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Sample records for c677t gene mutation

  1. Bilateral transverse sinus thrombosis secondary to a homozygous C677T MTHFR gene mutation.

    PubMed

    Kanaan, Ziad M; Mahfouz, Rami; Taher, Ali; Sawaya, Raja A

    2008-09-01

    We describe the case of a previously healthy young man who presented with headache, diplopia, nausea, vomiting, and bilateral papilledema. Magnetic resonance venography of the brain revealed thrombosis of the right transverse sinus. Blood tests showed elevated homocysteine levels, and coagulation studies revealed a homozygous C677T mutation and a heterozygous A1298C mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. The patient had no other etiology for venous thrombosis. We recommend screening patients who present with sinus thrombosis for MTHFR gene mutations. PMID:18666857

  2. Coexistence of Neurofibromatosis Type-1 and MTHFR C677T Gene Mutation in a Young Stroke Patient: A Case Report

    PubMed Central

    Yilmaz, Halim; Erkin, Gulten; Gumus, Haluk; Nalbant, Lutfiye

    2013-01-01

    In neurofibromatosis type-1 (NF1), cerebrovascular disorders are rarely encountered although vasculopathy is a well-known complication. Several mutations seen in methylenetetrahydrofolate reductase (MTHFR) give rise to the formation of hyperhomocysteinemia and homocystinuria, a considerable risk factor for cardiovascular and cerebrovascular disorders, by leading to enzymatic inactivation. In the paper, a 31-year-old young stroke female patient with the coexistence of neurofibromatosis and MTHFR C677T gene mutation was presented. PMID:23533858

  3. MTHFR Gene C677T Polymorphism in Autism Spectrum Disorders.

    PubMed

    Sener, Elif Funda; Oztop, Didem Behice; Ozkul, Yusuf

    2014-01-01

    Aim. Autism is a subgroup of autism spectrum disorders, classified as a heterogeneous neurodevelopmental disorder and symptoms occur in the first three years of life. The etiology of autism is largely unknown, but it has been accepted that genetic and environmental factors may both be responsible for the disease. Recent studies have revealed that the genes involved in the folate/homocysteine pathway may be risk factors for autistic children. In particular, C677T polymorphism in the MTHFR gene as a possible risk factor for autism is still controversial. We aimed to investigate the possible effect of C677T polymorphism in a Turkish cohort. Methods. Autism patients were diagnosed by child psychiatrists according to DSM-IV and DSM-V criteria. A total of 98 children diagnosed as autistic and 70 age and sex-matched children who are nonautistic were tested for C677T polymorphism. This polymorphism was studied by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Results. MTHFR 677T-allele frequency was found to be higher in autistic children compared with nonautistic children (29% versus 24%), but it was not found statistically significant. Conclusions. We conclude that other MTHFR polymorphisms such as A1298C or other folate/homocysteine pathway genes may be studied to show their possible role in autism. PMID:25431675

  4. MTHFR Gene C677T Polymorphism in Autism Spectrum Disorders

    PubMed Central

    Oztop, Didem Behice; Ozkul, Yusuf

    2014-01-01

    Aim. Autism is a subgroup of autism spectrum disorders, classified as a heterogeneous neurodevelopmental disorder and symptoms occur in the first three years of life. The etiology of autism is largely unknown, but it has been accepted that genetic and environmental factors may both be responsible for the disease. Recent studies have revealed that the genes involved in the folate/homocysteine pathway may be risk factors for autistic children. In particular, C677T polymorphism in the MTHFR gene as a possible risk factor for autism is still controversial. We aimed to investigate the possible effect of C677T polymorphism in a Turkish cohort. Methods. Autism patients were diagnosed by child psychiatrists according to DSM-IV and DSM-V criteria. A total of 98 children diagnosed as autistic and 70 age and sex-matched children who are nonautistic were tested for C677T polymorphism. This polymorphism was studied by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Results. MTHFR 677T-allele frequency was found to be higher in autistic children compared with nonautistic children (29% versus 24%), but it was not found statistically significant. Conclusions. We conclude that other MTHFR polymorphisms such as A1298C or other folate/homocysteine pathway genes may be studied to show their possible role in autism. PMID:25431675

  5. Association of C677T transition of the human methylenetetrahydrofolate reductase (MTHFR) gene with male infertility.

    PubMed

    Karimian, Mohammad; Colagar, Abasalt Hosseinzadeh

    2016-04-01

    The human methylenetetrahydrofolate reductase (MTHFR) gene encodes one of the key enzymes in folate metabolism. This gene is located on chromosome 1 (1p36.3), which has 12 exons. The aim of the present study was to investigate the possible association of the two (C677T and A1298C) polymorphisms of this gene with male infertility. In a case-control study, 250 blood samples were collected from IVF centres in Sari and Babol (Iran): 118 samples were from oligospermic men and 132 were from controls. Two single nucleotide polymorphisms of the MTHFR genotype were detected using polymerase chain reaction-restriction fragment length polymorphism. There was no association found between the A1298C variant and male infertility. However, carriers of the 677T allele (CT and TT genotypes) were at a higher risk of infertility than individuals with other genotypes (odds ratio 1.84; 95% confidence interval 1.11-3.04; P=0.0174). Structural analysis of human MTHFR flavoprotein showed that C677T transition played an important role in the change in affinity of the MTHFR-Flavin adenine dinucleotide binding site. Based on our results, we suggest that C677T transition in MTHFR may increase the risk of male infertility, and detection of the C677T polymorphism biomarker may be helpful in the screening of idiopathic male infertility. PMID:25412139

  6. Association between the methylenetetrahydrofolate reductase gene C677T polymorphism and sudden sensorineural hearing loss: a meta-analysis.

    PubMed

    Shu, Jingcheng; Yin, Shihua; Tan, An-Zhou; He, Meirong

    2015-09-01

    A variety of epidemiological studies have evaluated the association between methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism and sudden sensorineural hearing loss (SSNHL), but the results were inconsistent. The aim of this meta-analysis was to clarify more accurately the association of this polymorphism with SSNHL. A systematic literature search of the associated studies up to May 1, 2014, was conducted using the following electronic databases: PubMed, Embase, Medline, and the China National Knowledge Infrastructure. Statistical analyses were performed by STATA12.0 software, with odds ratios (ORs) and their 95 % confidence intervals (CIs). Six eligible studies including covering 1,271 objects were identified. A pooled analysis of these studies showed no significant association between C677T polymorphism and risk of SSNHL: T vs. C (OR = 1.334, POR = 0.105); TT vs. CC (OR = 1.580, POR = 0.231); CT vs. CC (OR = 1.500, POR = 0.123); TT vs. CC + CT (OR = 1.326, POR = 0.293); and TT + CT vs. CC (OR = 1.540, POR = 0.102). But in subgroup analysis, a significant association was found in European populations (T vs. C, OR = 1.542, 95 % CI 1.008-2.359, P = 0.046; TT vs. CT + CC, OR = 1.856, 95 % CI 1.245-2.767, P = 0.002). There was no significant association in any model in the Asian populations. The present meta-analysis suggests that MTHFR gene C677T polymorphism is significantly associated with increased risk of SSNHL disease in European populations, but no statistically significant association was found between the MTHFR C677T gene mutation and SSNHL in Asian. Further large and well-designed studies are needed to confirm this association. PMID:25012704

  7. Factor V Leiden, prothrombin 20210G-->A and the MTHFR C677T mutations in childhood stroke.

    PubMed

    McColl, M D; Chalmers, E A; Thomas, A; Sproul, A; Healey, C; Rafferty, I; McWilliam, R; Eunson, P

    1999-05-01

    Ischaemic stroke is a rare occurrence in children and in a proportion of cases the aetiology remains unknown. We have investigated the role of thrombophilia in the aetiology of this condition. Of 50 cases identified at two centres, 37 were available for detailed haematological analysis. No cases were identified with deficiencies of antithrombin, protein C or protein S. One case had elevated IgG anticardiolipin antibodies at low titre. The prevalence of the prothrombin 20210 G-->A mutation, factor V Leiden (FVL) mutation and the C677T mutation in the MTHFR gene was compared in cases to that observed in random unselected cord blood controls. The odds ratio for stroke was not significantly increased in carriers of the prothrombin mutation (OR 1.2; 95% CI 0.1-10.7), FVL (OR 2.5; 95% CI 0.5-13.5), or the C677T mutation (OR 1.7; 95% CI 0.6-4.5). Our findings suggest that thrombophilia may not play a significant role in the aetiology of stroke in children, although a large prospective study is required to investigate this area further. PMID:10365738

  8. A case of vascular parkinsonism associated with hyperhomocysteinemia and methylenetetrahydrofolate reductase gene variant (C677T).

    PubMed

    Hara, Kenju; Onda, Keigo; Ouchi, Haruka; Shibano, Ken; Ishiguro, Hideaki

    2016-03-01

    A 56-year-old man, who presented with 6 years history of difficulty in walking, was diagnosed as having vascular parkinsonism on the basis of the clinical findings of parkinsonism, pyramidal sign and the brain MRI findings of multiple lacunar infarction. Although he did not have hypertension, he had hyperhomocysteinemia and homozygous methylenetetrahydrofolate reductase (MTHFR) gene variant (C677T) as risk factors for ischemic stroke. Recent studies have shown that hyperhomocysteinemia and MTHFR gene variant are associated with small-vessel disease, suggesting that these risk factors may underlie vascular parkinsonism, particularly in patients lacking hypertension and in those with a relatively younger age at onset of this disease. PMID:26797478

  9. Methylenetetrahydrofolate reductase gene C677T polymorphism and breast cancer risk: Evidence for genetic susceptibility

    PubMed Central

    Kumar, Pradeep; Yadav, Upendra; Rai, Vandana

    2015-01-01

    There are several evidences supporting the role of 5–10 methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms in breast cancer (BC). Case control association studies on breast cancer have been repeatedly performed over the last two decades, but results are inconsistent. We performed a meta-analysis to confirm the association between MTHFR C677T polymorphism and BC risk. The articles were retrieved by searching the PubMed, Google Scholar, and Springer Link databases. Crude odds ratios (OR) with 95% confidence intervals (CIs) was used to assess the strength of association between C677T polymorphism and BC. Publication bias was assessed by Egger's and Begg-Mazumdar tests. Meta-analysis was performed with Open Meta Analyst. Total 75 studies with 31,315 cases and 35, 608 controls were found suitable for the inclusion in the present meta-analysis. The results of meta-analysis suggested that there were moderate significant association between C677T polymorphism and BC risk using overall comparisons in five genetic models (T vs. C: OR = 1.08, 95% CI = 1.03–1.13, p = < 0.001; TT + CT vs. CC: OR = 1.06, 95% CI = 1.02–1.09, p = < 0.001; TT vs. CC: OR = 1.17, 95% CI = 1.06–1.28, p = 0.001; CT vs. CC OR = 1.05, 95% CI = 1.01–1.08, p = 0.005; TT vs. CT + CC: OR = 1.12, 95% CI = 1.03–1.22, p = 0.005). In conclusion, results of present meta-analysis showed modest association between MTHFR C677T polymorphism with breast cancer in total studies. However, sub-group analysis results based on ethnicity showed strong significant association between TT genotype and breast cancer (TT vs. CC; OR°=°1.26; 95% CI: 1.06–1.51; p = 0.009) in Asian population but in Caucasian population such association was not observed (TT vs. CC; OR°=°1.08; 95% CI: 0.99–1.14; p = 0.05). PMID:26629412

  10. Methylenetetrahydrofolate reductase gene C677T polymorphism and breast cancer risk: Evidence for genetic susceptibility.

