G protein signaling (RGS domain of the AXIN2 protein. This is the first report indicating that a mutation in the RGS domain of AXIN2 is responsible for non-syndromic oligodontia. Our study supports the relationship between AXIN2 mutation and non-syndromic oligodontia and extends the mutation spectrum of the AXIN2 gene.

  4. Cancer-associated mutations are preferentially distributed in protein kinase functional sites.

    Science.gov (United States)

    Izarzugaza, Jose M G; Redfern, Oliver C; Orengo, Christine A; Valencia, Alfonso

    2009-12-01

    Protein kinases are a superfamily involved in many crucial cellular processes, including signal transmission and regulation of cell cycle. As a consequence of this role, kinases have been reported to be associated with many types of cancer and are considered as potential therapeutic targets. We analyzed the distribution of pathogenic somatic point mutations (drivers) in the protein kinase superfamily with respect to their location in the protein, such as in structural, evolutionary, and functionally relevant regions. We find these driver mutations are more clearly associated with key protein features than other somatic mutations (passengers) that have not been directly linked to tumor progression. This observation fits well with the expected implication of the alterations in protein kinase function in cancer pathogenicity. To explain the relevance of the detected association of cancer driver mutations at the molecular level in the human kinome, we compare these with genetically inherited mutations (SNPs). We find that the subset of nonsynonymous SNPs that are associated to disease, but sufficiently mild to the point of being widespread in the population, tend to avoid those key protein regions, where they could be more detrimental for protein function. This tendency contrasts with the one detected for cancer associated-driver-mutations, which seems to be more directly implicated in the alteration of protein function. The detailed analysis of protein kinase groups and a number of relevant examples, confirm the relation between cancer associated-driver-mutations and key regions for protein kinase structure and function.

  5. Mutations in planar cell polarity gene SCRIB are associated with spina bifida.

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    Yunping Lei

    Full Text Available Neural tube defects (NTDs (OMIM #182940 including anencephaly, spina bifida and craniorachischisis, are severe congenital malformations that affect 0.5-1 in 1,000 live births in the United States, with varying prevalence around the world. Mutations in planar cell polarity (PCP genes are believed to cause a variety of NTDs in both mice and humans. SCRIB is a PCP-associated gene. Mice that are homozygous for the Scrib p.I285K and circletail (Crc mutations, present with the most severe form of NTDs, namely craniorachischisis. A recent study reported that mutations in SCRIB were associated with craniorachischisis in humans, but whether SCRIB mutations contribute to increased spina bifida risk is still unknown. We sequenced the SCRIB gene in 192 infants with spina bifida and 190 healthy controls. Among the spina bifida patients, we identified five novel missense mutations that were predicted-to-be-deleterious by the PolyPhen software. Of these five mutations, three of them (p.P1043L, p.P1332L, p.L1520R significantly affected the subcellular localization of SCRIB. In addition, we demonstrated that the craniorachischisis mouse line-90 mutation I285K, also affected SCRIB subcellular localization. In contrast, only one novel missense mutation (p.A1257T was detected in control samples, and it was predicted to be benign. This study demonstrated that rare deleterious mutations of SCRIB may contribute to the multifactorial risk for human spina bifida.

  6. DiMeX: A Text Mining System for Mutation-Disease Association Extraction.

    Science.gov (United States)

    Mahmood, A S M Ashique; Wu, Tsung-Jung; Mazumder, Raja; Vijay-Shanker, K

    2016-01-01

    The number of published articles describing associations between mutations and diseases is increasing at a fast pace. There is a pressing need to gather such mutation-disease associations into public knowledge bases, but manual curation slows down the growth of such databases. We have addressed this problem by developing a text-mining system (DiMeX) to extract mutation to disease associations from publication abstracts. DiMeX consists of a series of natural language processing modules that preprocess input text and apply syntactic and semantic patterns to extract mutation-disease associations. DiMeX achieves high precision and recall with F-scores of 0.88, 0.91 and 0.89 when evaluated on three different datasets for mutation-disease associations. DiMeX includes a separate component that extracts mutation mentions in text and associates them with genes. This component has been also evaluated on different datasets and shown to achieve state-of-the-art performance. The results indicate that our system outperforms the existing mutation-disease association tools, addressing the low precision problems suffered by most approaches. DiMeX was applied on a large set of abstracts from Medline to extract mutation-disease associations, as well as other relevant information including patient/cohort size and population data. The results are stored in a database that can be queried and downloaded at http://biotm.cis.udel.edu/dimex/. We conclude that this high-throughput text-mining approach has the potential to significantly assist researchers and curators to enrich mutation databases.

  7. Effect of Native American ancestry on iron-related phenotypes of Alabama hemochromatosis probands with HFE C282Y homozygosity

    Directory of Open Access Journals (Sweden)

    Barton Ellen H

    2006-03-01

    Full Text Available Abstract Background In age-matched cohorts of screening study participants recruited from primary care clinics, mean serum transferrin saturation values were significantly lower and mean serum ferritin concentrations were significantly higher in Native Americans than in whites. Twenty-eight percent of 80 Alabama white hemochromatosis probands with HFE C282Y homozygosity previously reported having Native American ancestry, but the possible effect of this ancestry on hemochromatosis phenotypes was unknown. Methods We compiled observations in these 80 probands and used univariate and multivariate methods to analyze associations of age, sex, Native American ancestry (as a dichotomous variable, report of ethanol consumption (as a dichotomous variable, percentage transferrin saturation and loge serum ferritin concentration at diagnosis, quantities of iron removed by phlebotomy to achieve iron depletion, and quantities of excess iron removed by phlebotomy. Results In a univariate analysis in which probands were grouped by sex, there were no significant differences in reports of ethanol consumption, transferrin saturation, loge serum ferritin concentration, quantities of iron removed to achieve iron depletion, and quantities of excess iron removed by phlebotomy in probands who reported Native American ancestry than in those who did not. In multivariate analyses, transferrin saturation (as a dependent variable was not significantly associated with any of the available variables, including reports of Native American ancestry and ethanol consumption. The independent variable quantities of excess iron removed by phlebotomy was significantly associated with loge serum ferritin used as a dependent variable (p e serum ferritin was the only independent variable significantly associated with quantities of excess iron removed by phlebotomy used as a dependent variable (p Conclusion We conclude that the iron-related phenotypes of hemochromatosis probands with HFE

  8. Two cases of primarily palmoplantar keratoderma associated with novel mutations in keratin 1.

    Science.gov (United States)

    Terron-Kwiatkowski, Ana; Paller, Amy S; Compton, John; Atherton, David J; McLean, W H Irwin; Irvine, Alan D

    2002-10-01

    Mutations in keratin 1 were initially described in the classical form of bullous congenital ichthyosiform erythroderma (also known as epidermolytic hyperkeratosis). More recently the range of phenotypes associated with mutations in this gene has been extended to include annular ichthyosiform erythroderma and mild epidermolytic palmoplantar keratoderma. Here we present two novel mutations in the keratin 1 gene (KRT1): a 5' donor splice site mutation in exon 1 (591 + 2T > A) that predicts a 22 amino acid in-frame deletion in the keratin 1 1A domain; and an in-frame deletion in exon 7 (1376del24) that predicts a foreshortened 2B coiled-coil domain of keratin 1. In each case these mutations are associated with palmoplantar keratoderma and mild ichthyosis, largely limited to the flexural areas. These mutations appear to have a less damaging effect than previously reported mis-sense mutations sited in the helix boundary motifs. This report extends the range of phenotypes associated with mutations in KRT1.

  9. Association of FMF-related (MEFV) point mutations with secondary and FMF amyloidosis.

    Science.gov (United States)

    Atagunduz, M Pamir; Tuglular, Serhan; Kantarci, Gulcin; Akoglu, Emel; Direskeneli, Haner

    2004-01-01

    Familial Mediterranean fever (FMF) is the major cause of AA amyloidosis in Turkey. M694V mutation in MEFV gene was suggested to be associated with severe clinical features and amyloidosis of FMF. In this study, the frequencies of three FMF-related MEFV mutations (M694V, M680I and V726A) were investigated in FMF patients with (AA-FMF, n = 37) and without amyloidosis (non-AA-FMF, n = 35), in patients with secondary amyloidosis related to non-FMF inflammatory conditions (S-AA, n = 19) and in a non-inflammatory control group (n = 185) by molecular genetic studies using polymerase chain reaction with the ARMS (amplification refractory mutation system) method. Both AA and non-AA-FMF patients had significantly higher MEFV mutations compared to non-inflammatory controls (81 and 62.7% respectively vs. 4.2%, p = 0.0001). AA-FMF patients carried significantly more MEFV mutations than non-AA-FMF patients (p = 0.01). M694V was the most common mutation in both FMF groups (63.5 vs. 51.4%), however allele frequency (p = 0.17) and the number of homozygous patients for this mutation did not differ between the groups (p = 0.77). Although lower compared to FMF patients, S-AA patients also had a significantly higher incidence of MEFV mutations than non-inflammatory controls (21 vs. 4.2%) (p = 0.0002). M694V was the only MEFV mutation in this group. MEFV mutations are found to be increased both in FMF and non-FMF associated secondary amyloidosis in our study; however, no clear association between M694V and amyloidosis is observed, except in the non-FMF group. Our results suggest that MEVF mutations may also serve as a severity marker for other inflammatory conditions. Copyright 2004 S. Karger AG, Basel

  10. Exercise Intolerance and Myoglobinuria Associated with a Novel Maternally Inherited MT-ND1 Mutation

    DEFF Research Database (Denmark)

    Rafiq, Jabin; Duno, Morten; Østergaard, Elsebet

    2016-01-01

    The most common clinical phenotype caused by a mtDNA mutation in complex I of the mitochondrial respiratory chain is Leber hereditary optic neuropathy. We report a family with a novel maternally inherited homoplasmic mtDNA m.4087A>G mutation in the ND1 gene (MT-ND1) associated with isolated...... myopathy, recurrent episodes of myoglobinuria, and rhabdomyolysis. DNA from blood in seven family members and muscle from four family members were PCR amplified and sequenced directly and assessed for the m.4087A>G variation in MT-ND1. Mitochondrial enzyme activity in all muscle biopsies was measured. PCR...... myoglobinuria is a rare phenotype of mitochondrial myopathies. We report this phenotype in a family affected by a novel homoplasmic mutation in MT-ND1. It is the first time such a phenotype has been associated with complex I gene mutations and a homoplasmic mutation of mtDNA....

  11. Cerebral arteriopathy associated with Arg179His ACTA2 mutation.

    Science.gov (United States)

    Amans, Matthew R; Stout, Charles; Fox, Christine; Narvid, Jared; Hetts, Steven W; Cooke, Daniel L; Higashida, Randall T; Dowd, Christopher F; McSwain, Hugh; Halbach, Van V

    2014-11-01

    ACTA2 mutations have recently been shown to cause a multisystem smooth muscle dysfunction syndrome that may result in pediatric stroke. We report a case of ACTA2 mutation in a 3-year-old girl presenting with acute ischemic stroke and provide high resolution imaging of the cerebral arteries demonstrating novel findings of multiple tiny aneurysms (particularly in the posterior circulation), as well as the more characteristic imaging phenotype of straightened and narrowed proximal intracranial vessels, dilated cervical vessels and occlusion of the M1 MCA segment without lenticulostriate collateral formation. This newly identified disease should be added to the differential diagnosis of pediatric stroke and cerebral vasculopathy. Neuroradiologists, interventionalists, surgeons and neurologists should become familiar with this rare disease and its clinical sequelae. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  12. Cerebral arteriopathy associated with Arg179His ACTA2 mutation

    Science.gov (United States)

    Amans, Matthew R; Stout, Charles; Fox, Christine; Narvid, Jared; Hetts, Steven W; Cooke, Daniel L; Higashida, Randall T; Dowd, Christopher F; McSwain, Hugh; Halbach, Van V

    2013-01-01

    ACTA2 mutations have recently been shown to cause a multisystem smooth muscle dysfunction syndrome that may result in pediatric stroke. We report a case of ACTA2 mutation in a 3-year-old girl presenting with acute ischemic stroke and provide high resolution imaging of the cerebral arteries demonstrating novel findings of multiple tiny aneurysms (particularly in the posterior circulation), as well as the more characteristic imaging phenotype of straightened and narrowed proximal intracranial vessels, dilated cervical vessels and occlusion of the M1 MCA segment without lenticulostriate collateral formation. This newly identified disease should be added to the differential diagnosis of pediatric stroke and cerebral vasculopathy. Neuroradiologists, interventionalists, surgeons and neurologists should become familiar with this rare disease and its clinical sequelae. PMID:24293535

  13. Association of mtDNA mutation with Autism in Iranian patients

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    Massoud Houshmand

    2013-12-01

    Full Text Available The autism spectrum disorders (ASD are amongst the most heritable complex disorders. Although there have been many efforts to locate the genes associated with ASD risk, many has been remained to be disclosed about the genetics of ASD. Scrutiny's have only disclosed a small number of de novo and inherited variants significantly associated with susceptibility to ASD. These only comprise a small number of total genetic risk factors. Some studies confirm the contribution of mitochondrial genome mutations to the pathophysiology of the autism, but some other studies rejected such a contribution. In the current study we tried to scrutinize the association between mitochondrial tRNA genes mutations and the risk of Autism. DNA was extracted from the blood of 24 patients with ASD and 40 age-matched healthy controls from Special Medical Center in Tehran. 22 tRNA genes of mitochondrial genome were PCR amplified using 12 primer pairs and sequenced. Sequencing results were searched for mutations using clustalW Progran and then the association of mutations with the autism risk was assessed by statistical analysis using SPSS version 15. Many of the observed mutations were sporadic mutations without any significant relationship with the risk of autism, and the other mutations including those of high frequency showed no significant relationship with the risk of disease as well (p-value > 0.05 except mutations 16126T>C (p-value=0.01 , 14569G>A(pvalue=0.02 and 1811A>G(p-value=0.04. These three mutations were in the noncoding regions of the mitochondrial genome near tRNA genes. The mutation 16126T>C was in the mtDNA control region.

  14. New Topoisomerase I mutations are associated with resistance to camptothecin

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    Pourquier Philippe

    2011-05-01

    Full Text Available Abstract Background Topoisomerase I (TOP1 is a nuclear enzyme that catalyzes the relaxation of supercoiled DNA during DNA replication and transcription. TOP1 is the molecular target of camptothecin and related drugs such as irinotecan and SN38 (irinotecan's active metabolite. Irinotecan is widely used as an anti-cancer agent in the treatment of metastatic colon cancer. However, its efficacy is often limited by the development of resistance. Methods We previously established several SN38 resistant HCT116-derived clones to study the mechanisms underlying resistance to SN38. Here, we investigated whether resistance to SN38 in these cell lines could be linked to the presence of TOP1 mutations and changes in its expression and activity. Functional analyses were performed on these cell lines challenged with SN38 and we specifically monitored the double strands breaks with γH2AX staining and replication activity with molecular combing. Results In SN38 resistant HCT116 clones we identified three new TOP1 mutations, which are located in the core subdomain III (p.R621H and p.L617I and in the linker domain (p.E710G and are packed together at the interface between these two domains. The presence of these TOP1 mutations in SN38 resistant HCT116 cells did not modify TOP1 expression or intrinsic activity. Conversely, following challenge with SN38, we observed a decrease of TOP1-DNA cleavage complexes and a reduction in double-stranded break formation. In addition, we showed that SN38 resistant HCT116 cells present a strong decrease in the SN38-dependent asymmetry of replication forks that is characteristic of SN38 sensitive HCT116 cells. Conclusions These results indicate that the TOP1 mutations are involved in the development of SN38 resistance. We hypothesize that p.L617, p.R621 and p.E710 TOP1 residues are important for the functionality of the linker and that mutation of one of these residues is sufficient to alter or modulate its flexibility

  15. Genetic screening and functional characterization of PDGFRB mutations associated with Basal Ganglia Calcification of Unknown Etiology

    Science.gov (United States)

    Sanchez-Contreras, Monica; Baker, Matthew C.; Finch, NiCole A.; Nicholson, Alexandra; Wojtas, Aleksandra; Wszolek, Zbigniew K.; Ross, Owen A.; Dickson, Dennis W.; Rademakers, Rosa

    2014-01-01

    Three causal genes for Idiopathic Basal Ganglia Calcification (IBGC) have been identified. Most recently, mutations in PDGFRB, encoding a member of the platelet-derived growth factor receptor family type β, and PDGFB, encoding PDGF-B, the specific ligand of PDGFRβ, were found implicating the PDGF-B/PDGFRβ pathway in abnormal brain calcification. In this study we aimed to identify and study mutations in PDGFRB and PDGFB in a series of 26 patients from the Mayo Clinic Florida Brain Bank with moderate to severe basal ganglia calcification (BCG) of unknown etiology. No mutations in PDGFB were found. However, we identified one mutation in PDGFRB, p.R695C located in the tyrosine kinase domain, in one BGC patient. We further studied the function of p.R695C mutant PDGFRβ and two previously reported mutants, p.L658P and p.R987W PDGFRβ in cell culture. We show that, in response to PDGF-BB stimulation, the p.L658P mutation completely suppresses PDGFRβ autophosphorylation whereas the p.R695C mutation results in partial loss of autophosphorylation. For the p.R987W mutation, our data suggest a different mechanism involving reduced protein levels. These genetic and functional studies provide the first insight into the pathogenic mechanisms associated with PDGFRB mutations and provide further support for a pathogenic role of PDGFRB mutations in BGC. PMID:24796542

  16. Gender Specific Mutation Incidence and Survival Associations in Clear Cell Renal Cell Carcinoma (CCRCC.

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    Christopher J Ricketts

    Full Text Available Renal cell carcinoma (RCC is diagnosed in >200,000 individuals worldwide each year, accounting for ~2% of all cancers, but the spread of this disease amongst genders is distinctly uneven. In the U.S. the male:female incidence ratio is approximately 2:1. A potential hypothesis is mutation spectra may differ between tumors dependent upon the gender of the patient, such as mutations of X chromosome encoded genes being more prevalent in male-derived tumors. Combined analysis of three recent large-scale clear cell renal cell carcinoma (CCRCC mutation sequencing projects identified a significantly increased mutation frequency of PBRM1 and the X chromosome encoded KDM5C in tumors from male patients and BAP1 in tumors from female patients. Mutation of BAP1 had previously been significantly associated with poorer overall survival; however, when stratified by gender, mutation of BAP1 only significantly affected overall survival in female patients. Mutation of chromatin remodeling genes alters gene regulation, but the overall effect of these alterations may also be modified by the presence of other gender specific factors. Thus, the combination of gender and mutation of a specific gene, such as BAP1, may have implications not only for prognosis but also for understanding the role of chromatin remodeling gene mutations in kidney cancer progression.

  17. "Deafness –Associated Connexin 26 Gene (GJB2 Mutations in Iranian Population"

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    M Hashemzadeh Chaleshtori

    2002-09-01

    Full Text Available Mutations in the GJB2 gene at the DFNB1 locus on chromosome 13q12 are associated with autosomal recessive non syndromic hearing loss (ARNSHL in many populations. A single mutation, at position 35 (35delG accounts for approximately 30-63% of mutations in white populations with a carrier frequency of 1.5-2.5% in most European, North American and Mediterranean populations. In this study we have investigated the prevalence of the GJB2 gene mutations using direct sequencing in 43 presumed ARNSHL subjects from 34 families in an Iranian population. Eleven different genetic variants were identified. GJB2-related deafness mutations (35delG, 235delC, W24X, R184P and IVS1+1G>A were found in 9 of 34 families (26.5%. The 35delG was the most common mutation found in 5 of 34 families (14.7%. We found one novel variant (–3517G>A in the upstream region to the gene. The mutation frequency found in this study is lower than other ethnic groups with European ancestry, but it is indicating that mutation in GJB2 in Iranian population has contribution to ARNSHL. We have also developed a simple and accurate nested PCR assay to screen the 35delG mutation in 250 unrelated unaffected Iranian individual (controls. No 35delG heterozygous was found in the control population.

  18. IDH1 mutations in patients with myelodysplastic syndromes are associated with an unfavorable prognosis

    Science.gov (United States)

    Thol, Felicitas; Weissinger, Eva M.; Krauter, Jürgen; Wagner, Katharina; Damm, Frederik; Wichmann, Martin; Göhring, Gudrun; Schumann, Christiane; Bug, Gesine; Ottmann, Oliver; Hofmann, Wolf-Karsten; Schlegelberger, Brigitte; Ganser, Arnold; Heuser, Michael

    2010-01-01

    Background Myelodysplastic syndromes are a heterogeneous group of hematopoietic stem cell disorders with a high propensity to transform into acute myeloid leukemia. Heterozygous missense mutations in IDH1 at position R132 and in IDH2 at positions R140 and R172 have recently been reported in acute myeloid leukemia. However, little is known about the incidence and prognostic impact of IDH1 and IDH2 mutations in myelodysplastic syndromes. Design and Methods We examined 193 patients with myelodysplastic syndromes and 53 patients with acute myeloid leukemia arising from myelodysplastic syndromes for mutations in IDH1 (R132), IDH2 (R172 and R140), and NPM1 by direct sequencing. Results We found that mutations in IDH1 occurred with a frequency of 3.6% in myelodysplastic syndromes (7 mutations in 193 patients) and 7.5% in acute myeloid leukemia following myelodysplastic syndromes (4 mutations in 53 patients). Three mutations in codon R140 of IDH2 and one mutation in codon R172 were found in patients with acute myeloid leukemia following myelodysplastic syndromes (7.5%). No IDH2 R140 or R172 mutations were identified in patients with myelodysplastic syndromes. The presence of IDH1 mutations was associated with a shorter overall survival (HR 3.20; 95% CI 1.47–6.99) and a higher rate of transformation into acute myeloid leukemia (67% versus 28%, P=0.04). In multivariate analysis when considering karyotype, transfusion dependence and International Prognostic Scoring System score, IDH1 mutations remained an independent prognostic marker in myelodysplastic syndromes (HR 3.57; 95% CI 1.59–8.02; P=0.002). Conclusions These results suggest that IDH1 mutations are recurrent molecular aberrations in patients with myelodysplastic syndromes, and may become useful as a poor risk marker in these patients. These findings await validation in prospective trials. PMID:20494930

  19. Atypical presentation of Leigh syndrome associated with a Leber hereditary optic neuropathy primary mitochondrial DNA mutation.

    Science.gov (United States)

    Fruhman, Gary; Landsverk, Megan L; Lotze, Timothy E; Hunter, Jill V; Wangler, Michael F; Adesina, Adekunle M; Wong, Lee-Jun C; Scaglia, Fernando

    2011-06-01

    Leber hereditary optic neuropathy (LHON) is caused by point mutations in mitochondrial DNA (mtDNA), and is characterized by bilateral, painless sub-acute visual loss that develops during the second decade of life. Here we report the case of a five year old girl who presented with clinical and neuroradiological findings reminiscent of Leigh syndrome but carried a mtDNA mutation m.11778G>A (p.R340H) in the MTND4 gene usually observed in patients with LHON. This case is unusual for age of onset, gender, associated neurological findings and evolution, further expanding the clinical spectrum associated with primary LHON mtDNA mutations.

  20. Association between filaggrin null mutations and concomitant atopic dermatitis and contact allergy

    DEFF Research Database (Denmark)

    Carlsen, B C; Thyssen, J P; Menné, T

    2011-01-01

    The phenotypic traits of people with the filaggrin mutation (FLG) genotype and atopic dermatitis (AD) are still under elucidation, and the association with concomitant AD and contact allergy (CA) has not previously been examined.......The phenotypic traits of people with the filaggrin mutation (FLG) genotype and atopic dermatitis (AD) are still under elucidation, and the association with concomitant AD and contact allergy (CA) has not previously been examined....

  1. 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

    Directory of Open Access Journals (Sweden)

    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

  2. Acetazolamide-responsive exercise-induced episodic ataxia associated with a novel homozygous DARS2 mutation.

    Science.gov (United States)

    Synofzik, Matthis; Schicks, Julia; Lindig, Tobias; Biskup, Saskia; Schmidt, Thorsten; Hansel, Jochen; Lehmann-Horn, Frank; Schöls, Ludger

    2011-10-01

    Leukoencephalopathy with brain stem and spinal cord involvement and brain lactate elevation (LBSL) was recently shown to be caused by mutations in the DARS2 gene, encoding a mitochondrial aspartyl-tRNA synthetase. So far, affected individuals were invariably compound heterozygous for two mutations in DARS2, and drug treatments have remained elusive. Prospective 2-year follow-up of the natural history of the main presenting symptoms in a homozygous DARS2 mutation carrier, followed by a 60 day treatment with acetazolamide in two different doses and with two random treatment interruptions. The patient presented with exercise-induced paroxysmal gait ataxia and areflexia as an atypical phenotype associated with a novel homozygous DARS2 mutation. These features showed an excellent dose-dependent, sustained treatment response to a carbonic anhydrase inhibitor. Pathogenic mutations in episodic ataxia genes were excluded, thus making it highly unlikely that this phenotype was because of episodic ataxia as a second disorder besides LBSL. This case demonstrates that DARS2 mutation homozygosity is not lethal, as suggested earlier, but compatible with a rather benign disease course. More importantly, it extends the phenotypic spectrum of LBSL and reveals that at least some DARS2-associated phenotypic features might be readily treatable. However, future observations of paroxsymal ataxia and, possibly, areflexia in other DARS2-mutated patients are warranted to further corroborate our finding that DARS2 mutations can lead to a paroxsymal ataxia phenotype.

  3. Mutation of ataxia-telangiectasia mutated is associated with dysfunctional glutathione homeostasis in cerebellar astroglia.

    Science.gov (United States)

    Campbell, Andrew; Bushman, Jared; Munger, Joshua; Noble, Mark; Pröschel, Christoph; Mayer-Pröschel, Margot

    2016-02-01

    Astroglial dysfunction plays an important role in neurodegenerative diseases otherwise attributed to neuronal loss of function. Here we focus on the role of astroglia in ataxia-telangiectasia (A-T), a disease caused by mutations in the ataxia-telangiectasia mutated (ATM) gene. A hallmark of A-T pathology is progressive loss of cerebellar neurons, but the mechanisms that impact neuronal survival are unclear. We now provide a possible mechanism by which A-T astroglia affect the survival of cerebellar neurons. As astroglial functions are difficult to study in an in vivo setting, particularly in the cerebellum where these cells are intertwined with the far more numerous neurons, we conducted in vitro coculture experiments that allow for the generation and pharmacological manipulation of purified cell populations. Our analyses revealed that cerebellar astroglia isolated from Atm mutant mice show decreased expression of the cystine/glutamate exchanger subunit xCT, glutathione (GSH) reductase, and glutathione-S-transferase. We also found decreased levels of intercellular and secreted GSH in A-T astroglia. Metabolic labeling of l-cystine, the major precursor for GSH, revealed that a key component of the defect in A-T astroglia is an impaired ability to import this rate-limiting precursor for the production of GSH. This impairment resulted in suboptimal extracellular GSH supply, which in turn impaired survival of cerebellar neurons. We show that by circumventing the xCT-dependent import of L-cystine through addition of N-acetyl-L-cysteine (NAC) as an alternative cysteine source, we were able to restore GSH levels in A-T mutant astroglia providing a possible future avenue for targeted therapeutic intervention. © 2015 Wiley Periodicals, Inc.

  4. Familial adenomatous polyposis associated APC gene mutation - A case study

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    Avinash Bardia1, Santosh K. Tiwari1, Sandeep K. Vishwakarma1, Md. Aejaz Habeeb1, Pratibha Nallari2, Aleem A. Khan1

    2013-08-01

    Full Text Available Familial adenomatous polyposis (FAP is an autosomal dominant condition characterized by diffuse intestinal polyposis, specific gene mutation, and predisposition for developing colon cancer. Left untreated, patients with FAP will develop colorectal carcinoma during early adulthood. Hence, early detection and surgical intervention are of the utmost importance. Colectomy is required and may include an ileal pouch with ileo-anal anastomosis, which eli-minates the colon and rectal disease while preserving fecal continence and avoidance of a permanent ileostomy. We report a case of colorectal cancer along with FAP showed features consistent with adenomatous polyposis coli and no evidence of malignancy was seen after the surgery.

  5. Frequency and Distribution of Tuberculosis Resistance-Associated Mutations between Mumbai, Moldova, and Eastern Cape.

    Science.gov (United States)

    Georghiou, S B; Seifert, M; Catanzaro, D; Garfein, R S; Valafar, F; Crudu, V; Rodrigues, C; Victor, T C; Catanzaro, A; Rodwell, T C

    2016-07-01

    Molecular diagnostic assays, with their ability to rapidly detect resistance-associated mutations in bacterial genes, are promising technologies to control the spread of drug-resistant tuberculosis (DR-TB). Sequencing assays provide detailed information for specific gene regions and can help diagnostic assay developers prioritize mutations for inclusion in their assays. We performed pyrosequencing of seven Mycobacterium tuberculosis gene regions (katG, inhA, ahpC, rpoB, gyrA, rrs, and eis) for 1,128 clinical specimens from India, Moldova, and South Africa. We determined the frequencies of each mutation among drug-resistant and -susceptible specimens based on phenotypic drug susceptibility testing results and examined mutation distributions by country. The most common mutation among isoniazid-resistant (INH(r)) specimens was the katG 315ACC mutation (87%). However, in the Eastern Cape, INH(r) specimens had a lower frequency of katG mutations (44%) and higher frequencies of inhA (47%) and ahpC (10%) promoter mutations. The most common mutation among rifampin-resistant (RIF(r)) specimens was the rpoB 531TTG mutation (80%). The mutation was common in RIF(r) specimens in Mumbai (83%) and Moldova (84%) but not the Eastern Cape (17%), where the 516GTC mutation appeared more frequently (57%). The most common mutation among fluoroquinolone-resistant specimens was the gyrA 94GGC mutation (44%). The rrs 1401G mutation was found in 84%, 84%, and 50% of amikacin-resistant, capreomycin-resistant, and kanamycin (KAN)-resistant (KAN(r)) specimens, respectively. The eis promoter mutation -12T was found in 26% of KAN(r) and 4% of KAN-susceptible (KAN(s)) specimens. Inclusion of the ahpC and eis promoter gene regions was critical for optimal test sensitivity for the detection of INH resistance in the Eastern Cape and KAN resistance in Moldova. (This study has been registered at ClinicalTrials.gov under registration number NCT02170441.).

  6. Leukemia-Associated Somatic Mutations Drive Distinct Patterns of Age-Related Clonal Hemopoiesis

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    Thomas McKerrell

    2015-03-01

    Full Text Available Clonal hemopoiesis driven by leukemia-associated gene mutations can occur without evidence of a blood disorder. To investigate this phenomenon, we interrogated 15 mutation hot spots in blood DNA from 4,219 individuals using ultra-deep sequencing. Using only the hot spots studied, we identified clonal hemopoiesis in 0.8% of individuals under 60, rising to 19.5% of those ≥90 years, thus predicting that clonal hemopoiesis is much more prevalent than previously realized. DNMT3A-R882 mutations were most common and, although their prevalence increased with age, were found in individuals as young as 25 years. By contrast, mutations affecting spliceosome genes SF3B1 and SRSF2, closely associated with the myelodysplastic syndromes, were identified only in those aged >70 years, with several individuals harboring more than one such mutation. This indicates that spliceosome gene mutations drive clonal expansion under selection pressures particular to the aging hemopoietic system and explains the high incidence of clonal disorders associated with these mutations in advanced old age.

  7. Association between cigarette smoking, APC mutations and the risk of developing sporadic colorectal adenomas and carcinomas

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    Hagen Per

    2006-03-01

    Full Text Available Abstract Background The association between colorectal cancer (CRC and smoking has not been consistent. Incomplete smoking history and association to a specific subset of CRC tumors have been proposed as explanations. The adenomatous polyposis coli (APC gene has been reported to have a "gatekeeper" function in the colonic mucosa. Methods To evaluate the hypothesis that cigarette smoking is associated with adenoma and carcinoma development and further to investigate whether this association is due to mutations in the APC gene, we used a study population consisting of 133 cases (45 adenomas and 88 carcinomas and 334 controls. All tumors were sequenced in the mutation cluster region (MCR of the APC gene. Cases and controls were drawn from a homogeneous cohort of Norwegian origin. Results The mutational spectra of the APC gene revealed no difference in frequencies of mutations in cases based on ever and never smoking status. An overall case-control association was detected for adenomas and "ever smoking" OR = 1.73 (95% CI 0.83–3.58. For CRC cases several smoking parameters for dose and duration were used. We detected an association for all smoking parameters and "duration of smoking > 30 years", yielded a statistically significant OR = 2.86 (1.06–7.7. When cases were divided based on APC truncation mutation status, an association was detected in adenomas without APC mutation in relation to "ever smoking", with an OR = 3.97 (1.26–12.51. For CRC cases without APC mutation "duration of smoking > 30 years", yielded a statistically significant OR = 4.06 (1.20–13.7. The smoking parameter "starting smoking ≥ 40 years ago" was only associated with CRC cases with APC mutations, OR = 2.0 (0.34–11.95. A case-case comparison revealed similar findings for this parameter, OR = 2.24 (0.73–6.86. Conclusion Our data suggest an association between smoking and adenoma and CRC development. This association was strongest for cases without APC truncation

  8. Heterozygous mutations of the sodium chloride cotransporter in Chinese children: prevalence and association with blood pressure.

    Science.gov (United States)

    Hsu, Yu-Juei; Yang, Sung-Sen; Chu, Nain-Feng; Sytwu, Huey-Kang; Cheng, Chih-Jen; Lin, Shih-Hua

    2009-04-01

    Gitelman's syndrome (GS), which is caused by homozygous or compound heterozygous mutations of the thiazide-sensitive sodium chloride cotransporter (NCC), usually manifests in children and is associated with low blood pressure. However, the prevalence of heterozygous NCC mutations and their association with blood pressure in children have not yet been studied. Five hundred unrelated children from the Taipei Children Heart Study were enrolled. Genomic DNA was isolated from peripheral blood and the SLC12A3 gene was amplified by polymerase chain reaction (PCR). The 15 NCC mutations previously identified in Chinese patients with GS were evaluated using restriction fragment length polymorphism (RFLP) analysis. Blood pressure, biochemistry and urine pH were measured. The allelic frequency of heterozygous NCC mutations and their association with low blood pressure were also investigated. RFLP analysis for the 15 NCC mutations revealed heterozygous T60M in 1 child, T163M in 1, S283Y in 4, R642C in 2, W844X in 2, R928C in 9 and R959frameshift in 10 children. The overall incidence of positive heterozygous NCC mutations was approximately 2.9%. There were no significant differences in systolic or diastolic blood pressure, biochemical profiles or urine pH between children with heterozygous NCC mutations (n = 29) and non-affected controls (n = 471), except for slightly higher fasting plasma glucose concentrations in NCC-heterozygous children (91 +/- 2.3 versus 88 +/- 0.4 mg/dL, P pressures. We found a relatively high prevalence of heterozygous NCC mutations in Chinese children, suggesting that GS may not be rare in this population. Heterozygous NCC mutations were not associated with lower blood pressure in these Chinese children.

  9. Somatic mutations associated with MRI-derived volumetric features in glioblastoma

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    Gutman, David A.; Dunn, William D. [Emory University School of Medicine, Departments of Neurology, Atlanta, GA (United States); Emory University School of Medicine, Biomedical Informatics, Atlanta, GA (United States); Grossmann, Patrick; Alexander, Brian M. [Harvard Medical School, Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women' s Hospital, Boston, MA (United States); Cooper, Lee A.D. [Emory University School of Medicine, Biomedical Informatics, Atlanta, GA (United States); Georgia Institute of Technology, Department of Biomedical Engineering, Atlanta, GA (United States); Holder, Chad A. [Emory University School of Medicine, Radiology and Imaging Sciences, Atlanta, GA (United States); Ligon, Keith L. [Brigham and Women' s Hospital, Harvard Medical School, Pathology, Dana-Farber Cancer Institute, Boston, MA (United States); Aerts, Hugo J.W.L. [Harvard Medical School, Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women' s Hospital, Boston, MA (United States); Brigham and Women' s Hospital, Harvard Medical School, Radiology, Dana-Farber Cancer Institute, Boston, MA (United States)

    2015-12-15

    MR imaging can noninvasively visualize tumor phenotype characteristics at the macroscopic level. Here, we investigated whether somatic mutations are associated with and can be predicted by MRI-derived tumor imaging features of glioblastoma (GBM). Seventy-six GBM patients were identified from The Cancer Imaging Archive for whom preoperative T1-contrast (T1C) and T2-FLAIR MR images were available. For each tumor, a set of volumetric imaging features and their ratios were measured, including necrosis, contrast enhancing, and edema volumes. Imaging genomics analysis assessed the association of these features with mutation status of nine genes frequently altered in adult GBM. Finally, area under the curve (AUC) analysis was conducted to evaluate the predictive performance of imaging features for mutational status. Our results demonstrate that MR imaging features are strongly associated with mutation status. For example, TP53-mutated tumors had significantly smaller contrast enhancing and necrosis volumes (p = 0.012 and 0.017, respectively) and RB1-mutated tumors had significantly smaller edema volumes (p = 0.015) compared to wild-type tumors. MRI volumetric features were also found to significantly predict mutational status. For example, AUC analysis results indicated that TP53, RB1, NF1, EGFR, and PDGFRA mutations could each be significantly predicted by at least one imaging feature. MRI-derived volumetric features are significantly associated with and predictive of several cancer-relevant, drug-targetable DNA mutations in glioblastoma. These results may shed insight into unique growth characteristics of individual tumors at the macroscopic level resulting from molecular events as well as increase the use of noninvasive imaging in personalized medicine. (orig.)

  10. A spectrum of severe familial liver disorders associate with telomerase mutations.

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    Rodrigo T Calado

    Full Text Available BACKGROUND: Telomerase is an enzyme specialized in maintaining telomere lengths in highly proliferative cells. Loss-of-function mutations cause critical telomere shortening and are associated with the bone marrow failure syndromes dyskeratosis congenita and aplastic anemia and with idiopathic pulmonary fibrosis. Here, we sought to determine the spectrum of clinical manifestations associated with telomerase loss-of-function mutations. METHODOLOGY/PRINCIPAL FINDINGS: Sixty-nine individuals from five unrelated families with a variety of hematologic, hepatic, and autoimmune disorders were screened for telomerase complex gene mutations; leukocyte telomere length was measured by flow fluorescence in situ hybridization in mutation carriers and some non-carriers; the effects of the identified mutations on telomerase activity were determined; and genetic and clinical data were correlated. In six generations of a large family, a loss-of-function mutation in the telomerase enzyme gene TERT associated with severe telomere shortening and a range of hematologic manifestations, from macrocytosis to acute myeloid leukemia, with severe liver diseases marked by fibrosis and inflammation, and one case of idiopathic pulmonary fibrosis but not with autoimmune disorders. Additionally, we identified four unrelated families in which loss-of-function TERC or TERT gene mutations tracked with marrow failure, pulmonary fibrosis, and a spectrum of liver disorders. CONCLUSIONS/SIGNIFICANCE: These results indicate that heterozygous telomerase loss-of-function mutations associate with but are not determinant of a large spectrum of hematologic and liver abnormalities, with the latter sometimes occurring in the absence of marrow failure. Our findings, along with the link between pulmonary fibrosis and telomerase mutations, also suggest a common pathogenic mechanism for fibrotic diseases in which defective telomere repair plays important role.

  11. Mutations associated with occult hepatitis B in HIV-positive South Africans.

    Science.gov (United States)

    Powell, Eleanor A; Gededzha, Maemu P; Rentz, Michael; Rakgole, Nare J; Selabe, Selokela G; Seleise, Tebogo A; Mphahlele, M Jeffrey; Blackard, Jason T

    2015-03-01

    Occult hepatitis B is characterized by the absence of hepatitis B surface antigen (HBsAg) but the presence of HBV DNA. Because diagnosis of hepatitis B virus (HBV) typically includes HBsAg detection, occult HBV remains largely undiagnosed. Occult HBV is associated with increased risk of hepatocellular carcinoma, reactivation to chronic HBV during immune suppression, and transmission during blood transfusion and liver transplant. The mechanisms leading to occult HBV infection are unclear, although viral mutations are likely a significant factor. In this study, sera from 394 HIV-positive South Africans were tested for HBV DNA and HBsAg. For patients with detectable HBV DNA, the overlapping surface and polymerase open reading frames (ORFs) were sequenced. Occult-associated mutations-those mutations found exclusively in individuals with occult HBV infection but not in individuals with chronic HBV infection from the same cohort or GenBank references-were identified. Ninety patients (22.8%) had detectable HBV DNA. Of these, 37 had detectable HBsAg, while 53 lacked detectable surface antigen. The surface and polymerase ORFs were cloned successfully for 19 patients with chronic HBV and 30 patients with occult HBV. In total, 235 occult-associated mutations were identified. Ten occult-associated mutations were identified in more than one patient. Additionally, 15 amino acid positions had two distinct occult-associated mutations at the same residue. Occult-associated mutations were common and present in all regions of the surface and polymerase ORFs. Further study is underway to determine the effects of these mutations on viral replication and surface antigen expression in vitro.

  12. Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation.

    Science.gov (United States)

    Kato, Mitsuhiro; Das, Soma; Petras, Kristin; Kitamura, Kunio; Morohashi, Ken-ichirou; Abuelo, Diane N; Barr, Mason; Bonneau, Dominique; Brady, Angela F; Carpenter, Nancy J; Cipero, Karen L; Frisone, Francesco; Fukuda, Takayuki; Guerrini, Renzo; Iida, Eri; Itoh, Masayuki; Lewanda, Amy Feldman; Nanba, Yukiko; Oka, Akira; Proud, Virginia K; Saugier-Veber, Pascale; Schelley, Susan L; Selicorni, Angelo; Shaner, Rachel; Silengo, Margherita; Stewart, Fiona; Sugiyama, Noriyuki; Toyama, Jun; Toutain, Annick; Vargas, Ana Lía; Yanazawa, Masako; Zackai, Elaine H; Dobyns, William B

    2004-02-01

    We recently identified mutations of ARX in nine genotypic males with X-linked lissencephaly with abnormal genitalia (XLAG), and in several female relatives with isolated agenesis of the corpus callosum (ACC). We now report 13 novel and two recurrent mutations of ARX, and one nucleotide change of uncertain significance in 20 genotypic males from 16 families. Most had XLAG, but two had hydranencephaly and abnormal genitalia, and three males from one family had Proud syndrome or ACC with abnormal genitalia. We obtained detailed clinical information on all 29 affected males, including the nine previously reported subjects. Premature termination mutations consisting of large deletions, frameshifts, nonsense mutations, and splice site mutations in exons 1 to 4 caused XLAG or hydranencephaly with abnormal genitalia. Nonconservative missense mutations within the homeobox caused less severe XLAG, while conservative substitution in the homeodomain caused Proud syndrome. A nonconservative missense mutation near the C-terminal aristaless domain caused unusually severe XLAG with microcephaly and mild cerebellar hypoplasia. In addition, several less severe phenotypes without malformations have been reported, including mental retardation with cryptogenic infantile spasms (West syndrome), other seizure types, dystonia or autism, and nonsyndromic mental retardation. The ARX mutations associated with these phenotypes have included polyalanine expansions or duplications, missense mutations, and one deletion of exon 5. Together, the group of phenotypes associated with ARX mutations demonstrates remarkable pleiotropy, but also comprises a nearly continuous series of developmental disorders that begins with hydranencephaly, lissencephaly, and agenesis of the corpus callosum, and ends with a series of overlapping syndromes with apparently normal brain structure.

  13. Clinicopathologic and prognostic associations of KRAS and BRAF mutations in small intestinal adenocarcinoma.

    Science.gov (United States)

    Jun, Sun-Young; Kim, Misung; Jin Gu, Mi; Kyung Bae, Young; Chang, Hee-Kyung; Sun Jung, Eun; Jang, Kee-Taek; Kim, Jihun; Yu, Eunsil; Woon Eom, Dae; Hong, Seung-Mo

    2016-04-01

    Activating KRAS and/or BRAF mutations have been identified as predictors of resistance to anti-epidermal growth factor receptor (EGFR) chemotherapy in colorectal cancer. But the status of KRAS and BRAF mutations and their clinicopathologic and prognostic significance has not been extensively evaluated in small intestinal adenocarcinomas. In this work, the KRAS and BRAF genes in 190 surgically resected small intestinal adenocarcinoma cases were sequenced and their association with various clinicopathologic variables, including survival of the patients, was analyzed. KRAS or BRAF mutations were observed in 63 (33%) cases. Sixty-one cases had KRAS mutations and 2 had BRAF mutations and the two types of mutation were mutually exclusive. The majority of KRAS mutations were G>A transition (43/61 cases, 71%) or p.G12D (31/61 cases, 51%). The patients with mutant KRAS tended to have higher pT classifications (P=0.034) and more frequent pancreatic invasion (P=0.020) than those with wild-type KRAS. Multivariate logistic regression analysis showed that certain mutated KRAS subtypes (G>A transitions and G12D mutations) were significantly correlated with higher pT classification (P=0.015 and 0.004, respectively) than wild-type KRAS and other KRAS mutations. The patients with KRAS or BRAF mutation had a tendency to shorter overall survival than those with wild-type KRAS and BRAF (P=0.148), but subgroup analysis demonstrated the patients with KRAS mutations showed worse survival (median, 46.0 months; P=0.046) than those with wild-type KRAS (85.4 months) in lower pT classification (pT1-pT3) group. In summary, KRAS and, infrequently, BRAF mutations are observed in a subset of small intestinal adenocarcinomas, and are associated with higher pT classification and more frequent pancreatic invasion. KRAS mutation is a poor prognostic predictor in patients with lower pT classification tumors. Anti-EGFR targeted therapy could be applied to about two-thirds of small intestinal

  14. Mitochondrial Mutations are Associated with Atherosclerotic Lesions in the Human Aorta

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    Igor A. Sobenin

    2012-01-01

    Full Text Available Somatic mutations of the human mitochondrial genome can be a possible determinant of atherosclerosis. To test this possibility, forty mitochondrial mutations were analyzed in the present study in order to see which of these mutations might be associated with atherosclerosis. Ten mitochondrial mutations belonging to mitochondrial genes MT-RNR1 (rRNA 12S; MT-TL1 (tRNA-Leu, recognizes UUR; MT-TL2 (tRNA-Leu, recognizes CUN; MT-ND1, MT-ND2, MT-ND5, and MT-ND6 (subunits 1, 2, 5, and 6, respectively, of NADH dehydrogenase; and MT-CYB (cytochrome b were potentially associated with atherosclerosis. From 29% (2 of 7 aortic samples upto 86% (6 of 7 aortic samples of aortic samples had a significant difference between atherosclerotic plaques and unaffected tissue, with the respect to the level of heteroplasmy for each mutation. Further, the homogenates of affected and normal intimae of 22 aortas were compared to reveal the average level of heteroplasmy for the above-mentioned 10 mutations. For five mutations, the mean level of heteroplasmy was significantly different in atherosclerotic intimal homogenates in comparison with the unaffected tissue. These mutations were A1555G, C3256T, T3336C, G13513A, and G15059A. Thus, it was demonstrated that at least five mitochondrial mutations occurring in MT-RNR1, MT-TL1, MT-ND2, MT-ND5, and MT-CYB genes are associated with atherosclerosis.

  15. A structure-function study of MID1 mutations associated with a mild Opitz phenotype.

    Science.gov (United States)

    Mnayer, Laila; Khuri, Sawsan; Merheby, Hassan Al-Ali; Meroni, Germana; Elsas, Louis J

    2006-03-01

    The X-linked form of Opitz syndrome (OS) affects midline structures and produces a characteristic, but heterogeneous, phenotype that may include severe mental retardation, hypertelorism, broad nasal bridge, widow's peak, cleft lip/cleft palate, congenital heart disease, laryngotracheal defects, and hypospadias. The MID1 gene was implicated in OS by linkage to Xp22. It encodes a 667 amino acid protein that contains a RING finger motif, two B-box zinc fingers, a coiled-coil, a fibronectin type III (FNIII) domain, and a B30.2 domain. Several mutations in MID1 are associated with severe OS. Here, we describe an intelligent male with a milder phenotype characterized by hypertelorism, broad nasal bridge, widow's peak, mild hypospadias, pectus excavatum, and a surgically corrected tracheo-esophageal fistula. He has an above average intelligence and no cleft lip/palate or heart disease. We identified a novel mutation in MID1 (P441L) which is in exon 8 and functionally associated with the FNIII domain. While OS phenotypes have been attributed to mutations in the C-terminal part of MID1, little is currently known about the structure-function relationships of MID1 mutations, and how they affect phenotype. We find from a literature review that missense mutations within the FNIII domain of MID1 are associated with a milder presentation of OS than missense mutations elsewhere in MID1. All truncating mutations (frameshift, insertions/deletions) lead to severe OS. We used homology analysis of the MID1 FNIII domain to investigate structure-function changes caused by our missense mutation. This and other missense mutations probably cause disruption of protein-protein interactions, either within MID1 or between MID1 and other proteins. We correlate these protein structure-function findings to the absence of CNS or palatal changes and conclude that the FNIII domain of the MID1 protein may be involved in midline differentiation after neural tube and palatal structures are completed.

  16. Hypomyelinating leukodystrophy-associated missense mutation in HSPD1 blunts mitochondrial dynamics.

    Science.gov (United States)

    Miyamoto, Yuki; Eguchi, Takahiro; Kawahara, Kazuko; Hasegawa, Nanami; Nakamura, Kazuaki; Funakoshi-Tago, Megumi; Tanoue, Akito; Tamura, Hiroomi; Yamauchi, Junji

    2015-07-03

    Myelin-forming glial cells undergo dynamic morphological changes in order to produce mature myelin sheaths with multiple layers. In the central nervous system (CNS), oligodendrocytes differentiate to insulate neuronal axons with myelin sheaths. Myelin sheaths play a key role in homeostasis of the nervous system, but their related disorders lead not only to dismyelination and repeated demyelination but also to severe neuropathies. Hereditary hypomyelinating leukodystrophies (HLDs) are a group of such diseases affecting oligodendrocytes and are often caused by missense mutations of the respective responsible genes. Despite increasing identification of gene mutations through advanced nucleotide sequencing technology, studies on the relationships between gene mutations and their effects on cellular and subcellular aberrance have not followed at the same rapid pace. In this study, we report that an HLD4-associated (Asp-29-to-Gly) mutant of mitochondrial heat shock 60-kDa protein 1 (HSPD1) causes short-length morphologies and increases the numbers of mitochondria due to their aberrant fission and fusion cycles. In experiments using a fluorescent dye probe, this mutation decreases the mitochondrial membrane potential. Also, mitochondria accumulate in perinuclear regions. HLD4-associated HSPD1 mutant blunts mitochondrial dynamics, probably resulting in oligodendrocyte malfunction. This study constitutes a first finding concerning the relationship between disease-associated HSPD1 mutation and mitochondrial dynamics, which may be similar to the relationship between another disease-associated HSPD1 mutation (MitCHAP-60 disease) and aberrant mitochondrial dynamics.

  17. A single nucleotide mutation in Nppc is associated with a long bone abnormality in lbab mice

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    Roe Bruce A

    2007-04-01

    Full Text Available Abstract Background The long bone abnormality (lbab mouse is a new autosomal recessive mutant characterized by overall smaller body size with proportionate dwarfing of all organs and shorter long bones. Previous linkage analysis has located the lbab mutation on chromosome 1 between the markers D1Mit9 and D1Mit488. Results A genome-based positional approach was used to identify a mutation associated with lbab disease. A total of 122 genes and expressed sequence tags at the lbab region were screened for possible mutation by using genomic DNA from lbabl/lbab, lbab/+, and +/+ B6 mice and high throughput temperature gradient capillary electrophoresis. A sequence difference was identified in one of the amplicons of gene Nppc between lbab/lbab and +/+ mice. One-step reverse transcriptase polymerase chain reaction was performed to validate the difference of Nppc in different types of mice at the mRNA level. The mutation of Nppc was unique in lbab/lbab mice among multiple mouse inbred strains. The mutation of Nppc is co-segregated with lbab disease in 200 progenies produced from heterozygous lbab/+ parents. Conclusion A single nucleotide mutation of Nppc is associated with dwarfism in lbab/lbab mice. Current genome information and technology allow us to efficiently identify single nucleotide mutations from roughly mapped disease loci. The lbab mouse is a useful model for hereditary human achondroplasia.

  18. Mutations in ASXL1 are associated with poor prognosis across the spectrum of malignant myeloid diseases

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    Gelsi-Boyer Véronique

    2012-03-01

    Full Text Available Abstract The ASXL1 gene is one of the most frequently mutated genes in malignant myeloid diseases. The ASXL1 protein belongs to protein complexes involved in the epigenetic regulation of gene expression. ASXL1 mutations are found in myeloproliferative neoplasms (MPN, myelodysplastic syndromes (MDS, chronic myelomonocytic leukemia (CMML and acute myeloid leukemia (AML. They are generally associated with signs of aggressiveness and poor clinical outcome. Because of this, a systematic determination of ASXL1 mutational status in myeloid malignancies should help in prognosis assessment.

  19. Telomere length shows no association with BRCA1 and BRCA2 mutation status

    DEFF Research Database (Denmark)

    Killick, Emma; Tymrakiewicz, Malgorzata; Cieza-Borrella, Clara;

    2014-01-01

    This study aimed to determine whether telomere length (TL) is a marker of cancer risk or genetic status amongst two cohorts of BRCA1 and BRCA2 mutation carriers and controls. The first group was a prospective set of 665 male BRCA1/2 mutation carriers and controls (mean age 53 years), all healthy...... mutation carrier and telomere length. It is the first study investigating TL in a cohort of genetically predisposed males and although TL and BRCA status was previously studied in females our results don't support the previous finding of association between hereditary breast cancer and shorter TL....

  20. Antithrombin gene Arg197Stop mutation-associated venous sinus thrombosis in a Chinese family

    Institute of Scientific and Technical Information of China (English)

    Ang Li; Dexin Wang; Qiming Xue; Baoen Wang; Tianhui Liu; Zhandong Liu; Jimei Li; Chunling Zhang; Jun Chen; Jinmei Sun; YanfeiHan; Lili Wang

    2011-01-01

    This study sought to elucidate the genetic correlation of cerebral venous sinus thrombosis caused by a hereditary antithrombin deficiency in a Chinese family, at the genetic and protein levels. A nonsense mutation from C to T on locus 6431 in exon 3B of the antithrombin gene was observed,leading to an arginine (CGA) to stop codon (TGA) change in the protein. This is the first report of this mutation in China. Ineffective heparin therapy in the propositus patient is associated with a lack of heparin binding sites after antithrombin gene mutation. Characteristic low intracranial pressure in the acute phase might be specific to this patient with cerebral venous sinus thrombosis.

  1. Xerosis is associated with asthma in men independent of atopic dermatitis and filaggrin gene mutations

    DEFF Research Database (Denmark)

    Engebretsen, K A; Linneberg, Allan René; Thuesen, B H

    2015-01-01

    BACKGROUND: Epidermal filaggrin deficiency due to common filaggrin gene (FLG) mutations causes xerosis and strongly increases the risk of atopic dermatitis and even asthma. However, it is unknown whether xerosis independent of FLG mutations could also increase the risk of asthma. OBJECTIVE......: To evaluate whether generalized xerosis was associated with asthma, independent of atopic dermatitis and common FLG mutations in a cross-sectional study on adult Danes. METHODS: A total of 3396 adults from the general population participated in a health examination. Lung function and serum-specific IgE levels...... was observed between xerosis and 'allergic asthma' in men (OR 2.13; 95% CI 1.08-4.19). CONCLUSION: Our findings indicate an association between xerosis and asthma in men independent of atopic dermatitis and FLG mutations. Both facilitated allergen sensitization and secondary degradation of filaggrin following...

  2. Two Mutations in Surfactant Protein C Gene Associated with Neonatal Respiratory Distress

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    Anna Tarocco

    2015-01-01

    Full Text Available Multiple mutations of surfactant genes causing surfactant dysfunction have been described. Surfactant protein C (SP-C deficiency is associated with variable clinical manifestations ranging from neonatal respiratory distress syndrome to lethal lung disease. We present an extremely low birth weight male infant with an unusual course of respiratory distress syndrome associated with two mutations in the SFTPC gene: C43-7G>A and 12T>A. He required mechanical ventilation for 26 days and was treated with 5 subsequent doses of surfactant with temporary and short-term efficacy. He was discharged at 37 weeks of postconceptional age without any respiratory support. During the first 16 months of life he developed five respiratory infections that did not require hospitalization. Conclusion. This mild course in our patient with two mutations is peculiar because the outcome in patients with a single SFTPC mutation is usually poor.

  3. Association between loss-of-function mutations in the filaggrin gene and self-reported food allergy and alcohol sensitivity

    DEFF Research Database (Denmark)

    Linneberg, Allan René; Fenger, Runa V; Husemoen, Lise Lotte Nystrup

    2013-01-01

    Loss-of-function mutations of the filaggrin (FLG) gene cause an impaired skin barrier and increase the risk of atopic dermatitis. Interestingly, FLG mutations have also been found to be associated with a high risk of peanut allergy.......Loss-of-function mutations of the filaggrin (FLG) gene cause an impaired skin barrier and increase the risk of atopic dermatitis. Interestingly, FLG mutations have also been found to be associated with a high risk of peanut allergy....

  4. Functional Characterization of ABCB4 Mutations Found in Low Phospholipid-Associated Cholelithiasis (LPAC)

    OpenAIRE

    Kim, Tae Hee; Park, Hyo Jin; Choi, Ji Ha

    2013-01-01

    Multidrug resistance 3 (MDR3) is expressed on the canalicular membrane of the hepatocytes and plays an important role in protecting the liver from bile acids. Altered ABCB4 gene expression can lead to a rare hepatic disease, low phospholipid-associated cholelithiasis (LPAC). In this study, we characterized 3 ABCB4 mutations in LPAC patients using various in vitro assay systems. We first measured the ability of each mutant to transport paclitaxel and then the mechanisms by which these mutation...

  5. Molecular phenotype of the np 7472 deafness-associated mitochondrial mutation in osteosarcoma cell cybrids.

    Science.gov (United States)

    Toompuu, M; Tiranti, V; Zeviani, M; Jacobs, H T

    1999-11-01

    The nucleotide pair (np) 7472 insC mitochondrial DNA mutation in the tRNA(Ser)(UCN) gene is associated with sensorineural deafness, combined in some individuals with a wider syndrome including ataxia and myo-clonus. Previous studies in osteosarcoma cell cybrids revealed only a mild respiratory defect linked to the mutation. We have investigated the biochemical and molecular consequences of the mutation, using a panel of seven osteosarcoma cell cybrids containing 100% mutant mtDNA, plus two cybrids carrying 100% wild-type mtDNA from the same patient. The mutation is associated with a mild growth deficit in selective (galactose) medium that is only significant in combination with a reduced mtDNA copy number, suggesting a mechanism that might modulate clinical phenotype. The mutation results in a 65% drop in the steady-state level of tRNA(Ser)(UCN), but causes at most only a very mild and quantitative abnormality of mitochondrial protein synthesis, associated with modest hypersensitivity to doxycyclin. No evidence for a specific defect in aminoacylation was obtained, and unlike the case with the np 7445 mutation, the pattern of RNA processing of light strand transcripts of the ND6 region was not systematically altered. Comparing the np 7472 and np 7445 mutant phenotypes in cultured cells suggests that sensorineural deafness can result from a functional insufficiency of mitochondrial tRNA(Ser)(UCN), to which some cells of the auditory system are especially vulnerable.

  6. A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Alessandra Viel

    2017-06-01

    Full Text Available 8-Oxoguanine, a common mutagenic DNA lesion, generates G:C>T:A transversions via mispairing with adenine during DNA replication. When operating normally, the MUTYH DNA glycosylase prevents 8-oxoguanine-related mutagenesis by excising the incorporated adenine. Biallelic MUTYH mutations impair this enzymatic function and are associated with colorectal cancer (CRC in MUTYH-Associated Polyposis (MAP syndrome. Here, we perform whole-exome sequencing that reveals a modest mutator phenotype in MAP CRCs compared to sporadic CRC stem cell lines or bulk tumours. The excess G:C>T:A transversion mutations in MAP CRCs exhibits a novel mutational signature, termed Signature 36, with a strong sequence dependence. The MUTYH mutational signature reflecting persistent 8-oxoG:A mismatches occurs frequently in the APC, KRAS, PIK3CA, FAT4, TP53, FAT1, AMER1, KDM6A, SMAD4 and SMAD2 genes that are associated with CRC. The occurrence of Signature 36 in other types of human cancer indicates that DNA 8-oxoguanine-related mutations might contribute to the development of cancer in other organs.

  7. Molecular effects of novel mutations in Hesx1/HESX1 associated with human pituitary disorders

    DEFF Research Database (Denmark)

    Brickman, J M; Clements, M; Tyrell, R

    2001-01-01

    resulting in a single amino acid substitution, Arg160Cys (R160C), is associated with a heritable form of the human condition of septo-optic dysplasia (SOD). We have examined the phenotype of affected members in this pedigree in more detail and demonstrate for the first time a genetic basis for midline...... defects associated with an undescended or ectopic posterior pituitary. A similar structural pituitary abnormality was observed in a second patient heterozygous for another mutation in HESX1, Ser170Leu (S170L). Association of S170L with a pituitary phenotype may be a direct consequence of the HESX1...... mutation since S170L is also associated with a dominant familial form of pituitary disease. However, a third mutation in HESX1, Asn125Ser (N125S), occurs at a high frequency in the Afro-Caribbean population and may therefore reflect a population-specific polymorphism. To investigate the molecular basis...

  8. A missense mutation in PMEL17 is associated with the Silver coat color in the horse

    Directory of Open Access Journals (Sweden)

    Cothran Gus

    2006-10-01

    Full Text Available Abstract Background The Silver coat color, also called Silver dapple, in the horse is characterized by dilution of the black pigment in the hair. This phenotype shows an autosomal dominant inheritance. The effect of the mutation is most visible in the long hairs of the mane and tail, which are diluted to a mixture of white and gray hairs. Herein we describe the identification of the responsible gene and a missense mutation associated with the Silver phenotype. Results Segregation data on the Silver locus (Z were obtained within one half-sib family that consisted of a heterozygous Silver colored stallion with 34 offspring and their 29 non-Silver dams. We typed 41 genetic markers well spread over the horse genome, including one single microsatellite marker (TKY284 close to the candidate gene PMEL17 on horse chromosome 6 (ECA6q23. Significant linkage was found between the Silver phenotype and TKY284 (θ = 0, z = 9.0. DNA sequencing of PMEL17 in Silver and non-Silver horses revealed a missense mutation in exon 11 changing the second amino acid in the cytoplasmic region from arginine to cysteine (Arg618Cys. This mutation showed complete association with the Silver phenotype across multiple horse breeds, and was not found among non-Silver horses with one clear exception; a chestnut colored individual that had several Silver offspring when mated to different non-Silver stallions also carried the exon 11 mutation. In total, 64 Silver horses from six breeds and 85 non-Silver horses from 14 breeds were tested for the exon 11 mutation. One additional mutation located in intron 9, only 759 bases from the missense mutation, also showed complete association with the Silver phenotype. However, as one could expect to find several non-causative mutations completely associated with the Silver mutation, we argue that the missense mutation is more likely to be causative. Conclusion The present study shows that PMEL17 causes the Silver coat color in the horse and

  9. A novel distinctive cerebrovascular phenotype is associated with heterozygous Arg179 ACTA2 mutations

    Science.gov (United States)

    Munot, Pinki; Saunders, Dawn E.; Milewicz, Dianna M.; Regalado, Ellen S.; Ostergaard, John R.; Braun, Kees P.; Kerr, Timothy; Lichtenbelt, Klaske D.; Philip, Sunny; Rittey, Christopher; Jacques, Thomas S.; Cox, Timothy C.

    2012-01-01

    Mutations in the ACTA2 gene lead to diffuse and diverse vascular diseases; the Arg179His mutation is associated with an early onset severe phenotype due to global smooth muscle dysfunction. Cerebrovascular disease associated with ACTA2 mutations has been likened to moyamoya disease, but appears to have distinctive features. This study involved the analysis of neuroimaging of 13 patients with heterozygous missense mutations in ACTA2 disrupting Arg179. All patients had persistent ductus arteriosus and congenital mydriasis, and variable presentation of pulmonary hypertension, bladder and gastrointestinal problems associated with this mutation. Distinctive cerebrovascular features were dilatation of proximal internal carotid artery, occlusive disease of terminal internal carotid artery, an abnormally straight course of intracranial arteries, and absent basal ‘moyamoya’ collaterals. Patterns of brain injury supported both large and small vessel disease. Key differences from moyamoya disease were more widespread arteriopathy, the combination of arterial ectasia and stenosis and, importantly, absence of the typical basal ‘moyamoya’ collaterals. Evaluation of previously published cases suggests some of these features are also seen in the ACTA2 mutations disrupting Arg258. The observation that transition from dilated to normal/stenotic arterial calibre coincides with where the internal carotid artery changes from an elastic to muscular artery supports the hypothesis that abnormal smooth muscle cell proliferation caused by ACTA2 mutations is modulated by arterial wall components. Patients with persistent ductus arteriosus or congenital mydriasis with a label of ‘moyamoya’ should be re-evaluated to ensure the distinctive neuroimaging features of an ACTA2 mutation have not been overlooked. This diagnosis has prognostic and genetic implications, and mandates surveillance of other organ systems, in particular the aorta, to prevent life-threatening aortic dissection

  10. Specific filaggrin mutations cause ichthyosis vulgaris and are significantly associated with atopic dermatitis in Japan.

    Science.gov (United States)

    Nomura, Toshifumi; Akiyama, Masashi; Sandilands, Aileen; Nemoto-Hasebe, Ikue; Sakai, Kaori; Nagasaki, Akari; Ota, Mitsuhito; Hata, Hiroo; Evans, Alan T; Palmer, Colin N A; Shimizu, Hiroshi; McLean, W H Irwin

    2008-06-01

    Mutations in the gene encoding filaggrin (FLG) have been identified as the cause of ichthyosis vulgaris (IV) and shown to be major predisposing factors for atopic dermatitis (AD). However, these studies have been mainly carried out in European populations. In early 2007, we identified two Oriental-specific FLG mutations in four Japanese families with IV and reported that filaggrin mutations were also significant predisposing factors for AD in Japan. However, the frequency of FLG mutations observed in our Japanese AD cohort (5.6%), was much lower than that seen in Europeans (up to 48%). Here, we studied a further seven Japanese families with IV and identified two additional nonsense mutations in FLG, S2889X, and S3296X. We found that more than 20% of patients in our Japanese AD case series carry FLG mutations, and there is significant statistical association between the four mutations and AD (chi(2) P=8.4 x 10(-6); heterozygote odds ratio 7.57, 95% CI 2.84-23.03). These data emphasize that skin-barrier impairment due to reduced filaggrin expression plays an important role in the pathogenesis of AD and sheds further light on the genetic architecture of atopy in Japan.

  11. Succinate dehydrogenase gene mutations are strongly associated with paraganglioma of the organ of Zuckerkandl.

    Science.gov (United States)

    Lodish, Maya B; Adams, Karen T; Huynh, Thanh T; Prodanov, Tamara; Ling, Alex; Chen, Clara; Shusterman, Suzanne; Jimenez, Camilo; Merino, Maria; Hughes, Marybeth; Cradic, Kendall W; Milosevic, Dragana; Singh, Ravinder J; Stratakis, Constantine A; Pacak, Karel

    2010-09-01

    Organ of Zuckerkandl paragangliomas (PGLs) are rare neuroendocrine tumors that are derived from chromaffin cells located around the origin of the inferior mesenteric artery extending to the level of the aortic bifurcation. Mutations in the genes encoding succinate dehydrogenase subunits (SDH) B, C, and D (SDHx) have been associated with PGLs, but their contribution to PGLs of the organ of Zuckerkandl PGLs is not known. We aimed to describe the clinical presentation of patients with PGLs of the organ of Zuckerkandl and investigate the prevalence of SDHx mutations and other genetic defects among them. The clinical characteristics of 14 patients with PGL of the organ of Zuckerkandl were analyzed retrospectively; their DNA was tested for SDHx mutations and deletions. Eleven out of 14 (79%) patients with PGLs of the organ of Zuckerkandl were found to have mutations in the SDHB (9) or SDHD (2) genes; one patient was found to have the Carney-Stratakis syndrome (CSS), and his PGL was discovered during surgery for gastrointestinal stromal tumor. Our results show that SDHx mutations are prevalent in pediatric and adult PGLs of the organ of Zuckerkandl. Patients with PGLs of the organ of Zuckerkandl should be screened for SDHx mutations and the CSS; in addition, asymptomatic carriers of an SDHx mutation among the relatives of affected patients may benefit from tumor screening for early PGL detection.

  12. Progressive skeletal myopathy, a phenotypic variant of desmin myopathy associated with desmin mutations.

    Science.gov (United States)

    Dalakas, Marinos C; Dagvadorj, Ayush; Goudeau, Bertrand; Park, Kye-Yoon; Takeda, Kazuyo; Simon-Casteras, Monique; Vasconcelos, Olavo; Sambuughin, Nyamkhishig; Shatunov, Alexey; Nagle, James W; Sivakumar, Kumaraswamy; Vicart, Patrick; Goldfarb, Lev G

    2003-03-01

    Desmin myopathy is a familial or sporadic disorder characterized by the presence of desmin mutations that cause skeletal muscle weakness associated with cardiac conduction block, arrhythmia and heart failure. Distinctive histopathologic features include intracytoplasmic accumulation of desmin-reactive deposits and electron-dense granular aggregates in skeletal and cardiac muscle cells. We describe two families with features of adult-onset slowly progressive skeletal myopathy without cardiomyopathy. N342D point mutation was present in the desmin helical rod domain in patients of family 1, and I451M mutation was found in the non-helical tail domain in patients of family 2. Of interest, the same I451M mutation has previously been reported in patients with cardiomyopathy and no signs of skeletal myopathy. Some carriers of the I451M mutation did not develop any disease, suggesting incomplete penetrance. Expression studies demonstrated inability of the N342D mutant desmin to form cellular filamentous network, confirming the pathogenic role of this mutation, but the network was not affected by the tail-domain I451M mutation. Progressive skeletal myopathy is a rare phenotypic variant of desmin myopathy allelic to the more frequent cardio-skeletal form.

  13. Novel mutations in PTH1R associated with primary failure of eruption and osteoarthritis.

    Science.gov (United States)

    Frazier-Bowers, S A; Hendricks, H M; Wright, J T; Lee, J; Long, K; Dibble, C F; Bencharit, S

    2014-02-01

    Autosomal dominant mutations in PTH1R segregate with primary failure of eruption (PFE), marked by clinical eruption failure of adult teeth without mechanical obstruction. While the diagnosis of PFE conveys a poor dental prognosis, there are no reports of PFE patients who carry PTH1R mutations and exhibit any other skeletal problems. We performed polymerase chain reaction-based mutational analysis of the PTH1R gene to determine the genetic contribution of PTH1R in 10 families with PFE. Sequence analysis of the coding regions and intron-exon boundaries of the PTH1R gene in 10 families (n = 54) and 7 isolated individuals revealed 2 novel autosomal dominant mutations in PTH1R (c.996_997insC and C.572delA) that occur in the coding region and result in a truncated protein. One family showed incomplete penetrance. Of 10 families diagnosed with PFE, 8 did not reveal functional (nonsynonymous) mutations in PTH1R; furthermore, 4 families and 1 sporadic case carried synonymous single-nucleotide polymorphisms. Five PFE patients in 2 families carried PTH1R mutations and presented with osteoarthritis. We propose that the autosomal dominant mutations of PTH1R that cause PFE may also be associated with osteoarthritis; a dose-dependent model may explain isolated PFE and osteoarthritis in the absence of other known symptoms in the skeletal system.

  14. Low phospholipid associated cholelithiasis: association with mutation in the MDR3/ABCB4 gene

    Science.gov (United States)

    Rosmorduc, Olivier; Poupon, Raoul

    2007-01-01

    Low phospholipid-associated cholelithiasis (LPAC) is characterized by the association of ABCB4 mutations and low biliary phospholipid concentration with symptomatic and recurring cholelithiasis. This syndrome is infrequent and corresponds to a peculiar small subgroup of patients with symptomatic gallstone disease. The patients with the LPAC syndrome present typically with the following main features: age less than 40 years at onset of symptoms, recurrence of biliary symptoms after cholecystectomy, intrahepatic hyperechoic foci or sludge or microlithiasis along the biliary tree. Defect in ABCB4 function causes the production of bile with low phospholipid content, increased lithogenicity and high detergent properties leading to bile duct luminal membrane injuries and resulting in cholestasis with increased serum gamma-glutamyltransferase (GGT) activity. Intrahepatic gallstones may be evidenced by ultrasonography (US), computing tomography (CT) abdominal scan or magnetic resonance cholangiopancreatography, intrahepatic hyperechogenic foci along the biliary tree may be evidenced by US, and hepatic bile composition (phospholipids) may be determined by duodenoscopy. In all cases where the ABCB4 genotyping confirms the diagnosis of LPAC syndrome in young adults, long-term curative or prophylactic therapy with ursodeoxycholic acid (UDCA) should be initiated early to prevent the occurrence or recurrence of the syndrome and its complications. Cholecystectomy is indicated in the case of symptomatic gallstones. Biliary drainage or partial hepatectomy may be indicated in the case of symptomatic intrahepatic bile duct dilatations filled with gallstones. Patients with end-stage liver disease may be candidates for liver transplantation. PMID:17562004

  15. Associations between mutations and a VNTR in the human phenylalanine hydroxylase gene

    Energy Technology Data Exchange (ETDEWEB)

    Goltsov, A.A.; Eisensmith, R.C.; Woo, S.L.C. (Baylor College of Medicine, Houston, TX (United States)); Konecki, D.S.; Lichter-Konecki, U.

    1992-09-01

    The HindIII RFLP in the human phenylalanine hydroxylase (PAH) gene is caused by the presence of an AT-rich (70%) minisatellite region. This region contains various multiples of 30-bp tandem repeats and is located 3 kb downstream of the final exon of the gene. PCR-mediated amplification of this region from haplotyped PAH chromosomes indicates that the previously reported 4.0-kb HindIII allele contains three of these repeats, while the 4.4-kb HindIII allele contains 12 of these repeats. The 4.2-kb HindIII fragment can contain six, seven, eight, or nine copies of this repeat. These variations permit more detailed analysis of mutant haplotypes 1, 5, 6, and, possibly, others. Kindred analysis in phenylketonuria families demonstrates Mendelian segregation of these VNTR alleles, as well as associations between theses alleles and certain PAH mutations. The R261Q mutation, associated with haplotype 1, is associated almost exclusively with an allele containing eight repeats; the R408W mutation, when occurring on a haplotype 1 background, may also be associated with the eight-repeat VNTR allele. Other PAH mutations associated with haplotype 1, R252W and P281L, do not appear to segregate with specific VNTR alleles. The IVS-10 mutation, when associated with haplotype 6, is associated exclusively with an allele containing seven repeats. The combined use of this VNTR system and the existing RFLP haplotype system will increase the performance of prenatal diagnostic tests based on haplotype analysis. In addition, this VNTR may prove useful in studies concerning the origins and distributions of PAH mutations in different human populations. 32 refs., 3 figs., 3 tabs.

  16. A novel mutation in CRYAB associated with autosomal dominant congenital nuclear cataract in a Chinese family.

    Science.gov (United States)

    Chen, Qiang; Ma, Junjie; Yan, Ming; Mothobi, Maneo Emily; Liu, Yuanyuan; Zheng, Fang

    2009-07-10

    To identify the genetic defects associated with autosomal dominant congenital nuclear cataract in a Chinese family. Clinical data were collected, and the phenotypes of the affected members in this family were recorded by slit-lamp photography. Genomic DNA was isolated from peripheral blood. Mutations were screened in cataract-associated candidate genes through polymerase chain reaction (PCR) analyses and sequencing. Structural models of the wild-type and mutant alphaB-crystallin were generated and analyzed by SWISS-MODEL. Mutation screening identified only one heterozygous G-->A transition at nucleotide 32 in the first exon of alphaB-crystallin (CRYAB), resulting in an amino acid change from arginine to histidine at codon 11 (R11H). This mutation segregated in all available affected family members but was not observed in any of the unaffected persons of the family. The putative mutation disrupted a restriction site for the enzyme, Fnu4HI, in the affected family members. The disruption, however, was not found in any of the randomly selected ophthalmologically normal individuals or in 40 unrelated senile cataract patients. Computer-assisted prediction suggested that this mutation affected the biochemical properties as well as the structure of alphaB-crystallin. These results supported the idea that the novel R11H mutation was responsible for the autosomal dominant nuclear congenital cataract in this pedigree.

  17. A Heterozygous ZMPSTE24 Mutation Associated with Severe Metabolic Syndrome, Ectopic Fat Accumulation, and Dilated Cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Damien Galant

    2016-04-01

    Full Text Available ZMPSTE24 encodes the only metalloprotease, which transforms prelamin into mature lamin A. Up to now, mutations in ZMPSTE24 have been linked to Restrictive Dermopathy (RD, Progeria or Mandibulo-Acral Dysplasia (MAD. We report here the phenotype of a patient referred for severe metabolic syndrome and cardiomyopathy, carrying a mutation in ZMPSTE24. The patient presented with a partial lipodystrophic syndrome associating hypertriglyceridemia, early onset type 2 diabetes, and android obesity with truncal and abdominal fat accumulation but without subcutaneous lipoatrophy. Other clinical features included acanthosis nigricans, liver steatosis, dilated cardiomyopathy, and high myocardial and hepatic triglycerides content. Mutated fibroblasts from the patient showed increased nuclear shape abnormalities and premature senescence as demonstrated by a decreased Population Doubling Level, an increased beta-galactosidase activity and a decreased BrdU incorporation rate. Reduced prelamin A expression by siRNA targeted toward LMNA transcripts resulted in decreased nuclear anomalies. We show here that a central obesity without subcutaneous lipoatrophy is associated with a laminopathy due to a heterozygous missense mutation in ZMPSTE24. Given the high prevalence of metabolic syndrome and android obesity in the general population, and in the absence of familial study, the causative link between mutation and phenotype cannot be formally established. Nevertheless, altered lamina architecture observed in mutated fibroblasts are responsible for premature cellular senescence and could contribute to the phenotype observed in this patient.

  18. The association of factor V leiden mutation with recurrent pregnancy loss.

    Science.gov (United States)

    Kashif, Sumreen; Kashif, Muhammad Ali; Saeed, Anjum

    2015-11-01

    To determine the association of factor V Leiden mutation with recurrent pregnancy loss. The case-control study was conducted at the Department of Haematology, Armed Forces Institute of Pathology, Rawalpindi, Pakistan, from January to June 2012, and comprised women of 18 to 45 years of age who had a history of recurrent pregnancy loss, and controls with no history of pregnancy loss. All the subjects belonged to Punjabi ethnic group. Three ml blood was taken from cases and controls and deoxyribonucleic acid was extracted. In order to identify Factor V Leiden mutation, polymerase chain reaction method was utilised combined with the amplification refractory mutation system. Data was analysed using SPSS 17. Of the 112 subjects, 56(50%) were in each of the two groups. The presence of factor V Leiden mutation among the cases was 3(5.4%) while it was absent among the controls. The mutation was significantly associated with recurrent pregnancy loss (p=0.017).Recurrent pregnancy loss was higher in cases than controls (p=0.001). Factor V Leiden mutation, Recurrent pregnancy loss, PCR (Polymerase chain reaction).

  19. A mutation in PRKAG3 associated with excess glycogen content in pig skeletal muscle.

    Science.gov (United States)

    Milan, D; Jeon, J T; Looft, C; Amarger, V; Robic, A; Thelander, M; Rogel-Gaillard, C; Paul, S; Iannuccelli, N; Rask, L; Ronne, H; Lundström, K; Reinsch, N; Gellin, J; Kalm, E; Roy, P L; Chardon, P; Andersson, L

    2000-05-19

    A high proportion of purebred Hampshire pigs carries the dominant RN- mutation, which causes high glycogen content in skeletal muscle. The mutation has beneficial effects on meat content but detrimental effects on processing yield. Here, it is shown that the mutation is a nonconservative substitution (R200Q) in the PRKAG3 gene, which encodes a muscle-specific isoform of the regulatory gamma subunit of adenosine monophosphate-activated protein kinase (AMPK). Loss-of-function mutations in the homologous gene in yeast (SNF4) cause defects in glucose metabolism, including glycogen storage. Further analysis of the PRKAG3 signaling pathway may provide insights into muscle physiology as well as the pathogenesis of noninsulin-dependent diabetes mellitus in humans, a metabolic disorder associated with impaired glycogen synthesis.

  20. The R900S mutation in CACNA1S associated with hypokalemic periodic paralysis.

    Science.gov (United States)

    Ke, Qing; He, Fangping; Lu, Lingping; Yu, Ping; Jiang, Yajian; Weng, Chen; Huang, Hui; Yi, Xin; Qi, Ming

    2015-12-01

    Primary hypokalemic periodic paralysis is an autosomal dominant skeletal muscle channelopathy. In the present study, we investigated the genotype and phenotype of a Chinese hypokalemic periodic paralysis family. We used whole-exome next-generation sequencing to identify a mutation in the calcium channel, voltage-dependent, L type, alpha subunit gene (CACNA1S), R900S, which is a rare mutation associated with hypokalemic periodic paralysis. We first present a clinical description of hypokalemic periodic paralysis patients harboring CACNA1SR900S mutations: they were non-responsive to acetazolamide, but combined treatment with triamterene and potassium supplements decreased the frequency of muscle weakness attacks. All male carriers of the R900S mutation experienced such attacks, but all three female carriers were asymptomatic. This study provides further evidence for the phenotypic variation and pharmacogenomics of hypokalemic periodic paralysis. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Founder mutations and genotype-phenotype correlations in Meckel-Gruber syndrome and associated ciliopathies

    Directory of Open Access Journals (Sweden)

    Szymanska Katarzyna

    2012-10-01

    Full Text Available Abstract Background Meckel-Gruber syndrome (MKS is an autosomal recessive lethal condition that is a ciliopathy. MKS has marked phenotypic variability and genetic heterogeneity, with mutations in nine genes identified as causative to date. Methods Families diagnosed with Meckel-Gruber syndrome were recruited for research studies following informed consent. DNA samples were analyzed by microsatellite genotyping and direct Sanger sequencing. Results We now report the genetic analyses of 87 individuals from 49 consanguineous and 19 non-consanguineous families in an unselected cohort with reported MKS, or an associated severe ciliopathy in a kindred. Linkage and/or direct sequencing were prioritized for seven MKS genes (MKS1, TMEM216, TMEM67/MKS3, RPGRIP1L, CC2D2A, CEP290 and TMEM237 selected on the basis of reported frequency of mutations or ease of analysis. We have identified biallelic mutations in 39 individuals, of which 13 mutations are novel and previously unreported. We also confirm general genotype-phenotype correlations. Conclusions TMEM67 was the most frequently mutated gene in this cohort, and we confirm two founder splice-site mutations (c.1546 + 1 G > A and c.870-2A > G in families of Pakistani ethnic origin. In these families, we have also identified two separate founder mutations for RPGRIP1L (c. 1945 C > T p.R649X and CC2D2A (c. 3540delA p.R1180SfsX6. Two missense mutations in TMEM67 (c. 755 T > C p.M252T, and c. 1392 C > T p.R441C are also probable founder mutations. These findings will contribute to improved genetic diagnosis and carrier testing for affected families, and imply the existence of further genetic heterogeneity in this syndrome.

  2. Founder mutations and genotype-phenotype correlations in Meckel-Gruber syndrome and associated ciliopathies.

    Science.gov (United States)

    Szymanska, Katarzyna; Berry, Ian; Logan, Clare V; Cousins, Simon Rr; Lindsay, Helen; Jafri, Hussain; Raashid, Yasmin; Malik-Sharif, Saghira; Castle, Bruce; Ahmed, Mushtag; Bennett, Chris; Carlton, Ruth; Johnson, Colin A

    2012-10-01

    Meckel-Gruber syndrome (MKS) is an autosomal recessive lethal condition that is a ciliopathy. MKS has marked phenotypic variability and genetic heterogeneity, with mutations in nine genes identified as causative to date. Families diagnosed with Meckel-Gruber syndrome were recruited for research studies following informed consent. DNA samples were analyzed by microsatellite genotyping and direct Sanger sequencing. We now report the genetic analyses of 87 individuals from 49 consanguineous and 19 non-consanguineous families in an unselected cohort with reported MKS, or an associated severe ciliopathy in a kindred. Linkage and/or direct sequencing were prioritized for seven MKS genes (MKS1, TMEM216, TMEM67/MKS3, RPGRIP1L, CC2D2A, CEP290 and TMEM237) selected on the basis of reported frequency of mutations or ease of analysis. We have identified biallelic mutations in 39 individuals, of which 13 mutations are novel and previously unreported. We also confirm general genotype-phenotype correlations. TMEM67 was the most frequently mutated gene in this cohort, and we confirm two founder splice-site mutations (c.1546 + 1 G > A and c.870-2A > G) in families of Pakistani ethnic origin. In these families, we have also identified two separate founder mutations for RPGRIP1L (c. 1945 C > T p.R649X) and CC2D2A (c. 3540delA p.R1180SfsX6). Two missense mutations in TMEM67 (c. 755 T > C p.M252T, and c. 1392 C > T p.R441C) are also probable founder mutations. These findings will contribute to improved genetic diagnosis and carrier testing for affected families, and imply the existence of further genetic heterogeneity in this syndrome.

  3. Characterization of mutations in streptomycin-resistant Mycobacterium tuberculosis isolates in Sichuan, China and the association between Beijing-lineage and dual-mutation in gidB.

    Science.gov (United States)

    Sun, Honghu; Zhang, Congcong; Xiang, Ling; Pi, Rui; Guo, Zhen; Zheng, Chao; Li, Song; Zhao, Yuding; Tang, Ke; Luo, Mei; Rastogi, Nalin; Li, Yuqing; Sun, Qun

    2016-01-01

    Mutations in rpsL, rrs, and gidB are well linked to streptomycin (STR) resistance, some of which are suggested to be potentially associated with Mycobacterium tuberculosis genotypic lineages in certain geographic regions. In this study, we aimed to investigate the mutation characteristics of streptomycin resistance and the relationship between the polymorphism of drug-resistant genes and the lineage of M. tuberculosis isolates in Sichuan, China. A total of 227 M. tuberculosis clinical isolates, including 180 STR-resistant and 47 pan-susceptible isolates, were analyzed for presence of mutations in the rpsL, rrs and gidB loci. Mutation K43R in rpsL was strongly associated with high-level streptomycin resistance (P mutations in rrs and gidB potentially contributed to low-level resistance (P genotype, however, in STR-resistant strains, Beijing genotype was significantly correlated with high-level STR resistance, as well as the rpsL mutation K43R (P genotype has an evolutionary advantage under streptomycin pressure. Notably, in all isolates of Beijing genotype, a dual mutation E92D (a276c) and A205A (a615g) in gidB was detected, suggesting a highly significant association between this dual mutation and Beijing genotype.

  4. Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2

    Science.gov (United States)

    Alter, Blanche P; Rosenberg, Philip S; Brody, Lawrence C

    2007-01-01

    Patients with biallelic mutations in BRCA2 are in Fanconi anaemia group D1. We analysed the severity of the mutations in 27 cases, classified according to their association with breast cancer in heterozygotes, and their predicted functional effect. Twenty mutations were frameshifts or truncations, three involved splice sites, five were missense variants of unknown severity and two were benign polymorphisms. Five patients had VACTERL‐H association. Leukaemia was reported in 13 patients, and solid tumours in 15; 6 patients had two or more malignancies. The cumulative probability of any malignancy was 97% by age 5.2 years. IVS7+1G→A and IVS7+2T→G were associated with AML, and 886delGT and 6174delT with brain tumours. However, patients with other alleles remained at very high risk of these events. Missense mutations formed a distinct cluster in a highly conserved region of the BRCA2 protein. The small group of patients with biallelic mutations in BRCA2 is distinctive in the severity of the phenotype, and early onset and high rates of leukaemia and specific solid tumours, and may comprise an extreme variant of Fanconi anaemia. Several of the alleles were not associated with cancer in presumed carriers, and thus counselling presents more uncertainties than usual. PMID:16825431

  5. Is there a biological cost of protein disorder? Analysis of cancer-associated mutations.

    Science.gov (United States)

    Pajkos, Mátyás; Mészáros, Bálint; Simon, István; Dosztányi, Zsuzsanna

    2012-01-01

    As many diseases can be traced back to altered protein function, studying the effect of genetic variations at the level of proteins can provide a clue to understand how changes at the DNA level lead to various diseases. Cellular processes rely not only on proteins with well-defined structure but can also involve intrinsically disordered proteins (IDPs) that exist as highly flexible ensembles of conformations. Disordered proteins are mostly involved in signaling and regulatory processes, and their functional repertoire largely complements that of globular proteins. However, it was also suggested that protein disorder entails an increased biological cost. This notion was supported by a set of individual IDPs involved in various diseases, especially in cancer, and the increased amount of disorder observed among disease-associated proteins. In this work, we tested if there is any biological risk associated with protein disorder at the level of single nucleotide mutations. Specifically, we analyzed the distribution of mutations within ordered and disordered segments. Our results demonstrated that while neutral polymorphisms were more likely to occur within disordered segments, cancer-associated mutations had a preference for ordered regions. Additionally, we proposed an alternative explanation for the association of protein disorder and the involvement in cancer with the consideration of functional annotations. Individual examples also suggested that although disordered segments are fundamental functional elements, their presence is not necessarily accompanied with an increased mutation rate in cancer. The presented study can help to understand how the different structural properties of proteins influence the consequences of genetic mutations.

  6. A MITF mutation associated with a dominant white phenotype and bilateral deafness in German Fleckvieh cattle.

    Directory of Open Access Journals (Sweden)

    Ute Philipp

    Full Text Available A dominantly inherited syndrome associated with hypopigmentation, heterochromia irides, colobomatous eyes and bilateral hearing loss has been ascertained in Fleckvieh cattle (German White Fleckvieh syndrome. This syndrome has been mapped to bovine chromosome (BTA 22 using a genome-wide association study with the bovine high density single nucleotide polymorphism array. An R210I missense mutation has been identified within microphthalmia-associated transcription factor (MITF as responsible for this syndrome. The mutation is located in the highly conserved basic region of the protein and causes a negative-dominant effect. SOX10 and PAX3 promoter binding site mutations in MITF could be ruled out as causative for the German White Fleckvieh syndrome. Molecular characterization of this newly detected bovine syndrome means a large animal model is now available for the Tietz syndrome in humans.

  7. Brittle Cornea Syndrome Associated with a Missense Mutation in the Zinc-Finger 469 Gene

    DEFF Research Database (Denmark)

    Christensen, Anne Elisabeth; Knappskog, Per Morten; Midtbø, Marit

    2010-01-01

    Purpose: To investigate the diverse clinical manifestations, identify the causative mutation and explain the association with red hair in a family with brittle cornea syndrome (BCS). Methods: Eight family members in three generations underwent ophthalmic, dental, and general medical examination......, dental anomalies, hearing loss and minor cardiac defects. The morphologies of the skin biopsies were normal except that in some areas slightly thinner collagen fibrils were seen in one of the affected individuals. Molecular genetic analysis revealed a novel missense mutation of ZNF469, c.10016G....... Reduced BMD and atypical dental crown morphology have not been reported previously. We confirm that BCS is associated with mutations in ZNF469. The association with red hair in some individuals with BCS is likely to occur by chance....

  8. A MITF Mutation Associated with a Dominant White Phenotype and Bilateral Deafness in German Fleckvieh Cattle

    Science.gov (United States)

    Philipp, Ute; Lupp, Bettina; Mömke, Stefanie; Stein, Veronika; Tipold, Andrea; Eule, Johanna Corinna; Rehage, Jürgen; Distl, Ottmar

    2011-01-01

    A dominantly inherited syndrome associated with hypopigmentation, heterochromia irides, colobomatous eyes and bilateral hearing loss has been ascertained in Fleckvieh cattle (German White Fleckvieh syndrome). This syndrome has been mapped to bovine chromosome (BTA) 22 using a genome-wide association study with the bovine high density single nucleotide polymorphism array. An R210I missense mutation has been identified within microphthalmia-associated transcription factor (MITF) as responsible for this syndrome. The mutation is located in the highly conserved basic region of the protein and causes a negative-dominant effect. SOX10 and PAX3 promoter binding site mutations in MITF could be ruled out as causative for the German White Fleckvieh syndrome. Molecular characterization of this newly detected bovine syndrome means a large animal model is now available for the Tietz syndrome in humans. PMID:22174915

  9. Does bilirubin protect against hemochromatosis gene (HFE) related mortality?

    NARCIS (Netherlands)

    Alizadeh, Behrooz Z.; Njajou, Omer T.; Houwing-Duistermaat, Jeanine J.; de Jong, Gerard; Vergeer, Jeannette M.; Hofman, Albert; Pols, Huibert A.P.; van Duijn, Cornelia M.

    2004-01-01

    Serum bilirubin is an important antioxidant that is found at increased levels in hereditary hemochromatosis patients. We hypothesized that increased levels of serum bilirubin may play a protective role against oxidative stress induced by iron overload in carriers of mutations in the hereditary hemoc

  10. Putative compensatory mutations in the rpoC gene of rifampin-resistant Mycobacterium tuberculosis are associated with ongoing transmission.

    Science.gov (United States)

    de Vos, M; Müller, B; Borrell, S; Black, P A; van Helden, P D; Warren, R M; Gagneux, S; Victor, T C

    2013-02-01

    Rifampin resistance in clinical isolates of Mycobacterium tuberculosis arises primarily through the selection of bacterial variants harboring mutations in the 81-bp rifampin resistance-determining region of the rpoB gene. While these mutations were shown to infer a fitness cost in the absence of antibiotic pressure, compensatory mutations in rpoA and rpoC were identified which restore the fitness of rifampin-resistant bacteria carrying mutations in rpoB. To investigate the epidemiological relevance of these compensatory mutations, we analyzed 286 drug-resistant and 54 drug-susceptible clinical M. tuberculosis isolates from the Western Cape, South Africa, a high-incidence setting of multidrug-resistant tuberculosis. Sequencing of a portion of the RpoA-RpoC interaction region of the rpoC gene revealed that 23.5% of all rifampin-resistant isolates tested carried a nonsynonymous mutation in this region. These putative compensatory mutations in rpoC were associated with transmission, as 30.8% of all rifampin-resistant isolates with an IS6110 restriction fragment length polymorphism (RFLP) pattern belonging to a recognized RFLP cluster harbored putative rpoC mutations. Such mutations were present in only 9.4% of rifampin-resistant isolates with unique RFLP patterns (P mutations were associated with specific strain genotypes and the rpoB S531L rifampin resistance mutation. Among isolates harboring this rpoB mutation, 44.1% also harbored rpoC mutations, while only 4.1% of the isolates with other rpoB mutations exhibited mutations in rpoC (P mutations in the transmission of multidrug-resistant tuberculosis and illustrates how epistatic interactions between drug resistance-conferring mutations, compensatory mutations, and different strain genetic backgrounds might influence compensatory evolution in drug-resistant M. tuberculosis.