    PubMed

    Kumar, Pradeep; Yadav, Upendra; Rai, Vandana

    2015-12-01

    There are several evidences supporting the role of 5-10 methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms in breast cancer (BC). Case control association studies on breast cancer have been repeatedly performed over the last two decades, but results are inconsistent. We performed a meta-analysis to confirm the association between MTHFR C677T polymorphism and BC risk. The articles were retrieved by searching the PubMed, Google Scholar, and Springer Link databases. Crude odds ratios (OR) with 95% confidence intervals (CIs) was used to assess the strength of association between C677T polymorphism and BC. Publication bias was assessed by Egger's and Begg-Mazumdar tests. Meta-analysis was performed with Open Meta Analyst. Total 75 studies with 31,315 cases and 35, 608 controls were found suitable for the inclusion in the present meta-analysis. The results of meta-analysis suggested that there were moderate significant association between C677T polymorphism and BC risk using overall comparisons in five genetic models (T vs. C: OR = 1.08, 95% CI = 1.03-1.13, p = < 0.001; TT + CT vs. CC: OR = 1.06, 95% CI = 1.02-1.09, p = < 0.001; TT vs. CC: OR = 1.17, 95% CI = 1.06-1.28, p = 0.001; CT vs. CC OR = 1.05, 95% CI = 1.01-1.08, p = 0.005; TT vs. CT + CC: OR = 1.12, 95% CI = 1.03-1.22, p = 0.005). In conclusion, results of present meta-analysis showed modest association between MTHFR C677T polymorphism with breast cancer in total studies. However, sub-group analysis results based on ethnicity showed strong significant association between TT genotype and breast cancer (TT vs. CC; OR°=°1.26; 95% CI: 1.06-1.51; p = 0.009) in Asian population but in Caucasian population such association was not observed (TT vs. CC; OR°=°1.08; 95% CI: 0.99-1.14; p = 0.05). PMID:26629412

  11. Prevalence of factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations in 200 healthy Jordanians.

    PubMed

    Eid, Suhair S; Rihani, Ghada

    2004-01-01

    Thrombophilia is now considered a multi-causal condition, with interplay of acquired genetic risk factors. In order to estimate the frequency of the factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations in the Jordanian population, we screened 200 healthy Jordanian individuals. 40% were females. Mean age was 32.1 years for males and 30.0 years for female participants. A PCR method detected 15.0% factor V Leiden (87% heterozygous, 13% homozygous), 2% prothrombin G20210A (100% heterozygous), and 24% MTHFR C677T (67% heterozygous, 33% homozygous). We conclude that the prevalence of factor V Leiden and MTHFR C677T is elevated in this population of Jordanians. However the incidence of G20210A is relatively low. Quantification of these genetic thrombosis risk factors in various populations will contribute to a better understanding of the interaction of genetic and environmental risk factors. PMID:15559724

  12. Association between the MTHFR C677T gene polymorphism and essential hypertension in South West Cameroon.

    PubMed

    Ghogomu, S M; Ngolle, N E; Mouliom, R N; Asa, B F

    2016-01-01

    The association of the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism and essential hypertension has been reported but with controversial results in diverse populations in Asia and Europe, thereby suggesting a dependency on ethnicity. The aim of this study was to investigate the association between the MTHFR C677T polymorphism and essential hypertension in a Cameroonian population (Bantu ethnic group) of the South West Region. Analysis of anthropometric and biochemical data in hypertensive and normotensive subjects revealed that age, systolic blood pressure, diastolic blood pressure, low-density lipoprotein cholesterol, serum total cholesterol, and triglycerides are independent risk factors for essential hypertension. Substitution of thymine for cytosine at position 667 of the MTHFR gene was determined by polymerase chain reaction-restriction fragment length polymorphism. Genotype frequencies were found to be 7.3% CC, 58.5% CT, and 34.1% TT for hypertensive subjects compared to 90.0% CC, 10.0% CT, and 0.0% TT for normotensives. Allele frequencies were obtained as 36.6% C and 63.4% T for hypertensive subjects and 95.0% C and 5.0% T for normotensive subjects. These results reveal that the T allele predisposes individuals to hypertension. Therefore, there is an association between variants of the MTHFR gene and hypertension in Cameroonian patients from the South West region. PMID:27051013

  13. The C677T polymorphism of the methylenetetrahydrofolate reductase gene in Mexican mestizo neural-tube defect parents, control mestizo and native populations.

    PubMed

    Dávalos, I P; Olivares, N; Castillo, M T; Cantú, J M; Ibarra, B; Sandoval, L; Morán, M C; Gallegos, M P; Chakraborty, R; Rivas, F

    2000-01-01

    The C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene, associated with the thermolabile form of the enzyme, has reportedly been found to be increased in neural-tube defects (NTD), though this association is still unclear. A group of 107 mestizo parents of NTD children and five control populations: 101 mestizo (M), 50 Huichol (H), 38 Tarahumara (T), 21 Purepecha (P) and 20 Caucasian (C) individuals were typed for the MTHFR C677T variant by the PCR/RFLP (HinfI) method. Genotype frequencies were in agreement with the Hardy-Weinberg expectations in all six populations. Allele frequency (%) of the C677T variant was 45 in NTD, 44 in M, 56 in H, 36 in T, 57 in P, 35 in C. Pairwise inter-population comparisons of allele frequency disclosed a very similar distribution between NTD and M groups (exact test, P=0.92). Among controls, differences between M and individual native groups were NS (0.06C677T genotypes. Thus, the C677T variant cannot be regarded as a major genetic risk factor for NTD in Mexican mestizo parents. Otherwise, C677T in Mexico is very frequent, especially in Huichol and Purepecha natives, as compared with other groups world wide. PMID:10998450

  14. MTHFR gene C677T polymorphism and type 2 diabetic nephropathy in Asian populations: a meta-analysis

    PubMed Central

    Chen, Haiyan; Wei, Fang; Wang, Lihua; Wang, Zhe; Meng, Jia; Jia, Lan; Sun, Guijiang; Zhang, Ruining; Li, Bo; Yu, Haibo; Pang, Haiyan; Bi, Xueqing; Dong, Hongye; Jiang, Aili; Wang, Lin

    2015-01-01

    Background: Many studies have suggested a correlation between the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and diabetic nephropathy (DN), but their results are inconclusive. Methods: To confirm this correlation, we performed a meta-analysis of 15 studies. The dichotomous data are presented as odds ratios (OR) with 95% confidence intervals (CI). Results: The results of this study suggested that the MTHFR 677 T allele was more likely to increase the risk of DN in Asian (OR = 1.466, 95% CI = 1.143-1.880, P = 0.003), West Asian (OR = 1.750, 95% CI = 1.150-2.664, P = 0.009), and Chinese populations (OR = 2.162, 95% CI = 1.719-2.719, P = 0.001), but not in East Asian or Japanese populations. The carriers of the MTHFR 677 T allele were associated with progression of DN in the “5-10 year duration” group, but not in the “> 10 year duration” group (OR = 2.187, 95% CI = 1.787-2.677, P = 0.001). Conclusion: Development of DN is associated with MTHFR C677T polymorphisms in Asian populations, especially in early type 2 diabetes. PMID:26064261

  15. MTHFR (C677T) polymorphism and PR (PROGINS) mutation as genetic factors for preterm delivery, fetal death and low birth weight: A Northeast Indian population based study

    PubMed Central

    Tiwari, Diptika; Bose, Purabi Deka; Das, Somdatta; Das, Chandana Ray; Datta, Ratul; Bose, Sujoy

    2015-01-01

    Preterm delivery (PTD) is one of the most significant contributors to neonatal mortality, morbidity, and long-term adverse consequences for health; with highest prevalence reported from India. The incidence of PTD is alarmingly very high in Northeast India. The objective of the present study is to evaluate the associative role of MTHFR gene polymorphism and progesterone receptor (PR) gene mutation (PROGINS) in susceptibility to PTD, negative pregnancy outcome and low birth weights (LBW) in Northeast Indian population. Methods A total of 209 PTD cases {extreme preterm (<28weeks of gestation, n=22), very preterm (2832weeks of gestation, n=43) and moderate preterm (3237weeks of gestation, n=144) and 194 term delivery cases were studied for MTHFR C677T polymorphism and PR (PROGINS) gene mutation. Statistical analysis was performed using SPSS software. Results Distribution of MTHFR and PR mutation was higher in PTD cases. Presence of MTHFR C677T polymorphism was significantly associated and resulted in the increased risk of PTD (p<0.001), negative pregnancy outcome (p<0.001) and LBW (p=0.001); more significantly in extreme and very preterm cases. Presence of PR mutation (PROGINS) also resulted in increased risk of PTD and negative pregnancy outcome; but importantly was found to increase the risk of LBW significantly in case of very preterm (p<0.001) and moderately preterm (p<0.001) delivery cases. Conclusions Both MTHFR C677T polymorphism and PR (PROGINS) mutation are evident genetic risk factors associated with the susceptibility of PTD, negative pregnancy outcome and LBW. MTHFR C677T may be used as a prognostic marker to stratify subpopulation of pregnancy cases predisposed to PTD; thereby controlling the risks associated with PTD. PMID:25709895

  16. A Study on MTHFR C677T Gene Polymorphism and Alcohol Dependence among Meiteis of Manipur, India

    PubMed Central

    Singh, Huidrom Suraj; Salam, Kabita; Saraswathy, Kallur Nava

    2014-01-01

    Chronic alcohol consumption is reported to be associated with increase in plasma homocysteine levels which is further influenced by the polymorphism in methylenetetrahydrofolate reductase (MTHFR) gene. The present study aims to understand the extent of the MTHFR C677T polymorphism in alcohol dependent (AD) cases of Meiteis of Manipur, a Mendelian population of India. MTHFR C677T polymorphism was screened in 313 controls and 139 alcohol dependent (AD) cases who all met DSM-IV criteria for alcohol dependence. Both AD cases and controls were unrelated up to 1st cousin. Among the control group, different drinking patterns like abstainer/nondrinkers (NDs), occasional drinkers (ODs), and moderate drinkers (MDs) are included. Both the groups were found to be in Hardy-Weinberg equilibrium (P > 0.05). Genotypic and allelic frequency distribution of MTHFR C677T polymorphism did not differ significantly between AD cases and controls (P > 0.05). However, individuals carrying mutant (T) allele show more than 1-fold increased risk for AD though not significant (OR?=?1.43; 95% CI 0.415.01, P > 0.05). In conclusion, MTHFR C677T polymorphism is not found to be risk marker for AD in present studied population. However, higher prevalence of the mutant T allele may exacerbate deleterious health risk in future especially among alcohol drinkers. PMID:26317030

  17. Role of MTHFR C677T gene polymorphism in the susceptibility of schizophrenia: An updated meta-analysis.

    PubMed

    Yadav, Upendra; Kumar, Pradeep; Gupta, Sanjay; Rai, Vandana

    2016-04-01

    Methylenetetrahydrofolate reductase (MTHFR) is the key enzyme of folate/homocysteine metabolic pathway. C677T polymorphism of MTHFR gene was reported as risk factor for congenital defects, metabolic and neuropsychiatric disorders. Numerous case-control studies investigated C677T polymorphism as risk factor for schizophrenia but results of these studies were contradictory. To draw a conclusion, a meta-analysis of all available case-control studies was performed. PubMed, Google Scholar, Springer Link and Elsevier databases were searched for eligible case-control studies. Pooled odds ratio with 95%CI was used as an association measure and all statistical analyses were performed by Open Meta-Analyst and MIX software. Total 38 studies with 10,069 cases and 13,372 controls were included in the present meta-analysis. Results of meta-analysis showed significant associated between C677T polymorphism and risk of schizophrenia (ORTvsC=1.18, 95%CI=1.10-1.27, p=<0.001; ORCTvsCC=1.10, 95%CI=1.04-1.17, p=<0.001; ORTTvsCC=1.40, 95%CI=1.20-1.64, p=<0.001; ORTT+CTvsCC=1.19, 95%CI=1.09-1.30, p=<0.001). We also performed subgroup and sensitivity analyses. Subgroup analysis was done according to ethnicity and significant association was found between C677T polymorphism and risk of schizophrenia in all three ethnic populations-African (OR=2.51; 95%CI=1.86-3.40; p=<0.001), Asian (OR=1.21; 95%CI=1.10-1.33; p=<0.001) and Caucasian (OR=1.07; 95%CI=1.01-1.14; p=0.01). In conclusion the results of the present meta-analysis suggested that the MTHFR C677T polymorphism is a risk factor for schizophrenia. PMID:27025471

  18. Evidence of Paternal N5, N10 - Methylenetetrahydrofolate Reductase (MTHFR) C677T Gene Polymorphism in Couples with Recurrent Spontaneous Abortions (RSAs) in Kolar District- A South West of India

    PubMed Central

    Vanilla, Shiny; Kotur, Pushpa F; Kutty, Moideen A; Vegi, Pradeep Kumar

    2015-01-01

    Introduction: Recurrent spontaneous abortion (RSA) is a multifactorial clinical obstetrics complication commonly occurring in pregnancy. Many research studies have noted the mutations such as C677T in N5, N10 - Methylenetetrahydrofolate reductase (MTHFR)gene which is regarded as RSA risk factor. This study was carried out to determine the occurrence of frequency of C677T of the MTHFR gene mutations with RSA. Aim: The purpose of present study is to determine the frequency of MTHFR C677T polymorphisms in couples with recurrent pregnancy loss and the impact of paternal polymorphisms of MTHFR C677T in recurrent pregnancy loss in population of couples living in Kolar district of Karnataka with RSA. Design: A total of 15 couples with a history of two or more unexplained RSA were enrolled as subjects in the study and a total of 15 couples with normal reproductive history, having two or more children and no history of miscarriages were enrolled as controls. Materials and Methods: DNA extraction from samples case and control group couples and its quantification by Agarose gel electrophoresis, assessment of DNA purity, MTHFR C 677T gene mutation detection by PCR-RFLP method. Statistical analysis: Carried out by web based online SPSS tool. Results: The frequency of C677T genotype showed homozygous wild type CC (80%), heterozygous CT type (13.3%) and homozygous mutation TT type (6.67%) observed in males. Similarly from females homozygous wild type CC (86.6%), heterozygous type (13.3%), and homozygous type mutations TT (0%) was recorded. In couple control groups, we observed homozygous wild type CC (86.6%), heterozygous CT type (13.3%) and homozygous type mutations TT type (0%). Conclusion: We noticed a high frequency of MTHFR specifically T allele associated with paternal side.Therefore, the present study indicated the impact of paternal gene polymorphism of MTHFR C677T on screening in couples with recurrent pregnancy loss. PMID:25859445

  19. Geographical and Ethnic Distributions of the MTHFR C677T, A1298C and MTRR A66G Gene Polymorphisms in Chinese Populations: A Meta-Analysis