  11. Common FLG mutation K4671X not associated with atopic dermatitis in Han Chinese in a family association study.

    Directory of Open Access Journals (Sweden)

    Ruhong Cheng

    Full Text Available BACKGROUND: Filaggrin gene (FLG mutations have been identified as the cause of ichthyosis vulgaris (IV and major predisposing factors for atopic dermatitis (AD. The relationship among AD, IV and FLG mutations has not been clarified yet. Mutations 3321delA and K4671X, two of the most common mutations in Chinese patients, were both statistically associated with AD in case-control studies. MATERIALS AND METHODS: A group of 100 family trios (a total of 300 members with one affected AD proband and both parents were recruited and screened for three filaggrin null mutations (3222del4, 3321delA and K4671X. The subjects' manifestations of AD and IV were assessed by two experienced dermatologists and recorded in detail. The relationship of common mutations to AD were assessed using both case-control and family-based tests of association. Filaggrin expression was measured in skin of 3 subjects with K4671X heterozygote and the normal control using quantitative real-time RT-PCR and immunohistochemistry. RESULTS: Of 100 probands for AD, 22 were carriers for common FLG mutations and only 2 of them were from 40 none-IV family trios (5.00%, consistent with that of the healthy control group (3.99%, P>0.05. Significant statistical associations were revealed between AD and 3321delA (P<0.001, odds ratio 12.28, 95% confidence interval 3.35-44.98 as well as K4671X (P = 0.002, odds ratio 4.53, 95% confidence interval 1.77-11.60. The family-based approach revealed that 3321delA was over-transmitted to AD offspring from parents (T:U = 12∶1, P = 0.003 but failed to demonstrate transmission disequilibrium between K4671X and AD (T:U = 10∶8, P = 0.815. Moreover, compared to the normal control, filaggrin expression at both mRNA and protein levels in epidermis of subjects with K4671X(heter was not reduced. CONCLUSIONS: AD patients from none-IV family trios have low probability of carrying FLG mutations. The present family samples confirmed the

  12. Severe myoclonus-dystonia syndrome associated with a novel epsilon-sarcoglycan gene truncating mutation.

    Science.gov (United States)

    Maréchal, Lucie; Raux, Grégory; Dumanchin, Cécile; Lefebvre, Guillaume; Deslandre, Emmanuelle; Girard, Carole; Campion, Dominique; Parain, Dominique; Frebourg, Thierry; Hannequin, Didier

    2003-05-15

    Myoclonus-dystonia syndrome (MDS) is an autosomal dominant disorder characterized by myoclonic and dystonic muscle contractions, associated with psychiatric manifestations. MDS is usually considered as a benign disease. In most of the families, MDS is linked to chromosome 7q21 and mutations within epsilon-sarcoglycan (SGCE) gene have been recently described. We report a MDS family with a severe and heterogeneous phenotype, including myoclonus with important functional impact and several psychiatric features, characterized by obsessive-compulsive disorder, depression, and anxiety. This phenotype was shown to be associated with a novel truncating mutation located within exon 4 of SGCE.

  13. Emergence and prevalence of cytomegalovirus UL97 mutations associated with ganciclovir resistance in AIDS patients.

    Science.gov (United States)

    Gilbert, C; Handfield, J; Toma, E; Lalonde, R; Bergeron, M G; Boivin, G

    1998-01-22

    To evaluate the prevalence of the most common cytomegalovirus (CMV) UL97 mutations associated with ganciclovir resistance directly in polymorphonuclear leukocytes (PMNL) of patients with AIDS and CMV retinitis. Also to correlate the presence (or absence) of these mutations with the systemic CMV viral load and the ophthalmologic outcome of these subjects. Monthly blood samples were obtained from 19 patients with AIDS and CMV retinitis who had been treated with systemic ganciclovir for > or = 2 months. Detection of CMV UL97 mutations was done using nested PCR amplification followed by restriction enzyme analysis. The viral load was assessed with a polymerase chain reaction-based assay and non-isotopic hybridization detection. CMV UL97 mutations were detected in PMNL of four of 13 (30.8%) patients who had been treated with ganciclovir for > or = 3 months but in none of six patients who had been treated for 10000 copies per 10(5) PMNL contrasting with the copy numbers in the 15 subjects without mutations (mean, 492.9 copies per 10(5) PMNL after a mean of 146.8 days of ganciclovir). The prevalence of the most common CMV UL97 mutations associated with ganciclovir resistance in PMNL of patients with AIDS treated for > or = 3 months (30.8%) appears to be higher than the rate of emergence of ganciclovir-resistant CMV isolates as previously reported using phenotypic assays (about 8%). Moreover, the detection of these mutations is associated with a considerable increase in the CMV DNA load in the blood as well as with progression of CMV retinitis during ganciclovir therapy.

  14. Common Mediterranean Fever (MEFV Gene Mutations Associated with Ankylosing Spondylitis in Turkish Population

    Directory of Open Access Journals (Sweden)

    Serbulent Yigit

    2012-01-01

    Full Text Available Ankylosing spondylitis (AS is a common inflammatory rheumatic disease. Mediterranean fever (MEFV gene, which has already been identified as being responsible for familial Mediterranean fever (FMF, is also a suspicious gene for AS because of the clinical association of these two diseases. The aim of this study was to explore the frequency and clinical significance of MEFV gene mutations (M694V, M680I, V726A, E148Q and P369S in a cohort of Turkish patients with AS. Genomic DNAs of 103 AS patients and 120 controls were isolated and genotyped using polymerase chain reaction (PCR and restriction fragment length polymorphism (RFLP methods. There was a statistically significant difference of the MEFV gene mutation carrier rates between AS patients and healthy controls (p = 0.004, OR: 2.5, 95% CI: 1.32–4.76. This association was also observed in allele frequencies (p = 0.005, OR: 2.3, 95% CI: 1.27–4.2. A relatively higher frequency was observed for M694V mutation in AS patients than controls (10.7% versus 4.2% , p = 0.060. There were no significant differences between MEFV mutation carriers and non-carriers with respect to the clinical and demographic characteristics. The results of this study suggest that MEFV gene mutations are positively associated with a predisposition to develop AS.

  15. A novel BAP1 mutation is associated with melanocytic neoplasms and thyroid cancer.

    Science.gov (United States)

    McDonnell, Kevin J; Gallanis, Gregory T; Heller, Kathleen A; Melas, Marilena; Idos, Gregory E; Culver, Julie O; Martin, Sue-Ellen; Peng, David H; Gruber, Stephen B

    2016-03-01

    Germline mutations in the tumor suppressor gene, BRCA-1 associated protein (BAP1), underlie a tumor predisposition syndrome characterized by increased risk for numerous cancers including uveal melanoma, melanocytic tumors and mesothelioma, among others. In the present study we report the identification of a novel germline BAP1 mutation, c.1777C>T, which produces a truncated BAP1 protein product and segregates with cancer. Family members with this mutation demonstrated a primary clinical phenotype of autosomal dominant, early-onset melanocytic neoplasms with immunohistochemistry (IHC) of these tumors demonstrating lack of BAP1 protein expression. In addition, family members harboring the BAP1 c.1777C>T germline mutation developed other neoplastic disease including thyroid cancer. IHC analysis of the thyroid cancer, as well, demonstrated loss of BAP1 protein expression. Our investigation identifies a new BAP1 mutation, further highlights the relevance of BAP1 as a clinically important tumor suppressor gene, and broadens the range of cancers associated with BAP1 inactivation. Further study will be required to understand the full scope of BAP1-associated neoplastic disease.

  16. A novel mitochondrial mutation m.8989G>C associated with neuropathy, ataxia, retinitis pigmentosa - the NARP syndrome.

    Science.gov (United States)

    Duno, Morten; Wibrand, Flemming; Baggesen, Kirsten; Rosenberg, Thomas; Kjaer, Niels; Frederiksen, Anja L

    2013-02-25

    The archetypal NARP syndrome is almost exclusively associated with the m.8993T>C/G mutation in the sixth subunit of the mitochondrial ATP synthase, whereas other mutations in the MT-ATP6 gene primarily associate with Leigh syndrome or Leber's hereditary optic neuropathy (LHON). We report a novel mitochondrial point mutation, m.8989G>C, in a patient presenting with neuropathy, ataxia and retinitis pigmentosa constituting the classical NARP phenotype. This mutation alters the amino acid right next to canonical NARP mutation. We suggest that classic NARP syndrome relates to a defined dysfunction of p.MT-ATP6.

  17. A novel missense mutation of the DDHD1 gene associated with juvenile amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Chujun Wu

    2016-12-01

    Full Text Available Background: Juvenile amyotrophic lateral sclerosis (jALS is a rare form of ALS with an onset age of less than 25 years and is frequently thought to be genetic in origin. DDHD1 gene mutations have been reported to be associated with the SPG28 subtype of autosomal recessive HSP but have never been reported in jALS patients.Methods: Gene screens for the causative genes of ALS, HSP and CMT using next-generation sequencing (NGS technologies were performed on a jALS patient. Sanger sequencing was used to validate identified variants and perform segregation analysis.Results: We identified a novel c.1483A>G (p.Met495Val homozygous missense mutation of the DDHD1 gene in the jALS patient. All of his parents and young bother were heterozygous for this mutation. The mutation was not found in 800 Chinese control subjects or the data of dbSNP, ExAC and 1000G.Conclusion: The novel c.1483A>G (p.Met495Val missense mutation of the DDHD1 gene could be a causative mutation of autosomal recessive jALS.

  18. Isolated idiopathic chronic pancreatitis associated with a compound heterozygosity for two mutations of the CFTR gene.

    Science.gov (United States)

    Reboul, Marie-Pierre; Laharie, David; Amouretti, Michel; Lacombe, Didier; Iron, Albert

    2003-01-01

    We report the case of a patient suffering from idiopathic chronic pancreatitis (ICP) and compound heterozygous for mutations G542X and S1235R of the cystic fibrosis transmembrane regulator (CFTR) gene. The patient had normal sweat test and no other clinical sign usually linked with a typical or moderate pathology (bronchiectasis, nasal polyposis, congenital absence of the vas deferens) of the CFTR gene. G542X is a severe mutation, which is usually found in classical cystic fibrosis when associated with other severe mutations. S1235R is a quite rare abnormality recently reported as being potentially pathogenic when combined in trans with a second CF mutation. Our case is quite similar to the only other six patients in the literature in whom only the pancreas is affected and who bear a rare mutation with moderate effect. The history and the clinical features of our patient indicate an unambiguous isolated ICP in which the presence of the S1235R mutation--in trans with regard to G542X--is likely responsible for the ICP phenotype. This case could throw light on some of the as yet poorly known abnormalities of the CFTR gene in the ICP phenotype.

  19. SAMHD1 Gene Mutations Are Associated with Cerebral Large-Artery Atherosclerosis.

    Science.gov (United States)

    Li, Wei; Xin, Baozhong; Yan, Junpeng; Wu, Ying; Hu, Bo; Liu, Liping; Wang, Yilong; Ahn, Jinwoo; Skowronski, Jacek; Zhang, Zaiqiang; Wang, Yongjun; Wang, Heng

    2015-01-01

    To investigate whether one or more SAMHD1 gene mutations are associated with cerebrovascular disease in the general population using a Chinese stroke cohort. Patients with a Chinese Han background (N = 300) diagnosed with either cerebral large-artery atherosclerosis (LAA, n = 100), cerebral small vessel disease (SVD, n = 100), or other stroke-free neurological disorders (control, n = 100) were recruited. Genomic DNA from the whole blood of each patient was isolated, and direct sequencing of the SAMHD1 gene was performed. Both wild type and mutant SAMHD1 proteins identified from the patients were expressed in E. coli and purified; then their dNTPase activities and ability to form stable tetramers were analysed in vitro. Three heterozygous mutations, including two missense mutations c.64C>T (P22S) and c.841G>A (p.E281K) and one splice site mutation c.696+2T>A, were identified in the LAA group with a prevalence of 3%. No mutations were found in the patients with SVD or the controls (p = 0.05). The mutant SAMHD1 proteins were functionally impaired in terms of their catalytic activity as a dNTPase and ability to assemble stable tetramers. Heterozygous SAMHD1 gene mutations might cause genetic predispositions that interact with other risk factors, resulting in increased vulnerability to stroke.

  20. SAMHD1 Gene Mutations Are Associated with Cerebral Large-Artery Atherosclerosis

    Directory of Open Access Journals (Sweden)

    Wei Li

    2015-01-01

    Full Text Available Background. To investigate whether one or more SAMHD1 gene mutations are associated with cerebrovascular disease in the general population using a Chinese stroke cohort. Methods. Patients with a Chinese Han background (N=300 diagnosed with either cerebral large-artery atherosclerosis (LAA, n=100, cerebral small vessel disease (SVD, n=100, or other stroke-free neurological disorders (control, n=100 were recruited. Genomic DNA from the whole blood of each patient was isolated, and direct sequencing of the SAMHD1 gene was performed. Both wild type and mutant SAMHD1 proteins identified from the patients were expressed in E. coli and purified; then their dNTPase activities and ability to form stable tetramers were analysed in vitro. Results. Three heterozygous mutations, including two missense mutations c.64C>T (P22S and c.841G>A (p.E281K and one splice site mutation c.696+2T>A, were identified in the LAA group with a prevalence of 3%. No mutations were found in the patients with SVD or the controls (p=0.05. The mutant SAMHD1 proteins were functionally impaired in terms of their catalytic activity as a dNTPase and ability to assemble stable tetramers. Conclusions. Heterozygous SAMHD1 gene mutations might cause genetic predispositions that interact with other risk factors, resulting in increased vulnerability to stroke.

  1. CTNNB1 Mutations and Estrogen Receptor Expression in Neuromuscular Choristoma and Its Associated Fibromatosis.

    Science.gov (United States)

    Carter, Jodi M; Howe, Benjamin M; Hawse, John R; Giannini, Caterina; Spinner, Robert J; Fritchie, Karen J

    2016-10-01

    Neuromuscular choristoma (NMC) is a very rare, developmental malformation characterized by the endoneurial intercalation of mature muscle fibers among peripheral nerve fibers. NMC typically arises in the major proximal peripheral nerves, most commonly the sciatic nerve, and may involve the lumbosacral and brachial plexus. Patients present clinically with progressive neuropathy or plexopathy. NMC is strongly associated with development of a fibromatosis, histologically identical to conventional desmoid-type fibromatosis (NMC-fibromatosis). The development of NMC-fibromatosis is often precipitated by iatrogenic trauma (ie, biopsy). Desmoid-type fibromatosis is characterized by CTNNB1 exon 3 mutations, which result in aberrant nuclear β-catenin localization and dysregulated canonical Wnt signaling. In contrast, the pathogenesis of NMC and NMC-fibromatosis is unknown. Desmoid-type fibromatosis expresses estrogen receptors (ER), specifically the ER-beta isoform (ERβ), and endocrine therapies may be used in surgically unresectable cases. In contrast, the ER expression profile of NMC-fibromatosis is unknown. We evaluated a series of NMC and NMC-fibromatosis for CTNNB1 mutations, β-catenin expression, and ER isoform expression. Five NMCs occurred in 2 female and 3 male patients (median age: 14 y, range T (p.S45F) and 1 c.121 A>G (p.T41A). Four patients subsequently developed NMC-fibromatosis, and all 4 cases contained CTNNB1 mutations, including 1 p.T41A and 3 p.S45F mutations. In 3 patients, the NMC and NMC-fibromatosis had identical CTNNB1 mutations. Only 1 NMC had no detectable CTNNB1 mutation; however, the patient's subsequent NMC-fibromatosis had a CTNNB1 p.T41A mutation. All NMC and NMC-fibromatosis showed aberrant nuclear localization of β-catenin, nuclear ERβ expression, and no ERα expression. The presence of CTNNB1 mutations both in NMC and NMC-fibromatosis may be a shared molecular genetic abnormality underlying their pathogenesis.

  2. Blepharophimosis and bilateral Duane syndrome associated with a FOXL2 mutation.

    Science.gov (United States)

    Vincent, A L; Watkins, W J; Sloan, B H; Shelling, A N

    2005-12-01

    This case describes the novel coexistence of sporadic blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and bilateral type I Duane syndrome in a female infant, with a FOXL2 mutation. Mutational analysis of FOXL2 demonstrated a 30-nucleotide duplication (c.672(-)701dup30) within the polyalanine tract of FOXL2. The association of BPES and Duane syndrome represents a novel phenotype which may suggest a greater pleiotropic effect of FOXL2 in development. During the period of the 4-8th week of embryonic development, the cranial nerves, their nuclei and the corresponding innervation to the extraocular muscles develop, the extraocular muscles undergo development and differentiation. This coincides with the period of time that FOXL2 is expressed strongly in the developing eyelids and the surrounding tissues. Forkhead genes are transcription factors and likely to be involved in signal transduction pathways. This case expands the spectrum of FOXL2 mutations associated with BPES.

  3. A Young Male Patient With Multiple Thromboembolisms Associated With Factor V Leiden Mutation.

    Science.gov (United States)

    Çinier, Göksel; Öz, Ahmet; Tekkesin, Ahmet Ilker; Hayıroğlu, Mert İlker; Keskin, Muhammed; Avsar, Şahin

    2016-09-28

    Factor V Leiden (FVL) mutation is the most common hereditary thrombophilia. Association of this mutation with venous thrombosis is well established. However, there are several conflicting results regarding the association of FVL with arterial thrombosis, acute coronary syndrome, and intracardiac thrombosis. In this case report, we present a 44-yearold male patient with a medical history of both arterial and venous thrombosis who came to our emergency department with chest pain. After the initial evaluation he was diagnosed as having acute coronary syndrome and transthoracic echocardiography revealed an intracardiac apical thrombus. Coronary angiography showed non-critical stenosis. Thrombophilia panel was studied and the patient was found to be heterozygotic for FVL mutation. An apical thrombus was extracted surgically because of the high risk of systemic embolization.

  4. Missense mutations in desmin associated with familial cardiac and skeletal myopathy.

    Science.gov (United States)

    Goldfarb, L G; Park, K Y; Cervenáková, L; Gorokhova, S; Lee, H S; Vasconcelos, O; Nagle, J W; Semino-Mora, C; Sivakumar, K; Dalakas, M C

    1998-08-01

    Desmin-related myopathy (OMIM 601419) is a familial disorder characterized by skeletal muscle weakness associated with cardiac conduction blocks, arrhythmias and restrictive heart failure, and by intracytoplasmic accumulation of desmin-reactive deposits in cardiac and skeletal muscle cells. The underlying molecular mechanisms are unknown. Involvement of the desmin gene (DES) has been excluded in three families diagnosed with desmin-related myopathy. We report two new families with desmin-related cardioskeletal myopathy associated with mutations in the highly conserved carboxy-terminal end of the desmin rod domain. A heterozygous A337P mutation was identified in a family with an adult-onset skeletal myopathy and mild cardiac involvement. Compound heterozygosity for two other mutations, A360P and N393I, was detected in a second family characterized by childhood-onset aggressive course of cardiac and skeletal myopathy.

  5. Association between {sup 18}F-FDG avidity and the BRAF mutation in papillary thyroid carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Suk Hyun; Han, Sang Won; Lee, Hyo Sang; Chae, Sun Young; Lee, Jong Jin; Song, Dong Eun; Ryu, Jin Sook [Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of)

    2016-03-15

    The BRAF mutation, a potential prognostic factor in papillary thyroid carcinoma (PTC), is associated with a high expression of the glucose transporter gene. We investigated which clinicopathologic factors, including BRAF mutation status, influence {sup 18}F-fluoro-2-deoxyglucose ({sup 18}F-FDG) avidity. We retrospectively reviewed 55 patients who underwent BRAF analysis from biopsy-confirmed PTC and {sup 18}F-FDG positron emission tomography/computed tomography within 6 months before undergoing thyroid surgery from September 2008 to August 2014. Tumors were considered to be {sup 18}F-FDG avid if the uptake was greater than that of the liver. {sup 18}F-FDG uptake of PTCs was also analyzed semiquantitatively using SUV{sub max}. The association between {sup 18}F-FDG avidity and clinicopathologic variables (age, tumor size, perithyroidal extension, cervical lymph node status, and BRAF mutation status) was investigated. Twenty-nine (52.7 %) of 55 patients had {sup 18}F-FDG-avid PTCs. PTCs with the BRAF mutation showed higher {sup 18}F-FDG avidity (24/38, 63.2 %) than those without (5/17, 29.4 %). The BRAF mutation (p = 0.025) and tumor size (p = 0.003) were significantly associated with {sup 18}F-FDG avidity in univariate analysis, and the BRAF mutation status remained significant after adjusting for tumor size in multivariate analysis (p = 0.015). In the subgroup of tumor size ≥ 1 cm, the BRAF mutation was the only factor significantly associated with {sup 18}F-FDG avidity (p = 0.021). The mean SUV{sub max} of PTCs with the BRAF mutation was significantly higher than that of those without (4.89 ± 6.12 vs. 1.96 ± 1.10, p = 0.039). The BRAF mutation must be one of the most important factors influencing {sup 18}F-FDG avidity in PTCs, especially in those with a tumor size ≥ 1 cm.

  6. Mutations in the hereditary haemochromatosis gene HFE in professional endurance athletes

    OpenAIRE

    Chicharro, J.; Hoyos, J; Gomez-Gallego, F; Villa, J.; Bandres, F; Celaya, P; Jimenez, F.; Alonso, J.; Cordova, A; Lucia, A

    2004-01-01

    Background: Hereditary haemochromatosis, a disease that affects iron metabolism, progresses with a greater or lesser tendency to induce iron overload, possibly leading to severe organ dysfunction. Most elite endurance athletes take iron supplements during their active sporting life, which could aggravate this condition.

  7. Genetic studies of Polish migraine patients: screening for causative mutations in four migraine-associated genes.

    Science.gov (United States)

    Domitrz, Izabela; Kosiorek, Michalina; Żekanowski, Cezary; Kamińska, Anna

    2016-01-08

    Migraine is the most common neurological disorder, affecting approximately 12 % of the adult population worldwide, caused by both environmental and genetic factors. Three causative genes have been identified in familial hemiplegic migraine (FHM) families: CACNA1A, ATP1A2, and SCNA1A. Recently, several mutations in KCNK18 have also been found as causative factors in migraine development. The aim of our study was to identify the genetic background of migraine in the Polish population. Sixty patients with migraine without aura (MO) or with different types of migraine with aura (MA), including sporadic hemiplegic, familial hemiplegic, and probable familial hemiplegic, were screened for mutations in the four genes previously linked with different types of migraine (ATP1A2, CACNA1A, SCN1A, and KCNK18). Two missense mutations were found. One novel mutation in SCN1A, encoding α subunit of sodium channel, causing amino acid change M1500V localized to a region encoding inactivation loop between transmembrane domains III and IV of the channel, was detected in a female FHM patient. The M1500V mutation was absent in a group of 62 controls, as well as in the ExAC database. The second, already known missense mutation S231P in KCNK18 was found in a female MA patient. Additionally, a novel intronic polymorphism possibly affecting alternative splicing of SCN1A, at chr2:16685249, g.77659T>C, and c.4581+32A>G, located between exons 24 and 25, in a region encoding the inactivation loop of the sodium channel was found in a female MO patient. No mutations in ATP1A2 or CACNA1A were found in the study group. The presence of SCN1A mutations and absence of mutations in ATP1A2 or CACNA1A suggest that the Polish patients represent FHM type 3. On the other hand, the presence of KCNK18 mutation indicated another FHM subtype. It could be speculated that contrary to other European populations, the genetic basis of migraine in the Polish population involves mutations in genes not included in the

  8. Hypomyelinating leukodystrophy-associated missense mutation in HSPD1 blunts mitochondrial dynamics

    Energy Technology Data Exchange (ETDEWEB)

    Miyamoto, Yuki [Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535 (Japan); Eguchi, Takahiro [The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639 (Japan); Kawahara, Kazuko [Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535 (Japan); Hasegawa, Nanami [Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535 (Japan); Faculty of Pharmacy, Keio University, Minato, Tokyo 105-8512 (Japan); Nakamura, Kazuaki [Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535 (Japan); Funakoshi-Tago, Megumi [Faculty of Pharmacy, Keio University, Minato, Tokyo 105-8512 (Japan); Tanoue, Akito [Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535 (Japan); Tamura, Hiroomi [Faculty of Pharmacy, Keio University, Minato, Tokyo 105-8512 (Japan); Yamauchi, Junji, E-mail: yamauchi-j@ncchd.go.jp [Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535 (Japan); Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8510 (Japan)

    2015-07-03

    Myelin-forming glial cells undergo dynamic morphological changes in order to produce mature myelin sheaths with multiple layers. In the central nervous system (CNS), oligodendrocytes differentiate to insulate neuronal axons with myelin sheaths. Myelin sheaths play a key role in homeostasis of the nervous system, but their related disorders lead not only to dismyelination and repeated demyelination but also to severe neuropathies. Hereditary hypomyelinating leukodystrophies (HLDs) are a group of such diseases affecting oligodendrocytes and are often caused by missense mutations of the respective responsible genes. Despite increasing identification of gene mutations through advanced nucleotide sequencing technology, studies on the relationships between gene mutations and their effects on cellular and subcellular aberrance have not followed at the same rapid pace. In this study, we report that an HLD4-associated (Asp-29-to-Gly) mutant of mitochondrial heat shock 60-kDa protein 1 (HSPD1) causes short-length morphologies and increases the numbers of mitochondria due to their aberrant fission and fusion cycles. In experiments using a fluorescent dye probe, this mutation decreases the mitochondrial membrane potential. Also, mitochondria accumulate in perinuclear regions. HLD4-associated HSPD1 mutant blunts mitochondrial dynamics, probably resulting in oligodendrocyte malfunction. This study constitutes a first finding concerning the relationship between disease-associated HSPD1 mutation and mitochondrial dynamics, which may be similar to the relationship between another disease-associated HSPD1 mutation (MitCHAP-60 disease) and aberrant mitochondrial dynamics. - Highlights: • The HLD4 mutant of HSPD1 decreases mitochondrial fission frequency. • The HLD4 mutant decreases mitochondrial fusion frequency. • Mitochondria harboring the HLD4 mutant exhibit slow motility. • The HLD4 mutant of HSPD1 decreases mitochondrial membrane potential. • HLD4-related diseases may

  9. Change of point mutations in Helicobacter pylori rRNA associated with clarithromycin resistance in Italy.

    Science.gov (United States)

    De Francesco, Vincenzo; Zullo, Angelo; Giorgio, Floriana; Saracino, Ilaria; Zaccaro, Cristina; Hassan, Cesare; Ierardi, Enzo; Di Leo, Alfredo; Fiorini, Giulia; Castelli, Valentina; Lo Re, Giovanna; Vaira, Dino

    2014-03-01

    Primary clarithromycin resistance is the main factor affecting the efficacy of Helicobacter pylori therapy. This study aimed: (i) to assess the concordance between phenotypic (culture) and genotypic (real-time PCR) tests in resistant strains; (ii) to search, in the case of disagreement between the methods, for point mutations other than those reported as the most frequent in Europe; and (iii) to compare the MICs associated with the single point mutations. In order to perform real-time PCR, we retrieved biopsies from patients in whom H. pylori infection was successful diagnosed by bacterial culture and clarithromycin resistance was assessed using the Etest. Only patients who had never been previously treated, and with H. pylori strains that were either resistant exclusively to clarithromycin or without any resistance, were included. Biopsies from 82 infected patients were analysed, including 42 strains that were clarithromycin resistant and 40 that were clarithromycin susceptible on culture. On genotypic analysis, at least one of the three most frequently reported point mutations (A2142C, A2142G and A2143G) was detected in only 23 cases (54.8%), with a concordance between the two methods of 0.67. Novel point mutations (A2115G, G2141A and A2144T) were detected in a further 14 out of 19 discordant cases, increasing the resistance detection rate of PCR to 88% (Presistance; and (iii) none of the tested point mutations is associated with significantly higher MIC values than the others.

  10. Recessive mutations of TMC1 associated with moderate to severe hearing loss.

    Science.gov (United States)

    Imtiaz, Ayesha; Maqsood, Azra; Rehman, Atteeq U; Morell, Robert J; Holt, Jeffrey R; Friedman, Thomas B; Naz, Sadaf

    2016-04-01

    TMC1 encodes a protein required for the normal function of mechanically activated channels that enable sensory transduction in auditory and vestibular hair cells. TMC1 protein is localized at the tips of the hair cell stereocilia, the site of conventional mechanotransduction. In many populations, loss-of-function recessive mutations of TMC1 are associated with profound deafness across all frequencies tested. In six families reported here, variable moderate-to-severe or moderate-to-profound hearing loss co-segregated with STR (short tandem repeats) markers at the TMC1 locus DFNB7/11. Massively parallel and Sanger sequencing of genomic DNA revealed each family co-segregating hearing loss with a homozygous TMC1 mutation: two reported mutations (p.R34X and p.R389Q) and three novel mutations (p.S596R, p.N199I, and c.1404 + 1G > T). TMC1 cDNA sequence from affected subjects homozygous for the donor splice site transversion c.1404 + 1G > T revealed skipping of exon 16, deleting 60 amino acids from the TMC1 protein. Since the mutations in our study cause less than profound hearing loss, we speculate that there is hypo-functional TMC1 mechanotransduction channel activity and that other even less damaging variants of TMC1 may be associated with more common mild-to-severe sensorineural hearing loss.

  11. Mutations in multidomain protein MEGF8 identify a Carpenter syndrome subtype associated with defective lateralization.

    Science.gov (United States)

    Twigg, Stephen R F; Lloyd, Deborah; Jenkins, Dagan; Elçioglu, Nursel E; Cooper, Christopher D O; Al-Sannaa, Nouriya; Annagür, Ali; Gillessen-Kaesbach, Gabriele; Hüning, Irina; Knight, Samantha J L; Goodship, Judith A; Keavney, Bernard D; Beales, Philip L; Gileadi, Opher; McGowan, Simon J; Wilkie, Andrew O M

    2012-11-02

    Carpenter syndrome is an autosomal-recessive multiple-congenital-malformation disorder characterized by multisuture craniosynostosis and polysyndactyly of the hands and feet; many other clinical features occur, and the most frequent include obesity, umbilical hernia, cryptorchidism, and congenital heart disease. Mutations of RAB23, encoding a small GTPase that regulates vesicular transport, are present in the majority of cases. Here, we describe a disorder caused by mutations in multiple epidermal-growth-factor-like-domains 8 (MEGF8), which exhibits substantial clinical overlap with Carpenter syndrome but is frequently associated with abnormal left-right patterning. We describe five affected individuals with similar dysmorphic facies, and three of them had either complete situs inversus, dextrocardia, or transposition of the great arteries; similar cardiac abnormalities were previously identified in a mouse mutant for the orthologous Megf8. The mutant alleles comprise one nonsense, three missense, and two splice-site mutations; we demonstrate in zebrafish that, in contrast to the wild-type protein, the proteins containing all three missense alterations provide only weak rescue of an early gastrulation phenotype induced by Megf8 knockdown. We conclude that mutations in MEGF8 cause a Carpenter syndrome subtype frequently associated with defective left-right patterning, probably through perturbation of signaling by hedgehog and nodal family members. We did not observe any subject with biallelic loss-of function mutations, suggesting that some residual MEGF8 function might be necessary for survival and might influence the phenotypes observed.

  12. Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes.

    Science.gov (United States)

    Schubert, Julian; Siekierska, Aleksandra; Langlois, Mélanie; May, Patrick; Huneau, Clément; Becker, Felicitas; Muhle, Hiltrud; Suls, Arvid; Lemke, Johannes R; de Kovel, Carolien G F; Thiele, Holger; Konrad, Kathryn; Kawalia, Amit; Toliat, Mohammad R; Sander, Thomas; Rüschendorf, Franz; Caliebe, Almuth; Nagel, Inga; Kohl, Bernard; Kecskés, Angela; Jacmin, Maxime; Hardies, Katia; Weckhuysen, Sarah; Riesch, Erik; Dorn, Thomas; Brilstra, Eva H; Baulac, Stephanie; Møller, Rikke S; Hjalgrim, Helle; Koeleman, Bobby P C; Jurkat-Rott, Karin; Lehman-Horn, Frank; Roach, Jared C; Glusman, Gustavo; Hood, Leroy; Galas, David J; Martin, Benoit; de Witte, Peter A M; Biskup, Saskia; De Jonghe, Peter; Helbig, Ingo; Balling, Rudi; Nürnberg, Peter; Crawford, Alexander D; Esguerra, Camila V; Weber, Yvonne G; Lerche, Holger

    2014-12-01

    Febrile seizures affect 2-4% of all children and have a strong genetic component. Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2) have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encoding syntaxin-1B, that are associated with both febrile seizures and epilepsy. Whole-exome sequencing in independent large pedigrees identified cosegregating STX1B mutations predicted to cause an early truncation or an in-frame insertion or deletion. Three additional nonsense or missense mutations and a de novo microdeletion encompassing STX1B were then identified in 449 familial or sporadic cases. Video and local field potential analyses of zebrafish larvae with antisense knockdown of stx1b showed seizure-like behavior and epileptiform discharges that were highly sensitive to increased temperature. Wild-type human syntaxin-1B but not a mutated protein rescued the effects of stx1b knockdown in zebrafish. Our results thus implicate STX1B and the presynaptic release machinery in fever-associated epilepsy syndromes.

  13. Clusters of nucleotide substitutions and insertion/deletion mutations are associated with repeat sequences.

    Directory of Open Access Journals (Sweden)

    Michael J McDonald

    2011-06-01

    Full Text Available The genome-sequencing gold rush has facilitated the use of comparative genomics to uncover patterns of genome evolution, although their causal mechanisms remain elusive. One such trend, ubiquitous to prokarya and eukarya, is the association of insertion/deletion mutations (indels with increases in the nucleotide substitution rate extending over hundreds of base pairs. The prevailing hypothesis is that indels are themselves mutagenic agents. Here, we employ population genomics data from Escherichia coli, Saccharomyces paradoxus, and Drosophila to provide evidence suggesting that it is not the indels per se but the sequence in which indels occur that causes the accumulation of nucleotide substitutions. We found that about two-thirds of indels are closely associated with repeat sequences and that repeat sequence abundance could be used to identify regions of elevated sequence diversity, independently of indels. Moreover, the mutational signature of indel-proximal nucleotide substitutions matches that of error-prone DNA polymerases. We propose that repeat sequences promote an increased probability of replication fork arrest, causing the persistent recruitment of error-prone DNA polymerases to specific sequence regions over evolutionary time scales. Experimental measures of the mutation rates of engineered DNA sequences and analyses of experimentally obtained collections of spontaneous mutations provide molecular evidence supporting our hypothesis. This study uncovers a new role for repeat sequences in genome evolution and provides an explanation of how fine-scale sequence contextual effects influence mutation rates and thereby evolution.

  14. Clusters of nucleotide substitutions and insertion/deletion mutations are associated with repeat sequences.

    Science.gov (United States)

    McDonald, Michael J; Wang, Wei-Chi; Huang, Hsien-Da; Leu, Jun-Yi

    2011-06-01

    The genome-sequencing gold rush has facilitated the use of comparative genomics to uncover patterns of genome evolution, although their causal mechanisms remain elusive. One such trend, ubiquitous to prokarya and eukarya, is the association of insertion/deletion mutations (indels) with increases in the nucleotide substitution rate extending over hundreds of base pairs. The prevailing hypothesis is that indels are themselves mutagenic agents. Here, we employ population genomics data from Escherichia coli, Saccharomyces paradoxus, and Drosophila to provide evidence suggesting that it is not the indels per se but the sequence in which indels occur that causes the accumulation of nucleotide substitutions. We found that about two-thirds of indels are closely associated with repeat sequences and that repeat sequence abundance could be used to identify regions of elevated sequence diversity, independently of indels. Moreover, the mutational signature of indel-proximal nucleotide substitutions matches that of error-prone DNA polymerases. We propose that repeat sequences promote an increased probability of replication fork arrest, causing the persistent recruitment of error-prone DNA polymerases to specific sequence regions over evolutionary time scales. Experimental measures of the mutation rates of engineered DNA sequences and analyses of experimentally obtained collections of spontaneous mutations provide molecular evidence supporting our hypothesis. This study uncovers a new role for repeat sequences in genome evolution and provides an explanation of how fine-scale sequence contextual effects influence mutation rates and thereby evolution.

  15. SCN2A mutation associated with neonatal epilepsy, late-onset episodic ataxia, myoclonus, and pain.

    Science.gov (United States)

    Liao, Y; Anttonen, A-K; Liukkonen, E; Gaily, E; Maljevic, S; Schubert, S; Bellan-Koch, A; Petrou, S; Ahonen, V E; Lerche, H; Lehesjoki, A-E

    2010-10-19

    Inherited and de novo mutations in sodium channel genes underlie a variety of channelopathies. Mutations in SCN2A, encoding the brain sodium channel Na(V)1.2, have previously been reported to be associated with benign familial neonatal infantile seizures, febrile seizures plus, and intractable epilepsy of infancy. We evaluated the clinical characteristics in a patient with a neonatal-onset complex episodic neurologic phenotype. We screened SCN2A for mutations and carried out in vitro electrophysiologic analyses to study the consequences of the identified mutation. We studied the developmental expression of Na(V)1.2 in cerebellum by immunohistochemical analysis. The patient presented with neonatal-onset seizures and variable episodes of ataxia, myoclonia, headache, and back pain after 18 months of age. The patient carries a de novo missense mutation (p.Ala263Val) in SCN2A, which leads to a pronounced gain-of-function, in particular an increased persistent Na(+) current. Immunohistochemical studies suggest a developmentally increasing expression of Na(V)1.2 in granule cell axons projecting to Purkinje neurons. These results can explain a neuronal hyperexcitability resulting in seizures and other episodic symptoms extending the spectrum of SCN2A-associated phenotypes. The developmentally increasing expression of Na(V)1.2 in cerebellum may be responsible for the later onset of episodic ataxia.

  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

    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.

  17. Text mining facilitates database curation - extraction of mutation-disease associations from Bio-medical literature.

    Science.gov (United States)

    Ravikumar, Komandur Elayavilli; Wagholikar, Kavishwar B; Li, Dingcheng; Kocher, Jean-Pierre; Liu, Hongfang

    2015-06-06

    Advances in the next generation sequencing technology has accelerated the pace of individualized medicine (IM), which aims to incorporate genetic/genomic information into medicine. One immediate need in interpreting sequencing data is the assembly of information about genetic variants and their corresponding associations with other entities (e.g., diseases or medications). Even with dedicated effort to capture such information in biological databases, much of this information remains 'locked' in the unstructured text of biomedical publications. There is a substantial lag between the publication and the subsequent abstraction of such information into databases. Multiple text mining systems have been developed, but most of them focus on the sentence level association extraction with performance evaluation based on gold standard text annotations specifically prepared for text mining systems. We developed and evaluated a text mining system, MutD, which extracts protein mutation-disease associations from MEDLINE abstracts by incorporating discourse level analysis, using a benchmark data set extracted from curated database records. MutD achieves an F-measure of 64.3% for reconstructing protein mutation disease associations in curated database records. Discourse level analysis component of MutD contributed to a gain of more than 10% in F-measure when compared against the sentence level association extraction. Our error analysis indicates that 23 of the 64 precision errors are true associations that were not captured by database curators and 68 of the 113 recall errors are caused by the absence of associated disease entities in the abstract. After adjusting for the defects in the curated database, the revised F-measure of MutD in association detection reaches 81.5%. Our quantitative analysis reveals that MutD can effectively extract protein mutation disease associations when benchmarking based on curated database records. The analysis also demonstrates that incorporating

  18. Mutation of NPM1 and FLT3 Genes in Acute Myeloid Leukemia and Their Association with Clinical and Immunophenotypic Features

    Directory of Open Access Journals (Sweden)

    Pradeep Singh Chauhan

    2013-01-01

    Full Text Available Background. Mutations in NPM1 and FLT3 genes represent the most frequent genetic alterations and important diagnostic and prognostic indicators in patients with acute myeloid leukemia (AML. Objective. We investigated the prevalence and clinical characteristics of NPM1 and FLT3 mutations in 161 patients of de novo AML including adults and children. Results. NPM1 mutation was found in 21% and FLT3 mutation in 25% of the AML patients. Thirteen (8% samples were positive for both NPM1 and FLT3/ITD mutations. Adult patients had significantly higher frequency of NPM1 mutation than children (25.8% versus 8.8%; P=0.02. Further, NPM1 mutation was found to be more frequent in patients above 45 years of age (P=0.02. NPM1 mutation was significantly associated with higher platelet count (P=0.05 and absence of hepatosplenomegaly (P=0.01, while FLT3/ITD mutation was associated with higher white blood count (P=0.01. Immunophenotypically, NPM1 mutation was associated with the lack of CD34 (P<0.001 and HLD-DR expression (P<0.001, while FLT3/ITD mutation was positively associated with the expression of CD7 (P=0.04. No correlation was found between NPM1 mutation and fusion gene. Interestingly, FLT3/ITD mutation was found to be inversely associated with AML/ETO fusion gene (P=0.04. Conclusions. The results suggest that distinct clinical and immunophenotypic characteristics of NPM1 and FLT3/ITD mutations present further insight into the molecular mechanism of leukemogenesis.

  19. Candidate causative mutation on BTA18 associated with calving and conformation traits in Holstein bulls

    Science.gov (United States)

    Complementing quantitative methods with sequence data analysis is a major goal of the post-genome era of biology. In this study, we analyzed Illumina HiSeq sequence data derived from 11 US Holstein bulls in order to identify putative causal mutations associated with calving and conformation traits. ...

  20. Mitochondrial retinal dystrophy associated with the m.3243A>G mutation

    NARCIS (Netherlands)

    Laat, P. de; Smeitink, J.A.M.; Janssen, M.C.H.; Keunen, J.E.E.; Boon, C.J.F.

    2013-01-01

    OBJECTIVE: To describe the spectrum of retinal abnormalities associated with the m.3243A>G mutation in the mitochondrial MTTL1 gene and to analyze putative correlations among the severity of retinal abnormalities, disease severity in other organ systems, and heteroplasmy levels. DESIGN: Observati

  1. Pituitary dwarfism in Saarloos and Czechoslovakian wolfdogs is associated with a mutation in LHX3

    NARCIS (Netherlands)

    Voorbij, AMWY; Leegwater, Peter; Kooistra, Hans

    2014-01-01

    Background Pituitary dwarfism in German Shepherd Dogs is associated with autosomal recessive inheritance and a mutation in LHX3, resulting in combined pituitary hormone deficiency. Congenital dwarfism also is encountered in breeds related to German Shepherd Dogs, such as Saarloos and Czechoslovakian

  2. A MELAS-associated ND1 mutation causing leber hereditary optic neuropathy and spastic dystonia.

    NARCIS (Netherlands)

    Spruijt, L.; Smeets, H.J.M.; Hendrickx, A.; Bettink-Remeijer, M.W.; Maat-Kievit, A.; Schoonderwoerd, K.C.; Sluiter, W.; Coo, I.F.M. de; Hintzen, R.Q.

    2007-01-01

    OBJECTIVE: To report a novel mutation that is associated with Leber hereditary optic neuropathy (LHON) within the same family affected by spastic dystonia. DESIGN: Leber hereditary optic neuropathy is a mitochondrial disorder characterized by isolated central visual loss. Of patients with LHON, 95%

  3. Recurrent de novo BICD2 mutation associated with arthrogryposis multiplex congenita and bilateral perisylvian polymicrogyria.

    Science.gov (United States)

    Ravenscroft, Gianina; Di Donato, Nataliya; Hahn, Gabriele; Davis, Mark R; Craven, Paul D; Poke, Gemma; Neas, Katherine R; Neuhann, Teresa M; Dobyns, William B; Laing, Nigel G

    2016-11-01

    Autosomal dominantly inherited mutations of BICD2 are associated with congenital-onset spinal muscular atrophy characterised by lower limb predominance. A few cases have also showed upper motor neuron pathology, including presenting with features resembling hereditary spastic paraplegia. The age-of-onset for the published families is usually at birth but also included cases with childhood- and adult-onset disease. In this report we described two isolated probands that presented in utero with features associated with reduced fetal movements. Both cases were diagnosed at birth with arthrogryposis multiplex congenita (AMC) and hypotonia. Other variable features included congenital fractures, hip dislocation, micrognathia, respiratory insufficiency, microcephaly and bilateral perisylvian polymicrogyria. Patient 1 is 4 years of age and stable, but shows significant motor developmental delay and delayed speech. Patient 2 passed away at 7 weeks of age. Through next generation sequencing we identified the same missense substitution in BICD2 (p.Arg694Cys) in both probands. Sanger sequencing showed that in both cases the mutation arose de novo. The in utero onset in both cases suggests that the p.Arg694Cys substitution may have a more deleterious effect on BICD2 function than previously described mutations. Our results broaden the phenotypes associated with BICD2 mutations to include AMC and cortical malformations and therefore to a similar phenotypic spectrum to that associated with its binding partner DYNC1H1.

  4. Mitochondrial retinal dystrophy associated with the m.3243A>G mutation

    NARCIS (Netherlands)

    Laat, P. de; Smeitink, J.A.M.; Janssen, M.C.H.; Keunen, J.E.E.; Boon, C.J.F.

    2013-01-01

    OBJECTIVE: To describe the spectrum of retinal abnormalities associated with the m.3243A>G mutation in the mitochondrial MTTL1 gene and to analyze putative correlations among the severity of retinal abnormalities, disease severity in other organ systems, and heteroplasmy levels. DESIGN:

  5. Pituitary dwarfism in Saarloos and Czechoslovakian wolfdogs is associated with a mutation in LHX3

    NARCIS (Netherlands)

    Voorbij, AMWY; Leegwater, Peter; Kooistra, Hans

    Background Pituitary dwarfism in German Shepherd Dogs is associated with autosomal recessive inheritance and a mutation in LHX3, resulting in combined pituitary hormone deficiency. Congenital dwarfism also is encountered in breeds related to German Shepherd Dogs, such as Saarloos and Czechoslovakian

  6. A MELAS-associated ND1 mutation causing leber hereditary optic neuropathy and spastic dystonia.

    NARCIS (Netherlands)

    Spruijt, L.; Smeets, H.J.M.; Hendrickx, A.; Bettink-Remeijer, M.W.; Maat-Kievit, A.; Schoonderwoerd, K.C.; Sluiter, W.; Coo, I.F.M. de; Hintzen, R.Q.