    PubMed Central

    Zeng, Dingyuan

    2016-01-01

    Background The geographical and ethnic distributions of the polymorphic methylenetetrahydrofolate reductase (MTHFR) mutations (C677T and A1298C) and methionine synthase reductase (MTRR) mutation (A66G) remain heterogeneous in China. The goal of this study was to estimate the pooled frequencies of the alleles and associated genotypes of these gene polymorphisms among healthy populations in Mainland China. Objective and Methods We systematically reviewed published epidemiological studies on the distributions of 3 genetic variants in Chinese healthy populations living in Mainland China through a meta-analysis. The relevant electronic databases were searched. All of the raw data of the eligible citations were extracted. The frequency estimates were stratified by geography, ethnicity and sex. Results Sixty-six studies were identified with a total of 92277 study participants. The meta-analysis revealed that the frequencies of the MTHFR C677T, A1298C, and MTRR A66G gene polymorphisms varied significantly between different ethnic groups and along geographical gradients. The frequencies of the 677T allele and 677TT genotype increased along the southern-central-northern direction across Mainland China (all Pvalues≤0.001). The frequencies of the 1298C, 1298CC, 66G and 66GG genotypes decreased along the south-central-north direction across the country (all Pvalues≤0.001). Conclusions Our meta-analysis strongly indicates significant geographical and ethnic variations in the frequencies of the C677T, A1298C, and A66G gene polymorphisms in the folate metabolism pathway among Chinese populations. PMID:27089387

  20. The 844ins68 cystathionine beta-synthase and C677T MTHFR gene polymorphism and the vaso-occlusive event risk in sickle cell disease

    PubMed Central

    Alves Jacob, Maza; da Cunha Bastos, Celso; Regina Bonini-Domingos, Claudia

    2011-01-01

    Introduction Sickle cell disease (SCD) is an inflammatory condition with an increase in the adhesion of sickled erythrocytes, and it is a potential cause of vaso-occlusive episodes, an event related to clinical manifestations, morbidity and mortality. The cystathionine beta-synthase enzyme gene (CBS) and the methylenetetrahydrofolate reductase enzyme gene (MTHFR) are risk factors for thromboembolic disorders. This study evaluated the frequency of the 844ins68 CBS and C677T MTHFR gene polymorphisms and their possibility to be risk factors for vaso-occlusive crises. Material and methods In total 91 blood samples from SCD patients were studied by PCR-RFLP and PCR-allele-specific, for the SCD genotype confirmation and polymorphism identification. Results The presence of clinical manifestations related to vaso-occlusive crises were more frequent among patients with the Hb SS genotype (p = 0.007). The CBS enzyme gene was three times more frequent (p = 0.011) among patients with vaso-occlusive complications. The MTHFR gene mutation frequency showed no increased risk for vaso-occlusive crises in SCD patients (p = 0.193). The interaction between the two polymorphisms was evaluated in 12.08% of the SCD patients and doubled the vaso-occlusive disease risk (relative risk: 2.16). Conclusions We conclude that the presence of 844ins68 CBS and C677T MTHFR gene polymorphism was a risk factor for vaso-occlusive episodes in the SCD patients evaluated. PMID:22291740

  1. Neonatal and Fetal Methylenetetrahydrofolate Reductase Genetic Polymorphisms: An Examination of C677T and A1298C Mutations

    PubMed Central

    Isotalo, Phillip A.; Wells, George A.; Donnelly, James G.

    2000-01-01

    Methylenetetrahydrofolate reductase (MTHFR) mutations are commonly associated with hyperhomocysteinemia, and, through their defects in homocysteine metabolism, they have been implicated as risk factors for neural tube defects and unexplained, recurrent embryo losses in early pregnancy. Folate sufficiency is thought to play an integral role in the phenotypic expression of MTHFR mutations. Samples of neonatal cord blood (n=119) and fetal tissue (n=161) were analyzed for MTHFR C677T and A1298C mutations to determine whether certain MTHFR genotype combinations were associated with decreased in utero viability. Mutation analysis revealed that all possible MTHFR genotype combinations were represented in the fetal group, demonstrating that 677T and 1298C alleles could occur in both cis and trans configurations. Combined 677CT/1298CC and 677TT/1298CC genotypes, which contain three and four mutant alleles, respectively, were not observed in the neonatal group (P=.0402). This suggests decreased viability among fetuses carrying these mutations and a possible selection disadvantage among fetuses with increased numbers of mutant MTHFR alleles. This is the first report that describes the existence of human MTHFR 677CT/1298CC and 677TT/1298CC genotypes and demonstrates their potential role in compromised fetal viability. PMID:10958762

  2. [C677T AND A1298C ALLELE POLYMORPHISM GENE OF METHYLENETETRAHYDRAFOLATEREDUCTASE IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE AND TYPE 2 DIABETES].

    PubMed

    Orlovskiy, V; Kuchma, N; Murenets, N; Orlovskiy, A

    2015-10-01

    The article presents the results of the study C677T and A1298C polymorphisms of MTHFR gene and their influence on plasma homocysteine levels in patients with nonalcoholic fatty liver disease (NAFLD). The study involved 100 patients with NAFLD and 40 apparently healthy individuals (control group). Determination of allelic polymorphism was performed by polymerase chain reaction with the detection results of hybridization by fluorescence in real-time. Determination of plasma homocysteine levels was performed by ELISA. As a result, studies have not found significant differences in the distribution of genotypes investigated C677T and A1298C MTHFR gene between patients with NAFLD and control group. We have detected statistically significant relationship between the level of homocysteine plasma C677T polymorphism of the MTHFR gene in patients with NAFLD and lack of connection with the A1298C polymorphism of the gene MTHFR. PMID:26483372

  3. One carbon metabolism disturbances and the C677T MTHFR gene polymorphism in children with autism spectrum disorders.

    PubMed

    Paşca, Sergiu P; Dronca, Eleonora; Kaucsár, Tamás; Craciun, Elena C; Endreffy, Emõke; Ferencz, Beatrix K; Iftene, Felicia; Benga, Ileana; Cornean, Rodica; Banerjee, Ruma; Dronca, Maria

    2009-10-01

    Autism spectrum disorders (ASDs), which include the prototypic autistic disorder (AD), Asperger's syndrome (AS) and pervasive developmental disorders not otherwise specified (PDD-NOS), are complex neurodevelopmental conditions of unknown aetiology. The current study investigated the metabolites in the methionine cycle, the transsulphuration pathway, folate, vitamin B(12) and the C677T polymorphism of the MTHFR gene in three groups of children diagnosed with AD (n= 15), AS (n= 5) and PDD-NOS (n= 19) and their age- and sex-matched controls (n= 25). No metabolic disturbances were seen in the AS patients, while in the AD and PDD-NOS groups, lower plasma levels of methionine (P= 0.01 and P= 0.03, respectively) and alpha-aminobutyrate were observed (P= 0.01 and P= 0.001, respectively). Only in the AD group, plasma cysteine (P= 0.02) and total blood glutathione (P= 0.02) were found to be reduced. Although there was a trend towards lower levels of serine, glycine, N, N-dimethylglycine in AD patients, the plasma levels of these metabolites as well as the levels of homocysteine and cystathionine were not statistically different in any of the ASDs groups. The serum levels of vitamin B(12) and folate were in the normal range. The results of the MTHFR gene analysis showed a normal distribution of the C677T polymorphism in children with ASDs, but the frequency of the 677T allele was slightly more prevalent in AD patients. Our study indicates a possible role for the alterations in one carbon metabolism in the pathophysiology of ASDs and provides, for the first time, preliminary evidence for metabolic and genetic differences between clinical subtypes of ASDs. PMID:19267885

  4. Spectrum of MTHFR gene SNPs C677T and A1298C: a study among 23 population groups of India.

    PubMed

    Saraswathy, Kallur Nava; Asghar, Mohammad; Samtani, Ratika; Murry, Benrithung; Mondal, Prakash Ranjan; Ghosh, Pradeep Kumar; Sachdeva, Mohinder Pal

    2012-04-01

    Elevated homocysteine is a risk factor for many complex disorders. The role of methylenetetrahydrofolate reductase (MTHFR) gene in methylation of homocysteine makes it one of the most important candidate genes for these disorders. Considering the heterogeneity in its distribution in world populations, we screened MTHFR C677T and A1298C single nucleotide polymorphisms in a total of 23 Indian caste, tribal and religious population groups from five geographical regions of India and belonging to four major linguistic groups. The frequencies of MTHFR 677T and 1298C alleles were found to be 10.08 and 20.66%, respectively. MTHFR homozygous genotype 677TT was absent in eight population groups and homozygous 1298CC was absent in two population groups. 677T allele was found to be highest among north Indian populations with Indo-European tongue and 1298C was high among Dravidian-speaking tribes of east India and south India. The less common mutant haplotype 677T-1298C was observed among seven population groups and overall the frequency of this haplotype was 0.008, which is similar to that of African populations. cis configuration of 677T and 1298C was 0.94%. However, we could not find any individual with four mutant alleles which supports the earlier observation that presence of more than two mutant alleles may decrease the viability of foetus and possibly be a selective disadvantage in the population. PMID:22147263

  5. C677T (RS1801133 ) MTHFR gene polymorphism frequency in a colombian population

    PubMed Central

    Gómez-Gutierrez, Alberto; Gómez, Piedad Elena; Casas-Gomez, Maria Consuelo; Briceño, Ignacio

    2015-01-01

    Introduction: Abnormal levels of the enzyme methylenetetrahydrofolate reductase (MTHFR) are associated with an increased risk of both cardiovascular and cerebrovascular disease and higher concentrations of homocysteine. Abnormal levels are also related to birth defects, pregnancy complications, cancer and toxicity to methotrexate (MTX). Polymorphisms of MTHFR affect the activity of the enzyme. Genetic associations have been related to treatment efficacy. Objective: To establish the frequency of the C> T polymorphism at nucleotide 677 of the MTHFR gene in a group of Colombian individuals. Methods: Data from pharmacogenetic microarrays that include MTX sensibility-associated polymorphisms were retrospectively collected (Pathway Genomics®). The frequency of the C> T MTHFR rs1801133 marker polymorphism was analyzed. Results: Microarray data from 68 men and 84 women were analyzed. Comparisons of genotype C/C vs. C/T and T/T were statistically significantly different (p= 0.00, p= 0.026, respectively), as were C/T and T / T (p= 0.0001). Conclusions: Results for the C/C and C/T genotypes in a Colombian population are similar to other previously studied groups of healthy subjects. Subjects from our population might be at risk of developing diseases associated with MTHFR polymorphisms and might present toxicity and adverse effects if treated with MTX, which suggests the need to evaluate therapeutic alternatives based on individual pharmacogenetic studies. PMID:26309343

  6. Association between C677T and A1298C polymorphisms of the MTHFR gene and risk of male infertility: a meta-analysis.

    PubMed

    Yang, Y; Luo, Y Y; Wu, S; Tang, Y D; Rao, X D; Xiong, L; Tan, M; Deng, M Z; Liu, H

    2016-01-01

    Published studies on the association between the C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene and male infertility risk are controversial. To obtain a more precise evaluation, we performed a meta-analysis based on published case-control studies. We conducted an electronic search of PubMed, EMBASE, the Cochrane Library, the Web of Science, and the China Knowledge Resource Integrated Database for papers on MTHFR gene C677T and A1298C polymorphisms and male infertility risk. Pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were used to assess the strength of association in homozygote, heterozygote, dominant, recessive, and additive models. Statistical heterogeneity, test of publication bias, and sensitivity analysis were carried out using the STATA software (Version 13.0). Overall, 21 studies of C677T (4505 cases and 4024 controls) and 13 studies of A1298C (2785 cases and 3094 controls) were included in this meta-analysis. For C677T, the homozygote comparison results were OR = 1.629, 95%CI (1.215- 2.184), and the recessive model results were OR = 1.462 (1.155- 1.850). For A1298C, the homozygote comparison results were OR = 1.289 (1.029-1.616), and the recessive model results were OR = 1.288 (1.034-1.604). In conclusion, the current meta-analysis showed that the MTHFR C677T polymorphism was associated with a significantly increased male infertility risk in the Asian and overall populations, but not in the Caucasian population, and there was a significant association between the A1298C polymorphism and male infertility risk in the Asian, Caucasian, and overall groups. PMID:27173242

  7. MTHFR C677T Gene Polymorphism and Head and Neck Cancer Risk: A Meta-Analysis Based on 23 Publications

    PubMed Central

    Niu, Yu-Ming; Deng, Mo-Hong; Chen, Wen; Zeng, Xian-Tao; Luo, Jie

    2015-01-01

    Objective. Conflicting results on the association between MTHFR polymorphism and head and neck cancer (HNC) risk were reported. We therefore performed a meta-analysis to derive a more precise relationship between MTHFR C677T polymorphism and HNC risk. Methods. Three online databases of PubMed, Embase, and CNKI were researched on the associations between MTHFR C677T polymorphism and HNC risk. Twenty-three published case-control studies involving 4,955 cases and 8,805 controls were collected. Odds ratios (ORs) with 95% confidence interval (CI) were used to evaluate the relationship between MTHFR C677T polymorphism and HNC risk. Sensitivity analysis, cumulative analyses, and publication bias were conducted to validate the strength of the results. Results. Overall, no significant association between MTHFR C677T polymorphism and HNC risk was found in this meta-analysis (T versus C: OR = 1.04, 95% CI = 0.921.18; TT versus CC: OR = 1.15, 95% CI = 0.901.46; CT versus CC: OR = 1.00, 95% CI = 0.851.17; CT + TT versus CC: OR = 1.01, 95% CI = 0.871.18; TT versus CC + CT: OR = 1.11, 95% CI = 0.981.26). In the subgroup analysis by HWE, ethnicity, study design, cancer location, and negative significant associations were detected in almost all genetic models, except for few significant risks that were found in thyroid cancer. Conclusion. This meta-analysis demonstrates that MTHFR C677T polymorphism may not be a risk factor for the developing of HNC. PMID:25802478

  8. Association of the methylenetetrahydrofolate reductase gene C677T polymorphism with the risk of male infertility: a meta-analysis.