    2007-01-01

    OBJECTIVE: To report a novel mutation that is associated with Leber hereditary optic neuropathy (LHON) within the same family affected by spastic dystonia. DESIGN: Leber hereditary optic neuropathy is a mitochondrial disorder characterized by isolated central visual loss. Of patients with LHON, 95%

  7. Neurochemistry changes associated with mutations in familial Parkinson's disease.

    Science.gov (United States)

    Siddique, M M; Tan, E K

    2010-01-01

    Parkinson's disease (PD), a common neurodegenerative disease, is characterized by the progressive loss of dopamine neurons and the accumulation of Lewy bodies and neurites. The exact role of genetic and environmental factors in the pathogenesis of PD has frequently been debated. The association of MPTP (methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine) and toxins (such as rotenone) with parkinsonism highlights the potential etiologic role of environmental toxins in disease causation. The recent discoveries of monogenic (such as α-synuclein, Parkin, UCHL1, PINK1, DJ-1, LRRK2) forms of PD have provided considerable insights into its pathophysiology. Parkin, an ubiquitin protein ligase assists in the degradation of toxic substrates via the ubiquitin proteasome system. It can also mediate a nondegradative form of ubiquitination. PINK1 and LRRK2 are possibly involved in the phosphorylation of substrates important for various cellular functions. Some toxins could interact with α-synuclein, an endogenous protein that is implicated in pathology of PD. Increasing in vitro and in vivo studies suggest that deficits in mitochondrial function, oxidative and nitrosative stress, the accumulation of aberrant or misfolded proteins, and ubiquitin-proteasome system dysfunction underpin the pathogenesis of sporadic and familial forms of PD. Elucidation of the functions of the proteins encoded by the diseasecausing genes will provide an opportunity for identification of specific pathways that could be targeted in neurotherapeutics.

  8. HFE基因多态与云南汉族、彝族和哈尼族原发性高血压的关联研究%Association of HFE gene tag SNPs with essential hypertension among the Han, Yi and Hani populations from Yunnan Province

    Institute of Scientific and Technical Information of China (English)

    肖青; 李宝鑫; 李茜

    2016-01-01

    目的:探讨血色沉着病基因(hemochromatosis,HFE)标签单核苷酸多态(tag single nucleotide polymorphism,tag SNPs)与云南汉族、彝族和哈尼族原发性高血压发病的关联性.方法:采用病例-对照关联研究策略,运用聚合酶链式反应-限制性片段长度多态方法,对云南940例汉族人、598例彝族人和661例哈尼族人进行HFE基因5个标签SNPs(rs9366637、rs1799945、rs2071303、rs1800758、rs2858996)的多态进行检测.结果:检测到rs9366637位点在不同民族人群与高血压发病的关联性结果不一致.汉族整体人群和男性人群中,发现rs9366637位点C等位基因和CC基因型是高血压发病的风险因子;而在哈尼族混合和女性人群,发现该位点T等位基因和TT基因型是高血压发病的风险因子;在彝族人群,未发现rs9366637位点多态与高血压发生相关.此外,发现rs2858996 T等位基因和TT基因型在汉族整体和男性人群是高血压发病的保护因子.结论:HFE基因rs9366637和rs2858996位点可能是云南汉族和哈尼族高血压发生的易感标记,在云南汉族和哈尼族人群中值得关注.

  9. HELLP Syndrome and Cerebral Venous Sinus Thrombosis Associated with Factor V Leiden Mutation during Pregnancy.

    Science.gov (United States)

    Dag, Zeynep Ozcan; Işik, Yuksel; Simsek, Yavuz; Tulmac, Ozlem Banu; Demiray, Demet

    2014-01-01

    Preeclampsia is a leading cause of maternal mortality and morbidity worldwide. The neurological complications of preeclampsia and eclampsia are responsible for a major proportion of the morbidity and mortality for women and their infants alike. Hormonal changes during pregnancy and the puerperium carry an increased risk of venous thromboembolism including cerebral venous sinus thrombosis (CVST). Factor 5 leiden (FVL) is a procoagulant mutation associated primarily with venous thrombosis and pregnancy complications. We report a patient with FVL mutation who presented with CVST at 24th week of pregnancy and was diagnosed as HELLP syndrome at 34th week of pregnancy.

  10. HELLP Syndrome and Cerebral Venous Sinus Thrombosis Associated with Factor V Leiden Mutation during Pregnancy

    Directory of Open Access Journals (Sweden)

    Zeynep Ozcan Dag

    2014-01-01

    Full Text Available Preeclampsia is a leading cause of maternal mortality and morbidity worldwide. The neurological complications of preeclampsia and eclampsia are responsible for a major proportion of the morbidity and mortality for women and their infants alike. Hormonal changes during pregnancy and the puerperium carry an increased risk of venous thromboembolism including cerebral venous sinus thrombosis (CVST. Factor 5 leiden (FVL is a procoagulant mutation associated primarily with venous thrombosis and pregnancy complications. We report a patient with FVL mutation who presented with CVST at 24th week of pregnancy and was diagnosed as HELLP syndrome at 34th week of pregnancy.

  11. Carrier frequency of GJB2 and GALT mutations associated with sensorineural hearing loss and galactosemia in the Russian population

    OpenAIRE

    Abramov D.D.; Belousova M.V.; Kadochnikova V.V.; Ragimov A.A.; Trofimov D.Yu.

    2016-01-01

    This article continues a series of works estimating carrier frequencies of mutations associated with the development of common monogenic disorders in the Russian population. The study aimed to establish the frequency of GJB2 and GALT mutations in first-time blood donors. Genotyping of 1000 first-time blood donors who identify themselves as Russians and permanently reside in the Russian Federation detected 37 carriers of GJB2 mutations associated with sensorineural hearing loss (carrier freque...

  12. Molecular and biochemical characterisation of a novel mutation in POLG associated with Alpers syndrome

    Directory of Open Access Journals (Sweden)

    Chardot Christophe

    2011-01-01

    Full Text Available Abstract Background DNA polymerase γ (POLG is the only known mitochondrial DNA (mtDNA polymerase. It mediates mtDNA replication and base excision repair. Mutations in the POLG gene lead to reduction of functional mtDNA (mtDNA depletion and/or deletions and are therefore predicted to result in defective oxidative phosphorylation (OXPHOS. Many mutations map to the polymerase and exonuclease domains of the enzyme and produce a broad clinical spectrum. The most frequent mutation p.A467T is localised in the linker region between these domains. In compound heterozygote patients the p.A467T mutation has been described to be associated amongst others with fatal childhood encephalopathy. These patients have a poorer survival rate compared to homozygotes. Methods mtDNA content in various tissues (fibroblasts, muscle and liver was quantified using quantitative PCR (qPCR. OXPHOS activities in the same tissues were assessed using spectrophotometric methods and catalytic stain of BN-PAGE. Results We characterise a novel splice site mutation in POLG found in trans with the p.A467T mutation in a 3.5 years old boy with valproic acid induced acute liver failure (Alpers-Huttenlocher syndrome. These mutations result in a tissue specific depletion of the mtDNA which correlates with the OXPHOS-activities. Conclusions mtDNA depletion can be expressed in a high tissue-specific manner and confirms the need to analyse primary tissue. Furthermore, POLG analysis optimises clinical management in the early stages of disease and reinforces the need for its evaluation before starting valproic acid treatment.

  13. JAK2-V617F mutation in patients with myeloproliferative neoplasms: Association with FLT3-ITD mutation

    Directory of Open Access Journals (Sweden)

    Čolović Milica

    2010-01-01

    Full Text Available Introduction. An acquired somatic mutation V617F in Janus kinase 2 gene (JAK2 is the cause of uncontrolled proliferation in patients with myeloproliferative neoplasms. It is known that uncontrolled myeloid cell proliferation is also provoked by alteration in other genes, e.g. mutations in receptor tyrosine kinase FLT3 gene. FLT3 represents the most frequently mutated gene in acute myeloid leukaemia. Interestingly, mutated FLT3- ITD (internal tandem duplication protein is a member of the same signalling pathway as JAK2 protein, the STAT5 signalling pathway. STAT5 activation is recognized as important for selfrenewal of haematopoetic stem cells. Objective. The aim of this study was the detection of JAK2- V617F mutation in patients with myeloproliferative neoplasms. Additionally, we investigated the presence of FLT3-ITD mutation in JAK2-V617F-positive patients in order to shed the light on the hypothesis of a similar role of these two molecular markers in haematological malignancies. Methods. Using allele-specific PCR, 61 patients with known or suspected diagnosis of myeloproliferative neoplasms were tested for the presence of JAK2-V617F mutation. Samples that were positive for JAK2 mutation were subsequently tested for the presence of FLT3-ITD mutation by PCR. Results. Eighteen of 61 analysed patients were positive for JAK2-V617F mutation. Among them, 8/18 samples were diagnosed as polycythaemia vera, and 10/18 as essential thrombocythaemia. None of JAK2-V617F-positive patient was positive for FLT3-ITD mutation. Conclusion. This study suggests that one activating mutation is sufficient for aberrant cell proliferation leading to malignant transformation of haematopoetic stem cell.

  14. The Hereditary Hemochromatosis Protein, HFE, Inhibits Iron Uptake via Down-regulation of Zip14 in HepG2 Cells*

    OpenAIRE

    Gao, Junwei; Zhao, Ningning; Knutson, Mitchell D.; Enns, Caroline A

    2008-01-01

    Lack of functional hereditary hemochromatosis protein, HFE, causes iron overload predominantly in hepatocytes, the major site of HFE expression in the liver. In this study, we investigated the role of HFE in the regulation of both transferrin-bound iron (TBI) and non-transferrin-bound iron (NTBI) uptake in HepG2 cells, a human hepatoma cell line. Expression of HFE decreased both TBI and NTBI uptake. It also resulted in a decrease in the protein levels of Zip14 with no ...

  15. Novel Mutation in the α-Myosin Heavy Chain Gene Is Associated With Sick Sinus Syndrome

    OpenAIRE

    Ishikawa, Taisuke; Jou, Chuanchau J.; Nogami, Akihiko; Kowase, Shinya; Arrington, Cammon B.; Barnett, Spencer M.; Harrell, Daniel T.; Arimura, Takuro; Tsuji, Yukiomi; Kimura, Akinori; Makita, Naomasa

    2015-01-01

    Recent genome-wide association studies have demonstrated an association between MYH6, the gene encoding α-myosin heavy chain (α-MHC), and sinus node function in the general population. Moreover, a rare MYH6 variant, R721W, predisposing susceptibility to sick sinus syndrome has been identified. However, the existence of disease-causing MYH6 mutations for familial sick sinus syndrome and their underlying mechanisms remain unknown. Methods and Results-We screened 9 genotype-negative probands wit...

  16. Marfan syndrome caused by a novel FBN1 mutation with associated pigmentary glaucoma.

    Science.gov (United States)

    Kuchtey, John; Chang, Ta Chen; Panagis, Lampros; Kuchtey, Rachel W

    2013-04-01

    Mutations in fibrillin-1 (FBN1) cause a wide spectrum of disorders, including Marfan syndrome, which have in common defects in fibrillin-1 microfibrils. Ectopia lentis and myopia are frequently observed ocular manifestations of Marfan syndrome. Glaucoma is also associated with Marfan syndrome, though the form of glaucoma has not been well-characterized. In this report, ocular examination of a patient diagnosed with Marfan syndrome based on family history and aortic dilatation was performed, including measurement of facility of aqueous humor outflow by tonography. The patient did not have ectopia lentis at the age of 42 years. Based on optic nerve appearance, reduced outflow facility, elevated IOP with open angles and clear signs of pigment dispersion, the patient was diagnosed with pigmentary glaucoma. The patient was heterozygous for a novel truncating mutation in FBN1, p.Leu72Ter. Histology of normal human eyes revealed abundant expression of elastic fibers and fibrillin-1 in aqueous humor outflow structures. This is the first report of a patient with Marfan syndrome that is caused by a confirmed FBN1 mutation with associated pigmentary glaucoma. In addition to identifying a novel mutation of FBN1 and broadening the spectrum of associated ocular phenotypes in Marfan syndrome, our findings suggest that pigmentary glaucoma may involve defects in fibrillin-1 microfibrils.

  17. DNA transposon activity is associated with increased mutation rates in genes of rice and other grasses.

    Science.gov (United States)

    Wicker, Thomas; Yu, Yeisoo; Haberer, Georg; Mayer, Klaus F X; Marri, Pradeep Reddy; Rounsley, Steve; Chen, Mingsheng; Zuccolo, Andrea; Panaud, Olivier; Wing, Rod A; Roffler, Stefan

    2016-09-07

    DNA (class 2) transposons are mobile genetic elements which move within their 'host' genome through excising and re-inserting elsewhere. Although the rice genome contains tens of thousands of such elements, their actual role in evolution is still unclear. Analysing over 650 transposon polymorphisms in the rice species Oryza sativa and Oryza glaberrima, we find that DNA repair following transposon excisions is associated with an increased number of mutations in the sequences neighbouring the transposon. Indeed, the 3,000 bp flanking the excised transposons can contain over 10 times more mutations than the genome-wide average. Since DNA transposons preferably insert near genes, this is correlated with increases in mutation rates in coding sequences and regulatory regions. Most importantly, we find this phenomenon also in maize, wheat and barley. Thus, these findings suggest that DNA transposon activity is a major evolutionary force in grasses which provide the basis of most food consumed by humankind.

  18. Characterization of two new dominant ClC-1 channel mutations associated with myotonia

    DEFF Research Database (Denmark)

    Grunnet, Morten; Jespersen, Thomas; Colding-Jørgensen, Eskild

    2003-01-01

    Voltage-gated ClC-1 chloride channels encoded by the CLCN1 gene have a major role in setting the membrane potential in skeletal muscle. More than 60 CLCN1 mutations have been associated with myotonia congenita. These mutations are traditionally classified as recessive (Becker's disease) or dominant...... (Thomsen's disease). In this study, we have electrophysiologically characterized two new dominant ClC-1 mutations, thereby elucidating the observed phenotype in patients. The two ClC-1 mutants M128V and E193K were identified, and the DNA was isolated from patients and subsequently expressed in Xenopus...... revealed a change in reversal potential compared to wild-type channels. This finding supports the notion that the E193 amino acid is an important determinant in the selectivity filter of the human ClC-1 channel. The electrophysiological behavior of both mutants demonstrates a severe reduction in ClC-1...

  19. Malignant hyperthermia associated with ryanodine receptor 1 (C7360G) mutation in Quarter Horses.

    Science.gov (United States)

    Aleman, M; Nieto, J E; Magdesian, K G

    2009-01-01

    Anesthetic-induced malignant hyperthermia (MH) has been documented in Quarter Horses with a single point mutation in the ryanodine receptor 1 gene (RyR1) at nucleotide C7360G, generating a R2454G amino acid substitution. However, there have been no reports of nonanesthetic manifestations of MH in horses with the C7360G mutation. To describe clinical manifestations of Quarter Horses with the C7360G mutation. Eleven Quarter Horses with the RyR1 C7360G mutation. This prospective study included horses with suspected MH, undetermined etiology of sudden death, death within hours of onset of rhabdomyolysis, muscle rigidity, stiffness, intermittent sweating, and persistent increases in serum muscle enzyme activities. Whole blood in EDTA and skeletal muscle were processed for genetic and histochemical analysis. Medical records and pedigrees were collected when available. Both anesthetic- and non-anesthetic-associated myopathic manifestations of MH occurred in halter Quarter Horses with mutation of RyR1. The disease is inherited as an autosomal dominant trait. Clinical and laboratory abnormalities were similar in both forms. Rhabdomyolysis was a common finding in both groups of horses. Skeletal muscle histochemical findings were nonspecific and compatible with a noninflammatory myopathic process. MH is a potentially fatal disease of Quarter Horses that could be triggered by halogenated anesthetics and other nonanesthetic factors that may include exercise, stress, breeding, illnesses, and concurrent myopathies.

  20. Functional Characterization of ABCB4 Mutations Found in Low Phospholipid-Associated Cholelithiasis (LPAC).

    Science.gov (United States)

    Kim, Tae Hee; Park, Hyo Jin; Choi, Ji Ha

    2013-12-01

    Multidrug resistance 3 (MDR3) is expressed on the canalicular membrane of the hepatocytes and plays an important role in protecting the liver from bile acids. Altered ABCB4 gene expression can lead to a rare hepatic disease, low phospholipid-associated cholelithiasis (LPAC). In this study, we characterized 3 ABCB4 mutations in LPAC patients using various in vitro assay systems. We first measured the ability of each mutant to transport paclitaxel and then the mechanisms by which these mutations might change MDR3 transport activity were determined using immunoblotting, cell surface protein biotinylation, and immunofluorescence. Through a membrane vesicular transport assay, we observed that the uptake of paclitaxel was significantly reduced in membrane vesicles expressing 2 ABCB4 mutations, F165I and S320F. Both mutants showed significantly decreased total and cell surface MDR3 expression. These data suggest two missense mutations of ABCB4 may alter function of MDR3 and ultimately can be determined as LPAC-causing mutations.

  1. Novel SCN5A mutation associated with idiopathic ventricular fibrillation due to subclinical Brugada syndrome

    Directory of Open Access Journals (Sweden)

    Juan Jiménez-Jáimez

    2011-12-01

    Full Text Available Idiopathic ventricular fibrillation can be caused by subclinical channelopathies such as Brugada syndrome. Our objective is to study the clinical behaviour of a new SCN5A mutation found in a woman with idiopathic ventricular fibrillation. A 53-year-old woman presented with multiple episodes of ventricular fibrillation, a structurally normal heart and normal baseline electrocardiogram. Genetic testing included KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2 and KCNJ2 and identified a mutation in SCN5A (D1816fs/g98747-98748insT. We studied 15 immediate family members by means of electrocardiogram, echocardiogram, flecainide challenge test and genetic study. Eight subjects had the mutation. The flecainide challenge test was positive for Brugada syndrome in two subjects in the case group and none in the control group. The PR and QRS intervals on the baseline electrocardiogram were longer in the case group. The left atrial volume indexed to body surface was higher in the case group, likely due to the fact that two patients with the mutation had atrial fibrillation and none had it in the control group. The D1816fs/g98747-98748insT mutation in SCN5A may be associated with idiopathic ventricular fibrillation and Brugada syndrome with a broad phenotypic spectrum and incomplete penetrance. Genetic testing may be useful to identify the etiology of idiopathic ventricular fibrillation in patients with a negative thorough clinical evaluation.

  2. The evolution of transcription-associated biases of mutations across vertebrates

    Directory of Open Access Journals (Sweden)

    Arndt Peter F

    2010-06-01

    Full Text Available Abstract Background The interplay between transcription and mutational processes can lead to particular mutation patterns in transcribed regions of the genome. Transcription introduces several biases in mutational patterns; in particular it invokes strand specific mutations. In order to understand the forces that have shaped transcripts during evolution, one has to study mutation patterns associated with transcription across animals. Results Using multiple alignments of related species we estimated the regional single-nucleotide substitution patterns along genes in four vertebrate taxa: primates, rodents, laurasiatheria and bony fishes. Our analysis is focused on intronic and intergenic regions and reveals differences in the patterns of substitution asymmetries between mammals and fishes. In mammals, the levels of asymmetries are stronger for genes starting within CpG islands than in genes lacking this property. In contrast to all other species analyzed, we found a mutational pressure in dog and stickleback, promoting an increase of GC-contents in the proximity to transcriptional start sites. Conclusions We propose that the asymmetric patterns in transcribed regions are results of transcription associated mutagenic processes and transcription coupled repair, which both seem to evolve in a taxon related manner. We also discuss alternative mechanisms that can generate strand biases and involves error prone DNA polymerases and reverse transcription. A localized increase of the GC content near the transcription start site is a signature of biased gene conversion (BGC that occurs during recombination and heteroduplex formation. Since dog and stickleback are known to be subject to rapid adaptations due to population bottlenecks and breeding, we further hypothesize that an increase in recombination rates near gene starts has been part of an adaptive process.

  3. Disease-associated mutation in SRSF2 misregulates splicing by altering RNA-binding affinities.

    Science.gov (United States)

    Zhang, Jian; Lieu, Yen K; Ali, Abdullah M; Penson, Alex; Reggio, Kathryn S; Rabadan, Raul; Raza, Azra; Mukherjee, Siddhartha; Manley, James L

    2015-08-25

    Serine/arginine-rich splicing factor 2 (SRSF2) is an RNA-binding protein that plays important roles in splicing of mRNA precursors. SRSF2 mutations are frequently found in patients with myelodysplastic syndromes and certain leukemias, but how these mutations affect SRSF2 function has only begun to be examined. We used clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease to introduce the P95H mutation to SRSF2 in K562 leukemia cells, generating an isogenic model so that splicing alterations can be attributed solely to mutant SRSF2. We found that SRSF2 (P95H) misregulates 548 splicing events (RNA gel shift assays showed that a mutant SRSF2 derivative bound more tightly than its wild-type counterpart to RNA sites containing UCCAG but bound less tightly to UGGAG sites. Thus in most cases the pattern of exon inclusion or exclusion correlated with stronger or weaker RNA binding, respectively. We further show that the P95H mutation does not affect other functions of SRSF2, i.e., protein-protein interactions with key splicing factors. Our results thus demonstrate that the P95H mutation positively or negatively alters the binding affinity of SRSF2 for cognate RNA sites in target transcripts, leading to misregulation of exon inclusion. Our findings shed light on the mechanism of the disease-associated SRSF2 mutation in splicing regulation and also reveal a group of misspliced mRNA isoforms for potential therapeutic targeting.

  4. Pituitary dwarfism in Saarloos and Czechoslovakian wolfdogs is associated with a mutation in LHX3.

    Science.gov (United States)

    Voorbij, A M W Y; Leegwater, P A; Kooistra, H S

    2014-01-01

    Pituitary dwarfism in German Shepherd Dogs is associated with autosomal recessive inheritance and a mutation in LHX3, resulting in combined pituitary hormone deficiency. Congenital dwarfism also is encountered in breeds related to German Shepherd Dogs, such as Saarloos and Czechoslovakian wolfdogs. To investigate whether Saarloos and Czechoslovakian wolfdog dwarfs have the same LHX3 mutation as do Germans Shepherd Dog dwarfs. A specific aim was to determine the carrier frequency among Saarloos and Czechoslovakian wolfdogs used for breeding. Two client-owned Saarloos wolfdogs and 4 client-owned Czechoslovakian wolfdogs with pituitary dwarfism, 239 clinically healthy client-owned Saarloos wolfdogs, and 200 client-owned clinically healthy Czechoslovakian wolfdogs. Genomic DNA was amplified using polymerase chain reaction (PCR). In the Saarloos and Czechoslovakian wolfdog dwarfs, PCR products were analyzed by sequencing. DNA fragment length analysis was performed on the samples from the clinically healthy dogs. Saarloos and Czechoslovakian wolfdog dwarfs have the same 7 bp deletion in intron 5 of LHX3 as do German Shepherd Dog dwarfs. The frequency of carriers of this mutation among clinically healthy Saarloos and Czechoslovakian wolfdogs used for breeding was 31% and 21%, respectively. An LHX3 mutation is associated with pituitary dwarfism in Saarloos and Czechoslovakian wolfdogs. The rather high frequency of carriers of the mutated gene in the 2 breeds emphasizes the need for screening before breeding. If all breeding animals were genetically tested for the presence of the LHX3 mutation and a correct breeding policy would be implemented, this disease could be eradicated completely. Copyright © 2014 by the American College of Veterinary Internal Medicine.

  5. Two complex associations of an HBD mutation and a rare α hemoglobinopathy.

    Science.gov (United States)

    Joly, Philippe; Lacan, Philippe; Garcia, Caroline; Francina, Alain

    2013-01-01

    We present two case reports in which an HBD mutation is present with a rare α hemoglobinopathy that substantially complicates the associated phenotype. In the first case, a new δ-globin variant, Hb A2-Pierre-Bénite [δ83(EF7)Gly→Arg; HBD: c.250G>C] is associated with Hb Groene Hart [α119(H2)Pro→Ser (α1); HBA1: c.358C>T], an α-thalassemic variant. In the second case, a δ(+)-thalassemic variant, δ4(A1)Thr→Ile; HBD: c.14C>T, is associated with a newly described deletion of the hypersensitive site 40 (HS-40) region on the α-globin gene cluster. In both patients, a δ-globin mutation was suspected because of an abnormally low Hb A2 level, whereas the α hemoglobinopathy was sought to explain the slight microcytosis and hypochromia presented by the probands.

  6. C282Y and H63D Mutation Frequencies in a Population from Central Spain

    Directory of Open Access Journals (Sweden)

    S. Alvarez

    2001-01-01

    Full Text Available Objectives: To determine the frequency of hereditary hemochromatosis gene mutations, C282Y and H63D, from 125 autochthonous blood donors originating from a Central region of Spain, to provide epidemiological data about HFE gene in the Iberian Peninsula.

  7. Novel mutations in ataxia telangiectasia and AOA2 associated with prolonged survival.

    Science.gov (United States)

    Davis, Marie Y; Keene, C Dirk; Swanson, Phillip D; Sheehy, Conor; Bird, Thomas D

    2013-12-15

    Ataxia telangiectasia (AT) and ataxia oculomotor apraxia type 2 (AOA2) are autosomal recessive ataxias caused by mutations in genes involved in maintaining DNA integrity. Lifespan in AT is greatly shortened (20s-30s) due to increased susceptibility to malignancies (leukemia/lymphoma). Lifespan in AOA2 is uncertain. We describe a woman with variant AT with two novel mutations in ATM (IVS14+2T>G and 5825C>T, p.A1942V) who died at age 48 with pancreatic adenocarcinoma. Her mutations are associated with an unusually long life for AT and with a cancer rarely associated with that disease. We also describe two siblings with AOA2, heterozygous for two novel mutations in senataxin (3 bp deletion c.343-345 and 1398T>G, p.I466M) who have survived into their 70s, allowing us to characterize the longitudinal course of AOA2. In contrast to AT, we show that persons with AOA2 can experience a prolonged lifespan with considerable motor disability. Published by Elsevier B.V.

  8. De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy.

    Science.gov (United States)

    Klauke, Baerbel; Kossmann, Sabine; Gaertner, Anna; Brand, Kristina; Stork, Ines; Brodehl, Andreas; Dieding, Mareike; Walhorn, Volker; Anselmetti, Dario; Gerdes, Désirée; Bohms, Birte; Schulz, Uwe; Zu Knyphausen, Edzard; Vorgerd, Matthias; Gummert, Jan; Milting, Hendrik

    2010-12-01

    Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease, frequently accompanied by sudden cardiac death and terminal heart failure. Genotyping of ARVC patients might be used for palliative treatment of the affected family. We genotyped a cohort of 22 ARVC patients referred to molecular genetic screening in our heart center for mutations in the desmosomal candidate genes JUP, DSG2, DSC2, DSP and PKP2 known to be associated with ARVC. In 43% of the cohort, we found disease-associated sequence variants. In addition, we screened for desmin mutations and found a novel desmin-mutation p.N116S in a patient with ARVC and terminal heart failure, which is located in segment 1A of the desmin rod domain. The mutation leads to the aggresome formation in cardiac and skeletal muscle without signs of an overt clinical myopathy. Cardiac aggresomes appear to be prominent, especially in the right ventricle of the heart. Viscosimetry and atomic force microscopy of the desmin wild-type and N116S mutant isolated from recombinant Escherichia coli revealed severe impairment of the filament formation, which was supported by transfections in SW13 cells. Thus, the gene coding for desmin appears to be a novel ARVC gene, which should be included in molecular genetic screening of ARVC patients.

  9. Progressive nonfluent aphasia associated with a new mutation V363I in tau gene.

    Science.gov (United States)

    Munoz, David G; Ros, Raquel; Fatas, Marta; Bermejo, Felix; de Yebenes, Justo García

    2007-01-01

    Reported here is a new missense mutation V363I in exon 12 of the microtubule-associated protein tau (MAPT) gene associated with progressive nonfluent aphasia, with onset at the age of 69 years in a woman. Although near mute, she maintained complex activities and had no discernible deficits outside of language until the age of 75 years, when progressive gait and swallowing disturbances appeared. There was a history of late-onset aphasia and apraxia in her father. All of her children were asymptomatic adults, but psycholinguistic abnormalities were detected in those bearing the mutation, consisting of difficulties in comprehension, both reading (symbol discrimination and comprehension of oral spelling) and oral (matching sentences to pictures and comprehension of locative relationships). A mutation-bearing sibling showed no abnormalities at 70 years old, consistent with the limited penetrance expected in late-onset disease. The mutation, corresponding to a highly conserved residue in the fourth tubulin-binding repeat, was not present in 194 normal individuals with the same genetic background.

  10. Mutations in NR4A2 associated with familial Parkinson disease.

    Science.gov (United States)

    Le, Wei-Dong; Xu, Pingyi; Jankovic, Joseph; Jiang, Hong; Appel, Stanley H; Smith, Roy G; Vassilatis, Demetrios K

    2003-01-01

    NR4A2, encoding a member of nuclear receptor superfamily, is essential for the differentiation of the nigral dopaminergic neurons. To determine whether NR4A2 is a susceptibility gene for Parkinson disease, we carried out genetic analyses in 201 individuals affected with Parkinson disease and 221 age-matched unaffected controls. We identified two mutations in NR4A2 associated with Parkinson disease (-291Tdel and -245T-->G), which map to the first exon of NR4A2 and affect one allele in 10 of 107 individuals with familial Parkinson disease but not in any individuals with sporadic Parkinson disease (n = 94) or in unaffected controls (n = 221). The age at onset of disease and clinical features of these ten individuals were not different from those of individuals with typical Parkinson disease. The mutations resulted in a marked decrease in NR4A2 mRNA levels in transfected cell lines and in lymphocytes of affected individuals. Additionally, mutations in NR4A2 affect transcription of the gene encoding tyrosine hydroxylase. These data suggest that mutations in NR4A2 can cause dopaminergic dysfunction, associated with Parkinson disease.

  11. Animal Models of Congenital Cardiomyopathies Associated With Mutations in Z-Line Proteins.

    Science.gov (United States)

    Bang, Marie-Louise

    2017-01-01

    The cardiac Z-line at the boundary between sarcomeres is a multiprotein complex connecting the contractile apparatus with the cytoskeleton and the extracellular matrix. The Z-line is important for efficient force generation and transmission as well as the maintenance of structural stability and integrity. Furthermore, it is a nodal point for intracellular signaling, in particular mechanosensing and mechanotransduction. Mutations in various genes encoding Z-line proteins have been associated with different cardiomyopathies, including dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, and left ventricular noncompaction, and mutations even within the same gene can cause widely different pathologies. Animal models have contributed to a great advancement in the understanding of the physiological function of Z-line proteins and the pathways leading from mutations in Z-line proteins to cardiomyopathy, although genotype-phenotype prediction remains a great challenge. This review presents an overview of the currently available animal models for Z-line and Z-line associated proteins involved in human cardiomyopathies with special emphasis on knock-in and transgenic mouse models recapitulating the clinical phenotypes of human cardiomyopathy patients carrying mutations in Z-line proteins. Pros and cons of mouse models will be discussed and a future outlook will be given. J. Cell. Physiol. 232: 38-52, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  12. Upstream promoter mutation associated with a modest elevation of fetal hemoglobin expression in human adults.

    Science.gov (United States)

    Gilman, J G; Mishima, N; Wen, X J; Kutlar, F; Huisman, T H

    1988-07-01

    In hereditary persistence of fetal hemoglobin, Hb F (alpha 2 gamma 2) is elevated after birth. Screening of sickle cell patients has revealed a family with elevated Hb F and high A gamma values. The propositus was a sickle cell patient with approximately 25% Hb F and 68.4% A gamma. He was heterozygous for the Benin (#19) and Mor beta S haplotypes. Five AS relatives with the Mor haplotype had 2.5% +/- 0.9% fetal hemoglobin and 92.8% +/- 2.8% A gamma, whereas two with the Benin haplotype had normal fetal hemoglobin (0.5%). The Mor haplotype is thus associated with the elevated Hb F in this family. The 13-kilobase (kb) Bg/II fragment containing the G gamma and A gamma genes of the Mor haplotype was cloned, and the G gamma and A gamma promoters sequenced from -383 to beyond the Cap sites. The Mor G gamma gene was normal, but the A gamma gene had a unique C----T mutation at -202. A different mutation at -202 of G gamma (C----G) was previously detected by other researchers in association with considerably higher Hb F in AS cases (15% to 25%). These data suggest either that -202 mutations affect the G gamma and A gamma promoters differently or that different nucleotide substitutions at -202 have divergent effects. Alternatively, additional unknown mutations could cause the differences in gene expression.

  13. FAD-mutation of APP is associated with a loss of its synaptotrophic activity.

    Science.gov (United States)

    Seeger, Gudrun; Gärtner, Ulrich; Ueberham, Uwe; Rohn, Susanne; Arendt, Thomas

    2009-08-01

    Alzheimer's disease (AD) is a chronic neurodegenerative disorder associated with extracellular accumulation of Abeta peptide that derives from the amyloid precursor protein (APP). While amyloidogenic processing of APP has received most attention, the physiological function of APP and the sequelae of potentially impaired APP function are less understood. APP is a transmembrane glycoprotein being widely expressed in neurons in both central and peripheral nervous system. Its physiological function has been associated with neuronal survival, neurite outgrowth and neuronal plasticity. The aim of the present study was to determine whether FAD-linked mutations of APP, known to be associated with early onset of the disease, might impair its synaptotrophic function, potentially contributing to synaptic deficiencies seen in AD. We performed a quantitative electron microscopy study on synapses in well characterized expression-matched transgenic mice lines expressing either wildtype or FAD-mutated hAPP. Using serial electron microscopic sections, we comparatively analyzed by stereological methods the number and sizes of synaptic contacts and the number of synaptic vesicles in the neocortex. We could clearly show a synaptotrophic effect in mice overexpressing wildtype hAPP evidenced by a significant increase in the number of synapses and the number of vesicles per synapse. This effect was abolished when FAD-mutated APP(Sw,Ind) was expressed instead of wildtype APP. The present study demonstrates a synaptotrophic effect of APP which is lost in the presence of a FAD-mutation. This failure could either be due to a synaptotoxic effect of Abeta potentially counteracting the synaptotrophic effect of APP. Alternatively, the FAD-mutation might impair the physiological function of the extracellular domain of APP and its fragments which might be required for the synaptotrophic effect. This suggests that not only "too much Abeta" but also "too less functional intact APP" might be relevant

  14. Clinical phenotype and genetic mutation of fatty acid hydroxylase - associated neurodegeneration: analysis of four cases

    Directory of Open Access Journals (Sweden)

    Xiao-jun HUANG

    2017-07-01

    Full Text Available Objective To report 4 cases of fatty acid hydroxylase - associated neurodegeneration (FAHN and to summarize the clinical and genetic characteristics of FAHN by literatures review.  Methods Four cases of FAHN patients' clinical and family data were collected in detail. The gDNA of patients and their parents were extracted from peripheral blood. FA2H gene was conducted and followed by Sanger sequencing.  Results Among the 4 cases, 3 cases (Case 2, Case 3, Case 4 presented typical manifestations of FAHN while the other (Case 1 was atypical. Genetic sequencing showed FA2H gene mutation in all affected patients. Compound heterozygous mutation c.461G > A (p.Arg154His and c.794T > G (p.Phe265Cys were seen in Case 1. In Case 2, only one documented heterozygous mutation c.703C > T (p.Arg235Cys was found, and dificit mutation was not found in single nucleotide polymorphism (SNP chip test of the patient and her mother. Compound heterozygous mutation c.688G > A (p.Glu230Lys and insertion mutation c.172_173insGGGCCAGGAC (p.Ile58ArgfsX47 were presented in Case 3. In Case 4, compound heterozygous mutation c.688G > A (p.Glu230Lys, c.968C > A (p.Pro323Gln and c.976G > A (p. Gly326Asp were seen, while his father was the carrier of c.688G > A (p.Glu230Lys mutation and his mother was the carrier of c.968C > A (p.Pro323Gln and c.976G > A (p.Gly326Asp mutation. According to the standard of American College of Medical Genetics and Genomics (ACMG, c.461G > A (p.Arg154His and c.794T > G (p.Phe265Cys in Case 1, and c.703C > T (p.Arg235Cys in Case 2 were considered as "likely pathogenic", while FA2H gene compound heterozygous mutation c.688G > A (p.Glu230Lys, insertion mutation c.172_173insGGGCCAGGAC (p.Ile58ArgfsX47 in Case 3 was as "pathogenic", and in Case 4, the FA2H gene mutation c.688G > A (p.Glu230Lys and c.968C > A (p.Pro323Gln were "pathogenic" and c.976G > A (p.Gly326Asp was "likely pathogenic".  Conclusions FAHN has highly clinical and genetic

  15. Increased risk of death from iron overload among 422 treated probands with HFE hemochromatosis and serum levels of ferritin greater than 1000 μg/L at diagnosis.

    Science.gov (United States)

    Barton, James C; Barton, J Clayborn; Acton, Ronald T; So, Jeffrey; Chan, Susanne; Adams, Paul C

    2012-04-01

    We investigated the risk of death from iron overload among treated hemochromatosis probands who were homozygous for HFE C282Y and had serum levels of ferritin greater than 1000 μg/L at diagnosis. We compared serum levels of ferritin at diagnosis and other conditions with the rate of iron overload-associated death using data from 2 cohorts of probands with hemochromatosis who were homozygous for HFE C282Y (an Alabama cohort, n = 294, 63.9% men and an Ontario cohort, n = 128, 68.8% men). We defined iron overload-associated causes of death as cirrhosis (including hepatic failure and primary liver cancer) caused by iron deposition and cardiomyopathy caused by myocardial siderosis. All probands received phlebotomy and other appropriate therapy. The mean survival times after diagnosis were 13.2 ± 7.3 y and 12.5 ± 8.3 y in Alabama and Ontario probands, respectively. Serum levels of ferritin greater than 1000 μg/L at diagnosis were observed in 30.1% and 47.7% of Alabama and Ontario probands, respectively. In logistic regressions of serum ferritin greater than 1000 μg/L, there were significant positive associations with male sex and cirrhosis in Alabama probands and with age, male sex, increased levels of alanine and aspartate aminotransferases, and cirrhosis in Ontario probands. Of probands with serum levels of ferritin greater than 1000 μg/L at diagnosis, 17.9% of those from Alabama and 14.8% of those from Ontario died of iron overload. Among probands with serum levels of ferritin greater than 1000 μg/L, the relative risk of iron overload-associated death was 5.4 for the Alabama group (95% confidence interval [CI], 2.2-13.1; P = .0002) and 4.9 for the Ontario group (95% CI, 1.1-22.0; P = .0359). In hemochromatosis probands homozygous for HFE C282Y, serum levels of ferritin greater than 1000 μg/L at diagnosis were positively associated with male sex and cirrhosis. Even with treatment, the relative risk of death from iron overload was 5-fold greater in probands with

  16. A novel Kir2.6 mutation associated with hypokalemic periodic paralysis.

    Science.gov (United States)

    Zheng, Jinfan; Liang, Zonglai; Hou, Ying; Liu, Fuchen; Hu, Yuanyuan; Lin, Pengfei; Yan, Chuanzhu

    2016-06-01

    Mutations in KCNJ18, which encodes the inwardly rectifying potassium channel Kir2.6, have rarely been reported in hypokalemic periodic paralysis. We describe the clinical phenotype of a novel KCNJ18 gene mutation and perform functional characterization of this mutant Kir2.6. A long-term exercise test (ET) was conducted based on the McManis method. Whole-cell currents were recorded using patch clamp, and the HEK293 cells were transfected with wild-type or/and mutant Kir2.6 cDNA. A de novo conserved heterozygous mutation in Kir2.6, G169R, was found in a hypokalemic periodic paralysis patient. ET led to a decrease in the amplitude of compound muscle action potential (CMAP) by 64%. Patch clamp results showed that the potassium inward and outward current densities of the G169R mutant were, respectively, reduced by 65.6% and 84.7%; for co-expression with wild type, which more closely resembles the physiological conditions in vitro, the inward and outward current densities decreased, respectively, by 48.2% and 47.4%. A novel KCNJ18 mutation, G169R, was first reported to be associated with hypokalemic periodic paralysis without hyperthyroidism. Electrophysiological results demonstrated a significant functional defect of this mutant, which may predispose patients with this mutation to paralysis. This new G169R mutation of the potassium channel Kir2.6 provides insight into the pathogenic mechanisms of hypokalemic periodic paralysis. Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  17. Detection of genetic mutations associated with macrolide resistance of Mycoplasma pneumoniae

    Directory of Open Access Journals (Sweden)

    Chi Eun Oh

    2010-02-01

    Full Text Available Purpose : The aim of this study was to identify mutations associated with macrolide resistance in Mycoplasma pneumoniae (MP and to establish a cultural method to determine antimicrobial susceptibility. Methods : Nasopharyngeal aspirates (NPAs were collected from 62 children diagnosed with MP pneumonia by a serologic method or polymerase chain reaction. The 23S rRNA and L4 ribosomal protein genes of MP were amplified and sequenced. To identify mutations in these 2 genes, their nucleotide sequences were compared to those of the reference strain M129. MP cultivation was carried out for 32 (28 frozen and 5 refrigerated NPAs and M129 strain using Chanock’s glucose broth and agar plate in a 5% CO2 incubator at 37?#608;and examined at 2-3 day intervals for 6 weeks. Results : Among the 62 specimens, 17 had M144V mutations in ribosomal protein L4. The A2064G mutation was observed in 1 specimen; its 23S rRNA gene was successfully sequenced. Culture for MP was successful from the M129 strain and 2 of the 5 NPAs that were refrigerated for no longer than 3 days. However, MP did not grow from the 28 NPAs that were kept frozen at -80?#608;since 2003. Conclusion : We found the M144V mutation of L4 protein to be common and that of domain V of 23S rRNA gene was relatively rare among MP. Studies on the prevalence of macrolide-resistant MP and the relationship between the mutations of 23S rRNA gene and ribosomal protein L4 will aid in understanding the mechanism of macrolide resistance in MP.

  18. Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations

    Directory of Open Access Journals (Sweden)

    Kalback Walter M

    2008-11-01

    Full Text Available Abstract Background Mutations in the presenilin (PSEN genes are associated with early-onset familial Alzheimer's disease (FAD. Biochemical characterizations and comparisons have revealed that many PSEN mutations alter γ-secretase activity to promote accumulation of toxic Aβ42 peptides. In this study, we compared the histopathologic and biochemical profiles of ten FAD cases expressing independent PSEN mutations and determined the degradation patterns of amyloid-β precursor protein (AβPP, Notch, N-cadherin and Erb-B4 by γ-secretase. In addition, the levels of Aβ40/42 peptides were quantified by ELISA. Results We observed a wide variation in type, number and distribution of amyloid deposits and neurofibrillary tangles. Four of the ten cases examined exhibited a substantial enrichment in the relative proportions of Aβ40 over Aβ42. The AβPP N-terminal and C-terminal fragments and Tau species, assessed by Western blots and scanning densitometry, also demonstrated a wide variation. The Notch-1 intracellular domain was negligible by Western blotting in seven PSEN cases. There was significant N-cadherin and Erb-B4 peptide heterogeneity among the different PSEN mutations. Conclusion These observations imply that missense mutations in PSEN genes can alter a range of key γ-secretase activities to produce an array of subtly different biochemical, neuropathological and clinical manifestations. Beyond the broad common features of dementia, plaques and tangles, the various PSEN mutations resulted in a wide heterogeneity and complexity and differed from sporadic AD.

  19. A frequent tyrosinase gene mutation associated with type I-A (tyroinase-negative) oculocutaneous albinism in Puerto Rico

    Energy Technology Data Exchange (ETDEWEB)

    Oetting, W.S.; Witkop, C.J. Jr.; Brown, S.A.; Fryer, J.P.; Bloom, K.E.; King, R.A. (Univ. of Minnesota, Minneapolis (United States)); Colomer, R. (Servicio Medico de Empressa de la ONCE, Canary Islands (Spain))

    1993-01-01

    The authors have determined the mutations in the tyrosinase gene from 12 unrelated Puerto Rican individuals who have type I-A (tyrosinase-negative) oculocutaneous albinism (OCA). All but one individual are of Hispanic descent. Nine individuals were homozygous for a missense mutation (G47D) in exon I at codon 47. Two individuals were heterozygous for the G47D mutation, with one having a missense mutation at codon 373 (T373K) in the homologous allele and the other having an undetermined mutation in the homologous allele. One individual with negroid features was homozygous for a nonsense mutation (W236X). The population migration between Puerto Rico and the Canary Islands is well recognized. Analysis of three individuals with OCA from the Canary Islands showed that one was a compound heterozygote for the G47D mutation and for a novel missense mutation (L216M), one was homozygous for a missense mutation (P81L), and one was heterozygous for the missense mutation P81L. The G47D and P81L missense mutations have been previously described in extended families in the United States. Haplotypes were determined using four polymorphisms linked to the tyrosinase locus. Haplotype analysis showed that the G47D mutation occurred on a single haplotype, consistent with a common founder for all individuals having this mutation. Two different haplotypes were found associated with the P81L mutation, suggesting that this may be either a recurring mutation for the tyrosinase gene or a recombination between haplotypes. 28 refs., 1 fig., 3 tabs.

  20. Coexistence of TERT promoter and BRAF mutations in cutaneous melanoma is associated with more clinicopathological features of aggressiveness.

    Science.gov (United States)

    Macerola, Elisabetta; Loggini, Barbara; Giannini, Riccardo; Garavello, Giulia; Giordano, Mirella; Proietti, Agnese; Niccoli, Cristina; Basolo, Fulvio; Fontanini, Gabriella

    2015-08-01

    The recently described telomerase reverse transcriptase (TERT) promoter mutations are recurrent in cutaneous melanoma. Several authors have described an association between these molecular alterations, some histological parameters, and patient survival. BRAF mutations are very frequent in melanoma, but their actual role in the evolution of the disease is still unclear. Here, we investigated the relationship of TERT promoter mutations and BRAF mutations with the most relevant clinicopathological parameters, individually and coexisting, in order to evaluate their role as independent prognostic markers and to determine the effect of their coexistence. A TERT promoter alteration was found in 20 of 53 cases (38 %), significantly associated with histological type, increasing tumor thickness and mitotic rate, more advanced pathologic tumor (pT) stage, and absence of regression. A BRAF mutation was found in 21 of 53 cases (40 %), significantly associated with tumor thickness and presence of metastases in the sentinel lymph node. Coexistence of a TERT promoter and BRAF mutation was detected in 11 of 53 cases (21 %). This was associated with increasing thickness, high mitotic rate, lymph node metastasis, presence of ulceration, and absence of regression. Coexistence of a mutation in the TERT promoter and in the BRAF gene correlated with more prognostically relevant factors than either mutation alone. Our data lead us to hypothesize that TERT promoter and BRAF mutations cooperate in cutaneous melanoma. Further studies in larger cohorts of patients are needed to investigate how this synergistic effect is involved in the evolution of the disease.

  1. A de novo dominant mutation in ACTA1 causing congenital nemaline myopathy associated with a milder phenotype: expanding the spectrum of dominant ACTA1 mutations.

    Science.gov (United States)

    Levesque, L; Del Bigio, M R; Krawitz, S; Mhanni, A A

    2013-03-01

    We describe the presentation and six-year follow up of a child with nemaline myopathy due to a de novo mutation in the skeletal muscle α-actin gene (ACTA1) characterized by dramatic improvement during the early childhood years. The presentation in this female patient was infantile-onset weakness in the facial, bulbar, respiratory and neck flexor muscles. A six-year follow-up revealed continued progressive improvement in her muscle strength. Based upon the histopathologic and ultrastructural features of nemaline rod disease, ACTA1 was sequenced. This revealed a mutation in exon 4 of ACTA1 (c.557A>G). Our report further expands the phenotypic spectrum associated with ACTA1 mutations. Although it is difficult to infer any genotype-phenotype correlation, this report stimulates the discussion regarding the pathophysiologic mechanism of the clinical improvement seen in some patients with ACTA1 mutations. Copyright © 2012 Elsevier B.V. All rights reserved.