    PubMed

    Zhu, Xudong; Liu, Zhiguo; Zhang, Maochen; Gong, Ruihong; Xu, Yajun; Wang, Baoming

    2016-03-01

    Several molecular epidemiological studies have been conducted to examine the association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and male infertility susceptibility, but the results remain inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. In this meta-analysis, a total of 26 case-control studies including 5659 infertility cases and 5528 controls were selected to evaluate the possible association. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were used to assess the strength of association of C677T polymorphism with male infertility in the additive model, dominant model, recessive model and allele-frequency genetic model. In the overall analysis, the frequency of the 677T allele was significantly associated with male infertility susceptibility (OR = 2.32, 95%CI = 2.04-2.65 for TT vs. CC genotype; OR = 1.09, 95%CI = 1.00-1.19 for CT vs. CC genotype; OR = 1.19, 95%CI = 1.10-1.29 for CT/TT vs. CC genotype; OR = 1.54, 95%CI = 1.36-1.74 for TT vs. CC/TT genotype; OR = 1.22, 95%CI = 1.15-1.30 for T vs. C allele). A subgroup analysis of the subjects showed that significantly strong association between MTHFR C677T polymorphism and male infertility was present only in Asians, but not in Caucasians. Additionally, MTHFR C677T was associated with a significant increase in the risk of azoospermia in all genetic models. Meanwhile, no significantly increased risks of oligoasthenotertozoospermia (OAT) were found in most of the genetic models. In conclusion, this meta-analysis is in favor that the MTHFR C677T polymorphism is capable of causing male infertility susceptibility, especially in Asians and the subgroup of azoospermia. PMID:26584688

  9. [Genetic variant C677T in the MTHFR in women with recurrent early fetal loss].

    PubMed

    Ivanov, P; Kovacheva, K; Komsa-Penkova, R; Konova, E; Simeonova, M; Popov, I; Gecheva, S; Bozhinova, S; Tanchev, S; Tsafarov, M

    2007-01-01

    The aim of this study was to evaluate correlation of carrier status for thrombophilic gene mutation--C677T in the methylenetetrahydrofolate reductase (MTHFR) and recurrent early pregnancy loss. Recently inherited thrombophilia was discussed as a predisposed factor for early recurrent fetal loss (ERFL). We investigated carrier status for C677T genetic variant in 54 women with ERFL before 10 week of gestation and 67 women with one or more successful pregnancy. It was found significant prevalence of C677T genetic variant in MTHFR in women with ERFL compared with controls (p = 0.005). The significant high prevalence of C677T genetic variant in women with ERFL suggests that thrombophilia have an increased risk of early pregnancy loss and possibly, although the definition of the magnitude of risk will require prospective longitudinal studies. PMID:17974190

  10. Homocysteine Metabolism Gene Polymorphisms (MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) Jointly Elevate the Risk of Folate Deficiency

    PubMed Central

    Li, Wen-Xing; Dai, Shao-Xing; Zheng, Jun-Juan; Liu, Jia-Qian; Huang, Jing-Fei

    2015-01-01

    Folate deficiency is strongly associated with cardiovascular disease. We aimed to explore the joint effect of the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, and methionine synthase reductase (MTRR) A66G polymorphisms on folate deficiency in a Chinese hypertensive population. A total of 480 subjects aged 28–75 were enrolled in this study from September 2005–December 2005 from six hospitals in different Chinese regions. Known genotypes were detected by PCR-RFLP methods and serum folate was measured by chemiluminescence immunoassay. Our results showed that MTHFR 677TT and MTR 2756AG + GG were independently associated with a higher risk of folate deficiency (TT vs. CC + CT, p < 0.001 and AG + GG vs. AA p = 0.030, respectively). However, the MTHFR A1298C mutation may confer protection by elevating the serum folate level (p = 0.025). Furthermore, patients carrying two or more risk genotypes showed higher odds of folate deficiency than null risk genotype carriers, especially those carrying four risk genotypes. These findings were verified by generalized multifactor dimensionality reduction (p = 0.0107) and a cumulative effects model (p = 0.001). The results of this study have shown that interactions among homocysteine metabolism gene polymorphisms lead to dramatic elevations in the folate deficiency risk. PMID:26266420

  11. Homocysteine Metabolism Gene Polymorphisms (MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) Jointly Elevate the Risk of Folate Deficiency.

    PubMed

    Li, Wen-Xing; Dai, Shao-Xing; Zheng, Jun-Juan; Liu, Jia-Qian; Huang, Jing-Fei

    2015-08-01

    Folate deficiency is strongly associated with cardiovascular disease. We aimed to explore the joint effect of the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, and methionine synthase reductase (MTRR) A66G polymorphisms on folate deficiency in a Chinese hypertensive population. A total of 480 subjects aged 28-75 were enrolled in this study from September 2005-December 2005 from six hospitals in different Chinese regions. Known genotypes were detected by PCR-RFLP methods and serum folate was measured by chemiluminescence immunoassay. Our results showed that MTHFR 677TT and MTR 2756AG + GG were independently associated with a higher risk of folate deficiency (TT vs. CC + CT, p < 0.001 and AG + GG vs. AA p = 0.030, respectively). However, the MTHFR A1298C mutation may confer protection by elevating the serum folate level (p = 0.025). Furthermore, patients carrying two or more risk genotypes showed higher odds of folate deficiency than null risk genotype carriers, especially those carrying four risk genotypes. These findings were verified by generalized multifactor dimensionality reduction (p = 0.0107) and a cumulative effects model (p = 0.001). The results of this study have shown that interactions among homocysteine metabolism gene polymorphisms lead to dramatic elevations in the folate deficiency risk. PMID:26266420

  12. Methylenetetrahydrofolate reductase gene C677T, A1298C polymorphisms and pre-eclampsia risk: a meta-analysis.

    PubMed

    Li, Xing; Luo, Ya L; Zhang, Qiong H; Mao, Chen; Wang, Xi W; Liu, Shan; Chen, Qing

    2014-08-01

    To determine whether methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms are associated with pre-eclampsia susceptibility. Literature searches of the Pubmed, Embase, BIOSIS Previews and Web of Science were conducted to identify all eligible articles up to January 18th, 2013. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) of five genetic models were calculated by fixed-effects or random-effects model. Publication bias, subgroup analysis, meta-regression and sensitivity analysis were also performed. A number of 49 studies including 51 samples consisted of 18,009 subjects (6,238 patients and 11,771 controls) were finally included. MTHFR C677T allele (TT or CT) carriers were 1.12 times more likely to develop pre-eclampsia (95% CI 1.04-1.21) compared with 677CC homozygous individuals. Similar results were obtained under other genetic models. Restricted to severe pre-eclampsia, there was an increased risk for 677TT homozygotes compared with 677CC homozygotes (OR 1.43; 95% CI 1.12-1.83). Subgroup analysis revealed a significant positive association between the C677T polymorphism (TT or CT) and pre-eclampsia in Asians (OR 1.41; 95% CI 1.11-1.79) and white population (OR 1.14; 95% CI 1.03-1.25). Meta-regression showed that study population, blinded genotyping, matching of cases and controls were not substantial sources of heterogeneity. For the MTHFR A1298C, ORs for all genetic models yielded a null association. This meta-analysis suggests that the MTHFR 677T allele might be associated with increased pre-eclampsia risk in Asian and white ethnicity and the subgroup of severe pre-eclampsia, while no association is observed between the MTHFR A1298C polymorphism and pre-eclampsia. PMID:24898880

  13. MTHFR A1298C and C677T gene polymorphisms and susceptibility to chronic myeloid leukemia in Egypt.

    PubMed

    Aly, Rabab M; Taalab, Mona M; Ghazy, Hayam F

    2014-01-01

    Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating the intracellular folate metabolism which plays an important role in carcinogenesis through DNA methylation. We aimed to evaluate the association between MTHFR A1298C and C677T polymorphisms and the risks of chronic myeloid leukemia (CML). Eighty-five patients with CML and a control group containing 100 healthy, age and sex matched individuals were examined for MTHFR C677T and A1298C polymorphisms using polymerase chain reaction-restriction fragment-length (PCR-RFLP) method. The frequency of 677TT genotype in patients with CML was significantly higher compared to controls (OR=2.513, 95% CI: 0.722-4.086, P=0.025). No such association was shown for heterozygous 677CT (OR=1.010, 95% CI: 0.460-2.218, P=0.981). Moreover, for A1298C genotype, a statistically significant higher frequency of 1298CC was also detected in CML patients compared to control group (OR=1.1816, 95% CI: 0.952-3.573, P=0.036), 0.036). No such statistical significance was demonstrable for heterozygote 1298AC (OR=1.046, 95% CI: 0.740-1.759, P=0.092). In addition, patients with joint 677CT/1298AC or 677TT/1298CC genotypes showed an association with increased risk of CML (OR=1.849, 95% CI: 0.935-2.540, P=0.024; OR=1.915, 95% CI: 1.202-3.845, P=0.020 respectively). .A statistically significant increased risk of resistant to therapy was observed with 677CT and 1298AC genotypes (P=0.001, P=0.002 respectively). We conclude that both MTHFR 677TT and 1298CC polymorphisms have been associated with risk of CML and both 677CT and 1298AC genotypes are associated with higher risk of resistant to therapy. PMID:24966971

  14. Atherosclerosis in male patients with ankylosing spondylitis: the relation with methylenetetrahydrofolate reductase (C677T) gene polymorphism and plasma homocysteine levels.

    PubMed

    Geçene, Muharrem; Tuncay, Figen; Borman, Pınar; Yücel, Dogan; Senes, Mehmet; Yılmaz, Behice Kaniye

    2013-06-01

    The aim of this study was to determine the intima-media thickness (IMT) in carotid arteries and to assess the relation of these values with plasma homocysteine (pHcy) levels and methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in patients with Ankylosing spondylitis (AS). Serum lipids, vitamin B12, folic acid, pHcy and acute phase protein levels were measured in all cases. MTHFR C677T gene polymorphisms were determined, and IMT of main carotid artery were evaluated ultrasonographically in all subjects. Bath Ankylosing Spondylitis Disease Activity Index, Ankylosing Spondylitis Disease Activity score and Bath Ankylosing Spondylitis Metrology Index were used to assess disease activity and spinal mobility. Fifty AS patients (mean age of 36.6 ± 4.79 years) and 50 control subjects (36.34 ± 4.72 years) were included in the study. Plasma homocysteine levels of AS patients and control group were also similar (14.26 ± 9.96 vs. 11.81 ± 5.53 μmol/L). Hyperhomocysteinemia was present in 11 subjects in patient group (22.0 %), while it was seen in 5 subjects in the control group (10.0 %). The MTHFR C677T genotype distribution was as follows: CC 31 (62 %), CT 14 (28 %), TT 5 (10 %) in AS patients. The mean carotid IMT values were also found to be similar between the groups. The most important factor influencing pHcy level was found as MTHFR 677TT genotype. We indicated no difference of atherosclerosis indices revealed by IMT values and pHcy levels AS patients and control subjects. But an association between MTHFR 677 gene polymorphism and pHcy levels was concluded, which may suggest that MTHFR 677 TT polymorphism may be a potential prognostic factor for cardiovascular disease in patients with AS. PMID:23247802

  15. Relationship between MTHFR C677T and A1298C gene polymorphisms and complications of type 2 diabetes mellitus in an Emirati population

    PubMed Central

    El Hajj Chehadeh, Sarah W.; Jelinek, Herbert F.; Al Mahmeed, Wael A.; Tay, Guan K.; Odama, Unini O.; Elghazali, Gehad E.B.; Al Safar, Habiba S.

    2016-01-01

    Purpose Type 2 diabetes mellitus (T2DM) is the most common form of diabetes with clinical consequences giving rise to chronic multiple organ complications. Methylenetetrahydrofolate reductase (MTHFR) polymorphisms are genetic variations that have been linked to T2DM, and micro/macrovascular complications. The link between MTHFR and T2DM however is strongly dependent on the ethnic group studied. The objective of this study was to investigate the possible association between two MTHFR polymorphisms (C677T and A1298C) and T2DM and specifically examine if there are any associations with clinical and demographic characteristics among patients in the United Arab Emirates (UAE). Methods The study included 169 T2DM patients and 209 healthy controls. Genomic DNA was isolated and genotyped using TaqMan real-Time PCR assays for the MTHFR C677T and A1298C polymorphisms. Results There were no significant differences in genotype and haplotype distributions observed between groups. A significant association was observed between the C677T polymorphism and history of cerebrovascular accident (CVA) (p = 0.0330), history of nephropathy (p = 0.0280) and levels of LDL cholesterol (p = 0.0409). Also, the A1298C polymorphism was associated with hypertriglyceridemia (p = 0.0305) in T2DM patients. Conclusion These findings demonstrate that the MTHFR gene polymorphisms are not related to T2DM in the Emirati population. However, these polymorphisms can be used as risk markers for CVA, nephropathy, high LDL cholesterol and triglycerides in T2DM patients and allow timely treatment.