  2. A novel frameshift mutation in CX46 associated with hereditary dominant cataracts in a Chinese family

    Directory of Open Access Journals (Sweden)

    Xiu-Kun Cui

    2017-05-01

    Full Text Available AIM: To investigate the genetic mutations that are associated the hereditary autosomal dominant cataract in a Chinese family. METHODS: A Chinese family consisting of 20 cataract patients (including 9 male and 11 female and 2 unaffected individuals from 5 generations were diagnosed to be a typical autosomal dominant cataract pedigree. Genomic DNA samples were extracted from the peripheral blood cells of the participants in this pedigree. Exon sequence was used for genetic mutation screening. In silico analysis was used to study the structure characteristics of connexin 46 (CX46 mutant. Immunoblotting was conduceted for testing the expression of CX46. RESULTS: To determine the involved genetic mutations, 11 well-known cataract-associated genes (cryaa, cryab, crybb1, crybb2, crygc, crygd, Gja3, Gja8, Hsf4, Mip and Pitx3 were chosen for genetic mutation test by using exon sequencing. A novel cytosine insertion at position 1195 of CX46 cDNA (c.1194_1195ins C was found in the samples of 5 tested cataract patients but not in the unaffected 2 individuals nor in normal controls, which resulted in 30 amino acids more extension in CX46C-terminus (cx46fs400 compared with the wild-type CX46. In silico protein structure analysis indicated that the mutant showed distinctive hydrophobicity and protein secondary structure compared with the wild-type CX46. The immunoblot results revealed that CX46 protein, which expressed in the aging cataract lens tissues, was absence in the proband lens. In contrast, CX50, alpha A-crystallin and alphaB-crystallin expressed equally in both proband and aging cataract tissues. Those results revealed that the cx46fs400 mutation could impair CX46 protein expression. CONCLUSION: The insertion of cytosine at position 1195 of CX46 cDNA is a novel mutation site that is associated with the autosomal dominant cataracts in this Chinese family. The C-terminal frameshift mutation is involved in regulating CX46 protein expression.

  3. Mutations in the Hepatocyte Nuclear Factor-1β Gene Are Associated with Familial Hypoplastic Glomerulocystic Kidney Disease

    Science.gov (United States)

    Bingham, Coralie; Bulman, Michael P.; Ellard, Sian; Allen, Lisa I. S.; Lipkin, Graham W.; Hoff, William G. van't; Woolf, Adrian S.; Rizzoni, Gianfranco; Novelli, Giuseppe; Nicholls, Anthony J.; Hattersley, Andrew T.

    2001-01-01

    Familial glomerulocystic kidney disease (GCKD) is a dominantly inherited condition characterized by glomerular cysts and variable renal size and function; the molecular genetic etiology is unknown. Mutations in the gene encoding hepatocyte nuclear factor (HNF)–1β have been associated with early-onset diabetes and nondiabetic renal disease—particularly renal cystic disease. We investigated a possible role for the HNF-1β gene in four unrelated GCKD families and identified mutations in two families: a nonsense mutation in exon 1 (E101X) and a frameshift mutation in exon 2 (P159fsdelT). The family members with HNF-1β gene mutations had hypoplastic GCKD and early-onset diabetes or impaired glucose tolerance. We conclude that there is genetic heterogeneity in familial GCKD and that the hypoplastic subtype is a part of the clinical spectrum of the renal cysts and diabetes syndrome that is associated with HNF-1β mutations. PMID:11085914

  4. Acute Pancreatitis in Association with Campylobacter jejuni- Associated Diarrhea in a 15-Year-Old with CFTR Mutations: Is There a Link?

    OpenAIRE

    Leena Kandula; Lowe, Mark E.; Seema Khan; Whitcomb, David C.

    2006-01-01

    Context: Acute pancreatitis has occasionally been reported in association with Campylobacter jejuni infection in humans. However, the mechanism linking Campylobacter jejuni infection and pancreatitis isunclear. Acute pancreatitis in association with an infectious illness may be related to underlying genetic mutations. For instance, studies show that mutations in the cystic fibrosis transmembrane conductance regulator gene increase the susceptibility for acute and chronic pancreatitis. Case re...

  5. Association of the germline TP53 R337H mutation with breast cancer in southern Brazil

    Directory of Open Access Journals (Sweden)

    Srivastava Kumar

    2008-12-01

    Full Text Available Abstract Background The germline TP53-R337H mutation is strongly associated with pediatric adrenocortical tumors (ACT in southern Brazil; it has low penetrance and limited tissue specificity in most families and therefore is not associated with Li-Fraumeni syndrome. However, other tumor types, mainly breast cancer, have been observed in carriers of several unrelated kindreds, raising the possibility that the R337H mutation may also contribute to breast tumorigenesis in a genetic background-specific context. Methods We conducted a case-control study to determine the prevalence of the R337H mutation by sequencing TP53 exon 10 in 123 women with breast cancer and 223 age- and sex-matched control subjects from southern Brazil. Fisher's test was used to compare the prevalence of the R337H. Results The R337H mutation was found in three patients but in none of the controls (p = 0.0442. Among the carriers, two had familial history of cancer meeting the Li-Fraumeni-like criteria. Remarkably, tumors in each of these three cases underwent loss of heterozygosity by eliminating the mutant TP53 allele rather than the wild-type allele. Polymorphisms were identified within the TP53 (R72P and Ins16 and MDM2 (SNP309 genes that may further diminish TP53 tumor suppressor activity. Conclusion These results demonstrate that the R337H mutation can significantly increase the risk of breast cancer in carriers, which likely depends on additional cooperating genetic factors. These findings are also important for understanding how low-penetrant mutant TP53 alleles can differentially influence tumor susceptibility.

  6. Specific point mutations in key redox enzymes are associated with chemoresistance in epithelial ovarian cancer.

    Science.gov (United States)

    Fletcher, Nicole M; Belotte, Jimmy; Saed, Mohammed G; Memaj, Ira; Diamond, Michael P; Morris, Robert T; Saed, Ghassan M

    2017-01-01

    Oxidative stress plays an important role in the pathophysiology of ovarian cancer. Resistance to chemotherapy presents a significant challenge for ovarian cancer treatment. Specific single nucleotide polymorphisms (SNPs) in key redox enzymes have been associated with ovarian cancer survival and progression. The objective of this study was to determine whether chemotherapy induces point mutations in key redox enzymes that lead to the acquisition of chemoresistance in epithelial ovarian cancer (EOC). Human EOC cell lines and their chemoresistant counterpart were utilized for this study. Specific SNPs in key redox enzymes were analyzed by TaqMan SNP Genotyping. Activities and levels of key redox enzymes were determined by real-time RT-PCR, ELISA and a greiss assay. Point mutations in key redox enzymes were introduced into sensitive EOC cells via the CRISPR/Cas9 system. Cell viability and IC50 for cisplatin were determined by the MTT Cell Proliferation Assay. Data was analyzed with SPSS using Student's two-tailed t-tests and One-way ANOVA followed by Dunnett's or Tukey's post hoc tests, penhancement in oxidative stress as compared to sensitive counterparts. Additionally, chemoresistant EOC cells manifested specific point mutations, which are associated with altered enzymatic activity, in key redox enzymes that are not detected in sensitive counterparts. Supplementation of an antioxidant was able to successfully sensitize EOC cells to chemotherapeutics. Causality was established by the induction of these point mutations in sensitive EOC cells, which resulted in a significant increase in the level of chemoresistance. These findings indicate that chemotherapy induces specific point mutations in key redox enzymes that contribute to the acquisition of chemoresistance in EOC cells, highlighting a potential novel mechanism. Identification of targets for chemoresistance with either biomarker and/or screening potential will have a significant impact for the treatment of this

  7. Persistence of transmitted HIV-1 drug resistance mutations associated with fitness costs and viral genetic backgrounds.

    Directory of Open Access Journals (Sweden)

    Wan-Lin Yang

    2015-03-01

    Full Text Available Transmission of drug-resistant pathogens presents an almost-universal challenge for fighting infectious diseases. Transmitted drug resistance mutations (TDRM can persist in the absence of drugs for considerable time. It is generally believed that differential TDRM-persistence is caused, at least partially, by variations in TDRM-fitness-costs. However, in vivo epidemiological evidence for the impact of fitness costs on TDRM-persistence is rare. Here, we studied the persistence of TDRM in HIV-1 using longitudinally-sampled nucleotide sequences from the Swiss-HIV-Cohort-Study (SHCS. All treatment-naïve individuals with TDRM at baseline were included. Persistence of TDRM was quantified via reversion rates (RR determined with interval-censored survival models. Fitness costs of TDRM were estimated in the genetic background in which they occurred using a previously published and validated machine-learning algorithm (based on in vitro replicative capacities and were included in the survival models as explanatory variables. In 857 sequential samples from 168 treatment-naïve patients, 17 TDRM were analyzed. RR varied substantially and ranged from 174.0/100-person-years;CI=[51.4, 588.8] (for 184V to 2.7/100-person-years;[0.7, 10.9] (for 215D. RR increased significantly with fitness cost (increase by 1.6[1.3,2.0] per standard deviation of fitness costs. When subdividing fitness costs into the average fitness cost of a given mutation and the deviation from the average fitness cost of a mutation in a given genetic background, we found that both components were significantly associated with reversion-rates. Our results show that the substantial variations of TDRM persistence in the absence of drugs are associated with fitness-cost differences both among mutations and among different genetic backgrounds for the same mutation.

  8. Rhabdomyosarcoma-associated renal cell carcinoma: a link with constitutional Tp53 mutation.

    LENUS (Irish Health Repository)

    Curry, Sarah

    2012-02-01

    The 2004 World Health Organization classification includes the new entity "neuroblastoma-associated renal cell carcinoma." The pathogenetic link between these entities is unknown as yet. The patient reported herein developed renal cell carcinoma after anaplastic embryonal rhabdomyosarcoma, a previously unknown association. The 2nd malignancy developed very soon after the 1st one, prompting concern for inherent cancer predisposition rather than a therapy-induced 2nd malignancy. A variety of features raised suspicion for Tp53 mutation, and indeed a pathogenic germline Tp53 mutation was identified in this child, despite a negative family history for Li-Fraumeni syndrome. Consideration of underlying predisposition is advocated in the context of rapid evolution of 2nd childhood malignancy.

  9. Integration of published information into a resistance-associated mutation database for Mycobacterium tuberculosis.

    Science.gov (United States)

    Salamon, Hugh; Yamaguchi, Ken D; Cirillo, Daniela M; Miotto, Paolo; Schito, Marco; Posey, James; Starks, Angela M; Niemann, Stefan; Alland, David; Hanna, Debra; Aviles, Enrique; Perkins, Mark D; Dolinger, David L

    2015-04-01

    Tuberculosis remains a major global public health challenge. Although incidence is decreasing, the proportion of drug-resistant cases is increasing. Technical and operational complexities prevent Mycobacterium tuberculosis drug susceptibility phenotyping in the vast majority of new and retreatment cases. The advent of molecular technologies provides an opportunity to obtain results rapidly as compared to phenotypic culture. However, correlations between genetic mutations and resistance to multiple drugs have not been systematically evaluated. Molecular testing of M. tuberculosis sampled from a typical patient continues to provide a partial picture of drug resistance. A database of phenotypic and genotypic testing results, especially where prospectively collected, could document statistically significant associations and may reveal new, predictive molecular patterns. We examine the feasibility of integrating existing molecular and phenotypic drug susceptibility data to identify associations observed across multiple studies and demonstrate potential for well-integrated M. tuberculosis mutation data to reveal actionable findings.

  10. A mutation in the XPB/ERCC3 DNA repair transcription gene, associated with trichothiodystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Weeda, G.; Donker, I.; Vermeulen, W. [Erasmus Univ., Rotterdam (Netherlands)] [and others

    1997-02-01

    Trichothiodystrophy (TTD) is a rare, autosomal recessive disorder characterized by sulfur-deficient brittle hair and nails, mental retardation, impaired sexual development, and ichthyosis. Photosensitivity has been reported in {approximately}50% of the cases, but no skin cancer is associated with TTD. Virtually all photosensitive TTD patients have a deficiency in the nucleotide excision repair (NER) of UV-induced DNA damage that is indistinguishable from that of xeroderma pigmentosum (XP) complementation group D (XP-D) patients. DNA repair defects in XP-D are associated with two additional, quite different diseases; XP, a sun-sensitive and cancer-prone repair disorder, and Cockayne syndrome (CS), a photosensitive condition characterized by physical and mental retardation and wizened facial appearance. One photosensitive TTD case constitutes a new repair-deficient complementation group, TTD-A. Remarkably, both TTD-A and XP-D defects are associated with subunits of TFIIH, a basal transcription factor with a second function in DNA repair. Thus, mutations in TFIIH components may, on top of a repair defect, also cause transcriptional insufficiency, which may explain part of the non-XP clinical features of TTD. To date, three patients with the remarkable conjunction of XP and CS but not TM have been assigned to XP complementation group B (XP-B). Here we present the characterization of the NER defect in two mild TTD patients (TTD6VI and TTD4VI) and confirm the assignment to X-PB. The causative mutation was found to be a single base substitution resulting in a missense mutation (T119P) in a region of the XPB protein. These findings define a third TTD complementation group, extend the clinical heterogeneity associated with XP-B, stress the exclusive relationship between TTD and mutations in subunits of repair/transcription factor TFIIH, and strongly support the concept of {open_quotes}transcription syndromes.{close_quotes} 46 refs., 6 figs., 2 tabs.

  11. Association of KCNJ5 gene missense mutations with aldosterone-producing adenoma and primary hyperaldosteronism

    Institute of Scientific and Technical Information of China (English)

    邵丹

    2013-01-01

    Objective To detect the KCNJ5 gene variations in aldosterone-producing adenoma (APA) with primary hyperaldosteronism (PA) ,and to investigate the association of the KCNJ5 gene missense mutations with APA and PA.Methods A total of 46 APA tumors and their clinical characteristics were collected from Hypertension Center of the People’s Hospital of Xinjiang Uygur Autonomous Region,and all the tumors were confirmed by pathology.

  12. Idiopathic basal ganglia calcification-associated PDGFRB mutations impair the receptor signalling

    Science.gov (United States)

    Arts, Florence A; Velghe, Amélie I; Stevens, Monique; Renauld, Jean-Christophe; Essaghir, Ahmed; Demoulin, Jean-Baptiste

    2015-01-01

    Platelet-derived growth factors (PDGF) bind to two related receptor tyrosine kinases, which are encoded by the PDGFRA and PDGFRB genes. Recently, heterozygous PDGFRB mutations have been described in patients diagnosed with idiopathic basal ganglia calcification (IBGC or Fahr disease), a rare inherited neurological disorder. The goal of the present study was to determine whether these mutations had a positive or negative impact on the PDGFRB activity. We first showed that the E1071V mutant behaved like wild-type PDGFRB and may represent a polymorphism unrelated to IBGC. In contrast, the L658P mutant had no kinase activity and failed to activate any of the pathways normally stimulated by PDGF. The R987W mutant activated Akt and MAP kinases but did not induce the phosphorylation of signal transducer and activator of transcription 3 (STAT3) after PDGF stimulation. Phosphorylation of phospholipase Cγ was also decreased. Finally, we showed that the R987W mutant was more rapidly degraded upon PDGF binding compared to wild-type PDGFRB. In conclusion, PDGFRB mutations associated with IBGC impair the receptor signalling. PDGFRB loss of function in IBGC is consistent with recently described inactivating mutations in the PDGF-B ligand. These results raise concerns about the long-term safety of PDGF receptor inhibition by drugs such as imatinib. PMID:25292412

  13. A novel mutation in CLCN1 associated with feline myotonia congenita.

    Directory of Open Access Journals (Sweden)

    Barbara Gandolfi

    Full Text Available Myotonia congenita (MC is a skeletal muscle channelopathy characterized by inability of the muscle to relax following voluntary contraction. Worldwide population prevalence in humans is 1:100,000. Studies in mice, dogs, humans and goats confirmed myotonia associated with functional defects in chloride channels and mutations in a skeletal muscle chloride channel (CLCN1. CLCN1 encodes for the most abundant chloride channel in the skeletal muscle cell membrane. Five random bred cats from Winnipeg, Canada with MC were examined. All cats had a protruding tongue, limited range of jaw motion and drooling with prominent neck and proximal limb musculature. All cats had blepharospasm upon palpebral reflex testing and a short-strided gait. Electromyograms demonstrated myotonic discharges at a mean frequency of 300 Hz resembling the sound of a 'swarm of bees'. Muscle histopathology showed hypertrophy of all fiber types. Direct sequencing of CLCN1 revealed a mutation disrupting a donor splice site downstream of exon 16 in only the affected cats. In vitro translation of the mutated protein predicted a premature truncation and partial lack of the highly conserved CBS1 (cystathionine β-synthase domain critical for ion transport activity and one dimerization domain pivotal in channel formation. Genetic screening of the Winnipeg random bred population of the cats' origin identified carriers of the mutation. A genetic test for population screening is now available and carrier cats from the feral population can be identified.

  14. Dynein mutations associated with hereditary motor neuropathies impair mitochondrial morphology and function with age.

    Science.gov (United States)

    Eschbach, Judith; Sinniger, Jérôme; Bouitbir, Jamal; Fergani, Anissa; Schlagowski, Anna-Isabel; Zoll, Joffrey; Geny, Bernard; René, Frédérique; Larmet, Yves; Marion, Vincent; Baloh, Robert H; Harms, Matthew B; Shy, Michael E; Messadeq, Nadia; Weydt, Patrick; Loeffler, Jean-Philippe; Ludolph, Albert C; Dupuis, Luc

    2013-10-01

    Mutations in the DYNC1H1 gene encoding for dynein heavy chain cause two closely related human motor neuropathies, dominant spinal muscular atrophy with lower extremity predominance (SMA-LED) and axonal Charcot-Marie-Tooth (CMT) disease, and lead to sensory neuropathy and striatal atrophy in mutant mice. Dynein is the molecular motor carrying mitochondria retrogradely on microtubules, yet the consequences of dynein mutations on mitochondrial physiology have not been explored. Here, we show that mouse fibroblasts bearing heterozygous or homozygous point mutation in Dync1h1, similar to human mutations, show profoundly abnormal mitochondrial morphology associated with the loss of mitofusin 1. Furthermore, heterozygous Dync1h1 mutant mice display progressive mitochondrial dysfunction in muscle and mitochondria progressively increase in size and invade sarcomeres. As a likely consequence of systemic mitochondrial dysfunction, Dync1h1 mutant mice develop hyperinsulinemia and hyperglycemia and progress to glucose intolerance with age. Similar defects in mitochondrial morphology and mitofusin levels are observed in fibroblasts from patients with SMA-LED. Last, we show that Dync1h1 mutant fibroblasts show impaired perinuclear clustering of mitochondria in response to mitochondrial uncoupling. Our results show that dynein function is required for the maintenance of mitochondrial morphology and function with aging and suggest that mitochondrial dysfunction contributes to dynein-dependent neurological diseases, such as SMA-LED.

  15. Pediatric intracranial clear cell meningioma associated with a germline mutation of SMARCE1: a novel case.

    Science.gov (United States)

    Raffalli-Ebezant, Helen; Rutherford, Scott A; Stivaros, Stavros; Kelsey, Anna; Smith, Miriam; Evans, D Gareth; Kilday, John-Paul

    2015-03-01

    Intracranial clear cell meningioma (CCM) represents a rare and potentially more aggressive subgroup of meningioma that is observed more frequently in children and adolescents. Despite its characterization as a histological entity, there is little evidence identifying tumorigenic etiologies. Recently, a novel mutation in SMARCE1, encoding a subunit of the SWI/SNF chromatin remodeling complex, was identified in a cohort of spinal CCMs. To date, no intracranial CCM has been subjected to analysis. We report the case of an isolated intracranial CCM in a 14-year-old girl. Gross total resection was achieved following a two-stage approach with no evidence of tumor recurrence 8 months following presentation. Exon sequencing identified a germline mutation in SMARCE1, which was also present in tumor DNA. Extensive literature review confirmed our study is the first to seek and report a genetic anomaly for childhood intracranial CCMs outside of the NF2 gene locus, and the first to make an association between a germline SMARCE1 mutation and childhood intracranial CCMs. Together with the previous description of SMARCE1 mutations in spinal CCMs, our report suggests that SMARCE1 aberrations may be implicated in establishing a clear cell histology irrespective of meningioma location. We would advocate that, where feasible, genetic sequencing is performed on future new cases of childhood neuraxial CCMs and includes interrogation of the SMARCE1 gene.

  16. APP mutations in the Aβ coding region are associated with abundant cerebral deposition of Aβ38.

    Science.gov (United States)

    Moro, Maria Luisa; Giaccone, Giorgio; Lombardi, Raffaella; Indaco, Antonio; Uggetti, Andrea; Morbin, Michela; Saccucci, Stefania; Di Fede, Giuseppe; Catania, Marcella; Walsh, Dominic M; Demarchi, Andrea; Rozemuller, Annemieke; Bogdanovic, Nenad; Bugiani, Orso; Ghetti, Bernardino; Tagliavini, Fabrizio

    2012-12-01

    Aβ is the main component of amyloid deposits in Alzheimer disease (AD) and its aggregation into oligomers, protofibrils and fibrils is considered a seminal event in the pathogenesis of AD. Aβ with C-terminus at residue 42 is the most abundant species in parenchymal deposits, whereas Aβ with C-terminus at residue 40 predominates in the amyloid of the walls of large vessels. Aβ peptides with other C-termini have not yet been thoroughly investigated. We analysed Aβ38 in the brains of patients with Aβ deposition linked to sporadic and familial AD, hereditary cerebral haemorrhage with amyloidosis, or Down syndrome. Immunohistochemistry, confocal microscopy, immunoelectron microscopy, immunoprecipitation and the electrophoresis separation of low molecular weight aggregates revealed that Aβ38 accumulates consistently in the brains of patients carrying APP mutations in the Aβ coding region, but was not detected in the patients with APP mutations outside the Aβ domain, in the patients with presenilin mutations or in subjects with Down syndrome. In the patients with sporadic AD, Aβ38 was absent in the senile plaques, but it was detected only in the vessel walls of a small subset of patients with severe cerebral amyloid angiopathy. Our results suggest that APP mutations in the Aβ coding region favour Aβ38 accumulation in the brain and that the molecular mechanisms of Aβ deposition in these patients may be different from those active in patients with familial AD associated with other genetic defects and sporadic AD.

  17. ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor.

    Science.gov (United States)

    Divisato, Giuseppina; Formicola, Daniela; Esposito, Teresa; Merlotti, Daniela; Pazzaglia, Laura; Del Fattore, Andrea; Siris, Ethel; Orcel, Philippe; Brown, Jacques P; Nuti, Ranuccio; Strazzullo, Pasquale; Benassi, Maria Serena; Cancela, M Leonor; Michou, Laetitia; Rendina, Domenico; Gennari, Luigi; Gianfrancesco, Fernando

    2016-02-04

    Paget disease of bone (PDB) is a skeletal disorder characterized by focal abnormalities of bone remodeling, which result in enlarged and deformed bones in one or more regions of the skeleton. In some cases, the pagetic tissue undergoes neoplastic transformation, resulting in osteosarcoma and, less frequently, in giant cell tumor of bone (GCT). We performed whole-exome sequencing in a large family with 14 PDB-affected members, four of whom developed GCT at multiple pagetic skeletal sites, and we identified the c.2810C>G (p.Pro937Arg) missense mutation in the zinc finger protein 687 gene (ZNF687). The mutation precisely co-segregated with the clinical phenotype in all affected family members. The sequencing of seven unrelated individuals with GCT associated with PDB (GCT/PDB) identified the same mutation in all individuals, unravelling a founder effect. ZNF687 is highly expressed during osteoclastogenesis and osteoblastogenesis and is dramatically upregulated in the tumor tissue of individuals with GCT/PDB. Interestingly, our preliminary findings showed that ZNF687, indicated as a target gene of the NFkB transcription factor by ChIP-seq analysis, is also upregulated in the peripheral blood of PDB-affected individuals with (n = 5) or without (n = 6) mutations in SQSTM1, encouraging additional studies to investigate its potential role as a biomarker of PDB risk.

  18. Recurrent loss of sex is associated with accumulation of deleterious mutations in Oenothera.

    Science.gov (United States)

    Hollister, Jesse D; Greiner, Stephan; Wang, Wei; Wang, Jun; Zhang, Yong; Wong, Gane Ka-Shu; Wright, Stephen I; Johnson, Marc T J

    2015-04-01

    Sexual reproduction is nearly universal among eukaryotes. Theory predicts that the rarity of asexual eukaryotic species is in part caused by accumulation of deleterious mutations and heightened extinction risk associated with suppressed recombination and segregation in asexual species. We tested this prediction with a large data set of 62 transcriptomes from 29 species in the plant genus Oenothera, spanning ten independent transitions between sexual and a functionally asexual genetic system called permanent translocation heterozygosity. Illumina short-read sequencing and de novo transcript assembly yielded an average of 16.4 Mb of sequence per individual. Here, we show that functionally asexual species accumulate more deleterious mutations than sexual species using both population genomic and phylogenetic analysis. At an individual level, asexual species exhibited 1.8 × higher heterozygosity than sexual species. Within species, we detected a higher proportion of nonsynonymous polymorphism relative to synonymous variation within asexual compared with sexual species, indicating reduced efficacy of purifying selection. Asexual species also exhibited a greater proportion of transcripts with premature stop codons. The increased proportion of nonsynonymous mutations was also positively correlated with divergence time between sexual and asexual species, consistent with Muller's ratchet. Between species, we detected repeated increases in the ratio of nonsynonymous to synonymous divergence in asexual species compared with sexually reproducing sister taxa, indicating increased accumulation of deleterious mutations. These results confirm that an important advantage of sex is that it facilitates selection against deleterious alleles, which might help to explain the dearth of extant asexual species.

  19. Identification of a dieldrin resistance-associated mutation in Rhipicephalus (Boophilus) microplus (Acari: Ixodidae).

    Science.gov (United States)

    Hope, Michelle; Menzies, Moira; Kemp, David

    2010-08-01

    The southern cattle tick, Rhipicephalus (Boophilus) microplus (Canestrini) (Acari: Ixodidae), is a major vector of tick fever organisms affecting cattle in many parts of the world, including Australia, Africa, and South America. Control of the southern cattle tick through acaricide use is an important approach in disease management. Resistance has emerged to many of the acaricides currently and previously used, including the cyclodienes. Although cyclodiene resistance mechanisms have been characterized in many insect species, this report is the first to identify mutations associated with dieldrin resistance in the cattle tick. A novel two base pair mutation in the GABA-gated chloride channel gene has been identified at position 868-9 and causes a codon change from threonine to leucine. Analysis of a small number of field-collected samples resistant to dieldrin shows this mutation has been maintained without selection pressure since the withdrawal of dieldrin in Australia > 20 yr ago. The mutation is not found in other laboratory-maintained strains of R. microplus that were subject to selection pressure with various acaricides.

  20. Phenotype of retinitis pigmentosa associated with the Ser50Thr mutation in the NRL gene.

    Science.gov (United States)

    Bessant, David A R; Holder, Graham E; Fitzke, Frederick W; Payne, Annette M; Bhattacharya, Shomi S; Bird, Alan C

    2003-06-01

    We previously reported an Ser50Thr mutation in the NRL gene as a cause of autosomal dominant retinitis pigmentosa. To determine the characteristic features of the autosomal dominant retinitis pigmentosa phenotype associated with the NRL Ser50Thr mutation in affected individuals from 4 related families. Clinical records were available for 21 affected individuals; 7 underwent more extensive electrophysiologic and psychophysical testing. Night blindness was the first symptom to manifest, with onset between birth and age 16 years. Difficulty with peripheral vision was experienced between 20 and 37 years of age. Visual acuity was well preserved in younger individuals, but those older than 30 years frequently had substantial visual loss (6/36 or worse) associated with macular atrophy. Electrophysiologic testing revealed a nondetectable scotopic electroretinogram with relative preservation of the photopic electroretinogram and pattern electroretinography in the 3 youngest patients tested (aged 15-18 years). In older individuals, all components of the electroretinogram were nondetectable. Dark-adapted visual fields in younger individuals were greatly impaired, but their photopic fields remained relatively well preserved. Older patients had photopic fields limited to just a few degrees. Distinctive peripapillary chorioretinal atrophy seems to develop as the disorder progresses. The NRL Ser50Thr mutation is associated with selective loss of scotopic function before age 20 years. With time, however, the photopic system becomes affected, leading to loss of the photopic visual field and of visual acuity.

  1. Iron homeostasis and H63D mutations in alcoholics with and without liver disease

    Institute of Scientific and Technical Information of China (English)

    Mariana Verdelho Machado; Paula Ravasco; Alexandra Martins; Maria Ermelinda Camilo; Helena Cortez-Pinto; Maria Rosario Almeida

    2009-01-01

    AIM: To evaluate the prevalence of HFE gene mutation and indices of disturbed iron homeostasis in alcoholics with and without liver disease. METHODS: One hundred and fifty-three heavy drinkers (defined as alcohol consumption > 80 g/d for at least 5 years) were included in the study. These comprised 78 patients with liver disease [liver disease alcoholics (LDA)] in whom the presence of liver disease was confirmed by liver biopsy or clinical evidence of hepatic decompensation, and 75 subjects with no evidence of liver disease, determined by normal liver tests on two occasions [non-liver disease alcoholics (NLDA)], were consecutively enrolled. Serum markers of iron status and HFE C282Y and H63D mutations were determined. HFE genotyping was compared with data obtained in healthy blood donors from the same geographical area. RESULTS: Gender ratio was similar in both study groups. LDA patients were older than NLDA patients third and one fifth of the study population had serum transferrin saturation (TS) greater than 45% and 60% respectively. Serum iron levels were similar in both groups. However, LDA patients had higher TS for having liver disease with TS greater than 45% was 2.20 (95% confidence interval (CI): 1.37-3.54). There was no difference in C282Y allelic frequency between the two groups. However, H63D was more frequent in LDA patients (0.25 vs 0.16, P = 0.03). LDA patients had a greater probability of carrying at least one HFE mutation than NLDA patients (49.5% vs 31.6%, P = 0.02). The odds ratio for LDA in patients with H63D mutation was 1.57 (95% CI: 1.02-2.40).CONCLUSION: The present study confirms the presence of iron overload in alcoholics, which was more severe in the subset of subjects with liver disease,in parallel with an increased frequency of H63D HFE mutation.

  2. Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma

    Science.gov (United States)

    Zaretsky, Jesse M.; Garcia-Diaz, Angel; Shin, Daniel S.; Escuin-Ordinas, Helena; Hugo, Willy; Hu-Lieskovan, Siwen; Torrejon, Davis Y.; Abril-Rodriguez, Gabriel; Sandoval, Salemiz; Barthly, Lucas; Saco, Justin; Moreno, Blanca Homet; Mezzadra, Riccardo; Chmielowski, Bartosz; Ruchalski, Kathleen; Shintaku, I. Peter; Sanchez, Phillip J.; Puig-Saus, Cristina; Cherry, Grace; Seja, Elizabeth; Kong, Xiangju; Pang, Jia; Berent-Maoz, Beata; Comin-Anduix, Begoña; Graeber, Thomas G.; Tumeh, Paul C.; Schumacher, Ton N.M.; Lo, Roger S.; Ribas, Antoni

    2016-01-01

    BACKGROUND Approximately 75% of objective responses to anti–programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted long after initial objective tumor regression despite continuous therapy. Mechanisms of immune escape in this context are unknown. METHODS We analyzed biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma who had had an initial objective tumor regression in response to anti–PD-1 therapy (pembrolizumab) followed by disease progression months to years later. RESULTS Whole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptor–associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. A truncating mutation in the gene encoding the antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third patient. JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative effects on cancer cells. The B2M truncating mutation led to loss of surface expression of major histocompatibility complex class I. CONCLUSIONS In this study, acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with defects in the pathways involved in interferon-receptor signaling and in antigen presentation. (Funded by the National Institutes of Health and others.) PMID:27433843

  3. Recurrent HOXB13 mutations in the Dutch population do not associate with increased breast cancer risk.

    Science.gov (United States)

    Liu, Jingjing; Prager-van der Smissen, Wendy J C; Schmidt, Marjanka K; Collée, J Margriet; Cornelissen, Sten; Lamping, Roy; Nieuwlaat, Anja; Foekens, John A; Hooning, Maartje J; Verhoef, Senno; van den Ouweland, Ans M W; Hogervorst, Frans B L; Martens, John W M; Hollestelle, Antoinette

    2016-01-01

    The HOXB13 p.G84E mutation has been firmly established as a prostate cancer susceptibility allele. Although HOXB13 also plays a role in breast tumor progression, the association of HOXB13 p.G84E with breast cancer risk is less evident. Therefore, we comprehensively interrogated the entire HOXB13 coding sequence for mutations in 1,250 non-BRCA1/2 familial breast cancer cases and 800 controls. We identified two predicted deleterious missense mutations, p.G84E and p.R217C, that were recurrent among breast cancer cases and further evaluated their association with breast cancer risk in a larger study. Taken together, 4,520 familial non-BRCA1/2 breast cancer cases and 3,127 controls were genotyped including the cases and controls of the whole gene screen. The concordance rate for the genotyping assays compared with Sanger sequencing was 100%. The prostate cancer risk allele p.G84E was identified in 18 (0.56%) of 3,187 cases and 16 (0.70%) of 2,300 controls (OR = 0.81, 95% CI = 0.41-1.59, P = 0.54). Additionally, p.R217C was identified in 10 (0.31%) of 3,208 cases and 2 (0.087%) of 2,288 controls (OR = 3.57, 95% CI = 0.76-33.57, P = 0.14). These results imply that none of the recurrent HOXB13 mutations in the Dutch population are associated with breast cancer risk, although it may be worthwhile to evaluate p.R217C in a larger study.

  4. A novel missense mutation in SUCLG1 associated with mitochondrial DNA depletion, encephalomyopathic form, with methylmalonic aciduria

    DEFF Research Database (Denmark)

    Østergaard, Elsebet; Schwartz, Marianne; Batbayli, Mustafa;

    2010-01-01

    Mitochondrial DNA depletion, encephalomyopathic form, with methylmalonic aciduria is associated with mutations in SUCLA2, the gene encoding a beta subunit of succinate-CoA ligase, where 17 patients have been reported. Mutations in SUCLG1, encoding the alpha subunit of the enzyme, have been reported...

  5. Association between mutations in gyrA and parC genes of Acinetobacter baumannii clinical isolates and ciprofloxacin resistance

    Directory of Open Access Journals (Sweden)

    Abdollah Ardebili

    2015-06-01

    Conclusion: Simultaneous mutations in gyrA and parC genes are expected to play a major role in high-level fluoroquinolone resistance in A. baumannii; albeit a single mutation in DNA topoisomerase IV could occasionally be associated with intermediate-resistance to these antimicrobials.

  6. Association between thyroid cancer and epidermal growth factor receptor mutation in female with nonsmall cell lung cancer

    Directory of Open Access Journals (Sweden)

    Seo Yun Kim

    2017-01-01

    CONCLUSIONS: Our data suggest that thyroid cancer and a family history of thyroid cancer are associated with EGFR-mutated NSCLC in female patients. The differences in the incidence of thyroid cancer and a family history of thyroid cancer by EGFR mutational status provide new insight into pathogenesis of this genetic change.

  7. Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy

    NARCIS (Netherlands)

    Karakikes, Ioannis; Stillitano, Francesca; Nonnenmacher, Mathieu; Tzimas, Christos; Sanoudou, Despina; Termglinchan, Vittavat; Kong, Chi-Wing; Rushing, Stephanie; Hansen, Jens; Ceholski, Delaine; Kolokathis, Fotis; Kremastinos, Dimitrios; Katoulis, Alexandros; Ren, Lihuan; Cohen, Ninette; Gho, Johannes M. I. H.; Tsiapras, Dimitrios; Vink, Aryan; Wu, Joseph C.; Asselbergs, Folkert W.; Li, Ronald A.; Hulot, Jean-Sebastien; Kranias, Evangelia G.; Hajjar, Roger J.

    2015-01-01

    A number of genetic mutations is associated with cardiomyopathies. A mutation in the coding region of the phospholamban (PLN) gene (R14del) is identified in families with hereditary heart failure. Heterozygous patients exhibit left ventricular dilation and ventricular arrhythmias. Here we generate i

  8. Genetic Screening of Mutations Associated with Fabry Disease in a Nationwide Cohort of Juvenile Idiopathic Arthritis Patients

    Science.gov (United States)

    Gonçalves, Maria J.; Mourão, Ana F.; Martinho, António; Simões, Olívia; Melo-Gomes, José; Salgado, Manuel; Estanqueiro, Paula; Ribeiro, Célia; Brito, Iva; Fonseca, João E.; Canhão, Helena

    2017-01-01

    Fabry’s disease (FD) is a lysosomal storage disorder associated with an alpha-galactosidase A deficiency. The prevalence of FD among juvenile idiopathic arthritis (JIA) patients with established diagnosis is unknown, but as musculoskeletal pain may be an important complaint at presentation, misdiagnosed cases are anticipated. With this study, we aim to calculate the frequency of FD-associated mutations in a cohort of JIA patients. Children with JIA from a national cohort were selected. Clinical and laboratorial information was recorded in the Portuguese rheumatic diseases register (http://Reuma.pt). Molecular genetic testing to detect GLA gene mutations was performed. After the multiplex polymerase chain reactions technique for DNA amplification, direct sequencing of the complete sequence of GLA gene was completed. From a cohort of 292 patients with JIA (188 females, 104 males), mutations were identified in 5 patients (all female). Four patients had the mutation D313Y, a rare GLA variant, which is associated with low enzymatic levels in plasma, but normal lysosomal levels. One patient presented the missense mutation R118C, which was previously described in Mediterranean patients with FD. This is the first screening of FD mutations in a cohort of JIA patients. No “classic” pathogenic FD mutations were reported. The late-onset FD-associated mutation, R118C, was found in a frequency of 0.34% (1/292). PMID:28299312

  9. The prognostic IDH1( R132 ) mutation is associated with reduced NADP+-dependent IDH activity in glioblastoma

    NARCIS (Netherlands)

    Bleeker, F.E.; Atai, N.A.; Lamba, S.; Jonker, A.; Rijkeboer, D.; Bosch, K.S.; Tigchelaar, W.; Troost, D.; Vandertop, W.P.; Bardelli, A.; van Noorden, C.J.F.

    2010-01-01

    Somatic mutations in the isocitrate dehydrogenase 1 gene (IDH1) occur at high frequency in gliomas and seem to be a prognostic factor for survival in glioblastoma patients. In our set of 98 glioblastoma patients, IDH1 ( R132 ) mutations were associated with improved survival of 1 year on average, af

  10. Ser447stop mutation in lipoprotein lipase is associated with elevated HDL cholesterol levels in normolipidemic males

    NARCIS (Netherlands)

    Kuivenhoven, J A; Groenemeyer, B E; Boer, J. M.; Reymer, P W; Berghuis, Riteke; Bruin, T; Jansen, Hans; Seidell, J C; Kastelein, J J

    This report describes the association between a frequent mutation in the lipoprotein lipase (LPL) gene and HDL cholesterol levels. It concerns a previously described defect that predicts a premature truncation of the LPL protein (447stop). We determined the frequency of this mutation in three groups

  11. A proposed mutation, Val781Ile, associated with hyperkalemic periodic paralysis and cardiac dysrhythmia is a benign polymorphism.

    Science.gov (United States)

    Green, D S; Hayward, L J; George, A L; Cannon, S C

    1997-08-01

    Twenty different point mutations have been identified in the gene coding for the alpha subunit of the adult skeletal muscle sodium channel in families with hyperkalemic periodic paralysis, paramyotonia congenita, and the potassium-aggravated myotonias. One novel mutation (Val(781)Ile) was reported in an adopted boy with potassium-sensitive weakness and cardiac dysrhythmia. The confidence in establishing this rare amino acid substitution as a causative mutation was limited by the absence of family members for segregation analysis. Functional expression studies herein show that Val(781)Ile is most likely a benign polymorphism and not a disease-associated mutation.

  12. Familial isolated primary pigmented nodular adrenocortical disease associated with a novel low penetrance PRKAR1A gene splice site mutation

    DEFF Research Database (Denmark)

    Storr, Helen L; Metherell, Louise A; Dias, Renuka

    2010-01-01

    Primary pigmented nodular adrenocortical disease (PPNAD) is associated with inactivating germline protein kinase A regulatory subunit type 1-alpha (PRKAR1A) mutations and loss of heterozygosity at the 17q22-24 locus in approximately 50% patients. PRKAR1A mutations are observed in both isolated PP...... PPNAD (iPPNAD) and Carney complex (CNC). Most mutations result in a functionally null-allele and exhibit high penetrance. We genotyped members of an extended family for a novel PRKAR1A mutation and undertook detailed phenotyping for CNC in the affected individuals....

  13. A mild mutator phenotype arises in a mouse model for malignancies associated with neurofibromatosis type 1

    Energy Technology Data Exchange (ETDEWEB)

    Garza, Rene [Department of Cellular and Structural Biology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States); Hudson, Robert A. [Department of Cellular and Structural Biology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States); McMahan, C. Alex [Department of Pathology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States); Walter, Christi A. [Department of Cellular and Structural Biology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States); South Texas Veterans Healthcare System, San Antonio, TX 78229 (United States); Vogel, Kristine S. [Department of Cellular and Structural Biology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States)]. E-mail: vogelk@uthscsa.edu

    2007-02-03

    Defects in genes that control DNA repair, proliferation, and apoptosis can increase genomic instability, and thus promote malignant progression. Although most tumors that arise in humans with neurofibromatosis type 1 (NF1) are benign, these individuals are at increased risk for malignant peripheral nerve sheath tumors (MPNST). To characterize additional mutations required for the development of MPNST from benign plexiform neurofibromas, we generated a mouse model for these tumors by combining targeted null mutations in Nf1 and p53, in cis. CisNf1+/-; p53+/- mice spontaneously develop PNST, and these tumors exhibit loss-of-heterozygosity at both the Nf1 and p53 loci. Because p53 has well-characterized roles in the DNA damage response, DNA repair, and apoptosis, and because DNA repair genes have been proposed to act as modifiers in NF1, we used the cisNf1+/-; p53+/- mice to determine whether a mutator phenotype arises in NF1-associated malignancies. To quantitate spontaneous mutant frequencies (MF), we crossed the Big Blue mouse, which harbors a lacI transgene, to the cisNf1+/-; p53+/- mice, and isolated genomic DNA from both tumor and normal tissues in compound heterozygotes and wild-type siblings. Many of the PNST exhibited increased mutant frequencies (MF = 4.70) when compared to normal peripheral nerve and brain (MF = 2.09); mutations occurred throughout the entire lacI gene, and included base substitutions, insertions, and deletions. Moreover, the brains, spleens, and livers of these cisNf1+/-; p53+/- animals exhibited increased mutant frequencies when compared to tissues from wild-type littermates. We conclude that a mild mutator phenotype arises in the tumors and tissues of cisNf1+/-; p53+/- mice, and propose that genomic instability influences NF1 tumor progression and disease severity.

  14. Autosomal-dominant nystagmus, foveal hypoplasia and presenile cataract associated with a novel PAX6 mutation.

    Science.gov (United States)

    Thomas, Shery; Thomas, Mervyn G; Andrews, Caroline; Chan, Wai-Man; Proudlock, Frank A; McLean, Rebecca J; Pradeep, Archana; Engle, Elizabeth C; Gottlob, Irene

    2014-03-01

    Autosomal-dominant idiopathic infantile nystagmus has been linked to 6p12 (OMIM 164100), 7p11.2 (OMIM 608345) and 13q31-q33 (OMIM 193003). PAX6 (11p13, OMIM 607108) mutations can also cause autosomal-dominant nystagmus, typically in association with aniridia or iris hypoplasia. We studied a large multigenerational white British family with autosomal-dominant nystagmus, normal irides and presenile cataracts. An SNP-based genome-wide analysis revealed a linkage to a 13.4-MB region on chromosome 11p13 with a maximum lod score of 2.93. A mutation analysis of the entire coding region and splice junctions of the PAX6 gene revealed a novel heterozygous missense mutation (c.227C>G) that segregated with the phenotype and is predicted to result in the amino-acid substitution of proline by arginine at codon 76 p.(P76R). The amino-acid variation p.(P76R) within the paired box domain is likely to destabilise the protein due to steric hindrance as a result of the introduction of a polar and larger amino acid. Eye movement recordings showed a significant intrafamilial variability of horizontal, vertical and torsional nystagmus. High-resolution in vivo imaging of the retina using optical coherence tomography (OCT) revealed features of foveal hypoplasia, including rudimentary foveal pit, incursion of inner retinal layers, short photoreceptor outer segments and optic nerve hypoplasia. Thus, this study presents a family that segregates a PAX6 mutation with nystagmus and foveal hypoplasia in the absence of iris abnormalities. Moreover, it is the first study showing detailed characteristics using eye movement recordings of autosomal-dominant nystagmus in a multigenerational family with a novel PAX6 mutation.

  15. Functional characterization and structural modeling of obesity associated mutations in the melanocortin 4 receptor.

    Science.gov (United States)

    Tan, Karen; Pogozheva, Irina D; Yeo, Giles S H; Hadaschik, Dirk; Keogh, Julia M; Haskell-Leuvano, Carrie; O'Rahilly, Stephen; Mosberg, Henry I; Farooqi, I Sadaf

    2009-01-01

    Mutations in the melanocortin 4 receptor (MC4R) gene are the most common known cause of monogenic human obesity. The MC4R gene was sequenced in 2000 subjects with severe early-onset obesity. We detected seven different nonsense and 19 nonsynonymous mutations in a total of 94 probands, some of which have been reported previously by others. We functionally characterized the 11 novel obesity associated missense mutations. Seven of these mutants (L54P, E61K, I69T, S136P, M161T, T162I, and I269N) showed impaired cell surface trafficking, reduced level of maximal binding of the radioligand [125I]NDP-MSH, and reduced ability to generate cAMP in response to ligand. Four mutant MC4Rs (G55V, G55D, S136F, and A303T) displayed cell surface expression and agonist binding similar to the wild-type receptor but showed impaired cAMP production, suggesting that these residues are likely to be critical for conformational rearrangement essential for receptor activation. Homology modeling of these mutants using a model of MC4R based on the crystal structure of the beta2-adrenoreceptor was used to provide insights into the possible structural basis for receptor dysfunction. Transmembrane (TM) domains 1, 3, 6, 7, and peripheral helix 8 appear to participate in the agonist-induced conformational rearrangement necessary for coupling of ligand binding to signaling. We conclude that G55V, G55D, S136F, and A303T mutations are likely to strengthen helix-helix interactions between TM1 and TM2, TM3 and TM6, and TM7 and helix 8, respectively, preventing relative movement of these helices during receptor activation. The combination of functional studies and structural modeling of naturally occurring pathogenic mutations in MC4R can provide valuable information regarding the molecular mechanism of MC4R activation and its dysfunction in human disease.

  16. Prevalence of an inherited cancer predisposition syndrome associated with the germ line TP53 R337H mutation in Paraguay.