  16. Creatine kinase MM TaqI and methylenetetrahydrofolate reductase C677T and A1298C gene polymorphisms influence exercise-induced C-reactive protein levels.

    PubMed

    Miranda-Vilela, Ana Luisa; Akimoto, Arthur K; Lordelo, Graciana S; Pereira, Luiz C S; Grisolia, Cesar K; Klautau-Guimarães, Maria de Nazaré

    2012-03-01

    Physical training induces beneficial adaptations, but exhausting exercise increases reactive oxygen species, which can cause muscular injuries with consequent inflammatory processes, implying jeopardized performance and possibly overtraining. Acute strenuous exercise almost certainly exceeds the benefits of physical activity; it can compromise performance and may contribute to increased future risk of cardiovascular disease (CVD) in athletes. Polymorphisms in the muscle-type creatine kinase (CK-MM) gene may influence performance and adaptation to training, while many potentially significant genetic variants are reported as risk factors for CVD. Therefore, we investigated the influence of polymorphisms in CK-MM TaqI and NcoI, methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and C-reactive protein (CRP G1059C) genes on exercise-induced damage and inflammation markers. Blood samples were taken immediately after a race (of at least 4 km) that took place outdoors on flat tracks, and were submitted to genotyping and biochemical evaluation of aspartate aminotransferase (AST), CK, CRP and high-sensitivity CRP (hs-CRP). CK-MM TaqI polymorphism significantly influenced results of AST, CK and hs-CRP, and an association between MTHFR C677T and A1298C with CRP level was found, although these levels did not exceed reference values. The results indicate that these polymorphisms can indirectly influence performance, contribute to higher susceptibility to exercise-induced inflammation or protection against it, and perhaps affect future risks of CVD in athletes. PMID:21706313

  17. Creatine kinase MM TaqI and methylenetetrahydrofolate reductase C677T and A1298C gene polymorphisms influence exercise-induced C-reactive protein levels.

    PubMed

    Miranda-Vilela, Ana Luisa; Akimoto, Arthur K; Lordelo, Graciana S; Pereira, Luiz C S; Grisolia, Cesar K; Klautau-Guimarães, Maria de Nazaré

    2012-01-01

    Physical training induces beneficial adaptations, but exhausting exercise increases reactive oxygen species, which can cause muscular injuries with consequent inflammatory processes, implying jeopardized performance and possibly overtraining. Acute strenuous exercise almost certainly exceeds the benefits of physical activity; it can compromise performance and may contribute to increased future risk of cardiovascular disease (CVD) in athletes. Polymorphisms in the muscle-type creatine kinase (CK-MM) gene may influence performance and adaptation to training, while many potentially significant genetic variants are reported as risk factors for CVD. Therefore, we investigated the influence of polymorphisms in CK-MM TaqI and NcoI, methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and C-reactive protein (CRP G1059C) genes on exercise-induced damage and inflammation markers. Blood samples were taken immediately after a race (of at least 4 km) that took place outdoors on flat tracks, and were submitted to genotyping and biochemical evaluation of aspartate aminotransferase (AST), CK, CRP and high-sensitivity CRP (hs-CRP). CK-MM TaqI polymorphism significantly influenced results of AST, CK and hs-CRP, and an association between MTHFR C677T and A1298C with CRP level was found, although these levels did not exceed reference values. Results indicate that these polymorphisms can indirectly influence performance, contribute to higher susceptibility to exercise-induced inflammation or protection against it, and perhaps affect future risks of CVD in athletes. PMID:21516340

  18. Distribution of alleles of the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in familial spina bifida.

    PubMed

    Johnson, W G; Stenroos, E S; Heath, S C; Chen, Y; Carroll, R; McKoy, V V; Chatkupt, S; Lehner, T

    1999-12-22

    Spina bifida cystica (SB) is one of the most common and disabling of birth defects. Folic acid supplementation in mothers during the periconceptional period has been shown to prevent more than 70% of neural tube defects (NTD) including SB. However, the mechanism is unknown. We tested a series of multicase SB families in which 224 individuals were genotyped and a group of 215 unrelated unaffected (external) control individuals for association of SB with the T allele of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism that produces a heat-labile enzyme protein. The data were analyzed using first the transmission/disequilibrium test (TDT) and second a modified case-control study design with Monte Carlo sampling methods. No association of SB with the MTHFR T allele was found by either method. Presently, association between SB and the T allele has been found in four studies, a Dutch study, an Irish study, a North American study, and an Italian study. But no association was found in four other studies, a British study, a French study, a Turkish study, and a German study. A California population-based study found only modestly increased risk of SB with this allele that was not significant at the P < 0.05 level. The present study finds no evidence of the association. Only one other study, the German study, has used TDT analysis. The present study is the first to use a modified case-control study design with Monte Carlo sampling methods to test this association. Thus, it appears that the MTHFR T allele is a risk factor for SB in some populations but not others. Major genetic risk factors for folate-related SB remain to be found. PMID:10594879

  19. Common folate gene variant, MTHFR C677T, is associated with brain structure in two independent cohorts of people with mild cognitive impairment☆

    PubMed Central

    Rajagopalan, Priya; Jahanshad, Neda; Stein, Jason L.; Hua, Xue; Madsen, Sarah K.; Kohannim, Omid; Hibar, Derrek P.; Toga, Arthur W.; Jack, Clifford R.; Saykin, Andrew J.; Green, Robert C.; Weiner, Michael W.; Bis, Joshua C.; Kuller, Lewis H.; Riverol, Mario; Becker, James T.; Lopez, Oscar L.; Thompson, Paul M.

    2012-01-01

    A commonly carried C677T polymorphism in a folate-related gene, MTHFR, is associated with higher plasma homocysteine, a well-known mediator of neuronal damage and brain atrophy. As homocysteine promotes brain atrophy, we set out to discover whether people carrying the C677T MTHFR polymorphism which increases homocysteine, might also show systematic differences in brain structure. Using tensor-based morphometry, we tested this association in 359 elderly Caucasian subjects with mild cognitive impairment (MCI) (mean age: 75 ± 7.1 years) scanned with brain MRI and genotyped as part of Alzheimer's Disease Neuroimaging Initiative. We carried out a replication study in an independent, non-overlapping sample of 51 elderly Caucasian subjects with MCI (mean age: 76 ± 5.5 years), scanned with brain MRI and genotyped for MTHFR, as part of the Cardiovascular Health Study. At each voxel in the brain, we tested to see where regional volume differences were associated with carrying one or more MTHFR ‘T’ alleles. In ADNI subjects, carriers of the MTHFR risk allele had detectable brain volume deficits, in the white matter, of up to 2–8% per risk T allele locally at baseline and showed accelerated brain atrophy of 0.5–1.5% per T allele at 1 year follow-up, after adjusting for age and sex. We replicated these brain volume deficits of up to 5–12% per MTHFR T allele in the independent cohort of CHS subjects. As expected, the associations weakened after controlling for homocysteine levels, which the risk gene affects. The MTHFR risk variant may thus promote brain atrophy by elevating homocysteine levels. This study aims to investigate the spatially detailed effects of this MTHFR polymorphism on brain structure in 3D, pointing to a causal pathway that may promote homocysteine-mediated brain atrophy in elderly people with MCI. PMID:24179750

  20. Ethnic variation of the C677T and A1298C polymorphisms in the methylenetetrahydrofolate-reductase (MTHFR) gene in southwestern Mexico.

    PubMed

    Antonio-Véjar, V; Del Moral-Hernández, O; Alarcón-Romero, L C; Flores-Alfaro, E; Leyva-Vázquez, M A; Hernández-Sotelo, D; Illades-Aguiar, B

    2014-01-01

    In this study, we examined the distribution of genotype and allele frequencies of the C677T and A1298C polymorphisms in the methylenetetrahydrofolate-reductase gene (MTHFR) in two ethnic groups in the State of Guerrero, Mexico, which were compared with those of the Mestizo population of the region. A comparative study was conducted on 455 women from two ethnic groups and a group of Mestizo women of the State of Guerrero, Mexico: 135 Nahuas, 124 Mixtecas, and 196 Mestizas. Genotyping of both polymorphisms were performed by using polymerase chain reaction-restriction fragment length polymorphism methods. We found that the 677TT genotype was more frequent in Nahua and Mixteca women compared to Mestiza women (P = 0.008), and the most prevalent genotype in both ethnic groups was the 1298AA genotype (P < 0.001). We also compared the 677T allele frequency obtained from the groups studied with the frequencies reported in other ethnic groups of Mexico (Huichol, Tarahumara, and Purepecha). There were significant differences between the three ethnic groups compared to Nahuas (Huicholes, P = 0.004; Tarahumaras, P < 0.001; Purepechas, P = 0.042). Our results indicated significant differences in the frequencies of the C677T and A1298C polymorphisms between the two ethnic groups and the Mestizo population of the State of Guerrero. In addition, we found strong differences with other ethnic groups in Mexico. These results could be useful for future studies investigating diseases related to folate metabolism, and could help the government to design specific nutrition programs for different ethnic groups. PMID:25299110

  1. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases.

    PubMed

    Liew, Siaw-Cheok; Gupta, Esha Das

    2015-01-01

    The Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with various diseases (vascular, cancers, neurology, diabetes, psoriasis, etc) with the epidemiology of the polymorphism of the C677T that varies dependent on the geography and ethnicity. The 5,10-Methylenetetrahydrofolate reductase (MTHFR) locus is mapped on chromosome 1 at the end of the short arm (1p36.6). This enzyme is important for the folate metabolism which is an integral process for cell metabolism in the DNA, RNA and protein methylation. The mutation of the MTHFR gene which causes the C677T polymorphism is located at exon 4 which results in the conversion of valine to alanine at codon 222, a common polymorphism that reduces the activity of this enzyme. The homozygous mutated subjects have higher homocysteine levels while the heterozygous mutated subjects have mildly raised homocysteine levels compared with the normal, non-mutated controls. Hyperhomocysteinemia is an emerging risk factor for various cardiovascular diseases and with the increasing significance of this polymorphism in view of the morbidity and mortality impact on the patients, further prevention strategies and nutritional recommendations with the supplementation of vitamin B12 and folic acid which reduces plasma homocysteine level would be necessary as part of future health education. This literature review therefore focuses on the recent evidence-based reports on the associations of the MTHFR C677T polymorphism and the various diseases globally. PMID:25449138

  2. Association between MTHFR gene polymorphisms (C677T, A1298C) and genetic susceptibility to prostate cancer: a meta-analysis.

    PubMed

    Chen, P L; Li, W T; Wang, J; Jiang, Y D; Wu, P; Chen, T; Zheng, S B

    2015-01-01

    Genetic polymorphisms (C677T and A1298C) in methylenetetrahydrofolate reductase (MTHFR) were shown to be related to prostate cancer risk in previous studies; however, the results are controversial. We performed a meta-analysis of previous studies and quantitatively estimated these associations. Pubmed, Embase, and Cochrane Library Database were searched for published case-control studies evaluating the association between C677T (or A1298C) and prostate cancer risk. Pooled associations were presented as odds ratios (ORs) along with their 95% confidence intervals. Twenty-one case control studies were identified for meta-analysis that included 21,581 participants. No significant associations were found between the MTHFR polymorphisms C677T or A1298C and prostate cancer risk in our meta-analysis. However, in subgroup analyses, the C677T CT polymorphism was associated with increased prostate cancer risk in East Asians (CT vs CC+TT: OR = 1.324, P = 0.03). The A1298C CC polymorphism in MTHFR was also linked to slightly reduced prostate cancer risk in European residents (CC vs AC+AA: OR = 0.751, P = 0.004; CC vs AA: OR = 0.768, P = 0.011), whereas it was associated with a significantly increased prostate cancer risk in Asian residents (CC vs AA: OR = 1.862, P = 0.006). The C677T CT polymorphism of MTHFR may be a risk factor for prostate cancer in East Asians. The association between the MTHFR A1298C CC genotype and prostate cancer risk may vary within different populations. Large-scale well-designed studies are required to confirm these associations. PMID:26782572

  3. Evaluation of High Resolution Melting for MTHFR C677T Genotyping in Congenital Heart Disease

    PubMed Central

    Yue, Shuying; Zhang, Kun; Wang, Hui; Dong, Rui; Yang, Xiaomeng; Liu, Yi; Ma, Yanhui

    2016-01-01

    Background High resolution melting (HRM) is a simple, flexible and low-cost mutation screening technique. The methylenetetrahydrofolate reductase (MTHFR) gene encoding a critical enzyme, potentially affects susceptibility to some congenital defects like congenital heart disease (CHD). We evaluate the performance of HRM for genotyping of the MTHFR gene C677T locus in CHD cases and healthy controls of Chinese Han population. Methods A total of 315 blood samples from 147 CHD patients (male72, female 75) and 168 healthy controls (male 92, female 76) were enrolled in the study. HRM was utilized to genotype MTHFR C677T locus of all the samples. The results were compared to that of PCR-RFLP and Sanger sequencing. The association of the MTHFR C677T genotypes and the risk of CHD was analyzed using odds ratio with their 95% confidence interval (CIs) from unconditional logistic regression. Results All the samples were successfully genotyped by HRM within 1 hour and 30 minutes while at least 6 hours were needed for PCR-RFLP and sequencing. The genotypes of MTHFR C677T CC, CT, and TT were 9.52%, 49.66%, and 40.82% in CHD group but 29.17%, 50% and 20.83% in control group, which were identical using both methods of HRM and PCR-RFLP, demonstrating the sensitivity and specificity of HRM were all 100%. Conclusion MTHFR C677T is a potential risk factor for CHD in our local residents of Shandong province in China. HRM is a fast, sensitive, specific and reliable method for clinical application of genotyping. PMID:26990189

  4. Methylenetetrahydrofolate reductase gene germ-line C677T and A1298C SNPs are associated with colorectal cancer risk in the Turkish population.