    Science.gov (United States)

    Legal, Edith Falcon-de; Ascurra, Marta; Custódio, Gislaine; Ayala, Horacio Legal; Monteiro, Magna; Vega, Celeste; Fernández-Nestosa, María José; Vega, Sonia; Sade, Elis R; Coelho, Izabel M M; Ribeiro, Enilze M S F; Cavalli, Iglenir J; Figueiredo, Bonald C

    2015-04-01

    The tumor suppressor gene TP53 is the most frequently mutated gene in human cancer, and the germline TP53 R337H mutation is the most common mutation reported to date. However, this mutation is associated with a lower cumulative lifetime cancer risk than other mutations in the p53 DNA-binding domain. A detailed statistical analysis of 171,500 DNA tests in Brazilian neonates found that 0.27% of the general population is positive for this mutation, and some of the estimated 200,000 Brazilian R337H carriers in southern and southeastern Brazil have already developed cancer. The present study was designed to estimate R337H prevalence in neighboring Paraguay. To address this question, 10,000 dried blood samples stored in Guthrie cards since 2008 were randomly selected from the Paraguayan municipalities located at the border with Brazil. These samples were tested for R337H mutation using the PCR-restriction fragment length polymorphism assay. This germline mutation was detected in five samples (5/10,000), indicating that the total number of R337H carriers in Paraguay may be as high as 3500. Previous studies have shown that other countries (i.e., Portugal, Spain, and Germany) presented one family with this mutation, leading us to conclude that, besides Brazil and Paraguay, other countries may have multiple families carrying this mutation, which is an inherited syndrome that is difficult to control.

  17. Mutation pattern in the genome of Neisseria gonorrhoeae and its association with multidrug-resistant isolates from Delhi, India

    Directory of Open Access Journals (Sweden)

    Divya Sachdev

    2017-01-01

    Full Text Available Mutations in PenA, PorB, MtrE and MtrR genes responsible for antimicrobial resistance were checked in 27 drug-resistant clinical isolates of Neisseria gonorrhoeae (NG. Phenotype PIB (88.88% and mutation at G120 and A121 positions of porB were recurrent. N122K, a novel mutation, was observed in PorB in three resistant isolates. Substitution H105Y in MtrR was widespread (37% of clinical isolates. The presence of a novel mutation (L33V, along with G45D mutation in MtrR, was associated with less-resistant isolates, in contrast to isolates with G45D mutation alone. African-type penicillinase-producing NG plasmid was observed most frequently (17/27 in penicillin-resistant isolates.

  18. Mitochondrial tRNA(Thr) A15951G mutation may not be associated with Leber's Hereditary Optic Neuropathy.

    Science.gov (United States)

    Zhang, Xi; Yu, Shuaishuai; Tu, Yunhai; Huang, Wenjie

    2016-07-01

    Mutation in mitochondrial DNA (mtDNA) has been found to play an important role in the pathogenesis of Leber's Hereditary Optic Neuropathy (LHON). Three primary mutations, the ND4 G11778A, ND6 T14484C, and ND1 G3460A, have been found to account more than 90% of LHON patients in many families worldwide. In addition to the mutations in genes encoding the respiratory chain complex I, reports concerning the mt-tRNA gene mutations associated with LHON have increased, some pathogenic mutations caused the failure in mt-tRNA metabolism, thereby worsened the mitochondrial dysfunction that is responsible for LHON. Recently, the A15951G mutation in mt-tRNA(Thr) gene has been reported to be a "modified" factor in increasing the penetrance and expressivity of LHON-associated ND4 G11778A mutation in three Chinese families. However, evolutionary conservation analysis of this mutation suggested a poor conservation index and the pathogenicity scoring system showed that this mutation was a neutral polymorphism.

  19. Mutations in SPATA5 Are Associated with Microcephaly, Intellectual Disability, Seizures, and Hearing Loss.

    Science.gov (United States)

    Tanaka, Akemi J; Cho, Megan T; Millan, Francisca; Juusola, Jane; Retterer, Kyle; Joshi, Charuta; Niyazov, Dmitriy; Garnica, Adolfo; Gratz, Edward; Deardorff, Matthew; Wilkins, Alisha; Ortiz-Gonzalez, Xilma; Mathews, Katherine; Panzer, Karin; Brilstra, Eva; van Gassen, Koen L I; Volker-Touw, Catharina M L; van Binsbergen, Ellen; Sobreira, Nara; Hamosh, Ada; McKnight, Dianalee; Monaghan, Kristin G; Chung, Wendy K

    2015-09-03

    Using whole-exome sequencing, we have identified in ten families 14 individuals with microcephaly, developmental delay, intellectual disability, hypotonia, spasticity, seizures, sensorineural hearing loss, cortical visual impairment, and rare autosomal-recessive predicted pathogenic variants in spermatogenesis-associated protein 5 (SPATA5). SPATA5 encodes a ubiquitously expressed member of the ATPase associated with diverse activities (AAA) protein family and is involved in mitochondrial morphogenesis during early spermatogenesis. It might also play a role in post-translational modification during cell differentiation in neuronal development. Mutations in SPATA5 might affect brain development and function, resulting in microcephaly, developmental delay, and intellectual disability.

  20. Cosegregation of the ND4 G11696A mutation with the LHON-associated ND4 G11778A mutation in a four generation Chinese family.

    Science.gov (United States)

    Qu, Jia; Li, Ronghua; Zhou, Xiangtian; Tong, Yi; Yang, Li; Chen, Jie; Zhao, Fuxing; Lu, Chunjie; Qian, Yaping; Lu, Fan; Guan, Min-Xin

    2007-01-01

    We report here the characterization of a four-generation Han Chinese family with Leber's hereditary optic neuropathy (LHON). This Chinese family exhibited a variable severity and age-at-onset of visual loss. Notably, the average age-at-onset of vision impairment changed from 26 years (generation III) to 14 years (generation IV), with the average of 18 years in this family. In addition, 30% and 50% of matrilineal relatives in generation III and IV of this family developed visual loss with a variability of severity, ranging from blindness to normal vision. Sequence analysis of the complete mitochondrial DNA in this pedigree revealed the presence of the homoplasmic ND4 G11778A mutation and 33 other variants, belonging to the Asian haplogroup D4. Of other variants, the homoplasmic G11696A mutation in the ND4 gene is of special interest as it was implicated to be associated with LHON in a large Dutch family and five Chinese pedigrees with extremely penetrance of visual loss. In fact, the G11696A mutation caused the substitution of an isoleucine for valine at amino acid position 313, located in a predicted transmembrane region of ND4. These imply that the G11696A mutation may act in synergy with the primary LHON-associated G11778A mutation in this Chinese pedigree.

  1. BOR-syndrome-associated Eya1 mutations lead to enhanced proteasomal degradation of Eya1 protein.

    Directory of Open Access Journals (Sweden)

    Amna Musharraf

    Full Text Available Mutations in the human EYA1 gene have been associated with several human diseases including branchio-oto (BO and branchio-oto-renal (BOR syndrome, as well as congenital cataracts and ocular anterior segment anomalies. BOR patients suffer from severe malformations of the ears, branchial arches and kidneys. The phenotype of Eya1-heterozygous mice resembles the symptoms of human patients suffering from BOR syndrome. The Eya1 gene encodes a multifunctional protein that acts as a protein tyrosine phosphatase and a transcriptional coactivator. It has been shown that Eya1 interacts with Six transcription factors, which are also required for nuclear translocation of the Eya1 protein. We investigated the effects of seven disease-causing Eya1 missense mutations on Eya1 protein function, in particular cellular localization, ability to interact with Six proteins, and protein stability. We show here that the BOR-associated Eya1 missense mutations S454P, L472R, and L550P lead to enhanced proteasomal degradation of the Eya1 protein in mammalian cells. Moreover, Six proteins lead to a significant stabilization of Eya1, which is caused by Six-mediated protection from proteasomal degradation. In case of the mutant L550P, loss of interaction with Six proteins leads to rapid protein degradation. Our observations suggest that protein destabilization constitutes a novel disease causing mechanism for Eya1.

  2. Leukemia-Associated Mutations in Nucleophosmin Alter Recognition by CRM1: Molecular Basis of Aberrant Transport.

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    Igor Arregi

    Full Text Available Nucleophosmin (NPM is a nucleocytoplasmic shuttling protein, normally enriched in nucleoli, that performs several activities related to cell growth. NPM mutations are characteristic of a subtype of acute myeloid leukemia (AML, where mutant NPM seems to play an oncogenic role. AML-associated NPM mutants exhibit altered subcellular traffic, being aberrantly located in the cytoplasm of leukoblasts. Exacerbated export of AML variants of NPM is mediated by the nuclear export receptor CRM1, and due, in part, to a mutationally acquired novel nuclear export signal (NES. To gain insight on the molecular basis of NPM transport in physiological and pathological conditions, we have evaluated the export efficiency of NPM in cells, and present new data indicating that, in normal conditions, wild type NPM is weakly exported by CRM1. On the other hand, we have found that AML-associated NPM mutants efficiently form complexes with CRM1HA (a mutant CRM1 with higher affinity for NESs, and we have quantitatively analyzed CRM1HA interaction with the NES motifs of these mutants, using fluorescence anisotropy and isothermal titration calorimetry. We have observed that the affinity of CRM1HA for these NESs is similar, which may help to explain the transport properties of the mutants. We also describe NPM recognition by the import machinery. Our combined cellular and biophysical studies shed further light on the determinants of NPM traffic, and how it is dramatically altered by AML-related mutations.

  3. Mutations Associated with Functional Disorder of Xanthine Oxidoreductase and Hereditary Xanthinuria in Humans

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    Takeshi Nishino

    2012-11-01

    Full Text Available Xanthine oxidoreductase (XOR catalyzes the conversion of hypoxanthine to xanthine and xanthine to uric acid with concomitant reduction of either NAD+ or O2. The enzyme is a target of drugs to treat hyperuricemia, gout and reactive oxygen-related diseases. Human diseases associated with genetically determined dysfunction of XOR are termed xanthinuria, because of the excretion of xanthine in urine. Xanthinuria is classified into two subtypes, type I and type II. Type I xanthinuria involves XOR deficiency due to genetic defect of XOR, whereas type II xanthinuria involves dual deficiency of XOR and aldehyde oxidase (AO, a molybdoflavo enzyme similar to XOR due to genetic defect in the molybdenum cofactor sulfurase. Molybdenum cofactor deficiency is associated with triple deficiency of XOR, AO and sulfite oxidase, due to defective synthesis of molybdopterin, which is a precursor of molybdenum cofactor for all three enzymes. The present review focuses on mutation or chemical modification studies of mammalian XOR, as well as on XOR mutations identified in humans, aimed at understanding the reaction mechanism of XOR and the relevance of mutated XORs as models to estimate the possible side effects of clinical application of XOR inhibitors.

  4. The folliculin mutation database: an online database of mutations associated with Birt-Hogg-Dubé syndrome.

    Science.gov (United States)

    Wei, Ming-Hui; Blake, Patrick W; Shevchenko, Julia; Toro, Jorge R

    2009-09-01

    The folliculin gene (FLCN), also known as BHD, is the only known susceptibility gene for Birt-Hogg-Dubé syndrome. BHDS is the autosomal dominant predisposition to the development of follicular hamartomas, lung cysts, spontaneous pneumothorax, and/or kidney neoplasms. To date, 53 unique germline mutations have been reported. FLCN mutation detection rate is 88%. FLCN encodes a predicted 579-amino acid protein, designated folliculin that is highly conserved between humans and homologs in mice, Drosophila, and C. elegans. We developed the first online database detailing all FLCN variants identified in our laboratory and reported in the literature. The FLCN database applies, and assists researchers in applying HGVS nomenclature guidelines. To date, the FCLN database includes 84 variants: 53 unique germline mutations and 31 SNPs. The majority of FLCN germline mutations are predicted to produce a truncated folliculin, resulting in loss of function. The FLCN mutations consist of: 45% (24/53) deletions, 32% (17/53) substitutions (10 putative-splice site, 5 nonsense, and 2 missense), 15% (8/53) duplications, 6% (3/53) insertion/deletions and 2% (1/53) insertions. The database strives to systematically unify current knowledge of FLCN variants and will be useful to geneticists and genetic counselors while also providing a rapid and systematic resource for investigators.

  5. Mutational analysis of BRAF and KRAS in ovarian serous borderline (atypical proliferative) tumours and associated peritoneal implants

    Science.gov (United States)

    Ardighieri, Laura; Zeppernick, Felix; Hannibal, Charlotte G; Vang, Russell; Cope, Leslie; Junge, Jette; Kjaer, Susanne K; Kurman, Robert J; Shih, Ie-Ming

    2014-01-01

    There is debate as to whether peritoneal implants associated with serous borderline tumours/atypical proliferative serous tumours (SBT/APSTs) of the ovary are derived from the primary ovarian tumour or arise independently in the peritoneum. We analysed 57 SBT/APSTs from 45 patients with advanced-stage disease identified from a nation-wide tumour registry in Denmark. Mutational analysis for hotspots in KRAS and BRAF was successful in 55 APSTs and demonstrated KRAS mutations in 34 (61.8%) and BRAF mutations in eight (14.5%). Mutational analysis was successful in 56 peritoneal implants and revealed KRAS mutations in 34 (60.7%) and BRAF mutations in seven (12.5%). Mutational analysis could not be performed in two primary tumours and in nine implants, either because DNA amplification failed or because there was insufficient tissue for mutational analysis. For these specimens we performed VE1 immunohistochemistry, which was shown to be a specific and sensitive surrogate marker for a V600E BRAF mutation. VE1 staining was positive in one of two APSTs and seven of nine implants. Thus, among 63 implants for which mutation status was known (either by direct mutational analysis or by VE1 immunohistochemistry), 34 (53.9%) had KRAS mutations and 14 (22%) had BRAF mutations, of which identical KRAS mutations were found in 34 (91%) of 37 SBT/APST–implant pairs and identical BRAF mutations in 14 (100%) of 14 SBT/APST–implant pairs. Wild-type KRAS and BRAF (at the loci investigated) were found in 11 (100%) of 11 SBT/APST–implant pairs. Overall concordance of KRAS and BRAF mutations was 95% in 59 of 62 SBT/APST–implant (non-invasive and invasive) pairs (p < 0.00001). This study provides cogent evidence that the vast majority of peritoneal implants, non-invasive and invasive, harbour the identical KRAS or BRAF mutations that are present in the associated SBT/APST, supporting the view that peritoneal implants are derived from the primary ovarian tumour. PMID:24307542

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

    Science.gov (United States)

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

    2016-12-01

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

  7. [Neuropathic pain associated with Nav1.7 mutations: clinical picture and treatment].

    Science.gov (United States)

    Doppler, K; Sommer, C

    2013-12-01

    Voltage-gated sodium channels are essential for electrogenesis in excitable cells. The isoform Nav1.7 is primarily expressed in nociceptors. Mutations of the SCN9A gene, which codes for the α-subunit of Nav1.7, are the cause of primary erythromelalgia and paroxysmal extreme pain disorder, two rare neuropathic pain conditions. Recent studies have shown that mutations in the SCN9A gene are the cause of a subgroup of idiopathic small fiber neuropathies and that polymorphisms of SCN9A are associated with an increase in susceptibility to pain. These findings not only contribute to the understanding of the pathophysiology of neuropathic pain but also offer targets for a more specific pain therapy.

  8. Genotyping of HFE c.845G>A, HFE c.187C>G and HFE c.193A>T for hemochormatosis by Real Time-Polymerase Chain Reaction  : A quality improvement study in the Region Jönköping County

    OpenAIRE

    Chamoun, Stephanie; Medina, Sarajlic

    2016-01-01

    Hereditär hemokromatos (HH) är en vanlig multigenetisk defekt som leder till ett onormalt förhöjt järnupptag i tarmen och ses framförallt hos kaukasisk befolkning. Sjukdomen har på senare år visats orsakats av mutationen c.845G>A men även mer ovanliga varianter som c.187C>G och c.193A>T, vilka alla finns belägna i genen HFE. HFE som finns lokaliserad intill Human Leukocyte Antigen (HLA)-genen på kromosom sex korta arm kodar för ett HFE-protein som har till uppgift att reglera kroppen...

  9. Mutation in the sixth immunoglobulin domain of L1CAM is associated with migrational brain anomalies

    Science.gov (United States)

    Shieh, Christine; Moser, Franklin; Graham, John M.; Watiker, Valerie

    2015-01-01

    Objective: To describe the phenotype of a patient with classical features of X-linked L1 syndrome associated with novel brain malformations. Methods: Diagnostic analysis included physical and dysmorphology examinations, MRI of the brain, and exome sequencing of the family trio. Results: We report a 2.5-year-old boy with developmental delay, dysmorphic facies, and adducted thumbs. MRI of the brain showed a truncated corpus callosum and periventricular heterotopias associated with polymicrogyria (PMG). Variant segregation analysis with exome sequencing discovered a novel maternally derived hemizygous variant in exon 14 of the L1CAM gene (c.1759 G>C; p.G587R). Conclusions: This novel L1CAM mutation was located in the protein's sixth immunoglobin domain and involved glycine-587, a key residue in the structure of L1CAM because of its interactions with lysine-606, which indicates that any mutation at this site would likely affect the secondary structure and function of the protein. The replacement of the small nonpolar glycine residue with a large basic arginine would have an even more dramatic result. The presentation of periventricular nodular heterotopias with overlying PMG is very uncommon, and its association with L1CAM may provide insight into other similar cases. Furthermore, this presentation indicates the important role that L1CAM plays in neuronal migration and brain development and extends the phenotype associated with L1CAM-associated disorders. PMID:27066571

  10. Mutations associated with reduced surotomycin susceptibility in Clostridium difficile and Enterococcus species.

    Science.gov (United States)

    Adams, Hannah M; Li, Xiang; Mascio, Carmela; Chesnel, Laurent; Palmer, Kelli L

    2015-07-01

    Clostridium difficile infection (CDI) is an urgent public health concern causing considerable clinical and economic burdens. CDI can be treated with antibiotics, but recurrence of the disease following successful treatment of the initial episode often occurs. Surotomycin is a rapidly bactericidal cyclic lipopeptide antibiotic that is in clinical trials for CDI treatment and that has demonstrated superiority over vancomycin in preventing CDI relapse. Surotomycin is a structural analogue of the membrane-active antibiotic daptomycin. Previously, we utilized in vitro serial passage experiments to derive C. difficile strains with reduced surotomycin susceptibilities. The parent strains used included ATCC 700057 and clinical isolates from the restriction endonuclease analysis (REA) groups BI and K. Serial passage experiments were also performed with vancomycin-resistant and vancomycin-susceptible Enterococcus faecium and Enterococcus faecalis. The goal of this study is to identify mutations associated with reduced surotomycin susceptibility in C. difficile and enterococci. Illumina sequence data generated for the parent strains and serial passage isolates were compared. We identified nonsynonymous mutations in genes coding for cardiolipin synthase in C. difficile ATCC 700057, enoyl-(acyl carrier protein) reductase II (FabK) and cell division protein FtsH2 in C. difficile REA type BI, and a PadR family transcriptional regulator in C. difficile REA type K. Among the 4 enterococcal strain pairs, 20 mutations were identified, and those mutations overlap those associated with daptomycin resistance. These data give insight into the mechanism of action of surotomycin against C. difficile, possible mechanisms for resistance emergence during clinical use, and the potential impacts of surotomycin therapy on intestinal enterococci.

  11. A Frameshift Mutation in KIT is Associated with White Spotting in the Arabian Camel

    Science.gov (United States)

    Holl, Heather; Isaza, Ramiro; Mohamoud, Yasmin; Ahmed, Ayeda; Almathen, Faisal; Youcef, Cherifi; Gaouar, Semir; Antczak, Douglas F.; Brooks, Samantha

    2017-01-01

    While the typical Arabian camel is characterized by a single colored coat, there are rare populations with white spotting patterns. White spotting coat patterns are found in virtually all domesticated species, but are rare in wild species. Theories suggest that white spotting is linked to the domestication process, and is occasionally associated with health disorders. Though mutations have been found in a diverse array of species, fewer than 30 genes have been associated with spotting patterns, thus providing a key set of candidate genes for the Arabian camel. We obtained 26 spotted camels and 24 solid controls for candidate gene analysis. One spotted and eight solid camels were whole genome sequenced as part of a separate project. The spotted camel was heterozygous for a frameshift deletion in KIT (c.1842delG, named KITW1 for White spotting 1), whereas all other camels were wild-type (KIT+/KIT+). No additional mutations unique to the spotted camel were detected in the EDNRB, EDN3, SOX10, KITLG, PDGFRA, MITF, and PAX3 candidate white spotting genes. Sanger sequencing of the study population identified an additional five KITW1/KIT+ spotted camels. The frameshift results in a premature stop codon five amino acids downstream, thus terminating KIT at the tyrosine kinase domain. An additional 13 spotted camels tested KIT+/KIT+, but due to phenotypic differences when compared to the KITW1/KIT+ camels, they likely represent an independent mutation. Our study suggests that there are at least two causes of white spotting in the Arabian camel, the newly described KITW1 allele and an uncharacterized mutation. PMID:28282952

  12. Novel phenotype associated with a mutation in the KCNA1(Kv1.1) gene

    Science.gov (United States)

    D'Adamo, Maria C.; Gallenmüller, Constanze; Servettini, Ilenio; Hartl, Elisabeth; Tucker, Stephen J.; Arning, Larissa; Biskup, Saskia; Grottesi, Alessandro; Guglielmi, Luca; Imbrici, Paola; Bernasconi, Pia; Di Giovanni, Giuseppe; Franciolini, Fabio; Catacuzzeno, Luigi; Pessia, Mauro; Klopstock, Thomas

    2015-01-01

    Episodic ataxia type 1 (EA1) is an autosomal dominant K+ channelopathy which manifests with short attacks of cerebellar ataxia and dysarthria, and may also show interictal myokymia. Episodes can be triggered by emotional or physical stress, startle response, sudden postural change or fever. Here we describe a 31-year-old man displaying markedly atypical symptoms, including long-lasting attacks of jerking muscle contractions associated with hyperthermia, severe migraine, and a relatively short-sleep phenotype. A single nucleotide change in KCNA1 (c.555C>G) was identified that changes a highly conserved residue (p.C185W) in the first transmembrane segment of the voltage-gated K+ channel Kv1.1. The patient is heterozygous and the mutation was inherited from his asymptomatic mother. Next generation sequencing revealed no variations in the CACNA1A, CACNB4, KCNC3, KCNJ10, PRRT2 or SCN8A genes of either the patient or mother, except for a benign variant in SLC1A3. Functional analysis of the p.C185W mutation in KCNA1 demonstrated a deleterious dominant-negative phenotype where the remaining current displayed slower activation kinetics, subtle changes in voltage-dependence and faster recovery from slow inactivation. Structural modeling also predicts the C185W mutation to be functionally deleterious. This description of novel clinical features, associated with a Kv1.1 mutation highlights a possibly unrecognized relationship between K+ channel dysfunction, hyperthermia and migraine in EA1, and suggests that thorough assessments for these symptoms should be carefully considered for all patients affected by EA1. PMID:25642194

  13. ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects.

    Science.gov (United States)

    Qiu, Haiyan; Lee, Sebum; Shang, Yulei; Wang, Wen-Yuan; Au, Kin Fai; Kamiya, Sherry; Barmada, Sami J; Finkbeiner, Steven; Lui, Hansen; Carlton, Caitlin E; Tang, Amy A; Oldham, Michael C; Wang, Hejia; Shorter, James; Filiano, Anthony J; Roberson, Erik D; Tourtellotte, Warren G; Chen, Bin; Tsai, Li-Huei; Huang, Eric J

    2014-03-01

    Autosomal dominant mutations of the RNA/DNA binding protein FUS are linked to familial amyotrophic lateral sclerosis (FALS); however, it is not clear how FUS mutations cause neurodegeneration. Using transgenic mice expressing a common FALS-associated FUS mutation (FUS-R521C mice), we found that mutant FUS proteins formed a stable complex with WT FUS proteins and interfered with the normal interactions between FUS and histone deacetylase 1 (HDAC1). Consequently, FUS-R521C mice exhibited evidence of DNA damage as well as profound dendritic and synaptic phenotypes in brain and spinal cord. To provide insights into these defects, we screened neural genes for nucleotide oxidation and identified brain-derived neurotrophic factor (Bdnf) as a target of FUS-R521C-associated DNA damage and RNA splicing defects in mice. Compared with WT FUS, mutant FUS-R521C proteins formed a more stable complex with Bdnf RNA in electrophoretic mobility shift assays. Stabilization of the FUS/Bdnf RNA complex contributed to Bdnf splicing defects and impaired BDNF signaling through receptor TrkB. Exogenous BDNF only partially restored dendrite phenotype in FUS-R521C neurons, suggesting that BDNF-independent mechanisms may contribute to the defects in these neurons. Indeed, RNA-seq analyses of FUS-R521C spinal cords revealed additional transcription and splicing defects in genes that regulate dendritic growth and synaptic functions. Together, our results provide insight into how gain-of-function FUS mutations affect critical neuronal functions.

  14. Novel phenotype associated with a mutation in the KCNA1(Kv1.1 gene

    Directory of Open Access Journals (Sweden)

    Maria Cristina D'Adamo

    2015-01-01

    Full Text Available Episodic ataxia type 1 (EA1 is an autosomal dominant K+ channelopathy which manifests with short attacks of cerebellar ataxia and dysarthria, and may also show interictal myokymia. Episodes can be triggered by emotional or physical stress, startle response, sudden postural change or fever. Here we describe a 31-year-old man displaying markedly atypical symptoms, including long-lasting attacks of jerking muscle contractions associated with hyperthermia, severe migraine, and a relatively short-sleep phenotype. A single nucleotide change in KCNA1 (c.555C>G was identified that changes a highly conserved residue (p.C185W in the first transmembrane segment of the voltage-gated K+ channel Kv1.1. The patient is heterozygous and the mutation was inherited from his asymptomatic mother. Next generation sequencing revealed no variations in the CACNA1A, CACNB4, KCNC3, KCNJ10, PRRT2 or SCN8A genes of either the patient or mother, except for a benign variant in SLC1A3. Functional analysis of the p.C185W mutation in KCNA1 demonstrated a deleterious dominant-negative phenotype where the remaining current displayed slower activation kinetics, subtle changes in voltage-dependence and faster recovery from slow inactivation. Structural modeling also predicts the C185W mutation to be functionally deleterious. This description of novel clinical features, associated with a Kv1.1 mutation highlights a possibly unrecognized relationship between K+ channel dysfunction, hyperthermia and migraine in EA1, and suggests that thorough assessments for these symptoms should be carefully considered for all patients affected by EA1.

  15. Hip Dysplasia in Children With Osteogenesis Imperfecta: Association With Collagen Type I C-Propeptide Mutations.

    Science.gov (United States)

    Kishta, Waleed; Abduljabbar, Fahad H; Gdalevitch, Marie; Rauch, Frank; Hamdy, Reggie; Fassier, François

    Osteogenesis imperfecta (OI) is a heritable skeletal disorder characterized by bone fragility and short stature that is usually due to mutations in 1 of the 2 genes that code for collagen type I α-chains. The association between hip dysplasia and OI has not been systematically investigated. In this single-center study, we retrospectively reviewed all cases of OI associated with hip dysplasia to describe clinical characteristics and the effect of therapy. We reviewed the charts of 687 patients with OI who were seen at the Shriners Hospital for Children in Montreal between 1999 and 2013 to identify patients with a diagnosis of hip dysplasia. Clinical characteristics and the course after therapeutic interventions were extracted from the charts. Hip dysplasia was diagnosed in 8 hips of 5 patients (4 boys, 1 girl; age at diagnosis ranged between 3 wk and 27 mo old). The prevalence of hip dysplasia and OI was therefore 0.87% (per patient). In 4 of the 5 patients (80%), OI was caused by mutations affecting the C-propeptide of collagen type I, which is otherwise rare in OI. Among the 26 patients with C-propeptide mutations followed at our institution, 4 (15%) had hip dysplasia. Pavlik harness treatment was attempted in 2 patients (3 hips) but was not effective in either case and resulted in avascular necrosis of 1 hip. Femoral varus derotational shortening osteotomies using a telescopic rod were performed in all 8 hips along with a closed reduction in 4 hips and an open reduction in 4 hips. Concomitant pelvic osteotomies were performed in 2 hips (1 patient). Surgery resulted in redislocation of 1 hip; all other surgically treated hips remained reduced. Clinical screening for hip dysplasia is difficult in OI owing to the bowing of the proximal femur and the risk of causing fractures. OI patients with positive C-propeptide mutation should therefore be screened for hip dysplasia by use of ultrasound. Presence of a C-propeptide mutation appears to be a risk factor for hip

  16. Hereditary Angioedema Due to C1 Inhibitor Deficiency in Serbia: Two Novel Mutations and Evidence of Genotype-Phenotype Association.

    Directory of Open Access Journals (Sweden)

    Slađana Andrejević

    Full Text Available Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE is a rare autosomal dominant disease characterized by recurrent life-threatening oedemas and/or abdominal pain and caused by mutations affecting the C1 inhibitor gene, SERPING1. We sought to investigate the spectrum of SERPING1 mutations in Serbia and the possible genotype-phenotype association. C1-INH-HAE was diagnosed on the basis of clinical and laboratory criteria in 40 patients from 27 families; four were asymptomatic. Mutational analysis of the SERPING1 gene was performed by sequencing and multiplex ligation-dependent probe amplification. Disease-causing mutations in SERPING1 were identified in all patients. In C1-INH-HAE type I, we identified 19 different mutations, including 6 missense mutations, 6 nonsense mutations, 2 small deletions, 1 small insertion, 2 splicing defects and 2 large deletions. Two of the mutations (c.300C>T and c.1184_1185insTA are reported here for the first time. All C1-INH-HAE type II patients from three families harboured the same substitution (c.1396C>T. Based on the type of mutation identified in the SERPING1 gene, patients were divided into two groups: group 1 (nonsense, frameshift, large deletions/insertions, splicing defect, and mutations at Arg444 or group 2 (missense, excluding mutations at Arg444. Significant differences were found in the clinical severity score (P = 0.005, prevalence of laryngeal (P = 0.040 and facial (P = 0.013 oedema, and long-term prophylaxis (P = 0.023 between the groups with different types of mutations. Because our population consisted of related subjects, differences in the severity score between mutation groups were further confirmed using the generalized estimating equation (P = 0.038. Our study identified 20 different disease-causing mutations, including two novel mutations, in all C1-INH-HAE patients, highlighting the heterogeneity of mutations in the SERPING1 gene. Furthermore, it appears that mutations with a

  17. Constructional apraxia in frontotemporal dementia associated with the C9orf72 mutation: broadening the clinical and neuropsychological phenotype.

    Science.gov (United States)

    Floris, Gianluca; Borghero, Giuseppe; Cannas, Antonino; Di Stefano, Francesca; Ruiu, Elisa; Murru, Maria R; Corongiu, Daniela; Cuccu, Stefania; Tranquilli, Stefania; Sardu, Claudia; Marrosu, Maria G; Chiò, Adriano; Marrosu, Francesco

    2015-03-01

    In our study we analysed clinical and neuropsychological data in a cohort of 57 Sardinian patients with FTD (55 apparently unrelated and two belonging to the same family), who underwent genetic screening for the C9orf72 mutation. Eight out of 56 patients were found positive for the C9orf72 mutation representing 14% of the entire cohort and 31.6% of the familial cases (6/19). C9orf72 mutated patients differed from the other FTD cases of the cohort for a younger age of onset, higher frequency of familial history for FTD and higher prevalence of delusional psychotic symptoms and hallucinations. In the neuropsychological assessment, C9orf72 mutated patients differed from non-mutated for the high frequency of visuospatial dysfunction regarding constructional apraxia (p = 0.02). In conclusion, our study confirms that Sardinian FTD patients have peculiar genetic characteristics and that C9orf72 mutated patients have a distinctive clinical and neuropsychological profile that could help differentiate them from other FTD patients. In our cohort we found that constructional apraxia, rarely reported in FTD, can properly discriminate between C9orf72 mutated and non-mutated patients and contribute to broaden the neuropsychological profile in frontotemporal dementia associated with this mutation.

  18. PML-RARA-associated cooperating mutations belong to a transcriptional network that is deregulated in myeloid leukemias.

    Science.gov (United States)

    Ronchini, C; Brozzi, A; Riva, L; Luzi, L; Gruszka, A M; Melloni, G E M; Scanziani, E; Dharmalingam, G; Mutarelli, M; Belcastro, V; Lavorgna, S; Rossi, V; Spinelli, O; Biondi, A; Rambaldi, A; Lo-Coco, F; di Bernardo, D; Pelicci, P G

    2017-01-20

    It has been shown that individual acute myeloid leukemia (AML) patients are characterized by one of few initiating DNA mutations and 5-10 cooperating mutations not yet defined among hundreds identified by massive sequencing of AML genomes. We report an in vivo insertional-mutagenesis screen for genes cooperating with one AML initiating mutations (PML-RARA, oncogene of acute promyelocytic leukemia, APL), which allowed identification of hundreds of genetic cooperators. The cooperators are mutated at low frequency in APL or AML patients but are always abnormally expressed in a cohort of 182 APLs and AMLs analyzed. These deregulations appear non-randomly distributed and present in all samples, regardless of their associated genomic mutations. Reverse-engineering approaches showed that these cooperators belong to a single transcriptional gene network, enriched in genes mutated in AMLs, where perturbation of single genes modifies expression of others. Their gene-ontology analysis showed enrichment of genes directly involved in cell proliferation control. Therefore, the pool of PML-RARA cooperating mutations appears large and heterogeneous, but functionally equivalent and deregulated in the majority of APLs and AMLs. Our data suggest that the high heterogeneity of DNA mutations in APLs and AMLs can be reduced to patterns of gene expression deregulation of a single 'mutated' gene network.Leukemia advance online publication, 20 January 2017; doi:10.1038/leu.2016.386.

  19. Mutations in presenilin 2 and its implications in Alzheimer’s disease and other dementia-associated disorders

    Directory of Open Access Journals (Sweden)

    Cai Y

    2015-07-01

    Full Text Available Yan Cai,1 Seong Soo A An,1 SangYun Kim2 1Department of Bionano Technology, Gachon Medical Research Institute, Gachon University, 2Department of Neurology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, South Korea Abstract: Alzheimer’s disease (AD is the most common form of dementia. Mutations in the genes encoding presenilin 1 (PSEN1, presenilin 2 (PSEN2, and amyloid precursor protein have been identified as the main genetic causes of familial AD. To date, more than 200 mutations have been described worldwide in PSEN1, which is highly homologous with PSEN2, while mutations in PSEN2 have been rarely reported. We performed a systematic review of studies describing the mutations identified in PSEN2. Most PSEN2 mutations were detected in European and in African populations. Only two were found in Korean populations. Interestingly, PSEN2 mutations appeared not only in AD patients but also in patients with other disorders, including frontotemporal dementia, dementia with Lewy bodies, breast cancer, dilated cardiomyopathy, and Parkinson’s disease with dementia. Here, we have summarized the PSEN2 mutations and the potential implications of these mutations in dementia-associated disorders. Keywords: mutations in presenilin 2, Alzheimer’s disease

  20. BoLA-DRB3 exon 2 mutations associated with paratuberculosis in cattle.

    Science.gov (United States)

    Rastislav, Mucha; Mangesh, Bhide

    2012-06-01

    A single nucleotide polymorphism at the antigen recognition site of the bovine leucocyte antigen (BoLA) DRB3 gene was assessed in healthy and Mycobacterium avium subsp. paratuberculosis (MAP) - infected cattle, in order to determine if there was a correlation between mutations and altered susceptibility to infection. Of a sample of 200 animals, 19.6% were found to be infected with MAP. PCR - single strand conformational polymorphism analysis of the BoLA DRB3 gene found 19 genotypes (16 in the heterozygous and three in homozygous state, respectively). Four mutations, Val53Glu (OR 453.7), Val53Leu (OR 453.7), Asp57His (OR 1.944) and Arg84Gly (OR 1.458), were linked with increased susceptibility to infection, whereas, Asp57Asn (OR 0) and Phe60Tyr (OR 0.453) were associated with increased resistance. The findings indicate potentially important mutations in the protein-binding site of DRB3, which may be crucial to the activation of an appropriate immune response against MAP.

  1. XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.

    Science.gov (United States)

    Hoch, Nicolas C; Hanzlikova, Hana; Rulten, Stuart L; Tétreault, Martine; Komulainen, Emilia; Ju, Limei; Hornyak, Peter; Zeng, Zhihong; Gittens, William; Rey, Stephanie A; Staras, Kevin; Mancini, Grazia M S; McKinnon, Peter J; Wang, Zhao-Qi; Wagner, Justin D; Yoon, Grace; Caldecott, Keith W

    2017-01-05

    XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair. Here we show that biallelic mutations in the human XRCC1 gene are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. Cells from a patient with mutations in XRCC1 exhibited not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation. This latter phenotype is recapitulated in a related syndrome caused by mutations in the XRCC1 partner protein PNKP and implicates hyperactivation of poly(ADP-ribose) polymerase/s as a cause of cerebellar ataxia. Indeed, remarkably, genetic deletion of Parp1 rescued normal cerebellar ADP-ribose levels and reduced the loss of cerebellar neurons and ataxia in Xrcc1-defective mice, identifying a molecular mechanism by which endogenous single-strand breaks trigger neuropathology. Collectively, these data establish the importance of XRCC1 protein complexes for normal neurological function and identify PARP1 as a therapeutic target in DNA strand break repair-defective disease.

  2. Enhanced Fitness of Adult Spermatogonial Stem Cells Bearing a Paternal Age-Associated FGFR2 Mutation

    Directory of Open Access Journals (Sweden)

    Laura A. Martin

    2014-08-01

    Full Text Available Pathogenic de novo mutations increase with fathers’ age and could be amplified through competition between genetically distinct subpopulations of spermatogonial stem cells (SSCs. Here, we tested the fitness of SSCs bearing wild-type human FGFR2 or an Apert syndrome mutant, FGFR2 (S252W, to provide experimental evidence for SSC competition. The S252W allele conferred enhanced FGFR2-mediated signaling, particularly at very low concentrations of ligand, and also subtle changes in gene expression. Mutant SSCs exhibited improved competitiveness in vitro and increased stem cell activity in vivo upon transplantation. The fitness advantage in vitro only occurred in low concentrations of fibroblast growth factor (FGF, was independent of FGF-driven proliferation, and was accompanied by increased response to glial cell line-derived neurotrophic factor (GDNF. Our studies provide experimental evidence of enhanced stem cell fitness in SSCs bearing a paternal age-associated mutation. Our model will be useful for interrogating other candidate mutations in the future to reveal mechanisms of disease risk.

  3. [HPV-associated head and neck cancer : mutational signature and genomic aberrations].

    Science.gov (United States)

    Wagner, S; Würdemann, N; Hübbers, C; Reuschenbach, M; Prigge, E-S; Wichmann, G; Hess, J; Dietz, A; Dürst, M; Tinhofer, I; von Knebel-Döberitz, M; Wittekindt, C; Klussmann, J P

    2015-11-01

    A significantly increasing proportion of oropharyngeal head and neck carcinomas (OSCC) in North America and Europe are associated with human papillomavirus (HPV) infections. HPV-related OSCC is regarded as a distinct tumor type with regard to its cellular, biologic, and clinical characteristics. Patients with HPV-related OSCC have significantly better local control, but higher rates of regional lymph node and distant metastases as compared to patients with HPV-negative OSCC. Classical molecular genetic investigations demonstrated specific chromosomal aberration signatures in HPV-related OSCC, and recent developments in next generation sequencing (NGS) technology have rendered possible the sequencing of entire genomes, and thus detection of specific mutations, in just a few days. Initial data from The Cancer Genome Atlas (TCGA) project obtained by using genome-wide high throughput methods have confirmed that HPV-related OSCC contain fewer, albeit more specific mutations than HPV-negative tumors. Additionally, these data revealed the presence of specific-potentially therapeutically targetable-activating driver mutations in subgroups of HPV-positive OSCC, some of which have a prognostic impact. Specific targeted NGS technologies provide new possibilities for identification of diagnostic, prognostic, and predictive biomarkers and the development of personalized cancer treatment. Patients with HPV-positive tumors are likely to profit from these developments in the future, since the genetic alterations are relatively homogenous and frequently lead to signal pathway activation. There is an urgent need for network research activities to carry out the necessary basic research in prospective cohort studies.

  4. Myotonia congenita-associated mutations in chloride channel-1 affect zebrafish body wave swimming kinematics.

    Directory of Open Access Journals (Sweden)

    Wei Cheng

    Full Text Available Myotonia congenita is a human muscle disorder caused by mutations in CLCN1, which encodes human chloride channel 1 (CLCN1. Zebrafish is becoming an increasingly useful model for human diseases, including muscle disorders. In this study, we generated transgenic zebrafish expressing, under the control of a muscle specific promoter, human CLCN1 carrying mutations that have been identified in human patients suffering from myotonia congenita. We developed video analytic tools that are able to provide precise quantitative measurements of movement abnormalities in order to analyse the effect of these CLCN1 mutations on adult transgenic zebrafish swimming. Two new parameters for body-wave kinematics of swimming reveal changes in body curvature and tail offset in transgenic zebrafish expressing the disease-associated CLCN1 mutants, presumably due to their effect on muscle function. The capability of the developed video analytic tool to distinguish wild-type from transgenic zebrafish could provide a useful asset to screen for compounds that reverse the disease phenotype, and may be applicable to other movement disorders besides myotonia congenita.

  5. Myotonia Congenita-Associated Mutations in Chloride Channel-1 Affect Zebrafish Body Wave Swimming Kinematics

    Science.gov (United States)

    Cheng, Wei; Tian, Jing; Burgunder, Jean-Marc; Hunziker, Walter; Eng, How-Lung

    2014-01-01

    Myotonia congenita is a human muscle disorder caused by mutations in CLCN1, which encodes human chloride channel 1 (CLCN1). Zebrafish is becoming an increasingly useful model for human diseases, including muscle disorders. In this study, we generated transgenic zebrafish expressing, under the control of a muscle specific promoter, human CLCN1 carrying mutations that have been identified in human patients suffering from myotonia congenita. We developed video analytic tools that are able to provide precise quantitative measurements of movement abnormalities in order to analyse the effect of these CLCN1 mutations on adult transgenic zebrafish swimming. Two new parameters for body-wave kinematics of swimming reveal changes in body curvature and tail offset in transgenic zebrafish expressing the disease-associated CLCN1 mutants, presumably due to their effect on muscle function. The capability of the developed video analytic tool to distinguish wild-type from transgenic zebrafish could provide a useful asset to screen for compounds that reverse the disease phenotype, and may be applicable to other movement disorders besides myotonia congenita. PMID:25083883

  6. Postoperative Atypical Hemolytic Uremic Syndrome Associated with Complement C3 Mutation

    Directory of Open Access Journals (Sweden)

    Eiji Matsukuma

    2014-01-01

    Full Text Available Atypical hemolytic uremic syndrome (aHUS can be distinguished from typical or Shiga-like toxin-induced HUS. The clinical outcome is unfavorable; up to 50% of affected patients progress to end-stage renal failure and 25% die during the acute phase. Multiple conditions have been associated with aHUS, including infections, drugs, autoimmune conditions, transplantation, pregnancy, and metabolic conditions. aHUS in the nontransplant postsurgical period, however, is rare. An 8-month-old boy underwent surgical repair of tetralogy of Fallot. Neurological disturbances, acute renal failure, thrombocytopenia, and microangiopathic hemolytic anemia developed 25 days later, and aHUS was diagnosed. Further evaluation revealed that his complement factor H (CFH level was normal and that anti-FH antibodies were not detected in his plasma. Sequencing of his CFH, complement factor I, membrane cofactor protein, complement factor B, and thrombomodulin genes was normal. His ADAMTS-13 (a disintegrin-like and metalloprotease with thrombospondin-1 repeats 13 activity was also normal. However, he had a potentially causative mutation (R425C in complement component C3. Restriction fragment length polymorphism analysis revealed that his father and aunt also had this mutation; however, they had no symptoms of aHUS. We herein report a case of aHUS that developed after cardiovascular surgery and was caused by a complement C3 mutation.

  7. NOTCH1 Mutations in Aortic Stenosis: Association with Osteoprotegerin/RANK/RANKL

    Science.gov (United States)

    Zhiduleva, Ekaterina; Freylikhman, Olga; Rotar, Oxana; Tarnovskaya, Svetlana; Kostareva, Anna; Moiseeva, Olga

    2017-01-01

    Background. The NOTCH pathway is known to be important in the pathogenesis of calcific aortic valve disease, possibly through regulators of osteoprotegerin (OPG), receptor activator of nuclear factor κB (RANK), and its ligand (RANKL) system. The purpose of the present study was to search for possible associations between NOTCH1 gene mutations and circulating levels of OPG and soluble RANKL (sRANKL) in patients with aortic stenosis (AS). Methods. The study was performed on 61 patients with AS including 31 with bicuspid and 30 with tricuspid aortic valves. We applied a strategy of targeted mutation screening for 10 out of 34 exons of the NOTCH1 gene by direct sequencing. Serum OPG and sRANKL levels were assessed. Results. In total, 6 genetic variants of the NOTCH1 gene including two new mutations were identified in the study group. In an age- and arterial hypertension-adjusted multivariable regression analysis, the serum OPG levels and the OPG/sRANKL ratio were correlated with NOTCH1 missense variants. All studied missense variants in NOTCH1 gene were found in Ca(2+)-binding EGF motif of the NOTCH extracellular domain bound to Delta-like 4. Conclusion. Our results suggest that the OPG/RANKL/RANK system might be directly influenced by genetic variants of NOTCH1 in aortic valve calcification.

  8. Rapid Mutation Scanning of Genes Associated with Familial Cancer Syndromes Using Denaturing High-Performance Liquid Chromatography

    Directory of Open Access Journals (Sweden)

    Deborah J. Marsh

    2001-01-01

    Full Text Available Germline mutations in tumor suppressor genes, or less frequently oncogenes, have been identified in up to 19 familial cancer syndromes including Li-Fraumeni syndrome, familial paraganglioma, familial adenomatous polyposis coli and breast and ovarian cancers. Multiple genes have been associated with some syndromes as approximately 26 genes have been linked to the development of these familial cancers. With this increased knowledge of the molecular determinants of familial cancer comes an equal expectation for efficient genetic screening programs. We have trialled denaturing highperformance liquid chromatography (dHPLC as a tool for rapid germline mutation scanning of genes implicated in three familial cancer syndromes - Cowden syndrome (PTEN mutation, multiple endocrine neoplasia type 2 (RET mutation and von Hippel-Lindau disease (VHL mutation. Thirty-two mutations, including 21 in PTEN, 9 in RET plus a polymorphism, and 2 in VHL, were analyzed using the WAVE DNA fragment analysis system with 100% detection efficiency. In the case of the tumor suppressor gene PTEN, mutations were scattered along most of the gene. However, mutations in the RET proto-oncogene associated with multiple endocrine neoplasia type 2 were limited to specific clusters or “hot spots”. The use of GC-clamped primers to scan for mutations scattered along PTEN exons was shown to greatly enhance the sensitivity of detection of mutant hetero- and homoduplex peaks at a single denaturation temperature compared to fragments generated using non-GC-clamped primers. Thus, when scanning tumor suppressor genes for germline mutation using dHPLC, the incorporation of appropriate GCclamped primers will likely increase the efficiency of mutation detection.

  9. Introducing Pitt-Hopkins syndrome-associated mutations of TCF4 to Drosophila daughterless

    Directory of Open Access Journals (Sweden)

    Laura Tamberg

    2015-12-01

    Full Text Available Pitt-Hopkins syndrome (PTHS is caused by haploinsufficiency of Transcription factor 4 (TCF4, one of the three human class I basic helix-loop-helix transcription factors called E-proteins. Drosophila has a single E-protein, Daughterless (Da, homologous to all three mammalian counterparts. Here we show that human TCF4 can rescue Da deficiency during fruit fly nervous system development. Overexpression of Da or TCF4 specifically in adult flies significantly decreases their survival rates, indicating that these factors are crucial even after development has been completed. We generated da transgenic fruit fly strains with corresponding missense mutations R578H, R580W, R582P and A614V found in TCF4 of PTHS patients and studied the impact of these mutations in vivo. Overexpression of wild type Da as well as human TCF4 in progenitor tissues induced ectopic sensory bristles and the rough eye phenotype. By contrast, overexpression of DaR580W and DaR582P that disrupt DNA binding reduced the number of bristles and induced the rough eye phenotype with partial lack of pigmentation, indicating that these act dominant negatively. Compared to the wild type, DaR578H and DaA614V were less potent in induction of ectopic bristles and the rough eye phenotype, respectively, suggesting that these are hypomorphic. All studied PTHS-associated mutations that we introduced into Da led to similar effects in vivo as the same mutations in TCF4 in vitro. Consequently, our Drosophila models of PTHS are applicable for further studies aiming to unravel the molecular mechanisms of this disorder.

  10. Fen1 mutations that specifically disrupt its interaction with PCNA cause aneuploidy-associated cancer

    Institute of Scientific and Technical Information of China (English)

    Li Zheng; Sankar Mitra; Qin Huang; Kemp H Kernstine; Gerd P Pfeifer; Binghui Shen; Huifang Dai; Muralidhar L Hegde; Mian Zhou; Zhigang Guo; Xiwei Wu; Jun WU; Lei Su; Xueyan Zhong

    2011-01-01

    DNA replication and repair are critical processes for all living organisms to ensure faithful duplication and transmission of genetic information. Flap endonuclease 1 (Feni), a structure-specific nuclease, plays an important role in multiple DNA metabolic pathways and maintenance of genome stability. Human FEN1 mutations that impair its exonuclease activity have been linked to cancer development. FEN1 interacts with multiple proteins, including proliferation cell nuclear antigen (PCNA), to form various functional complexes. Interactions with these proteins are considered to be the key molecular mechanisms mediating FEN1's key biological functions. The current challenge is to experimentally demonstrate the biological consequence of a specific interaction without compromising other functions of a desired protein. To address this issue, we established a mutant mouse model harboring a FEN1 point mutation (F343A/F344A, FFAA), which specifically abolishes the FEN1/PCNA interaction. We show that the FFAA mutation causes defects in RNA primer removal and long-patch base excision repair, even in the heterozygous state, resulting in numerous DNA breaks. These breaks activate the G2/M checkpoint protein, Chk1, and induce neartetraploid aneuploidy, commonly observed in human cancer, consequently elevating the transformation frequency. Consistent with this, inhibition of aneupioidy formation by a Chk1 inhibitor significantly suppressed the cellular transformation. WT/FFAA FEN1 mutant mice develop aneuploidy-associated cancer at a high frequency. Thus, this study establishes an exemplary case for investigating the biological significance of protein-protein interactions by knock-in of a point mutation rather than knock-out of a whole gene.

  11. Impact of LCA-Associated E14L LRAT Mutation on Protein Stability and Retinoid Homeostasis.

    Science.gov (United States)

    Chelstowska, Sylwia; Widjaja-Adhi, Made Airanthi K; Silvaroli, Josie A; Golczak, Marcin

    2017-08-29

    Vitamin A (all-trans-retinol) is metabolized to the visual chromophore (11-cis-retinal) in the eyes and to all-trans-retinoic acid, a hormone like compound, in most tissues. A key enzyme in retinoid metabolism is lecithin:retinol acyltransferase (LRAT), which catalyzes the esterification of vitamin A. The importance of LRAT is indicated by pathogenic missense and nonsense mutations, which cause devastating blinding diseases. Retinoid-based chromophore replacement therapy has been proposed as treatment for these types of blindness based on studies in LRAT null mice. Here, we analyzed the structural and biochemical basis for retinal pathology caused by mutations in the human LRAT gene. Most LRAT missense mutations associated with retinal degeneration are localized within the catalytic domain, whereas E14L substitution is localized in an N-terminal α-helix, which has been implicated in interaction with the phospholipid bilayer. To elucidate the biochemical consequences of this mutation, we determined LRAT(E14L)'s enzymatic properties, protein stability, and impact on ocular retinoid metabolism. Bicistronic expression of LRAT(E14L) and enhanced green fluorescence protein revealed instability and accelerated proteosomal degradation of this mutant isoform. Surprisingly, instability of LRAT(E14L) did not abrogate the production of the visual chromophore in a cell-based assay. Instead, expression of LRAT(E14L) led to a rapid increase in cellular levels of retinoic acid upon retinoid supplementation. Thus, our study unveils the potential role of retinoic acid in the pathology of a degenerative retinal disease with important implications for the use of retinoid-based therapeutics in affected patients.

  12. Splicing mutation in CYP21 associated with delayed presentation of salt-wasting congenital adrenal hyperplasia

    Energy Technology Data Exchange (ETDEWEB)

    Kohn, B.; Patel, S.V.; Pelczar, J.V. [North Shore Univ. Hospital, Manhasset, NY (United States)] [and others

    1995-07-03

    Patients with salt-wasting congenital adrenal hyperplasia (SW-CAH) most commonly carry an A-G transition at nucleotide 656 (nt 656 A{r_arrow}G), causing abnormal splicing of exons 2 and 3 in CYP21, the gene encoding active steroid 21-hydroxylase. Affected infants are severely deficient in cortisol and aldosterone, and usually come to medical attention during the neonatal period. We report on 2 affected boys, homozygous for the nt 656 mutation, who thrived in early infancy, but suffered salt-wasting crises unusually late in infancy, at 3.5 and 5.5 months, respectively. Laboratory studies at presentation showed hyponatremia, hyperkalemia, dehydration, and acidosis; serum aldosterone was low in spite of markedly elevated plasma renin activity. Basal 17-hydroxyprogesterone levels were only moderately elevated, yet the stimulated levels were more typical of severe, classic CAH due to 21-hydroxylase deficiency. Genomic DNA from the patients was analyzed. Southern blot showed no major deletions or rearrangements. CYP21-specific amplification by polymerase chain reaction, coupled with allele-specific hybridization using wild-type and mutant probes at each of 9 sites for recognized disease-causing mutations, revealed a single, homozygous mutation in each patient: nt 656 A{r_arrow}G. These results were confirmed by sequence analysis. We conclude that the common nt 656 A{r_arrow}G mutation is sometimes associated with delayed phenotypic expression of SW-CAH. We speculate that variable splicing of the mutant CYP21 may modify the clinical manifestation of this disease. 22 refs., 1 fig., 1 tab.

  13. Novel Lethal Form of Congenital Hypopituitarism Associated With the First Recessive LHX4 Mutation

    Science.gov (United States)

    Gregory, L. C.; Humayun, K. N.; Turton, J. P. G.; McCabe, M. J.; Rhodes, S. J.

    2015-01-01

    Background: LHX4 encodes a member of the LIM-homeodomain family of transcription factors that is required for normal development of the pituitary gland. To date, only incompletely penetrant heterozygous mutations in LHX4 have been described in patients with variable combined pituitary hormone deficiencies. Objective/Hypothesis: To report a unique family with a novel recessive variant in LHX4 associated with a lethal form of congenital hypopituitarism that was identified through screening a total of 97 patients. Method: We screened 97 unrelated patients with combined pituitary hormone deficiency, including 65% with an ectopic posterior pituitary, for variants in the LHX4 gene using Sanger sequencing. Control databases (1000 Genomes, dbSNP, Exome Variant Server, ExAC Browser) were consulted upon identification of variants. Results: We identified the first novel homozygous missense variant (c.377C>T, p.T126M) in two deceased male patients of Pakistani origin with severe panhypopituitarism associated with anterior pituitary aplasia and posterior pituitary ectopia. Both were born small for gestational age with a small phallus, undescended testes, and mid-facial hypoplasia. The parents' first-born child was a female with mid-facial hypoplasia (DNA was unavailable). Despite rapid commencement of hydrocortisone and T4 in the brothers, all three children died within the first week of life. The LHX4(p.T126M) variant is located within the LIM2 domain, in a highly conserved location. The absence of homozygosity for the variant in over 65 000 controls suggests that it is likely to be responsible for the phenotype. Conclusion: We report, for the first time to our knowledge, a novel homozygous mutation in LHX4 associated with a lethal phenotype, implying that recessive mutations in LHX4 may be incompatible with life. PMID:25871839

  14. RUNX1 mutations in acute myeloid leukemia are associated with distinct clinico-pathologic and genetic features.

    Science.gov (United States)

    Gaidzik, V I; Teleanu, V; Papaemmanuil, E; Weber, D; Paschka, P; Hahn, J; Wallrabenstein, T; Kolbinger, B; Köhne, C H; Horst, H A; Brossart, P; Held, G; Kündgen, A; Ringhoffer, M; Götze, K; Rummel, M; Gerstung, M; Campbell, P; Kraus, J M; Kestler, H A; Thol, F; Heuser, M; Schlegelberger, B; Ganser, A; Bullinger, L; Schlenk, R F; Döhner, K; Döhner, H

    2016-11-01

    We evaluated the frequency, genetic architecture, clinico-pathologic features and prognostic impact of RUNX1 mutations in 2439 adult patients with newly-diagnosed acute myeloid leukemia (AML). RUNX1 mutations were found in 245 of 2439 (10%) patients; were almost mutually exclusive of AML with recurrent genetic abnormalities; and they co-occurred with a complex pattern of gene mutations, frequently involving mutations in epigenetic modifiers (ASXL1, IDH2, KMT2A, EZH2), components of the spliceosome complex (SRSF2, SF3B1) and STAG2, PHF6, BCOR. RUNX1 mutations were associated with older age (16-59 years: 8.5%; ⩾60 years: 15.1%), male gender, more immature morphology and secondary AML evolving from myelodysplastic syndrome. In univariable analyses, RUNX1 mutations were associated with inferior event-free (EFS, P<0.0001), relapse-free (RFS, P=0.0007) and overall survival (OS, P<0.0001) in all patients, remaining significant when age was considered. In multivariable analysis, RUNX1 mutations predicted for inferior EFS (P=0.01). The effect of co-mutation varied by partner gene, where patients with the secondary genotypes RUNX1(mut)/ASXL1(mut) (OS, P=0.004), RUNX1(mut)/SRSF2(mut) (OS, P=0.007) and RUNX1(mut)/PHF6(mut) (OS, P=0.03) did significantly worse, whereas patients with the genotype RUNX1(mut)/IDH2(mut) (OS, P=0.04) had a better outcome. In conclusion, RUNX1-mutated AML is associated with a complex mutation cluster and is correlated with distinct clinico-pathologic features and inferior prognosis.

  15. Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency.

    OpenAIRE

    1998-01-01

    Leigh disease associated with cytochrome c oxidase deficiency (LD[COX-]) is one of the most common disorders of the mitochondrial respiratory chain, in infancy and childhood. No mutations in any of the genes encoding the COX-protein subunits have been identified in LD(COX-) patients. Using complementation assays based on the fusion of LD(COX-) cell lines with several rodent/human rho0 hybrids, we demonstrated that the COX phenotype was rescued by the presence of a normal human chromosome 9. L...

  16. Microfluidic screening and whole-genome sequencing identifies mutations associated with improved protein secretion by yeast

    DEFF Research Database (Denmark)

    Huang, Mingtao; Bai, Yunpeng; Sjostrom, Staffan L.

    2015-01-01

    interest in improving its protein secretion capacity. Due to the complexity of the secretory machinery in eukaryotic cells, it is difficult to apply rational engineering for construction of improved strains. Here we used high-throughput microfluidics for the screening of yeast libraries, generated by UV...... to construct efficient cell factories for protein secretion. The combined use of microfluidics screening and whole-genome sequencing to map the mutations associated with the improved phenotype can easily be adapted for other products and cell types to identify novel engineering targets, and this approach could...

  17. Association of radiotherapy with preferential depletion of luminal epithelial cells in a BRCA1 mutation carrier

    Directory of Open Access Journals (Sweden)

    Chiang Huai-Chin

    2012-10-01

    Full Text Available Abstract Radiation therapy (RT after breast conservation therapy has recently been linked with significant reduction in risk of ipsilateral breast cancer among BRCA1 mutation carriers. However, the exact mechanism by which RT reduces incidence of BRCA1-associated cancer remains unclear. Here we studied fresh breast tissue from a BRCA1 mutation carrier who was initially treated with a lumpectomy and RT for a unilateral cancer and two years later chose a prophylactic bilateral mastectomy while remaining cancer-free. Flow cytometry analysis demonstrated a strikingly lower luminal cell population in the irradiated breast as compared to the non-irradiated breast, which was confirmed by immunohistochemistry. Furthermore, the irradiated breast tissue exhibited very low progenitor cell activity in vitro. Given the emerging evidence that BRCA1 tumors originate from luminal progenitor cells, our observations suggest that preferential and long-lasting elimination of luminal ductal epithelium may partly underlie the mechanism of RT-associated reduction in recurrence of BRCA1-associated cancer.

  18. Proteomic analysis of cytosolic proteins associated with petite mutations in Candida glabrata

    Directory of Open Access Journals (Sweden)

    C.V. Loureiro y Penha

    2010-12-01

    Full Text Available The incidence of superficial or deep-seated infections due to Candida glabrata has increased markedly, probably because of the low intrinsic susceptibility of this microorganism to azole antifungals and its relatively high propensity to acquire azole resistance. To determine changes in the C. glabrata proteome associated with petite mutations, cytosolic extracts from an azole-resistant petite mutant of C. glabrata induced by exposure to ethidium bromide, and from its azole-susceptible parent isolate were compared by two-dimensional polyacrylamide gel electrophoresis. Proteins of interest were identified by peptide mass fingerprinting or sequence tagging using a matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometer. Tryptic peptides from a total of 160 Coomassie-positive spots were analyzed for each strain. Sixty-five different proteins were identified in the cytosolic extracts of the parent strain and 58 in the petite mutant. Among the proteins identified, 10 were higher in the mutant strain, whereas 23 were lower compared to the parent strain. The results revealed a significant decrease in the enzymes associated with the metabolic rate of mutant cells such as aconitase, transaldolase, and pyruvate kinase, and changes in the levels of specific heat shock proteins. Moreover, transketolase, aconitase and catalase activity measurements decreased significantly in the ethidium bromide-induced petite mutant. These data may be useful for designing experiments to obtain a better understanding of the nuclear response to impairment of mitochondrial function associated with this mutation in C. glabrata.

  19. Convergent Evolution of Head Crests in Two Domesticated Columbids Is Associated with Different Missense Mutations in EphB2.

    Science.gov (United States)

    Vickrey, Anna I; Domyan, Eric T; Horvath, Martin P; Shapiro, Michael D

    2015-10-01

    Head crests are important display structures in wild bird species and are also common in domesticated lineages. Many breeds of domestic rock pigeon (Columba livia) have crests of reversed occipital feathers, and this recessive trait is associated with a nonsynonymous coding mutation in the intracellular kinase domain of EphB2 (Ephrin receptor B2). The domestic ringneck dove (Streptopelia risoria) also has a recessive crested morph with reversed occipital feathers, and interspecific crosses between crested doves and pigeons produce crested offspring, suggesting a similar genetic basis for this trait in both species. We therefore investigated EphB2 as a candidate for the head crest phenotype of ringneck doves and identified a nonsynonymous coding mutation in the intracellular kinase domain that is significantly associated with the crested morph. This mutation is over 100 amino acid positions away from the crest mutation found in rock pigeons, yet both mutations are predicted to negatively affect the function of ATP-binding pocket. Furthermore, bacterial toxicity assays suggest that "crest" mutations in both species severely impact kinase activity. We conclude that head crests are associated with different mutations in the same functional domain of the same gene in two different columbid species, thereby representing striking evolutionary convergence in morphology and molecules. © The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  20. The "silver" Japanese quail and the MITF gene: causal mutation, associated traits and homology with the "blue" chicken plumage

    Directory of Open Access Journals (Sweden)

    Ito Shin'ichi

    2010-02-01

    Full Text Available Abstract Background The MITF (microphthalmia-associated transcription factor gene has been investigated in mice and various vertebrates but its variations and associated effects have not yet been explored much in birds. The present study describes the causal mutation B at the MITF gene responsible for the "silver" plumage colour in the Japanese quail (Coturnix japonica, and its associated effects on growth and body composition, and tests its allelism with the "blue" plumage colour mutation Bl in Gallus gallus. Results The semi dominant B mutation results from a premature stop codon caused by a 2 bp deletion in exon 11 of MITF. Homozygous "white" (B/B quail which have a white plumage also show a slightly lower growth, lower body temperature, smaller heart, and lighter pectoralis muscles but more abdominal adipose tissue than the recessive homozygous "wild-type" (+/+ and heterozygous "silver" (B/+ quail. Similar observations on cardiac and body growth were made on mice (Mus musculus homozygous for mutations at MITF. The production of chicken-quail hybrids with a white plumage obtained by crossing Bl/+ chicken heterozygous for the blue mutation with B/B white quail indicated that the mutations were allelic. Conclusion The "silver" Japanese quail is an interesting model for the comparative study of the effects of MITF in birds and mammals. Further investigation using a chicken family segregating for the "blue" plumage and molecular data will be needed to confirm if the "blue" plumage in chicken results from a mutation in MITF.

  1. Serum Iron Parameters, HFE C282Y Genotype, and Cognitive Performance in Older Adults: Results From the FACIT Study

    NARCIS (Netherlands)

    Schiepers, O.J.G.; Boxtel, van M.P.J.; Groot, R.H.M.; Jolles, J.; Kort, de W.L.A.M.; Swinkels, D.W.; Kok, F.J.; Verhoef, P.; Durga, J.

    2010-01-01

    Although iron homeostasis is essential for brain functioning, the effects of iron levels on cognitive performance in older individuals have scarcely been investigated. In the present study, serum iron parameters and hemochromatosis (HFE) C282Y genotype were determined in 818 older individuals who pa

  2. Serum Iron Parameters, HFE C282Y Genotype, and Cognitive Performance in Older Adults: Results From the FACIT Study

    NARCIS (Netherlands)

    Schiepers, O.J.G.; Boxtel, van M.P.J.; Groot, R.H.M.; Jolles, J.; Kort, de W.L.A.M.; Swinkels, D.W.; Kok, F.J.; Verhoef, P.; Durga, J.

    2010-01-01

    Although iron homeostasis is essential for brain functioning, the effects of iron levels on cognitive performance in older individuals have scarcely been investigated. In the present study, serum iron parameters and hemochromatosis (HFE) C282Y genotype were determined in 818 older individuals who pa

  3. Association between thyroid cancer and epidermal growth factor receptor mutation in female with nonsmall cell lung cancer

    Science.gov (United States)

    Kim, Seo Yun; Kim, Hye-Ryoun; Kim, Cheol Hyeon; Koh, Jae Soo; Baek, Hee Jong; Choi, Chang-Min; Song, Joon Seon; Lee, Jae Cheol; Na, Im II

    2017-01-01

    BACKGROUND: The aim of this study was to investigate the association between epidermal growth factor receptor (EGFR) mutation and thyroid cancer in female patients with nonsmall-cell lung cancer (NSCLC). METHODS: In a retrospective study, we examined 835 female patients who were diagnosed with NSCLC and underwent an EGFR mutation test between June 2003 and August 2013. The associations of EGFR mutation with thyroid cancer and a family history of thyroid cancer were evaluated using logistic regression models. RESULTS: EGFR mutation was found in 378 of 835 patients. In addition to adenocarcinoma (P cancer (5.8% versus 2.6%; P = 0.020), while showing a trend toward inverse association with a personal history of nonthyroid cancer (5.8% vs. 9.0%; P = 0.086). Likewise, the incidence of EGFR mutations was associated with a family history of thyroid cancer (2.9% vs. 0.9%; P = 0.028), while showing a trend toward inverse association with a family history of nonthyroid cancer (27.8% vs. 33.7%; P = 0.066). Multivariate logistic regression showed that the incidence of EGFR mutations was different in women with thyroid or nonthyroid cancer (P = 0.035) and in women with a family history of thyroid or nonthyroid cancer (P = 0.023). CONCLUSIONS: Our data suggest that thyroid cancer and a family history of thyroid cancer are associated with EGFR-mutated NSCLC in female patients. The differences in the incidence of thyroid cancer and a family history of thyroid cancer by EGFR mutational status provide new insight into pathogenesis of this genetic change.

  4. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain.

    Directory of Open Access Journals (Sweden)

    William Pao

    2005-03-01

    Full Text Available BACKGROUND: Lung adenocarcinomas from patients who respond to the tyrosine kinase inhibitors gefitinib (Iressa or erlotinib (Tarceva usually harbor somatic gain-of-function mutations in exons encoding the kinase domain of the epidermal growth factor receptor (EGFR. Despite initial responses, patients eventually progress by unknown mechanisms of "acquired" resistance. METHODS AND FINDINGS: We show that in two of five patients with acquired resistance to gefitinib or erlotinib, progressing tumors contain, in addition to a primary drug-sensitive mutation in EGFR, a secondary mutation in exon 20, which leads to substitution of methionine for threonine at position 790 (T790M in the kinase domain. Tumor cells from a sixth patient with a drug-sensitive EGFR mutation whose tumor progressed on adjuvant gefitinib after complete resection also contained the T790M mutation. This mutation was not detected in untreated tumor samples. Moreover, no tumors with acquired resistance had KRAS mutations, which have been associated with primary resistance to these drugs. Biochemical analyses of transfected cells and growth inhibition studies with lung cancer cell lines demonstrate that the T790M mutation confers resistance to EGFR mutants usually sensitive to either gefitinib or erlotinib. Interestingly, a mutation analogous to T790M has been observed in other kinases with acquired resistance to another kinase inhibitor, imatinib (Gleevec. CONCLUSION: In patients with tumors bearing gefitinib- or erlotinib-sensitive EGFR mutations, resistant subclones containing an additional EGFR mutation emerge in the presence of drug. This observation should help guide the search for more effective therapy against a specific subset of lung cancers.

  5. Visual short-term memory deficits associated with GBA mutation and Parkinson's disease.

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    Zokaei, Nahid; McNeill, Alisdair; Proukakis, Christos; Beavan, Michelle; Jarman, Paul; Korlipara, Prasad; Hughes, Derralynn; Mehta, Atul; Hu, Michele T M; Schapira, Anthony H V; Husain, Masud

    2014-08-01

    Individuals with mutation in the lysosomal enzyme glucocerebrosidase (GBA) gene are at significantly high risk of developing Parkinson's disease with cognitive deficit. We examined whether visual short-term memory impairments, long associated with patients with Parkinson's disease, are also present in GBA-positive individuals-both with and without Parkinson's disease. Precision of visual working memory was measured using a serial order task in which participants observed four bars, each of a different colour and orientation, presented sequentially at screen centre. Afterwards, they were asked to adjust a coloured probe bar's orientation to match the orientation of the bar of the same colour in the sequence. An additional attentional 'filtering' condition tested patients' ability to selectively encode one of the four bars while ignoring the others. A sensorimotor task using the same stimuli controlled for perceptual and motor factors. There was a significant deficit in memory precision in GBA-positive individuals-with or without Parkinson's disease-as well as GBA-negative patients with Parkinson's disease, compared to healthy controls. Worst recall was observed in GBA-positive cases with Parkinson's disease. Although all groups were impaired in visual short-term memory, there was a double dissociation between sources of error associated with GBA mutation and Parkinson's disease. The deficit observed in GBA-positive individuals, regardless of whether they had Parkinson's disease, was explained by a systematic increase in interference from features of other items in memory: misbinding errors. In contrast, impairments in patients with Parkinson's disease, regardless of GBA status, was explained by increased random responses. Individuals who were GBA-positive and also had Parkinson's disease suffered from both types of error, demonstrating the worst performance. These findings provide evidence for dissociable signature deficits within the domain of visual short

  6. Novel association of neurofibromatosis type 1-causing mutations in families with neurofibromatosis-Noonan syndrome.

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    Ekvall, Sara; Sjörs, Kerstin; Jonzon, Anders; Vihinen, Mauno; Annerén, Göran; Bondeson, Marie-Louise

    2014-03-01

    Neurofibromatosis-Noonan syndrome (NFNS) is a rare condition with clinical features of both neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). All three syndromes belong to the RASopathies, which are caused by dysregulation of the RAS-MAPK pathway. The major gene involved in NFNS is NF1, but co-occurring NF1 and PTPN11 mutations in NFNS have been reported. Knowledge about possible involvement of additional RASopathy-associated genes in NFNS is, however, very limited. We present a comprehensive clinical and molecular analysis of eight affected individuals from three unrelated families displaying features of NF1 and NFNS. The genetic etiology of the clinical phenotypes was investigated by mutation analysis, including NF1, PTPN11, SOS1, KRAS, NRAS, BRAF, RAF1, SHOC2, SPRED1, MAP2K1, MAP2K2, and CBL. All three families harbored a heterozygous NF1 variant, where the first family had a missense variant, c.5425C>T;p.R1809C, the second family a recurrent 4bp-deletion, c.6789_6792delTTAC;p.Y2264Tfs*6, and the third family a splice-site variant, c.2991-1G>A, resulting in skipping of exon 18 and an in-frame deletion of 41 amino acids. These NF1 variants have all previously been reported in NF1 patients. Surprisingly, both c.6789_6792delTTAC and c.2991-1G>A are frequently associated with NF1, but association to NFNS has, to our knowledge, not previously been reported. Our results support the notion that NFNS represents a variant of NF1, genetically distinct from NS, and is caused by mutations in NF1, some of which also cause classical NF1. Due to phenotypic overlap between NFNS and NS, we propose screening for NF1 mutations in NS patients, preferentially when café-au-lait spots are present. © 2013 Wiley Periodicals, Inc.

  7. Confirmation of mutation landscape of NF1-associated malignant peripheral nerve sheath tumors.

    Science.gov (United States)

    Sohier, Pierre; Luscan, Armelle; Lloyd, Angharad; Ashelford, Kevin; Laurendeau, Ingrid; Briand-Suleau, Audrey; Vidaud, Dominique; Ortonne, Nicolas; Pasmant, Eric; Upadhyaya, Meena

    2017-05-01

    The commonest tumors associated with neurofibromatosis type 1 (NF1) are benign peripheral nerve sheath tumors, called neurofibromas. Malignant transformation of neurofibromas into aggressive MPNSTs may occur with a poor patient prognosis. A cooperative role of SUZ12 or EED inactivation, along with NF1, TP53, and CDKN2A loss-of-function, has been proposed to drive progression to MPNSTs. An exome sequencing analysis of eight MPNSTs, one plexiform neurofibroma, and seven cutaneous neurofibromas was undertaken. Biallelic inactivation of the NF1 gene was observed in the plexiform neurofibroma and the MPNSTs, underlining that somatic biallelic NF1 inactivation is likely to be the initiating event for plexiform neurofibroma genesis, although it is unlikely to be sufficient for the subsequent MPNST development. The majority (5/8) of MPNSTs in our analyses demonstrated homozygous or heterozygous deletions of CDKN2A, which may represent an early event following NF1 LOH in the malignant transformation of Schwann cells from plexiform neurofibroma to MPNST. Biallelic somatic alterations of SUZ12 was also found in 4/8 MPNSTs. EED biallelic alterations were detected in 2 of the other four MPNSTs, with one tumor having a homozygous EED deletion. A missense mutation in the chromatin regulator KDM2B was also identified in one MPNST. No TP53 point mutations were found in this study, confirming previous data that TP53 mutations may be relatively rare in NF1-associated MPNSTs. Our study confirms the frequent biallelic inactivation of PRC2 subunits SUZ12 and EED in MPNSTs, and suggests the implication of KDM2B.

  8. Drosophila type IV collagen mutation associates with immune system activation and intestinal dysfunction.

    Science.gov (United States)

    Kiss, Márton; Kiss, András A; Radics, Monika; Popovics, Nikoletta; Hermesz, Edit; Csiszár, Katalin; Mink, Mátyás

    2016-01-01

    The basal lamina (BM) contains numerous components with a predominance of type IV collagens. Clinical manifestations associated with mutations of the human COL4A1 gene include perinatal cerebral hemorrhage and porencephaly, hereditary angiopathy, nephropathy, aneurysms and muscle cramps (HANAC), ocular dysgenesis, myopathy, Walker–Warburg syndrome and systemic tissue degeneration. In Drosophila, the phenotype associated with dominant temperature sensitive mutations of col4a1 include severe myopathy resulting from massive degradation of striated muscle fibers, and in the gut, degeneration of circular visceral muscle cells and epithelial cells following detachment from the BM. In order to determine the consequences of altered BMfunctions due to aberrant COL4A1 protein, we have carried out a series of tests using Drosophila DTS-L3 mutants from our allelic series of col4a1 mutations with confirmed degeneration of various cell types and lowest survival rate among the col4a1 mutant lines at restrictive temperature. Results demonstrated epithelial cell degeneration in the gut, shortened gut, enlarged midgut with multiple diverticulae, intestinal dysfunction and shortened life span. Midgut immunohistochemistry analyses confirmed altered expression and distribution of BM components integrin PSI and PSII alpha subunits, laminin gamma 1, and COL4A1 both in larvae and adults. Global gene expression analysis revealed activation of the effector AMP genes of the primary innate immune system including Metchnikowin, Diptericin, Diptericin B, and edin that preceded morphological changes. Attacin::GFP midgut expression pattern further supported these changes. An increase in ROS production and changes in gut bacterial flora were also noted and may have further enhanced an immune response. The phenotypic features of Drosophila col4a1 mutants confirmed an essential role for type IV collagen in maintaining epithelial integrity, gut morphology and intestinal function and suggest that

  9. Biallelic Mutations in MYPN, Encoding Myopalladin, Are Associated with Childhood-Onset, Slowly Progressive Nemaline Myopathy.

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    Miyatake, Satoko; Mitsuhashi, Satomi; Hayashi, Yukiko K; Purevjav, Enkhsaikhan; Nishikawa, Atsuko; Koshimizu, Eriko; Suzuki, Mikiya; Yatabe, Kana; Tanaka, Yuzo; Ogata, Katsuhisa; Kuru, Satoshi; Shiina, Masaaki; Tsurusaki, Yoshinori; Nakashima, Mitsuko; Mizuguchi, Takeshi; Miyake, Noriko; Saitsu, Hirotomo; Ogata, Kazuhiro; Kawai, Mitsuru; Towbin, Jeffrey; Nonaka, Ikuya; Nishino, Ichizo; Matsumoto, Naomichi

    2017-01-05

    Nemaline myopathy (NM) is a common form of congenital nondystrophic skeletal muscle disease characterized by muscular weakness of proximal dominance, hypotonia, and respiratory insufficiency but typically not cardiac dysfunction. Wide variation in severity has been reported. Intranuclear rod myopathy is a subtype of NM in which rod-like bodies are seen in the nucleus, and it often manifests as a severe phenotype. Although ten mutant genes are currently known to be associated with NM, only ACTA1 is associated with intranuclear rod myopathy. In addition, the genetic cause remains unclear in approximately 25%-30% of individuals with NM. We performed whole-exome sequencing on individuals with histologically confirmed but genetically unsolved NM. Our study included individuals with milder, later-onset NM and identified biallelic loss-of-function mutations in myopalladin (MYPN) in four families. Encoded MYPN is a sarcomeric protein exclusively localized in striated muscle in humans. Individuals with identified MYPN mutations in all four of these families have relatively mild, childhood- to adult-onset NM with slowly progressive muscle weakness. Walking difficulties were recognized around their forties. Decreased respiratory function, cardiac involvement, and intranuclear rods in biopsied muscle were observed in two individuals. MYPN was localized at the Z-line in control skeletal muscles but was absent from affected individuals. Homozygous knockin mice with a nonsense mutation in Mypn showed Z-streaming and nemaline-like bodies adjacent to a disorganized Z-line on electron microscopy, recapitulating the disease. Our results suggest that MYPN screening should be considered in individuals with mild NM, especially when cardiac problems or intranuclear rods are present. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  10. Assessing the pathogenic potential of human Nephronophthisis disease-associated NPHP-4 missense mutations in C. elegans.

    Science.gov (United States)

    Masyukova, Svetlana V; Winkelbauer, Marlene E; Williams, Corey L; Pieczynski, Jay N; Yoder, Bradley K

    2011-08-01

    A spectrum of complex oligogenic disorders called the ciliopathies have been connected to dysfunction of cilia. Among the ciliopathies are Nephronophthisis (NPHP), characterized by cystic kidney disease and retinal degeneration, and Meckel-Gruber syndrome (MKS), a gestational lethal condition with skeletal abnormalities, cystic kidneys and CNS malformation. Mutations in multiple genes have been identified in NPHP and MKS patients, and an unexpected finding has been that mutations within the same gene can cause either disorder. Further, there is minimal genotype-phenotype correlation and despite recessive inheritance, numerous patients were identified as having a single heterozygous mutation. This has made it difficult to determine the significance of these mutations on disease pathogenesis and led to the hypothesis that clinical presentation in an individual will be determined by genetic interactions between mutations in multiple cilia-related genes. Here we utilize Caenorhabditis elegans and cilia-associated behavioral and morphologic assays to evaluate the pathogenic potential of eight previously reported human NPHP4 missense mutations. We assess the impact of these mutations on C. elegans NPHP-4 function, localization and evaluate potential interactions with mutations in MKS complex genes, mksr-2 and mksr-1. Six out of eight nphp-4 mutations analyzed alter ciliary function, and three of these modify the severity of the phenotypes caused by disruption of mksr-2 and mksr-1. Collectively, our studies demonstrate the utility of C. elegans as a tool to assess the pathogenicity of mutations in ciliopathy genes and provide insights into the complex genetic interactions contributing to the diversity of phenotypes associated with cilia disorders.

  11. Delineation of the Marfan phenotype associated with mutations in exons 23-32 of the FBN1 gene

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    Putnam, E.A.; Cho, M.; Milewicz, D.M. [Univ. of Texas-Houston Medical School, Houston, TX (United States)] [and others

    1996-03-29

    Marfan syndrome is a dominantly inherited connective tissue disorder with a wide range of phenotypic severity. The condition is the result of mutations in FBN1, a large gene composed of 65 exons encoding the fibrillin-1 protein. While mutations causing classic manifestations of Marfan syndrome have been identified throughout the FBN1 gene, the six previously characterized mutations resulting in the severe, perinatal lethal form of Marfan syndrome have clustered in exons 24-32 of the gene. We screened 8 patients with either neonatal Marfan syndrome or severe cardiovascular complications of Marfan syndrome for mutations in this region of the gene. Using intron-based exon-specific primers, we amplified exons 23-32 from genomic DNAs, screened these fragments by single-stranded conformational polymorphism analysis, and sequenced indicated exons. This analysis documented mutations in exons 25-27 of the FBN1 mutations in 6 of these patients. These results, taken together with previously published FBN1 mutations in this region, further define the phenotype associated with mutations in exons 24-32 of the FBN1 gene, information important for the development of possible diagnostic tests and genetic counseling. 49 refs., 4 figs., 2 tabs.

  12. Different mutations at V363 MAPT codon are associated with atypical clinical phenotypes and show unusual structural and functional features.

    Science.gov (United States)

    Rossi, Giacomina; Bastone, Antonio; Piccoli, Elena; Morbin, Michela; Mazzoleni, Giulia; Fugnanesi, Valeria; Beeg, Marten; Del Favero, Elena; Cantù, Laura; Motta, Simona; Salsano, Ettore; Pareyson, Davide; Erbetta, Alessandra; Elia, Antonio Emanuele; Del Sorbo, Francesca; Silani, Vincenzo; Morelli, Claudia; Salmona, Mario; Tagliavini, Fabrizio

    2014-02-01

    Microtubule-associated protein tau gene (MAPT) is one of the major genes linked to frontotemporal lobar degeneration, a group of neurodegenerative diseases clinically, pathologically, and genetically heterogeneous. In particular, MAPT mutations give rise to the subgroup of tauopathies. The pathogenetic mechanisms underlying the MAPT mutations so far described are the decreased ability of tau protein to promote microtubule polymerization (missense mutations) or the altered ratio of tau isoforms (splicing mutations), both leading to accumulation of hyperphosphorylated filamentous tau protein. Following a genetic screening of patients affected by frontotemporal lobar degeneration, we identified 2 MAPT mutations, V363I and V363A, leading to atypical clinical phenotypes, such as posterior cortical atrophy. We investigated in vitro features of the recombinant mutated tau isoforms and revealed unusual functional and structural characteristics such as an increased ability to promote microtubule polymerization and a tendency to form oligomeric instead of filamentous aggregates. Thus, we disclosed a greater than expected complexity of abnormal features of mutated tau isoforms. Overall our findings suggest a high probability that these mutations are pathogenic.

  13. Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy.

    Science.gov (United States)

    Spiegel, Ronen; Saada, Ann; Halvardson, Jonatan; Soiferman, Devorah; Shaag, Avraham; Edvardson, Simon; Horovitz, Yoseph; Khayat, Morad; Shalev, Stavit A; Feuk, Lars; Elpeleg, Orly

    2014-07-01

    Isolated metabolic myopathies encompass a heterogeneous group of disorders, with mitochondrial myopathies being a subgroup, with depleted skeletal muscle energy production manifesting either by recurrent episodes of myoglobinuria or progressive muscle weakness. In this study, we investigated the genetic cause of a patient from a consanguineous family who presented with adolescent onset autosomal recessive mitochondrial myopathy. Analysis of enzyme activities of the five respiratory chain complexes in our patients' skeletal muscle showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III and mitochondrial aconitase. We employed exome sequencing combined with homozygosity mapping to identify a homozygous mutation, c.1A>T, in the FDX1L gene, which encodes the mitochondrial ferredoxin 2 (Fdx2) protein. The mutation disrupts the ATG initiation translation site resulting in severe reduction of Fdx2 content in the patient muscle and fibroblasts mitochondria. Fdx2 is the second component of the Fe-S cluster biogenesis machinery, the first being IscU that is associated with isolated mitochondrial myopathy. We suggest adding genetic analysis of FDX1L in cases of mitochondrial myopathy especially when associated with reduced activity of the respiratory chain complexes I, II and III.

  14. Case of Small Vessel Disease Associated with COL4A1 Mutations following Trauma

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    Joao McONeil Plancher

    2015-06-01

    Full Text Available With this case report, we would like to heighten the awareness of clinicians about COL4A1 as a single-gene disorder causing cerebral small vessel disease and describe a previously unreported pathogenic missense substitution in COL4A1 (p.Gly990Val and a new clinical presentation. We identified a heterozygous putatively pathogenic mutation of COL4A1 in a 50-year-old female with a history of congenital cataracts and glaucoma who presented with multiple diffusion-positive infarcts and areas of contrast enhancement following mild head trauma. We believe that this presentation of multiple areas of acute brain and vascular injury in the setting of mild head trauma is a new manifestation of this genetic disorder. Imaging findings of multiple acute infarcts and regions of contrast enhancement with associated asymptomatic old deep microhemorrhages and leukomalacia in adults after head trauma should raise a high suspicion for a COL4A1 genetic disorder. Radiographic patterns of significant leukoaraiosis and deep microhemorrhages can also be seen in patients with long-standing vasculopathy associated with hypertension, which our patient lacked. Our findings demonstrate the utility of genetic screening for COL4A1 mutations in young patients who have small vessel vasculopathy on brain imaging but who do not have significant cardiovascular risk factors.

  15. Cerebral venous and sinus thrombosis and thrombophilic mutations in Western Iran: association with factor V Leiden.

    Science.gov (United States)

    Rahimi, Zohreh; Mozafari, Hadi; Bigvand, Amir Hossein Amiri; Doulabi, Reza Mohammad; Vaisi-Raygani, Asad; Afshari, Dariush; Razazian, Nazanin; Rezaei, Mansour

    2010-08-01

    The present study aimed at investigating the prevalence of factor V Leiden G1691A, prothrombin G20210A, and MTHFR C677T in cerebral venous and sinus thrombosis (CVST) patients and their possible association with CVST in Western Iran. A total of 24 CVST patients with the mean age of 37.1 +/- 11.7 years and 100 sex- and age-matched healthy individuals from Kermanshah Province of Iran with ethnic background of Kurd were studied for factor V Leiden G1691A, prothrombin G20210A and MTHFR C677T by PCR-RFLP method using Mnl I, Hind III, and Hinf I restriction enzymes, respectively. Prevalence of factor V Leiden was 16.7% in patients and 2% in control group. A significant association was found between factor V Leiden mutation and CVST with odds ratio (OR) of 9.8 (95% confidence intervals [CI] 1.68-57.2, P = .01). No prothrombin G20210A was found among patients. In patients, MTHFR C677T tended to be higher (58.3%) compared to control (44%), OR of 1.8 (95% CI 0.73-4.5, P = .2). Our study for the first time has determined the prevalence of inherited thrombophilia in a homogenous ethnic group of CVST patients and suggests that factor V Leiden, and not the prothrombin gene mutation is a risk factor for CVST in Western Iran.

  16. Biallelic Mutations in LIPT2 Cause a Mitochondrial Lipoylation Defect Associated with Severe Neonatal Encephalopathy.

    Science.gov (United States)

    Habarou, Florence; Hamel, Yamina; Haack, Tobias B; Feichtinger, René G; Lebigot, Elise; Marquardt, Iris; Busiah, Kanetee; Laroche, Cécile; Madrange, Marine; Grisel, Coraline; Pontoizeau, Clément; Eisermann, Monika; Boutron, Audrey; Chrétien, Dominique; Chadefaux-Vekemans, Bernadette; Barouki, Robert; Bole-Feysot, Christine; Nitschke, Patrick; Goudin, Nicolas; Boddaert, Nathalie; Nemazanyy, Ivan; Delahodde, Agnès; Kölker, Stefan; Rodenburg, Richard J; Korenke, G Christoph; Meitinger, Thomas; Strom, Tim M; Prokisch, Holger; Rotig, Agnes; Ottolenghi, Chris; Mayr, Johannes A; de Lonlay, Pascale

    2017-08-03

    Lipoate serves as a cofactor for the glycine cleavage system (GCS) and four 2-oxoacid dehydrogenases functioning in energy metabolism (α-oxoglutarate dehydrogenase [α-KGDHc] and pyruvate dehydrogenase [PDHc]), or amino acid metabolism (branched-chain oxoacid dehydrogenase, 2-oxoadipate dehydrogenase). Mitochondrial lipoate synthesis involves three enzymatic steps catalyzed sequentially by lipoyl(octanoyl) transferase 2 (LIPT2), lipoic acid synthetase (LIAS), and lipoyltransferase 1 (LIPT1). Mutations in LIAS have been associated with nonketotic hyperglycinemia-like early-onset convulsions and encephalopathy combined with a defect in mitochondrial energy metabolism. LIPT1 deficiency spares GCS deficiency and has been associated with a biochemical signature of combined 2-oxoacid dehydrogenase deficiency leading to early death or Leigh-like encephalopathy. We report on the identification of biallelic LIPT2 mutations in three affected individuals from two families with severe neonatal encephalopathy. Brain MRI showed major cortical atrophy with white matter abnormalities and cysts. Plasma glycine was mildly increased. Affected individuals' fibroblasts showed reduced oxygen consumption rates, PDHc, α-KGDHc activities, leucine catabolic flux, and decreased protein lipoylation. A normalization of lipoylation was observed after expression of wild-type LIPT2, arguing for LIPT2 requirement in intramitochondrial lipoate synthesis. Lipoic acid supplementation did not improve clinical condition nor activities of PDHc, α-KGDHc, or leucine metabolism in fibroblasts and was ineffective in yeast deleted for the orthologous LIP2. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  17. Furthering the link between the sarcomere and primary cardiomyopathies: restrictive cardiomyopathy associated with multiple mutations in genes previously associated with hypertrophic or dilated cardiomyopathy.

    Science.gov (United States)

    Caleshu, Colleen; Sakhuja, Rahul; Nussbaum, Robert L; Schiller, Nelson B; Ursell, Philip C; Eng, Celeste; De Marco, Teresa; McGlothlin, Dana; Burchard, Esteban González; Rame, J Eduardo

    2011-09-01

    Mutations in genes that encode components of the sarcomere are well established as the cause of hypertrophic and dilated cardiomyopathies. Sarcomere genes, however, are increasingly being associated with other cardiomyopathies. One phenotype more recently recognized as a disease of the sarcomere is restrictive cardiomyopathy (RCM). We report on two patients with RCM associated with multiple mutations in sarcomere genes not previously associated with RCM. Patient 1 presented with NYHA Class III/IV heart failure at 22 years of age. She was diagnosed with RCM and advanced heart failure requiring heart transplantation. Sequencing of sarcomere genes revealed previously reported homozygous p.Glu143Lys mutations in MYL3, and a novel heterozygous p.Gly57Glu mutation in MYL2. The patient's mother is a double heterozygote for these mutations, with no evidence of cardiomyopathy. Patient 2 presented at 35 years of age with volume overload while hospitalized for oophorectomy. She was diagnosed with RCM and is being evaluated for heart transplantation. Sarcomere gene sequencing identified homozygous p.Asn279His mutations in TPM1. The patient's parents are consanguineous and confirmed heterozygotes. Her father was diagnosed with HCM at 42 years of age. This is the first report of mutations in TPM1, MYL3, and MYL2 associated with primary, non-hypertrophied RCM. The association of more sarcomere genes with RCM provides further evidence that mutations in the various sarcomere genes can cause different cardiomyopathy phenotypes. These cases also contribute to the growing body of evidence that multiple mutations have an additive effect on the severity of cardiomyopathies.

  18. Association of Telomerase Reverse Transcriptase Promoter Mutations with the Prognosis of Glioma Patients: a Meta-Analysis.

    Science.gov (United States)

    Wang, Xiaogang; Li, Xiaoming; Xu, Feng; Zhang, Youqian; Liu, Hongwei; Tao, Yingqun

    2016-05-01

    Previous studies have found that telomerase reverse transcriptase (TERT) has vital roles in the development of malignant diseases including glioma. The occurrence of TERT promoter mutations in gliomas is frequent. So far, several studies on the association between TERT promoter mutations and prognosis of gliomas had been published, but the conclusion was still not uncertain. The aim of the present meta-analysis was to assess the association between TERT promoter mutations and survival of glioma patients by pooling data from published studies. PubMed, Embase, and Web of Science were searched for articles on the association between TERT promoter mutations and survival of glioma patients until June 30, 2015. Hazard ratios (HR) and the 95% confidence intervals (CIs) were utilized to analyze the prognosis of glioma patients with TERT promoter mutations. Heterogeneity of included studies was assessed using Cochrane's Q test and I (2) method. Eleven studies with a total of 3,444 glioma patients were finally included into the meta-analysis. Nine studies reported the HRs adjusting for other confounding factors. Meta-analysis of total 11 studies suggested that TERT promoter mutations were significantly associated with worse prognosis of patients with gliomas (HR = 2.07, 95% CI = 1.58-2.71, P promoter mutations were independently associated with worse prognosis of patients with gliomas (HR = 2.28, 95% CI = 1.72-3.01, P promoter mutation is a promising biomarker for predicting worse prognosis for patients with gliomas. More prospective well-designed cohort studies are needed to further validate its prognostic role in gliomas.

  19. BRAFV600E mutation and its association with clinicopathological features of colorectal cancer: a systematic review and meta-analysis.