    PubMed

    Ozen, Filiz; Sen, Metin; Ozdemir, Ozturk

    2014-01-01

    Colorectal cancer (CRC) is the third most common cause of death due to cancer in the worldwide and the incidence is also increasing in Turkey. Our present aim was to investigate any association between germ-line methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and CRC risk in Turkey. A total of 86 CRC cases and 212 control individuals of the same ethnicity were included in the current study. Peripheral blood-DNA samples were used for genotyping by StripAssay technique, based on the reverse- hybridization principle and real-time PCR methods. Results were compared in Pearson Chi-square and multiple logistic regression models. The MTHFR 677TT (homozygous) genotype was found in 20.9% and the T allele frequency 4.2-fold increased in CRC when compared with the control group.The second SNP MTHFR 1298CC (homozygous) genotype was found in 14.0% and the C allele frequency 1.4-fold elevated in the CRC group. The current data suggest strong associations between both SNPs of germ-line MTHFR 677 C>T and 1298 A>C genotypes and CRC susceptibility in the Turkish population. Now the results need to be confirmed with a larger sample size. PMID:25292054

  5. Association between Hcy levels and the CBS844ins68 and MTHFR C677T polymorphisms with essential hypertension

    PubMed Central

    CAI, WEIJUAN; YIN, LIANG; YANG, FANG; ZHANG, LEI; CHENG, JIANG

    2014-01-01

    The aim of the present study was to investigate the association between the homocysteine (Hcy) levels and polymorphisms of the CBS844ins68 and MTHFR C677T genes in essential hypertension (EH). The effects of the MTHFR C677T and CBS844ins68 haploid genotypes and the combined genotypes on EH and levels of Hcy were further explored. The polymorphisms of CBS844ins68 and MTHFR C677T genes in 200 EH and 200 normal tensive (NT) patients were detected using polymerase chain reaction-restriction fragment length polymorphism and analysis of the distribution of genotypes. An automated biochemical analyzer was used to measure the plasma Hcy levels and the clinical biochemistry data. The plasma Hcy levels in EH were significantly higher than those of the NT group (P<0.05). There were no significant differences (P>0.05) between males and females. Two genotypes, deletion/deletion (DD) and deletion/insertion (DI), of the CBS844ins68 polymorphism were found in two groups with no clear differences in two genotypes and allele frequency distribution (P>0.05). There were significant differences in the three genotype frequencies (?2=6.658, ?2=4.410, P<0.05) for MTHFR C677T locus genotypes CC, CT and TT. The Hcy levels in genotypes DD and DI had no significant differences (P>0.05) and the CT and TT types were significantly higher compared to the CC genotype (P<0.05). The CC/DD combined genotype in the two groups was significantly different (P<0.05), and the odds ratio (OR), 0.569 showed that the CC/DD genotype may be a protective factor of hypertension. In the two groups, the Hcy levels for combined genotypes CC/DD, CT/DD, TT/DD and TT/DI were significantly different (P<0.05). The SHEsis software analysis linkage disequilibrium coefficient=0.216, indicates that there is probably a weak linkage for MTHFR C677T and CBS844ins68. Haplotype analysis suggested that the C-D haplotype was negatively correlated with EH (OR, 0.727) and that there was a positive correlation between T-D haplotype and EH (OR, 1.376). MTHFR C677T and CBS844ins68 polymorphisms were present in the populations studied and the CBS844ins68 homozygous mutation was not present. Therefore, there is a correlation between the polymorphisms of the MTHFR C677T gene and EH, and allele T may be one of the predisposing factors. MTHFR C677T and CBS844ins68 may exist with a certain linkage and the T-D haplotype may be a risk factor for EH. PMID:25279160

  6. Association between Hcy levels and the CBS844ins68 and MTHFR C677T polymorphisms with essential hypertension.

    PubMed

    Cai, Weijuan; Yin, Liang; Yang, Fang; Zhang, Lei; Cheng, Jiang

    2014-11-01

    The aim of the present study was to investigate the association between the homocysteine (Hcy) levels and polymorphisms of the CBS844ins68 and MTHFR C677T genes in essential hypertension (EH). The effects of the MTHFR C677T and CBS844ins68 haploid genotypes and the combined genotypes on EH and levels of Hcy were further explored. The polymorphisms of CBS844ins68 and MTHFR C677T genes in 200 EH and 200 normal tensive (NT) patients were detected using polymerase chain reaction-restriction fragment length polymorphism and analysis of the distribution of genotypes. An automated biochemical analyzer was used to measure the plasma Hcy levels and the clinical biochemistry data. The plasma Hcy levels in EH were significantly higher than those of the NT group (P<0.05). There were no significant differences (P>0.05) between males and females. Two genotypes, deletion/deletion (DD) and deletion/insertion (DI), of the CBS844ins68 polymorphism were found in two groups with no clear differences in two genotypes and allele frequency distribution (P>0.05). There were significant differences in the three genotype frequencies (?(2)=6.658, ?(2)=4.410, P<0.05) for MTHFR C677T locus genotypes CC, CT and TT. The Hcy levels in genotypes DD and DI had no significant differences (P>0.05) and the CT and TT types were significantly higher compared to the CC genotype (P<0.05). The CC/DD combined genotype in the two groups was significantly different (P<0.05), and the odds ratio (OR), 0.569 showed that the CC/DD genotype may be a protective factor of hypertension. In the two groups, the Hcy levels for combined genotypes CC/DD, CT/DD, TT/DD and TT/DI were significantly different (P<0.05). The SHEsis software analysis linkage disequilibrium coefficient=0.216, indicates that there is probably a weak linkage for MTHFR C677T and CBS844ins68. Haplotype analysis suggested that the C-D haplotype was negatively correlated with EH (OR, 0.727) and that there was a positive correlation between T-D haplotype and EH (OR, 1.376). MTHFR C677T and CBS844ins68 polymorphisms were present in the populations studied and the CBS844ins68 homozygous mutation was not present. Therefore, there is a correlation between the polymorphisms of the MTHFR C677T gene and EH, and allele T may be one of the predisposing factors. MTHFR C677T and CBS844ins68 may exist with a certain linkage and the T-D haplotype may be a risk factor for EH. PMID:25279160

  7. Contraception-related deep venous thrombosis and pulmonary embolism in a 17-Year-old girl heterozygous for factor V leiden, prothrombin G20210A mutation, MTHFR C677T and homozygous for PAI-1 mutation: report of a family with multiple genetic risk factors and review of the literature.

    PubMed

    Lenicek Krleza, Jasna; Jakovljevic, Gordana; Bronic, Ana; Coen Herak, Désirée; Bonevski, Aleksandra; Stepan-Giljevic, Jasminka; Roic, Goran

    2010-01-01

    We present the case of a 17-year-old girl who suddenly woke up with localized pain in the left groin and the inability to twist her leg. After comprehensive physician and laboratory examinations, deep venous thrombosis with consequent pulmonary embolism was ascertained. She had not experienced any recent trauma, but she had started to take oral contraceptives 6 months prior to the onset of the symptoms. Her parents and sisters had been asymptomatic throughout their lives, but the family history revealed a few thromboembolic accidents. Using DNA analysis, heterozygosity for factor V Leiden, prothrombin gene mutation G20210A and methylenetetrahydrofolate reductase C677T, as well as the homozygous 4G/4G genotype in the plasminogen activator inhibitor 1 were identified in our patient. Subsequently, DNA analysis was performed in all living family members, and multiple factors associated with thrombophilia were discovered. Our case confirms the multifactorial cause of thromboembolic events and emphasizes the importance of oral contraceptive use in the onset of venous thrombosis, especially in teenage females. In addition, this case indicates that teenage females with a family history of thrombosis who are making choices about contraception could most likely benefit from advanced thrombophilia testing. PMID:20664190

  8. Methylenetetrahydrofolate reductase polymorphisms C677T and risk of autism in the Chinese Han population.

    PubMed

    Guo, Tianyou; Chen, Hong; Liu, Bing; Ji, Weidong; Yang, Chuang

    2012-08-01

    Causes of autism are still unknown. Some studies have shown that autism might be associated with metabolic abnormalities in the folate/homocysteine pathway, which is involved in DNA methylation, thus altering gene expression. The association between the methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphisms and the risk of autism is still controversial and ambiguous. The purpose of this study was to examine the effect of the MTHFR C677T polymorphism on the autism risk in the Chinese Han population. A population-based case-control study was conducted in 186 children with autism and 186 controls. The MTHFR C677T polymorphisms were determined by using a polymerase chain reaction-restriction fragment length polymorphism assay. The frequency of genotype MTHFR 677TT in children with autism (16.1%) was significantly higher (odds ratio [OR]=2.04; 95% confidence interval [CI]=1.07, 3.89; p=0.03] than those in controls (8.6%). When stratifying by select-item scores on the Autism Diagnostic Interview-Revised, it was found that children with current overactivity had a significantly higher frequency of the MTHFR 677TT genotype (OR=2.77, 95% CI=1.17, 6.60; p=0.02) than those without. This study suggested that MTHFR C677T is a risk factor of autism in Chinese Han children. PMID:22775456

  9. Incidence Assessment of MTHFR C677T and A1298C Polymorphisms in Iranian Non-syndromic Cleft Lip and/or Palate Patients.

    PubMed

    Ebadifar, Asghar; Ameli, Nazila; Khorramkhorshid, Hamid Reza; Salehi Zeinabadi4, Mehdi; Kamali, Kourosh; Khoshbakht, Tayyebeh

    2015-01-01

    Background and aims. The aim of the present study is to determine the incidence of MTHFR C677 T and A1298C muta-tions in Iranian patients with cleft lip and/or cleft palate. Materials and methods. We screened 61 Iranian patients with cleft lip and/or cleft palate for mutations in the two alleles of MTHFR gene associated with cleft lip and/or palate: A1298C and C677T, using Polymerase Chain Reaction following by RFLP. Results. The 677T and 1298C homozygote genotypes showed a frequency of 36.1% and 11.4%, respectively. Combined genotype frequencies in newborns having oral clefts showed that the highest genotype was 677TT/1298AA (22.9%) and 677TT/1298CC genotypes were not observed. Conclusion. The results showed that 65.6% of all patients had at least one T mutant allele in C677T and 58.9% C mutant allele for A1298C. According to the frequencies of homozygosity of mutant alleles, it could be said that MTHFR genotype of 677TT shows a greater role in having oral clefts. PMID:26236436

  10. Incidence Assessment of MTHFR C677T and A1298C Polymorphisms in Iranian Non-syndromic Cleft Lip and/or Palate Patients

    PubMed Central

    Ebadifar, Asghar; Ameli, Nazila; Khorramkhorshid, Hamid Reza; Salehi Zeinabadi4, Mehdi; Kamali, Kourosh; Khoshbakht, Tayyebeh

    2015-01-01

    Background and aims. The aim of the present study is to determine the incidence of MTHFR C677 T and A1298C muta-tions in Iranian patients with cleft lip and/or cleft palate. Materials and methods. We screened 61 Iranian patients with cleft lip and/or cleft palate for mutations in the two alleles of MTHFR gene associated with cleft lip and/or palate: A1298C and C677T, using Polymerase Chain Reaction following by RFLP. Results. The 677T and 1298C homozygote genotypes showed a frequency of 36.1% and 11.4%, respectively. Combined genotype frequencies in newborns having oral clefts showed that the highest genotype was 677TT/1298AA (22.9%) and 677TT/1298CC genotypes were not observed. Conclusion. The results showed that 65.6% of all patients had at least one T mutant allele in C677T and 58.9% C mutant allele for A1298C. According to the frequencies of homozygosity of mutant alleles, it could be said that MTHFR genotype of 677TT shows a greater role in having oral clefts. PMID:26236436

  11. Prevalence of MTHFR C677T single nucleotide polymorphism in genetically isolated populations in Jordan.

    PubMed

    Dajani, Rana; Fathallah, Raja; Arafat, Ala; AbdulQader, Mohammed Emad; Hakooz, Nancy; Al-Motassem, Yousef; El-Khateeb, Mohammad

    2013-10-01

    Methylenetetrahydrofolate reductase (MTHFR) C677T single nucleotide polymorphism is a major inherited risk factor of venous thromboembolism. We sought to determine its prevalence in genetically isolated populations of Chechens and Circassians in Jordan. The MTHFR C677T mutation was analyzed from blood samples taken from 120 random unrelated Chechens and 72 Circassians. The prevalence of the MTHFR mutation in the Chechen population was 27.5% (allele frequency 15%); the prevalence among the Circassians was 50% (allele frequency 29.2%). The prevalence in the Chechen population is similar to that in Jordan and other world populations, but it is higher in the Circassian population. This study will contribute to understanding the interaction between genetic and environmental risk factors underlying thrombosis and will be useful in deciding which genetic variants should be tested in a clinical genetic testing service. PMID:23749065

  12. C677T methylenetetrahydrofolate reductase and plasma homocysteine levels among Thai vegans and omnivores.

    PubMed

    Kajanachumpol, Saowanee; Atamasirikul, Kalayanee; Tantibhedhyangkul, Phieuvit

    2013-01-01

    Hyperhomocysteinemia among vegetarians and vegans is caused mostly by vitamin B12 deficiency. A C-to-T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene results in a thermolabile MTHFR, which may affect homocysteine (Hcy) levels. The importance of this gene mutation among populations depends on the T allele frequency. Blood Hcy, vitamin B12, folate, vitamin B6, and MTHFR C677T mutation status were determined in 109 vegans and 86 omnivores aged 30 - 50 years. The vegans had significantly higher Hcy levels than the omnivores, geometric means (95 % CI) 19.2 (17.0 - 21.7) µmol/L vs. 8.53 (8.12 - 8.95) µmol/L, p < 0.001. A C-to-T mutation in the vegans increased plasma Hcy, albeit insignificantly; geometric means 18.2 µmol/L, 20.4 µmol/L, and 30.0 µmol/L respectively in CC, CT, and TT MTHFR genotypes. There was also a significant decrease in serum folate; geometric means 12.1 ng/mL, 9.33 ng/mL, and 7.20 ng/mL respectively, in the CC, CT, and TT mutants, p = 0.006, and particularly, in the TT mutant compared with the CC wild type, 7.20 ng/mL vs. 12.1 ng/mL, p = 0.023. These findings were not seen in the omnivores. It was concluded that hyperhomocysteinemia is prevalent among Thai vegans due to vitamin B12 deficiency. C-to-T MTHFR mutation contributes only modestly to the hyperhomocysteinemia. PMID:24491881

  13. Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and fluorouracil-based treatment in Taiwan colorectal cancer.

    PubMed

    Wu, Nai-Chun; Su, Shih-Ming; Lin, Tai-Jung; Chin, Jen; Hou, Chun-Fang; Yang, Jhong-Ying; Liu, Wen-Sheng; Chang, Li-Ching

    2015-09-01

    This study aimed to investigate the association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and the prognosis of colorectal cancer (CRC) patients undergoing 5-fluorouracil (5-FU)-based chemotherapy in Taiwan. We investigated 126 CRC cases. The most common polymorphisms C677T (rs1801133) and A1298C (rs1801131) in MTHFR were genotyped using PCR-restriction fragment length polymorphism. The frequencies of C677T and A1298C were further compared with those in the HapMap database for Whites and Asians. In this study, we found that TT-homozygosity at MTHFR C677T was significantly associated with survival in CRC patients [P<0.001; 95% confidence interval (CI)=0.068-0.212]. In CRC patients receiving 5-FU-based chemotherapy, the TT genotype at C677T was also significantly associated with survival (P=0.001; 95% CI=0.113-0.400) and recurrence after surgery (P<0.001; 95% CI=0.295-0.609). The A1298C genotypes had a significant impact on survival (χ=7.103; P=0.029). The MTHFR A1298C CC genotype may increase the risk of death in Taiwanese CRC patients. The MTHFR C677T TT genotype was present at a lower frequency in our CRC patients than in the HapMap Asian population, but the frequency was similar to that in Whites in the HapMap database. The distribution of MTHFR A1298C genotypes was similar in our CRC and in the HapMap Asian population, but was different from that in the White population. This study suggested that MTHFR C677T and A1298C are associated with prognosis in CRC patients undergoing 5-FU-based chemotherapy. PMID:26111049

  14. Prevalence of MTHFR C677T Polymorphism in North Indian Mothers Having Babies with Trisomy 21 Down Syndrome

    ERIC Educational Resources Information Center

    Kohli, Utkarsh; Arora, Sadhna; Kabra, Madhulika; Ramakrishnan, Lakshmy; Gulati, Sheffali; Pandey, Ravindra

    2008-01-01

    Recent studies have evaluated possible links between polymorphisms in maternal folate metabolism genes and Down syndrome. Some of these studies show a significantly increased prevalence of the C677T polymorphism of the 5,10-methylene tetrahydrofolate reductase (NADPH) gene (MTHFR) among mothers who have had babies with Down syndrome. This study

  15. Prevalence of MTHFR C677T Polymorphism in North Indian Mothers Having Babies with Trisomy 21 Down Syndrome

    ERIC Educational Resources Information Center

    Kohli, Utkarsh; Arora, Sadhna; Kabra, Madhulika; Ramakrishnan, Lakshmy; Gulati, Sheffali; Pandey, Ravindra

    2008-01-01

    Recent studies have evaluated possible links between polymorphisms in maternal folate metabolism genes and Down syndrome. Some of these studies show a significantly increased prevalence of the C677T polymorphism of the 5,10-methylene tetrahydrofolate reductase (NADPH) gene (MTHFR) among mothers who have had babies with Down syndrome. This study…

  16. Risk association of meningiomas with MTHFR C677T and GSTs polymorphisms: a meta-analysis.

    PubMed

    Ding, Hao; Liu, Wei; Yu, Xinyuan; Wang, Lei; Shao, Lingmin; Yi, Wei

    2014-01-01

    Previous studies have shown that the single nucleotide polymorphisms (SNPs) in Methylenetetrahydrofolate reductase (MTHFR) and Glutathione S-transferases (GSTs, including GSTM1, GSTT1) genes play an important role in determining the response of an individual to environmental pathogenesis and significantly relate to incidences of various human tumors, including brain tumors. However, these genes' polymorphisms on meningioma risk remains poorly understood. The relevant inferences from previous studies are hindered by their limited statistical power and conflicting results. The aim of this meta-analysis is to provide a relatively comprehensive account of the association between these polymorphisms and human meningioma risk. A literature search for eligible studies published before January 1, 2014 was conducted in PubMed, Embase, Web of Science, Cochrane Library, and CNKI databases. Pooled odds ratios (OR) with their corresponding 95% confidence intervals (95% CI) were used to evaluate the strength of the association under a fixed or random effect model according to heterogeneity test results. Heterogeneity and publication bias were evaluated. All statistical analyses were conducted by using the software of STATA 12.0 (STATA Corporation, College Station, TX, USA). For MTHFR C677T (dbSNP: rs1801133) (C T) polymorphism, 9 individual case-control studies from six publications with 1,615 cases and 1,909 controls were obtained. For GSTM1 null polymorphism, there were 4 studies with 417 cases and 1,735 controls. For GSTT1 null polymorphism, there were 4 studies with 405 cases and 1,622 controls. The combined results for the MTHFR C677T show that carriers of the CT genotype may be associated with a higher meningioma risk (OR = 1.20, 95% CI 1.05-1.38, P = 0.009). Stratified analyses show that Caucasians have significantly higher risk if they carry the CT genotype of MTHFR (OR = 1.31, 95% CI 1.05-1.63, P = 0.02). Risk of Caucasians carrying TT + CT genotype is also significantly higher (OR = 1.27, 95% CI 1.02-1.58, P = 0.03). Risk of Caucasians carrying TT genotype is not significantly different compared to control population (OR = 0.96, 95% CI 0.69-1.34, P = 0.82). All of the enrolled studies about GSTM1/GSTT1 are on Caucasians. The pooled ORGSTM1 and ORGSTT1 were not significant in Caucasian population. These results indicate SNPs of MTHFR C677T are related to meningioma risk with ethnic differences. Caucasians carrying CT genotype of MTHFR C677T have significantly higher meningioma susceptibility. SNPs of GSTM1/GSTT1 are not related to meningioma risk. PMID:25550898

  17. Status of vitamin B-12 and B-6 but not of folate, homocysteine and the methylenetetrahydrofolate reductase C677T polymorphism are associated with impaired cognition and depression in adults

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene differs in frequency in different ethnic groups which have differing prevalence of age-related cognitive impairments. We used a battery of neuropsychological tests to examine association of the MTHFR C677T polymorphism w...

  18. MTHFR C677T is not a risk factor for autism spectrum disorders in South Brazil.

    PubMed

    dos Santos, Pollyanna Almeida Costa; Longo, Dânae; Brandalize, Ana Paula Carneiro; Schüler-Faccini, Lavínia

    2010-08-01

    Many studies have suggested that autism may be associated with metabolic abnormalities in the folate/homocysteine pathway, which is involved in DNA methylation, thus altering gene expression. One of the most important polymorphisms in this pathway is C677T of the methylenetetrahydrofolate reductase gene, because the T allele is associated with a decrease in enzymatic activity. We evaluated the association between C677T polymorphism and autism spectrum disorders through a case--control study. In addition, we analyzed the influence of this polymorphism on certain autistic behaviors like complex body movements, self-injury and averted gaze according to the Autism Diagnostic Interview-Revised. The analyses involved 151 children with idiopathic autism spectrum disorder and 100 healthy control children. The frequency of the T allele was 0.38 for the case group and 0.35 for the control group (P=0.77). The genotypic distribution did not show significant differences between cases and controls (P=0.72), nor association between the T allele and selected behaviors. PMID:20440228

  19. In human alleles specific variation of MTHFR C677T and A1298C associated "risk factor" for the development of ovarian cancer.

    PubMed

    Singh, Anupama; Pandey, S; Pandey, L K; Saxena, Ajit K

    2015-01-01

    Etiopathology of tumor biology is highly complex and ovarian cancer is one of the important gynaecological neoplasia associated with high risk of mortality rate. Methlenetetrahydrofolate reductase (MTHFR) mutation are commonly linked to folate metabolism with increased risk factor for the development of neural tube defects, recurrent pregnancy loss and development of several type of cancer but genetic interaction between two alleles of MTHFR has been poorly defined in ovarian cancer in India. Hence, present study becomes imperative with the aim to assess the alleles frequency of MTHFR (C677T & A1298C) gene polymorphism using PCR based RFLP analysis. The O.R at 95% confidence interval (C.I.) was computed between cases and their respective controls to determine "risk factor". Interestingly, our findings reveals highly significant (p < 0.001) difference in heterozygous (CT) condition of C677T allele by computing odd ratio (0.12 at 95% C.I, 0.021-0.0428; P for trend = 0.001) in controls and (0.34 at 95% C.I, 0.074-1.530; P for trend = 0.198) cases, suggesting that three time increase the "risk factor" for genetic susceptibility of MTHFR "T" allele for the development of ovarian carcinoma. PMID:26259392

  20. MTHFR C677T polymorphism and differential methylation status in gastric cancer: an association with Helicobacter pylori infection.

    PubMed

    Neves Filho, Eduardo Henrique Cunha; Alves, Markenia Kelia Santos; Lima, Valeska Portela; Rabenhorst, Silvia Helena Barem

    2010-12-01

    MTHFR C677T and Helicobacter pylori infection are believed to play critical roles in the DNA methylation process, an epigenetic feature frequently found in gastric cancer. The aim of this study was to verify the associations between the MTHFR C677T polymorphism and the methylation status of three gastric cancer-related genes. The influence of H. pylori strains was also assessed. DNA extracted from 71 gastric tumor samples was available for MTHFR C677T genotyping by PCR-RFLP, promoter methylation identification by MS-PCR and H. pylori detection and posterior subtyping (cagA and vacA genes) by PCR. In the distal tumors, a positive correlation was found between the methylation of CDKN2A and the allele T carriers (r=0.357; p=0.009). Considering the eldest patients (age ?60 years old), this correlation was even higher (r=0,417; p=0.014). H. pylori infection by highly pathogenic strains (cagA+/vacAs1m1) was also found correlated to promoter methylation of CDKN2A and the allele T carriers in distal tumors (r=0.484; p=0.026). No significant correlation was verified between MTHFR C677T genotype and promoter methylation status when we analyzed the general sample. DNA methylation in CDKN2A associated to the MTHFR 677T carrier is suggested to be a distal tumor characteristic, especially in those 60 years old or older, and it seems to depend on the infection by H. pylori cagA/vacAs1m1 strains. PMID:20957490

  1. Role of MTHFR C677T and MTR A2756G polymorphisms in thyroid and breast cancer development.

    PubMed

    Zara-Lopes, T; Gimenez-Martins, A P A; Nascimento-Filho, C H V; Castanhole-Nunes, M M U; Galbiatti-Dias, A L S; Padovani-Júnior, J A; Maniglia, J V; Francisco, J L E; Pavarino, E C; Goloni-Bertollo, E M