    Directory of Open Access Journals (Sweden)

    Dong Chen

    Full Text Available BACKGROUND: Colorectal cancer (CRC is a heterogeneous disease with multiple underlying causative genetic mutations. The B-type Raf proto-oncogene (BRAF plays an important role in the mitogen-activated protein kinase (MAPK signaling cascade during CRC. The presence of BRAFV600E mutation can determine the response of a tumor to chemotherapy. However, the association between the BRAFV600E mutation and the clinicopathological features of CRC remains controversial. We performed a systematic review and meta-analysis to estimate the effect of BRAFV600E mutation on the clinicopathological characteristics of CRC. METHODS: We identified studies that examined the effect of BRAFV600E mutation on CRC within the PubMed, ISI Science Citation Index, and Embase databases. The effect of BRAFV600E on outcome parameters was estimated by odds ratios (ORs with 95% confidence intervals (CIs for each study using a fixed effects or random effects model. RESULTS: 25 studies with a total of 11,955 CRC patients met inclusion criteria. The rate of BRAFV600 was 10.8% (1288/11955. The BRAFV600E mutation in CRC was associated with advanced TNM stage, poor differentiation, mucinous histology, microsatellite instability (MSI, CpG island methylator phenotype (CIMP. This mutation was also associated with female gender, older age, proximal colon, and mutL homolog 1 (MLH1 methylation. CONCLUSIONS: This meta-analysis demonstrated that BRAFV600E mutation was significantly correlated with adverse pathological features of CRC and distinct clinical characteristics. These data suggest that BRAFV600E mutation could be used to supplement standard clinical and pathological staging for the better management of individual CRC patients, and could be considered as a poor prognostic marker for CRC.

  20. Mutations in the KDM5C ARID Domain and Their Plausible Association with Syndromic Claes-Jensen-Type Disease

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    Yunhui Peng

    2015-11-01

    Full Text Available Mutations in KDM5C gene are linked to X-linked mental retardation, the syndromic Claes-Jensen-type disease. This study focuses on non-synonymous mutations in the KDM5C ARID domain and evaluates the effects of two disease-associated missense mutations (A77T and D87G and three not-yet-classified missense mutations (R108W, N142S, and R179H. We predict the ARID domain’s folding and binding free energy changes due to mutations, and also study the effects of mutations on protein dynamics. Our computational results indicate that A77T and D87G mutants have minimal effect on the KDM5C ARID domain stability and DNA binding. In parallel, the change in the free energy unfolding caused by the mutants A77T and D87G were experimentally measured by urea-induced unfolding experiments and were shown to be similar to the in silico predictions. The evolutionary conservation analysis shows that the disease-associated mutations are located in a highly-conserved part of the ARID structure (N-terminal domain, indicating their importance for the KDM5C function. N-terminal residues’ high conservation suggests that either the ARID domain utilizes the N-terminal to interact with other KDM5C domains or the N-terminal is involved in some yet unknown function. The analysis indicates that, among the non-classified mutations, R108W is possibly a disease-associated mutation, while N142S and R179H are probably harmless.

  1. Sex-specific incidence of EGFR mutation and its association with age and obesity in lung adenocarcinomas: a retrospective analysis.

    Science.gov (United States)

    Kim, Hye-Ryoun; Kim, Seo Yun; Kim, Cheol Hyeon; Yang, Sung Hyun; Lee, Jae Cheol; Choi, Chang-Min; Na, Im Il

    2017-07-08

    Age and obesity are well-known risk factors for various cancers, but the potential roles of age and obesity in lung cancer, especially in those with activating EGFR mutations, have not been thoroughly evaluated. The aim of this retrospective study is to evaluate the associations between the sex-specific incidence of EGFR mutations and age and obesity. We conducted a retrospective study based on the data from 1378 lung adenocarcinoma cases. The degree of obesity was categorized by body mass index (BMI). The associations between EGFR mutational status and clinical factors, including stage, smoking history, age group (≤45 years, 46-55, 56-65 and >65), and BMI group (obesity (adjusted OR for BMI group = 1.23, p-trend = 0.04). In contrast, in women, the incidence of EGFR mutation was positively associated with age (adjusted OR for age group = 1.19, p-trend = 0.02). However, the incidence of EGFR mutation was not statistically associated with obesity (adjusted OR for BMI group = 1.03, p-trend = 0.76). Our data suggests that age and obesity may contribute to the sex-specific incidence of EGFR mutation in lung adenocarcinoma in different manners.

  2. Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort.

    LENUS (Irish Health Repository)

    Davidson, G L

    2012-08-01

    The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1\\/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1\\/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN.

  3. Analysis of embCAB mutations associated with ethambutol resistance in multidrug-resistant mycobacterium tuberculosis isolates from China.

    Science.gov (United States)

    Zhao, Li-Li; Sun, Qing; Liu, Hai-Can; Wu, Xiao-Cui; Xiao, Tong-Yang; Zhao, Xiu-Qin; Li, Gui-Lian; Jiang, Yi; Zeng, Chun-Yan; Wan, Kang-Lin

    2015-04-01

    Ethambutol (EMB) plays a pivotal role in the chemotherapy of drug-resistant tuberculosis (TB), including multidrug-resistant tuberculosis (MDR-TB). Resistance to EMB is considered to be caused by mutations in the embCAB operon (embC, embA, and embB). In this study, we analyzed the embCAB mutations among 139 MDR-TB isolates from China and found a possible association between embCAB operon mutation and EMB resistance. Our data indicate that 56.8% of MDR-TB isolates are resistant to EMB, and 82.2% of EMB-resistant isolates belong to the Beijing family. Overall, 110 (79.1%) MDR-TB isolates had at least one mutation in the embCAB operon. The majority of mutations were present in the embB gene and the embA upstream region, which also displayed significant correlations with EMB resistance. The most common mutations occurred at codon 306 in embB (embB306), followed by embB406, embA(-16), and embB497. Mutations at embB306 were associated with EMB resistance. DNA sequencing of embB306-497 was the best strategy for detecting EMB resistance, with 89.9% sensitivity, 58.3% specificity, and 76.3% accuracy. Additionally, embB306 had limited value as a candidate predictor for EMB resistance among MDR-TB infections in China.

  4. An homozygous mutation in KCNK3 is associated with an aggressive form of hereditary pulmonary arterial hypertension.

    Science.gov (United States)

    Navas Tejedor, P; Tenorio Castaño, J; Palomino Doza, J; Arias Lajara, P; Gordo Trujillo, G; López Meseguer, M; Román Broto, A; Lapunzina Abadía, P; Escribano Subía, P

    2017-03-01

    Pulmonary arterial hypertension (PAH) is a rare devastating disease characterized by a high genetic heterogeneity with several related genes recently described, including BMPR2,TBX4 and KCNK3. The association between KCNK3 and PAH has been recently identified, but the prognosis and phenotype associated with these mutations have been poorly described. We studied a series of 136 idiopathic and hereditary PAH Spanish patients for BMPR2, TBX4 and KCNK3 mutations. We report the results of KCNK3 in which we were able to describe two new mutations (p.Gly106Arg and p.Leu214Arg) in three patients. The first one was found in a patient belonging to a consanguineous Romani family, who carried a homozygous mutation in KCNK3 and developed a severe and early form of the disease. To the best of our knowledge, this is the first time that a homozygous mutation in KCNK3 is reported in a PAH patient. The second one was found in a patient who presented at the young adult age a severe form of the disease. The present report supports the contribution of KCNK3 mutations to the genetic etiology of PAH and strongly suggests that mutations in KCNK3 follow incomplete dominance with worsening of the clinical features in homozygous patients.

  5. Association of hTcf-4 gene expression and mutation with clinicopathological characteristics of hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Ying Jiang; Xin-Da Zhou; Yin-Kun Liu; Xin Wu; Xiao-Wu Huang

    2002-01-01

    AIM: Hepatocellular carcinoma(HCC) is a significant healthproblem in China. But the molecular mechanisms of HCCremains unclear. APC/β-Catenin/Tcf signaling pathway, alsoknown as Wnt pathway, plays a critical role in thedevelopment and oncogenesis. As little is known about thealteration of human T-cell transcription factor-4 (hTcf-4) genein HCC, it is of interest to study the expression and mutationof hTcf-4 gene in HCC and the relationship between hTcf-4gene and progression of HCC.METHODS: Reverse transcription-polymerase chain reaction(RT-PCR) method was used to detect the expression of hTcf-4 mRNA in 32 HCC and para-cancerous tissues and 5 normalliver tissues. PCR-single strand conformation polymorphism(PCR-SSCP) method was used to detect the mutation ofhTcf-4 exons 1, 4, 9 and 15 in HCC. The correlation ofexpression and mutation of the hTcf-4 gene withclinicopathological characteristics of HCC was also analyzed.RESULTS: RT-PCR showed that the expression rate of hTcf-4 mRNA in HCC, para-cancerous tissues and normal livertissues was 90.6 %, 71.9 % and 80 %, respectively. Thegene expression level in tumor was 0.71±0.13, much higherthan that in para-cancerous liver 0.29±0.05 and normal liver0.26±0.05 (P<0.001), although there was no significantdifference in gene expression level between para-canceroustissues and normal liver (P>0.05). Furthermore, hTcf-4 geneexpression was closely associated with tumor capsule statusand intrahepatic metastasis of HCC. On SSCP, 2 of 32 casesof HCC (6.25 %) displayed characteristic mutational mobilityshifts in exon 15 of the hTcf-4 gene. No abnormal shiftingbands were observed in para-cancerous tissues.CONCLUSION: The high expression level of hTcf-4 in HCC,especially in tumors with metastasis, suggests that the over-expression of hTcf-4 gene may be closely associated withdevelopment and progression of HCC, but the mutation ofthis gene seemed to play less important role in this respect.

  6. [The gene mutation screening of a family with congenital fibrosis of the extraocular muscles associated with corpus callosum agenesis].

    Science.gov (United States)

    Zhang, Jun-tao; Zhou, Lian-hong; Zha, Yun-fei; Liu, Tian; Tian, Ming-xing; Yuan, Jing; Xing, Yi-qiao

    2013-07-01

    To identify TUBB3 gene mutations in a Chinese family with congenital fibrosis of the extraocular muscle associated with corpus callosum agenesis. We have found a family with CFEOM associated with corpus callosum agenesis, including 4 affected individuals in three generations of 11 familial members. 4 affected individuals were sequenced by direct TUBB3 sequencing, 4 unaffected individuals in the family and 100 cases of unrelated normal person as a control. This family is in line with Mendelian autosomal dominant inheritance. Clinical manifestations belongs to CFEOM3. All affected individuals were detected with TUBB3 c.1249G > A mutation, the mutation is in exon 4, resulting in wild-type gene encoding the Aspartic acid ( Asp or D ) replaced .by Asparagine (Asn or N ). Our study supports that TUBB3 gene mutation c.1249G > A (p. Asp417Asn), is the underlying molecular pathogenesis of this family with CFEOM3.

  7. Association of FTO Mutations with Risk and Survival of Breast Cancer in a Chinese Population

    Directory of Open Access Journals (Sweden)

    Xianxu Zeng

    2015-01-01

    Full Text Available Recently, several studies have reported associations between fat mass and obesity-associated (FTO gene mutations and cancer susceptibility. But little is known about their association with risk and survival of breast cancer in Chinese population. The aim of this study is to examine whether cancer-related FTO polymorphisms are associated with risk and survival of breast cancer and BMI levels in controls in a Chinese population. We genotyped six FTO polymorphisms in a case-control study, including 537 breast cancer cases and 537 controls. FTO rs1477196 AA genotype had significant decreased breast cancer risk [odds ratio (OR = 0.54, 95% confidence interval (CI: 0.34–0.86] compared to GG genotype, and this association was only found in women with BMI < 24 kg/m2 (OR = 0.41, 95% CI: 0.22–0.76; and rs16953002 AA genotype conferred significant increased breast cancer risk (OR = 1.80, 95% CI: 1.23–2.63 compared to GG genotype. Haplotype analysis showed that FTO TAC haplotype (rs9939609-rs1477196-rs1121980 had significant reduced breast cancer risk (OR = 0.76, 95% CI: 0.62–0.93 compared with TGC haplotype. But we failed to find any association between FTO polymorphisms and breast cancer survival. These findings suggest that variants in FTO gene may influence breast cancer susceptibility.

  8. In utero copper treatment for Menkes disease associated with a severe ATP7A mutation.

    Science.gov (United States)

    Haddad, Marie Reine; Macri, Charles J; Holmes, Courtney S; Goldstein, David S; Jacobson, Beryl E; Centeno, Jose A; Popek, Edwina J; Gahl, Willam A; Kaler, Stephen G

    2012-09-01

    Menkes disease is a lethal X-linked recessive neurodegenerative disorder of copper transport caused by mutations in ATP7A, which encodes a copper-transporting ATPase. Early postnatal treatment with copper injections often improves clinical outcomes in affected infants. While Menkes disease newborns appear normal neurologically, analyses of fetal tissues including placenta indicate abnormal copper distribution and suggest a prenatal onset of the metal transport defect. In an affected fetus whose parents found termination unacceptable and who understood the associated risks, we began in utero copper histidine treatment at 31.5 weeks gestational age. Copper histidine (900 μg per dose) was administered directly to the fetus by intramuscular injection (fetal quadriceps or gluteus) under ultrasound guidance. Percutaneous umbilical blood sampling enabled serial measurement of fetal copper and ceruloplasmin levels that were used to guide therapy over a four-week period. Fetal copper levels rose from 17 μg/dL prior to treatment to 45 μg/dL, and ceruloplasmin levels from 39 mg/L to 122 mg/L. After pulmonary maturity was confirmed biochemically, the baby was delivered at 35.5 weeks and daily copper histidine therapy (250 μg sc b.i.d.) was begun. Despite this very early intervention with copper, the infant showed hypotonia, developmental delay, and electroencephalographic abnormalities and died of respiratory failure at 5.5 months of age. The patient's ATP7A mutation (Q724H), which severely disrupted mRNA splicing, resulted in complete absence of ATP7A protein on Western blots. These investigations suggest that prenatally initiated copper replacement is inadequate to correct Menkes disease caused by severe loss-of-function mutations, and that postnatal ATP7A gene addition represents a rational approach in such circumstances.

  9. Genetic Testing for TMEM154 Mutations Associated with Lentivirus Susceptibility in Sheep

    Science.gov (United States)

    Petrik, Dustin T.; Simpson, Barry; Kijas, James W.; Clawson, Michael L.; Chitko-McKown, Carol G.; Harhay, Gregory P.; Leymaster, Kreg A.

    2013-01-01

    In sheep, small ruminant lentiviruses cause an incurable, progressive, lymphoproliferative disease that affects millions of animals worldwide. Known as ovine progressive pneumonia virus (OPPV) in the U.S., and Visna/Maedi virus (VMV) elsewhere, these viruses reduce an animal’s health, productivity, and lifespan. Genetic variation in the ovine transmembrane protein 154 gene (TMEM154) has been previously associated with OPPV infection in U.S. sheep. Sheep with the ancestral TMEM154 haplotype encoding glutamate (E) at position 35, and either form of an N70I variant, were highly-susceptible compared to sheep homozygous for the K35 missense mutation. Our current overall aim was to characterize TMEM154 in sheep from around the world to develop an efficient genetic test for reduced susceptibility. The average frequency of TMEM154 E35 among 74 breeds was 0.51 and indicated that highly-susceptible alleles were present in most breeds around the world. Analysis of whole genome sequences from an international panel of 75 sheep revealed more than 1,300 previously unreported polymorphisms in a 62 kb region containing TMEM154 and confirmed that the most susceptible haplotypes were distributed worldwide. Novel missense mutations were discovered in the signal peptide (A13V) and the extracellular domains (E31Q, I74F, and I102T) of TMEM154. A matrix-assisted laser desorption/ionization–time-of flight mass spectrometry (MALDI-TOF MS) assay was developed to detect these and six previously reported missense and two deletion mutations in TMEM154. In blinded trials, the call rate for the eight most common coding polymorphisms was 99.4% for 499 sheep tested and 96.0% of the animals were assigned paired TMEM154 haplotypes (i.e., diplotypes). The widespread distribution of highly-susceptible TMEM154 alleles suggests that genetic testing and selection may improve the health and productivity of infected flocks. PMID:23408992

  10. Genetic testing for TMEM154 mutations associated with lentivirus susceptibility in sheep.

    Directory of Open Access Journals (Sweden)

    Michael P Heaton

    Full Text Available In sheep, small ruminant lentiviruses cause an incurable, progressive, lymphoproliferative disease that affects millions of animals worldwide. Known as ovine progressive pneumonia virus (OPPV in the U.S., and Visna/Maedi virus (VMV elsewhere, these viruses reduce an animal's health, productivity, and lifespan. Genetic variation in the ovine transmembrane protein 154 gene (TMEM154 has been previously associated with OPPV infection in U.S. sheep. Sheep with the ancestral TMEM154 haplotype encoding glutamate (E at position 35, and either form of an N70I variant, were highly-susceptible compared to sheep homozygous for the K35 missense mutation. Our current overall aim was to characterize TMEM154 in sheep from around the world to develop an efficient genetic test for reduced susceptibility. The average frequency of TMEM154 E35 among 74 breeds was 0.51 and indicated that highly-susceptible alleles were present in most breeds around the world. Analysis of whole genome sequences from an international panel of 75 sheep revealed more than 1,300 previously unreported polymorphisms in a 62 kb region containing TMEM154 and confirmed that the most susceptible haplotypes were distributed worldwide. Novel missense mutations were discovered in the signal peptide (A13V and the extracellular domains (E31Q, I74F, and I102T of TMEM154. A matrix-assisted laser desorption/ionization-time-of flight mass spectrometry (MALDI-TOF MS assay was developed to detect these and six previously reported missense and two deletion mutations in TMEM154. In blinded trials, the call rate for the eight most common coding polymorphisms was 99.4% for 499 sheep tested and 96.0% of the animals were assigned paired TMEM154 haplotypes (i.e., diplotypes. The widespread distribution of highly-susceptible TMEM154 alleles suggests that genetic testing and selection may improve the health and productivity of infected flocks.

  11. Hypothesis: Obesity Is Associated with a Lower Mutation Threshold in Colon Cancer.

    Science.gov (United States)

    Bordonaro, Michael; Lazarova, Darina

    2015-01-01

    Neoplastic progression requires accumulation of several mutations (mutation threshold). We hypothesize that obesity raises the risk of microsatellite stable (MSS) colon cancer (CC) at least in part by decreasing the mutation threshold. Thus, we posit that obese patients require fewer mutations, particularly driver mutations, compared to their normal BMI counterparts. Further, we suggest that the reduced number of required mutations in obese patients could be due to several factors, including the high levels of cytokines that accompany obesity. Cytokine-activated ERK, AKT, and JAK/STAT signaling could synergize with CC-initiating mutations to promote intestinal neoplastic development. Therefore, driver mutations that induce these specific pathways may not be "required" for neoplastic development in obesity; alteration in cell signaling consequent to obesity can substitute for some driver mutations in neoplastic progression. This hypothesis is supported by preliminary analyses of data from The Cancer Genome Atlas (TCGA). Thus, we observed that, compared to normal weight patients, cancer genomes of obese MSS CC patients exhibit fewer somatic mutations, and correspondingly lower numbers of mutations in driver genes (P = 0.026).The most striking observation was the lower number of KRAS mutations detected in patients with high body-mass index (BMI). These intriguing observations require further validation with increased number of patients, taking into account all possible confounding factors. If the hypothesis is confirmed, future studies should also address several possible explanations for the observed lower mutation threshold in obese MSS CC patients.

  12. DYNC1H1 mutations associated with neurological diseases compromise processivity of dynein-dynactin-cargo adaptor complexes.

    Science.gov (United States)

    Hoang, Ha Thi; Schlager, Max A; Carter, Andrew P; Bullock, Simon L

    2017-02-28

    Mutations in the human DYNC1H1 gene are associated with neurological diseases. DYNC1H1 encodes the heavy chain of cytoplasmic dynein-1, a 1.4-MDa motor complex that traffics organelles, vesicles, and macromolecules toward microtubule minus ends. The effects of the DYNC1H1 mutations on dynein motility, and consequently their links to neuropathology, are not understood. Here, we address this issue using a recombinant expression system for human dynein coupled to single-molecule resolution in vitro motility assays. We functionally characterize 14 DYNC1H1 mutations identified in humans diagnosed with malformations in cortical development (MCD) or spinal muscular atrophy with lower extremity predominance (SMALED), as well as three mutations that cause motor and sensory defects in mice. Two of the human mutations, R1962C and H3822P, strongly interfere with dynein's core mechanochemical properties. The remaining mutations selectively compromise the processive mode of dynein movement that is activated by binding to the accessory complex dynactin and the cargo adaptor Bicaudal-D2 (BICD2). Mutations with the strongest effects on dynein motility in vitro are associated with MCD. The vast majority of mutations do not affect binding of dynein to dynactin and BICD2 and are therefore expected to result in linkage of cargos to dynein-dynactin complexes that have defective long-range motility. This observation offers an explanation for the dominant effects of DYNC1H1 mutations in vivo. Collectively, our results suggest that compromised processivity of cargo-motor assemblies contributes to human neurological disease and provide insight into the influence of different regions of the heavy chain on dynein motility.

  13. [P1208fs mutation in the cardiac myosin binding protein C is associated with hypertrophic cardiomyopathy in a Chinese pedigree].

    Science.gov (United States)

    Li, J; Liu, L W; Na, L S; Zuo, L; Qi, W; Liu, Y; Shao, H; Ma, Z L; Wang, L F

    2016-04-24

    To identify the potential mutations in a Chinese pedigree with hypertrophic cardiomyopathy (HCM), and to analyze the genotype-phenotype relationship in this pedigree. Clinical history and physical examinations, electrocardiography (ECG), echocardiography (UCG), cardiac magnetic resonance (CMR) data were obtained from 10 members of a three-generation Chinese family with HCM. A total of 96 genes related to hereditary cardiomyopathy were detected by exon and boarding intron analyses in the proband using second-generation sequencing. Mutations identified in the proband were confirmed by bi-directional Sanger sequencing in the rest 9 family members and 300 healthy controls. Three mutations, including MYBPC3-P1208fs, ANK2-H556R and ANK2-P1974H, were identified in this pedigree. MYBPC3-P1208fs gene mutation was detected in 3 family members (proband, his mother and son), while this mutation was not detected in the rest family members. HCM was diagnosed in the proband and his mother by ECG, UCG and CMR. Son of the proband demonstrated early phenotype of HCM: although UCG and CMR were normal, ECG showed sinus bradycardia and paroxysmal supraventricular arrhythmias as well as ST segment changes. The onset age of HCM diagnosis of the proband and his mother was 42 and 50 years old, presented with palpitation and chest pain, and myocardial fibrosis sign in CMR. Furthermore, we found that left ventricular myocardial fibrosis is related to ECG changes (increasing r wave, ST segment change) in the proband and his mother. No HCM phenotype was evidenced in the 7 family members carrying ANK2-H556R and ANK2-P1974H mutations. Our results show that MYBPC3-P1208fs gene mutation is associated HCM phenotype in this Chinses pedigree. This mutation is associated with myocardial fibrosis and ST changes in HCM phenotype in this pedigree while ANK2-H556R and ANK2-P1974H mutations are not related to HCM phenotype in this family.

  14. Review of advanced control rooms: Methodological considerations for the use of HFE guidelines

    Energy Technology Data Exchange (ETDEWEB)

    O`Hara, J.M.

    1994-03-01

    Control rooms for advanced nuclear power plants use advanced human-system interface (HSI) technologies that may have significant implications for plant safety in that they will affect the operator`s overall role in the system and the ways in which operators interact with the system. The US Nuclear Regulatory Commission (NRC) reviews HSIs to ensure that they are designed to accepted human factors engineering (HFE) principles. The principal review guidance, however, is more than ten-years old (US NRC, 1981). Accordingly, an Advanced HSI Design Review Guideline (DRG) was developed to provide criteria for these reviews. The DRG contains seven major sections: Information Display, User-System Interaction, Process Control and Input Devices, Alarms, Analysis and Decision Aids, Inter-Personnel Communication, and Workplace Design (see O`Hara & Brown, 1993). The purpose of this paper is to describe the methodology for DRG use.

  15. Lack of association between mutation size and cognitive/behavior deficits in fragile X males: A brief report

    Energy Technology Data Exchange (ETDEWEB)

    Fisch, G.S. [SUNY/Health Science Center and Kings County Hospital Center, Brooklyn, NY (United States); Carpenter, N. [Chapman Institute of Medical Genetics, Tulsa, OK (United States); Simensen, R. [Greenwood Genetics Center, SC (United States)] [and others

    1996-08-09

    Previously, researchers reported molecular-neurobehavioral or molecular-cognitive associations in individuals with fra(X) (fragile X) mutation. However, not all investigators have noted molecular-behavioral relationships. Consequently, we examined prospectively 30 fra(X) males age 3-15 years from four testing sites to determine whether there was a relationship between mutation size and degree of either cognitive or adaptive behavior deficit. To measure cognitive abilities, all individuals were administered the Stanford-Binet (4th edition) IQ test. To evaluate adaptive behavior (DQ) skills, all individuals were assessed using the Vineland Adaptive Behavior Scale. To determine fra(X) status, genomic DNA from all individuals was extracted and digested with EcoRI and EagI restriction enzymes. Southern blots were prepared and hybridized with the pE5.1 probe. The Pearson correlation coefficient between full mutation size and composite IQ score revealed a non-significant, near-zero association (r = 0.06; P > .76). The Pearson coefficient between mutation size and DQ also showed a non-significant, near-zero association (r = 0.06; P >.73). We conclude that while fra(X) mutation produces cognitive and behavior deficits in males who inherit the defective gene, there is no relationship between mutation size and degree of deficit. 14 refs., 2 figs.

  16. Effects of FSGS-associated mutations on the stability and function of myosin-1 in fission yeast

    Directory of Open Access Journals (Sweden)

    Jing Bi

    2015-08-01

    Full Text Available Point mutations in the human MYO1E gene, encoding class I myosin Myo1e, are associated with focal segmental glomerulosclerosis (FSGS, a primary kidney disorder that leads to end-stage kidney disease. In this study, we used a simple model organism, fission yeast Schizosaccharomyces pombe, to test the effects of FSGS-associated mutations on myosin activity. Fission yeast has only one class I myosin, Myo1, which is involved in actin patch assembly at the sites of endocytosis. The amino acid residues mutated in individuals with FSGS are conserved between human Myo1e and yeast Myo1, which allowed us to introduce equivalent mutations into yeast myosin and use the resulting mutant strains for functional analysis. Yeast strains expressing mutant Myo1 exhibited defects in growth and endocytosis similar to those observed in the myo1 deletion strain. These mutations also disrupted Myo1 localization to endocytic actin patches and resulted in mis-localization of Myo1 to eisosomes, linear membrane microdomains found in yeast cells. Although both mutants examined in this study exhibited loss of function, one of these mutants was also characterized by the decreased protein stability. Thus, using the yeast model system, we were able to determine that the kidney-disease-associated mutations impair myosin functional activity and have differential effects on protein stability.

  17. Penetrance of Hemochromatosis in HFE Genotypes Resulting in p.Cys282Tyr and p.[Cys282Tyr];[His63Asp] in the eMERGE Network.

    Science.gov (United States)

    Gallego, Carlos J; Burt, Amber; Sundaresan, Agnes S; Ye, Zi; Shaw, Christopher; Crosslin, David R; Crane, Paul K; Fullerton, S Malia; Hansen, Kris; Carrell, David; Kuivaniemi, Helena; Derr, Kimberly; de Andrade, Mariza; McCarty, Catherine A; Kitchner, Terrie E; Ragon, Brittany K; Stallings, Sarah C; Papa, Gabriella; Bochenek, Joseph; Smith, Maureen E; Aufox, Sharon A; Pacheco, Jennifer A; Patel, Vaibhav; Friesema, Elisha M; Erwin, Angelika Ludtke; Gottesman, Omri; Gerhard, Glenn S; Ritchie, Marylyn; Motulsky, Arno G; Kullo, Iftikhar J; Larson, Eric B; Tromp, Gerard; Brilliant, Murray H; Bottinger, Erwin; Denny, Joshua C; Roden, Dan M; Williams, Marc S; Jarvik, Gail P

    2015-10-01

    Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder associated with pathogenic HFE variants, most commonly those resulting in p.Cys282Tyr and p.His63Asp. Recommendations on returning incidental findings of HFE variants in individuals undergoing genome-scale sequencing should be informed by penetrance estimates of HH in unselected samples. We used the eMERGE Network, a multicenter cohort with genotype data linked to electronic medical records, to estimate the diagnostic rate and clinical penetrance of HH in 98 individuals homozygous for the variant coding for HFE p.Cys282Tyr and 397 compound heterozygotes with variants resulting in p.[His63Asp];[Cys282Tyr]. The diagnostic rate of HH in males was 24.4% for p.Cys282Tyr homozygotes and 3.5% for compound heterozygotes (p 50%; p = 0.003), serum ferritin levels (77.8% versus 33.3% with serum ferritin > 300 ng/ml; p = 0.006), and diabetes (44.7% versus 28.0%; p = 0.03). No differences were found in the prevalence of heart disease, arthritis, or liver disease, except for the rate of liver biopsy (10.9% versus 1.8% [p = 0.013] in males; 9.1% versus 2% [p = 0.035] in females). Given the higher rate of HH diagnosis than in prior studies, the high penetrance of iron overload, and the frequency of at-risk genotypes, in addition to other suggested actionable adult-onset genetic conditions, opportunistic screening should be considered for p.[Cys282Tyr];[Cys282Tyr] individuals with existing genomic data.

  18. Penetrance of Hemochromatosis in HFE Genotypes Resulting in p.Cys282Tyr and p.[Cys282Tyr];[His63Asp] in the eMERGE Network

    Science.gov (United States)

    Gallego, Carlos J.; Burt, Amber; Sundaresan, Agnes S.; Ye, Zi; Shaw, Christopher; Crosslin, David R.; Crane, Paul K.; Fullerton, S. Malia; Hansen, Kris; Carrell, David; Kuivaniemi, Helena; Derr, Kimberly; de Andrade, Mariza; McCarty, Catherine A.; Kitchner, Terrie E.; Ragon, Brittany K.; Stallings, Sarah C.; Papa, Gabriella; Bochenek, Joseph; Smith, Maureen E.; Aufox, Sharon A.; Pacheco, Jennifer A.; Patel, Vaibhav; Friesema, Elisha M.; Erwin, Angelika Ludtke; Gottesman, Omri; Gerhard, Glenn S.; Ritchie, Marylyn; Motulsky, Arno G.; Kullo, Iftikhar J.; Larson, Eric B.; Tromp, Gerard; Brilliant, Murray H.; Bottinger, Erwin; Denny, Joshua C.; Roden, Dan M.; Williams, Marc S.; Jarvik, Gail P.

    2015-01-01

    Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder associated with pathogenic HFE variants, most commonly those resulting in p.Cys282Tyr and p.His63Asp. Recommendations on returning incidental findings of HFE variants in individuals undergoing genome-scale sequencing should be informed by penetrance estimates of HH in unselected samples. We used the eMERGE Network, a multicenter cohort with genotype data linked to electronic medical records, to estimate the diagnostic rate and clinical penetrance of HH in 98 individuals homozygous for the variant coding for HFE p.Cys282Tyr and 397 compound heterozygotes with variants resulting in p.[His63Asp];[Cys282Tyr]. The diagnostic rate of HH in males was 24.4% for p.Cys282Tyr homozygotes and 3.5% for compound heterozygotes (p 50%; p = 0.003), serum ferritin levels (77.8% versus 33.3% with serum ferritin > 300 ng/ml; p = 0.006), and diabetes (44.7% versus 28.0%; p = 0.03). No differences were found in the prevalence of heart disease, arthritis, or liver disease, except for the rate of liver biopsy (10.9% versus 1.8% [p = 0.013] in males; 9.1% versus 2% [p = 0.035] in females). Given the higher rate of HH diagnosis than in prior studies, the high penetrance of iron overload, and the frequency of at-risk genotypes, in addition to other suggested actionable adult-onset genetic conditions, opportunistic screening should be considered for p.[Cys282Tyr];[Cys282Tyr] individuals with existing genomic data. PMID:26365338

  19. Isocitrate dehydrogenase-1 is mutated in inflammatory bowel disease-associated intestinal adenocarcinoma with low-grade tubuloglandular histology but not in sporadic intestinal adenocarcinoma.

    Science.gov (United States)

    Hartman, Douglas J; Binion, David; Regueiro, Miguel; Schraut, Wolfgang; Bahary, Nathan; Sun, Weijing; Nikiforova, Marina; Pai, Reetesh K

    2014-08-01

    The underlying molecular alterations in chronic idiopathic inflammatory bowel disease-associated intestinal adenocarcinoma remain largely unknown. Somatic IDH mutations are often seen in gliomas and myeloid leukemia but have also been recently reported in a subset of other neoplasms. We analyzed a series of intestinal adenocarcinomas with (n=23) and without (n=39) associated chronic idiopathic inflammatory bowel disease treated at our institution for IDH1 and IDH2 mutations and correlated the clinicopathologic findings with mutation status. Compared with intestinal adenocarcinomas not associated with inflammatory bowel disease, adenocarcinomas associated with inflammatory bowel disease more frequently demonstrated IDH mutations (13% vs. 0%, P=0.047). All IDH mutations were identified in IDH1 and resulted in substitution of arginine by cysteine at position 132 (p.R132C, c.394C>T). IDH1 mutations were frequently (66%) associated with concurrent KRAS mutations (p.G12D, c.35G>A). IDH1-mutated intestinal adenocarcinomas were seen in the setting of both Crohn disease and ulcerative colitis and were located in both the ileum and colon. Compared with IDH1-negative inflammatory bowel disease-associated adenocarcinoma, IDH1-positive adenocarcinomas more frequently demonstrated tubuloglandular histology (100% vs. 25%, P=0.032) and were more frequently associated with precursor lesions exhibiting serrated morphology (66% vs. 6%, P=0.034). IDH1 mutations were also identified in the precursor dysplastic lesions associated with IDH1-positive adenocarcinomas. In conclusion, we demonstrate that IDH1 mutations are occasionally identified in inflammatory bowel disease-associated intestinal adenocarcinoma but not in intestinal adenocarcinoma not associated with inflammatory bowel disease. In addition, IDH1-mutated intestinal adenocarcinoma is associated with a characteristic low-grade tubuloglandular histology and often harbors concurrent KRAS mutations. Identification of patients

  20. A frameshift mutation in GON4L is associated with proportionate dwarfism in Fleckvieh cattle.

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    Schwarzenbacher, Hermann; Wurmser, Christine; Flisikowski, Krzysztof; Misurova, Lubica; Jung, Simone; Langenmayer, Martin C; Schnieke, Angelika; Knubben-Schweizer, Gabriela; Fries, Ruedi; Pausch, Hubert

    2016-03-31

    Low birth weight and postnatal growth restriction are the most evident symptoms of dwarfism. Accompanying skeletal aberrations may compromise the general condition and locomotion of affected individuals. Several paternal half-sibs with a low birth weight and a small size were born in 2013 in the Fleckvieh cattle population. Affected calves were strikingly underweight at birth in spite of a normal gestation length and had craniofacial abnormalities such as elongated narrow heads and brachygnathia inferior. In spite of a normal general condition, their growth remained restricted during rearing. We genotyped 27 affected and 10,454 unaffected animals at 44,672 single nucleotide polymorphisms and performed association tests followed by homozygosity mapping, which allowed us to map the locus responsible for growth failure to a 1.85-Mb segment on bovine chromosome 3. Analysis of whole-genome re-sequencing data from one affected and 289 unaffected animals revealed a 1-bp deletion (g.15079217delC, rs723240647) in the coding region of the GON4L gene that segregated with the dwarfism-associated haplotype. We showed that the deletion induces intron retention and premature termination of translation, which can lead to a severely truncated protein that lacks domains that are likely essential to normal protein function. The widespread use of an undetected carrier bull for artificial insemination has resulted in a tenfold increase in the frequency of the deleterious allele in the female population. A frameshift mutation in GON4L is associated with autosomal recessive proportionate dwarfism in Fleckvieh cattle. The mutation has segregated in the population for more than 50 years without being recognized as a genetic disorder. However, the widespread use of an undetected carrier bull for artificial insemination caused a sudden accumulation of homozygous calves with dwarfism. Our findings provide the basis for genome-based mating strategies to avoid the inadvertent mating of carrier

  1. A nonsense mutation in CRYGC associated with autosomal dominant congenital nuclear cataract in a Chinese family.

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    Yao, Ke; Jin, Chongfei; Zhu, Ning; Wang, Wei; Wu, Renyi; Jiang, Jin; Shentu, Xingchao

    2008-07-09

    To identify the genetic defect associated with autosomal dominant congenital nuclear cataract in a Chinese family. Family history and phenotypic data were recorded, and the phenotypes were documented by slit lamp photography. The genomic DNA was extracted from peripheral blood leukocytes. All the exons and flanking intronic sequences of CRYGC and CRYGD were amplified by polymerase chain reaction (PCR) and screened for mutation by direct DNA sequencing. Structural models of the wild type and mutant gammaC-crystallin were generated and analyzed by SWISS-MODEL. Sequencing of the coding regions of CRYGC and CRYGD showed the presence of a heterozygous C>A transversion at c.327 of the coding sequence in exon 3 of CRYGC (c.327C>A), which results in the substitution of a wild type cysteine to a nonsense codon (C109X). One and a half Greek key motifs at the COOH-terminus were found to be absent in the structural model of the mutant truncated gammaC-crystallin. A novel nonsense mutation in CRYGC was detected in a Chinese family with consistent autosomal dominant congenital nuclear cataract, providing clear evidence of a relationship between the genotype and the corresponding cataract phenotype.

  2. Mutations of complement lectin pathway genes MBL2 and MASP2 associated with placental malaria

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    Holmberg Ville

    2012-03-01

    Full Text Available Abstract Background Innate immunity plays a crucial role in the host defense against malaria including Plasmodium falciparum malaria in pregnancy, but the roles of the various underlying genes and mechanisms predisposing to the disease are poorly understood. Methods 98 single-nucletoide polymorphisms were genotyped in a set of 17 functionally related genes of the complement system in 145 primiparous Ghanaian women with placental malaria, defined by placental parasitaemia or malaria pigment, and as a control, in 124 non-affected primiparae. Results Placental malaria was significantly associated with SNPs in the lectin pathway genes MBL2, MASP2, FCN2 and in properdin. In particular, the main African mannose-binding lectin deficiency variant (MBL2*G57E, rs1800451 increased the odds of placental malaria (OR 1.6; permuted p-value 0.014. In contrast, a common MASP2 mutation (R439H, rs12085877, which reduces the activity of MBL-MASP2 complexes occurred in 33% of non-affected women and in 22% primiparae with placental malaria (OR 0.55, permuted p-value 0.020. Conclusions Excessive complement activation is of importance in the pathogenesis of placental malaria by mediating inflammation, coagulation, and endothelial dysfunction. Mutated MBL and MASP2 proteins could have direct intrinsic effects on the susceptibility to placental malaria, in addition to their roles in regulation of downstream complement activation.

  3. Simple recessive mutation in ENAM is associated with amelogenesis imperfecta in Italian Greyhounds.

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    Gandolfi, Barbara; Liu, Hongwei; Griffioen, Layle; Pedersen, Niels C

    2013-08-01

    We report a familial enamel hypoplasia in Italian Greyhounds resembling non-syndromic autosomal recessive amelogenesis imperfecta (AI) of humans. The condition uniformly affects deciduous and permanent teeth and is manifested by enamel roughening/thinning and brownish mottling. Affected teeth are often small and pointed with increased gaps. However, basic tooth structure is usually maintained throughout life, and fractures and dental cavities are not a serious problem as in humans. No tissues or organs other than teeth were affected by this mutation, and there was no relationship between enamel hypoplasia and either autoimmunity or periodontal disease, which also are prevalent in the breed. The enamel hypoplasia was associated with a 5-bp deletion in exon 10 of the enamelin (ENAM) gene. The prevalence of the enamel defect in Italian Greyhounds was 14%, and 30% of dogs with normal teeth were carriers. Genome analyses suggest that the trait is under inadvertent positive selection. Based on the deletion detected in the ENAM gene, a genetic test was developed for identifying mutation carriers, which would enable breeders to manage the trait.

  4. Hemiconvulsion-hemiplegia-epilepsy syndrome associated with CACNA1A S218L mutation.

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    Yamazaki, Sawako; Ikeno, Kanju; Abe, Tokinari; Tohyama, Jun; Adachi, Yoshiki

    2011-09-01

    Hemiconvulsion-hemiplegia-epilepsy syndrome involves sudden and prolonged unilateral seizures, followed by transient or permanent hemiplegia and epilepsy during infancy or early childhood. Some patients with familial hemiplegic migraine and demonstrating the S218L mutation in CACNA1A experience severe attacks with unilateral cerebral edema after trivial head trauma. We report on a 5-year-old Japanese girl presenting with hemiconvulsion-hemiplegia-epilepsy syndrome after infection with parvovirus B19. Magnetic resonance imaging performed 2 days after admission revealed cerebellar atrophy and marked hyperintensity in the left hemisphere on T(2)-weighted and diffusion-weighted imaging. Magnetic resonance angiography performed 7 days after admission demonstrated obliteration of the left proximal middle cerebral artery in the acute phase. However, this finding was not evident on brain angiography performed 25 hours after magnetic resonance angiography. Genetic analysis of familial hemiplegic migraine revealed a heterozygous S218L mutation in CACNA1A. Taken together, these results suggest that vasospasms of cerebral vascular smooth muscle, with possible cortical spreading depression, may have caused the hemiconvulsions and hemiplegia in the left hemisphere. This case report is the first, to the best of our knowledge, to associate CACNA1A with hemiconvulsion-hemiplegia-epilepsy syndrome and familial hemiplegic migraine, and to suggest that similar pathogenic mechanisms may underlie these two disorders.

  5. Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency.

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    Tiranti, V; Hoertnagel, K; Carrozzo, R; Galimberti, C; Munaro, M; Granatiero, M; Zelante, L; Gasparini, P; Marzella, R; Rocchi, M; Bayona-Bafaluy, M P; Enriquez, J A; Uziel, G; Bertini, E; Dionisi-Vici, C; Franco, B; Meitinger, T; Zeviani, M

    1998-12-01

    Leigh disease associated with cytochrome c oxidase deficiency (LD[COX-]) is one of the most common disorders of the mitochondrial respiratory chain, in infancy and childhood. No mutations in any of the genes encoding the COX-protein subunits have been identified in LD(COX-) patients. Using complementation assays based on the fusion of LD(COX-) cell lines with several rodent/human rho0 hybrids, we demonstrated that the COX phenotype was rescued by the presence of a normal human chromosome 9. Linkage analysis restricted the disease locus to the subtelomeric region of chromosome 9q, within the 7-cM interval between markers D9S1847 and D9S1826. Candidate genes within this region include SURF-1, the yeast homologue (SHY-1) of which encodes a mitochondrial protein necessary for the maintenance of COX activity and respiration. Sequence analysis of SURF-1 revealed mutations in numerous DNA samples from LD(COX-) patients, indicating that this gene is responsible for the major complementation group in this important mitochondrial disorder.

  6. FASTKD2 nonsense mutation in an infantile mitochondrial encephalomyopathy associated with cytochrome c oxidase deficiency.

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    Ghezzi, Daniele; Saada, Ann; D'Adamo, Pio; Fernandez-Vizarra, Erika; Gasparini, Paolo; Tiranti, Valeria; Elpeleg, Orly; Zeviani, Massimo

    2008-09-01

    In two siblings we found a mitochondrial encephalomyopathy, characterized by developmental delay, hemiplegia, convulsions, asymmetrical brain atrophy, and low cytochrome c oxidase (COX) activity in skeletal muscle. The disease locus was identified on chromosome 2 by homozygosity mapping; candidate genes were prioritized for their known or predicted mitochondrial localization and then sequenced in probands and controls. A homozygous nonsense mutation in the KIAA0971 gene segregated with the disease in the proband family. The corresponding protein is known as fas activated serine-threonine kinase domain 2, FASTKD2. Confocal immunofluorescence colocalized a tagged recombinant FASTKD2 protein with mitochondrial markers, and membrane-potential-dependent in vitro mitochondrial import was demonstrated in isolated mitochondria. In staurosporine-induced-apoptosis experiments, decreased nuclear fragmentation was detected in treated mutant versus control fibroblasts. In conclusion, we found a loss-of-function mutation in a gene segregating with a peculiar mitochondrial encephalomyopathy associated with COX deficiency in skeletal muscle. The corresponding protein is localized in the mitochondrial inner compartment. Preliminary data indicate that FASTKD2 plays a role in mitochondrial apoptosis.

  7. Hereditary breast cancer associated with Cowden syndrome-related PTEN mutation with Lhermitte-Duclos disease.

    Science.gov (United States)

    Kimura, Fuyo; Ueda, Ai; Sato, Eiichi; Akimoto, Jiro; Kaise, Hiroshi; Yamada, Kimito; Hosonaga, Mari; Kawai, Yuko; Teraoka, Saeko; Okazaki, Miki; Ishikawa, Takashi

    2017-12-01

    Cowden syndrome is characterized by multiple hamartomas in various tissues, including the skin, brain, breast, thyroid, mucous membrane, and gastrointestinal tract, and is reported to increase the risk of malignant disease. We describe the case of a 52-year-old woman in whom a tumor was diagnosed in the left cerebellar hemisphere and treated by surgical resection. Phosphatase and tensin homolog (PTEN) mutation in exon 8 insertion was found in the brain tumor tissue and leukocytes. This finding supported the diagnosis of Cowden syndrome. She consequently developed endometrial cancer and underwent abdominal total hysterectomy with bilateral salpingo-oophorectomy. Four years later, hormone receptor-positive breast cancer was found in the right breast, and breast-conserving surgery with radiation therapy and sentinel lymph node biopsy was performed. Herein, we describe a patient who was diagnosed as having familial breast cancer associated with PTEN mutation-related Cowden syndrome. We also reviewed reports of this syndrome in the literature for disease appraisal.

  8. Mycoplasma genitalium infection: current treatment options, therapeutic failure, and resistance-associated mutations

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    Couldwell DL

    2015-05-01

    Full Text Available Deborah L Couldwell,1,2 David A Lewis1,21Western Sydney Sexual Health Centre, Parramatta, 2Centre for Infectious Diseases and Microbiology and Marie Bashir Institute for Infectious Diseases and Biosecurity, Westmead Clinical School, University of Sydney, Sydney, NSW, Australia Abstract: Mycoplasma genitalium is an important cause of non-gonococcal urethritis, cervicitis, and related upper genital tract infections. The efficacy of doxycycline, used extensively to treat non-gonococcal urethritis in the past, is relatively poor for M. genitalium infection; azithromycin has been the preferred treatment for several years. Research on the efficacy of azithromycin has primarily focused on the 1 g single-dose regimen, but some studies have also evaluated higher doses and longer courses, particularly the extended 1.5 g regimen. This extended regimen is thought to be more efficacious than the 1 g single-dose regimen, although the regimens have not been directly compared in clinical trials. Azithromycin treatment failure was first reported in Australia and has subsequently been documented in several continents. Recent reports indicate an upward trend in the prevalence of macrolide-resistant M. genitalium infections (transmitted resistance, and cases of induced resistance following azithromycin therapy have also been documented. Emergence of antimicrobial-resistant M. genitalium, driven by suboptimal macrolide dosage, now threatens the continued provision of effective and convenient treatments. Advances in techniques to detect resistance mutations in DNA extracts have facilitated correlation of clinical outcomes with genotypic resistance. A strong and consistent association exists between presence of 23S rRNA gene mutations and azithromycin treatment failure. Fluoroquinolones such as moxifloxacin, gatifloxacin, and sitafloxacin remain highly active against most macrolide-resistant M. genitalium. However, the first clinical cases of moxifloxacin treatment