    2016-01-01

    Folate metabolism is essential for DNA synthesis and repair. Alterations in genes that participate in folate metabolism can be associated with several types of malignant neoplasms, including thyroid and breast cancer. In the present case-control study, we examined the association between methylenetetrahydrofolate reductase (MTHFR C677T, rs1801133) and methionine synthase (MTR A2756G, rs1805087) polymorphisms and risk for thyroid and breast cancer. Polymerase chain reaction-restriction fragment length technique was used to determine the specific genotypes in the genes of interest. Statistical analysis was performed by multiple logistic regression test. We found an association between MTHFR C677T polymorphism and risks to both thyroid (OR = 2.50; 95%CI = 1.15-5.46; P = 0.02) and breast cancer (OR = 2.53; 95%CI = 1.08-5.93; P = 0.03). Tobacco consumption and high body mass index were also associated with thyroid cancer. In addition, increased age (≥50 years) and alcohol consumption were found to be associated with breast cancer. Our results indicated that MTHFR C677T is significantly associated with thyroid and breast cancer risks. Thus, these factors may be used as potential prognostic markers for thyroid and breast cancers. PMID:27173331

  2. Association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and age of onset in schizophrenia.

    PubMed

    Vares, Maria; Saetre, Peter; Deng, Hong; Cai, Guiqing; Liu, Xiehe; Hansen, Thomas; Rasmussen, Henrik B; Werge, Thomas; Melle, Ingrid; Djurovic, Srdjan; Andreassen, Ole A; Agartz, Ingrid; Hall, Hkan; Terenius, Lars; Jnsson, Erik G

    2010-03-01

    Different lines of evidence indicate that methylenetetrahydrofolate reductase (MTHFR) functional gene polymorphisms, causative in aberrant folate-homocysteine metabolism, are associated with increased vulnerability to several heritable developmental disorders. Opposing views are expressed considering the possible association between MTHFR and susceptibility for schizophrenia. In order to evaluate if age of onset could explain some of this discrepancy we investigated the relationship between two functional MTHFR gene polymorphisms and age at onset in this disorder. Scandinavian patients (n = 820) diagnosed with schizophrenia, schizoaffective disorder, and schizophreniform disorder were investigated. Two functional MTHFR single nucleotide polymorphisms (SNPs; rs1801131 and rs1801133) were genotyped and the effect of MTHFR polymorphisms on the age of onset was examined with survival analysis. In an attempt to replicate the findings from the Scandinavian sample, the association between rs1801133 and age at onset was also analyzed in Chinese high-risk families, with two or more affected siblings (n = 243). Among the Scandinavian patients the functional MTHFR SNP rs1801133 (C677T) significantly affected age at onset of schizophrenia in a dose-dependent manner (P = 0.0015), with lower age of onset with increasing numbers of the mutant T-allele. There was no evidence of rs1801131 (A1298C) affecting age of onset in schizophrenia. Within the Chinese high-risk families carriers of the MTHFR 677T allele showed earlier age at onset than siblings being homozygous for the wild-type allele (P = 0.008). The MTHFR C677T polymorphism may play a role as a modifying factor for age of onset in schizophrenia. PMID:19746410

  3. Association of the Maternal MTHFR C677T Polymorphism with Susceptibility to Neural Tube Defects in Offsprings: Evidence from 25 Case-Control Studies

    PubMed Central

    Zou, Peng; Ji, Guixiang; Gu, Aihua; Zhao, Peng

    2012-01-01

    Background Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism and is involved in DNA methylation, DNA synthesis, and DNA repair. In addition, it is a possible risk factor in neural tube defects (NTDs). The association of the C677T polymorphism in the MTHFR gene and NTD susceptibility has been widely demonstrated, but the results remain inconclusive. In this study, we performed a meta-analysis with 2429 cases and 3570 controls to investigate the effect of the MTHFR C677T polymorphism on NTDs. Methods An electronic search of PubMed and Embase database for papers on the MTHFR C677T polymorphism and NTD risk was performed. All data were analysed with STATA (version 11). Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association. Sensitivity analysis, test of heterogeneity, cumulative meta-analysis, and assessment of bias were performed in our meta-analysis. Results A significant association between the MTHFR C677T polymorphism and NTD susceptibility was revealed in our meta-analysis ( TT versus CC: OR ?=?2.022, 95% CI: 1.508, 2.712; CT+TT versus CC: OR ?=?1.303, 95% CI: 1.089, 1.558; TT versus CC+CT: OR ?=?1.716, 95% CI: 1.448, 2.033; 2TT+CT versus 2CC+CT: OR ?=?1.330, 95% CI: 1.160, 1.525). Moreover, an increased NTD risk was found after stratification of the MTHFR C677T variant data by ethnicity and source of controls. Conclusion The results suggested the maternal MTHFR C677T polymorphism is a genetic risk factor for NTDs. Further functional studies to investigate folate-related gene polymorphisms, periconceptional multivitamin supplements, complex interactions, and the development of NTDs are warranted. PMID:23056169

  4. Association between methylenetetrahydrofolate reductase C677T polymorphism and psoriasis: A meta-analysis.

    PubMed

    Wu, Dongze; Shi, Deshun; Yang, Li; Zhu, Xiaoliang

    2016-02-01

    Several studies have evaluated the associations between methylenetetrahydrofolate reductase (MTHFR) C677T and psoriasis. However, the results remain inconclusive. The objective of the present study was to conduct a qualitative and quantitative meta-analysis investigating the associations between MTHFR C677T and psoriasis. A published work search of PubMed, Embase, Web of Science and Chinese National Knowledge Infrastructure database were conducted to identify all publications concerning MTHFR C677T polymorphism and psoriasis on 1 October 2014. The principal outcome measure for evaluating the strength of the association was crude odds ratios along with their corresponding 95% confidence intervals. Data were extracted and statistical analyses were implemented using STATA version 12.0 software. A total of 1179 psoriatic cases and 937 controls from five case-control studies concentrating on the association between MTHFR C677T polymorphism and psoriasis were included in this qualitative meta-analysis. Pooled analysis revealed that there is no association between this polymorphism and susceptibility to psoriasis in dominant, recessive, allele and additive models under a random-effect model. However, a marginal significant association was found in the overdominant model under fixed-effect model. Subgroup analysis of ethnicity demonstrated that there is no association between MTHFR C677T polymorphism and either Asian or European psoriatic patients. In conclusion, MTHFR C677T polymorphism, qualitatively, is not a genetic factor for the pathogenesis of psoriasis but could quantitatively reflect the severity of psoriasis to some extent. PMID:26212228

  5. Prevalence of MTHFR C677T and MS A2756G polymorphisms in major depressive disorder, and their impact on response to fluoxetine treatment

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To examine the prevalence of the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and the A2756G polymorphism of methionine synthase (MS), and their impact on antidepressant response. We screened 224 subjects (52% female, mean age 39 +/- 11 years) with SCID-diagnosed major...

  6. The MTHFR C677T Polymorphism and Risk of Intracerebral Hemorrhage in a Chinese Han Population.

    PubMed

    Hu, Xin; Tao, Chuanyuan; Xie, Zhiyi; Li, Yunke; Zheng, Jun; Fang, Yuan; Lin, Sen; Li, Hao; You, Chao

    2016-01-01

    BACKGROUND Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism has been speculated to be and extensively investigated as a risk factor for various vascular diseases, including intracerebral hemorrhage (ICH). However, results from published studies regarding the role of C677T polymorphism in ICH risk in Chinese populations were contradictory rather than conclusive. MATERIAL AND METHODS In this study, a total of 180 ICH patients and 180 matched controls of Chinese Han ethnicity were enrolled. The MTHFR C677T polymorphism was genotyped by polymerase chain reaction-ligation detection reaction (PCR-LDR). A meta-analysis was conducted by combining our data with previous relevant studies in Chinese populations. RESULTS In our case-control study, similar allele frequency (p=0.492) and genotype distribution (p=0.748) of MTHFR C677T polymorphism were detected between ICH patients and controls. Further analysis based on hematoma location did not show a significant association. When combined with previous studies, however, C677T polymorphism was found to be significantly associated with an increased risk for ICH in Chinese populations (recessive model: OR=1.57, 95%CI=1.29-1.91). When focusing on the Han ethnicity, carriers of the TT genotype had an increased risk of ICH (recessive model: OR=1.36, 95%CI=1.05-1.75). CONCLUSIONS In this case-control study we did not observe that the MTHFR C677T polymorphism was associated with ICH risk in people of Chinese Han ethnicity. However, when combined with previous published studies, a significant association of C677T polymorphism with an increased risk of ICH was detected in Chinese populations, and also in the subgroup analysis focusing on Han ethnicity. PMID:26757363

  7. The MTHFR C677T Polymorphism and Risk of Intracerebral Hemorrhage in a Chinese Han Population

    PubMed Central

    Hu, Xin; Tao, Chuanyuan; Xie, Zhiyi; Li, Yunke; Zheng, Jun; Fang, Yuan; Lin, Sen; Li, Hao; You, Chao

    2016-01-01

    Background Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism has been speculated to be and extensively investigated as a risk factor for various vascular diseases, including intracerebral hemorrhage (ICH). However, results from published studies regarding the role of C677T polymorphism in ICH risk in Chinese populations were contradictory rather than conclusive. Material/Methods In this study, a total of 180 ICH patients and 180 matched controls of Chinese Han ethnicity were enrolled. The MTHFR C677T polymorphism was genotyped by polymerase chain reaction-ligation detection reaction (PCR-LDR). A meta-analysis was conducted by combining our data with previous relevant studies in Chinese populations. Results In our case-control study, similar allele frequency (p=0.492) and genotype distribution (p=0.748) of MTHFR C677T polymorphism were detected between ICH patients and controls. Further analysis based on hematoma location did not show a significant association. When combined with previous studies, however, C677T polymorphism was found to be significantly associated with an increased risk for ICH in Chinese populations (recessive model: OR=1.57, 95%CI=1.29–1.91). When focusing on the Han ethnicity, carriers of the TT genotype had an increased risk of ICH (recessive model: OR=1.36, 95%CI=1.05–1.75). Conclusions In this case-control study we did not observe that the MTHFR C677T polymorphism was associated with ICH risk in people of Chinese Han ethnicity. However, when combined with previous published studies, a significant association of C677T polymorphism with an increased risk of ICH was detected in Chinese populations, and also in the subgroup analysis focusing on Han ethnicity. PMID:26757363

  8. A novel lateral flow assay based on GoldMag nanoparticles and its clinical applications for genotyping of MTHFR C677T polymorphisms.

    PubMed

    Hui, Wenli; Zhang, Sinong; Zhang, Chao; Wan, Yinsheng; Zhu, Juanli; Zhao, Gang; Wu, Songdi; Xi, Dujuan; Zhang, Qinlu; Li, Ningning; Cui, Yali

    2016-02-14

    Current techniques for single nucleotide polymorphism (SNP) detection require tedious experimental procedures and expensive and sophisticated instruments. In this study, a visual genotyping method has been successfully established via combining ARMS-PCR with gold magnetic nanoparticle (GoldMag)-based lateral flow assay (LFA) and applied to the genotyping of methylenetetrahydrofolate reductase (MTHFR) C677T. C677T substitution of the gene MTHFR leads to an increased risk of diseases. The genotyping result is easily achievable by visual observation within 5 minutes after loading of the PCR products onto the LFA device. The system is able to accurately assess a broad detection range of initial starting genomic DNA amounts from 5 ng to 1200 ng per test sample. The limit of detection reaches 5 ng. Furthermore, our PCR-LFA system was applied to clinical trials for screening 1721 individuals for the C677T genotypes. The concordance rate of the genotyping results detected by PCR-LFA was up to 99.6% when compared with the sequencing results. Collectively, our PCR-LFA has been proven to be rapid, accurate, sensitive, and inexpensive. This new method is highly applicable for C677T SNP screening in laboratories and clinical practices. More promisingly, it could also be extended to the detection of SNPs of other genes. PMID:26804455

  9. A novel lateral flow assay based on GoldMag nanoparticles and its clinical applications for genotyping of MTHFR C677T polymorphisms

    NASA Astrophysics Data System (ADS)

    Hui, Wenli; Zhang, Sinong; Zhang, Chao; Wan, Yinsheng; Zhu, Juanli; Zhao, Gang; Wu, Songdi; Xi, Dujuan; Zhang, Qinlu; Li, Ningning; Cui, Yali

    2016-02-01

    Current techniques for single nucleotide polymorphism (SNP) detection require tedious experimental procedures and expensive and sophisticated instruments. In this study, a visual genotyping method has been successfully established via combining ARMS-PCR with gold magnetic nanoparticle (GoldMag)-based lateral flow assay (LFA) and applied to the genotyping of methylenetetrahydrofolate reductase (MTHFR) C677T. C677T substitution of the gene MTHFR leads to an increased risk of diseases. The genotyping result is easily achievable by visual observation within 5 minutes after loading of the PCR products onto the LFA device. The system is able to accurately assess a broad detection range of initial starting genomic DNA amounts from 5 ng to 1200 ng per test sample. The limit of detection reaches 5 ng. Furthermore, our PCR-LFA system was applied to clinical trials for screening 1721 individuals for the C677T genotypes. The concordance rate of the genotyping results detected by PCR-LFA was up to 99.6% when compared with the sequencing results. Collectively, our PCR-LFA has been proven to be rapid, accurate, sensitive, and inexpensive. This new method is highly applicable for C677T SNP screening in laboratories and clinical practices. More promisingly, it could also be extended to the detection of SNPs of other genes.

  10. Homocysteine and methylenetetrahydrofolate reductase C677T and A1298C polymorphisms in Tunisian patients with severe coronary artery disease.

    PubMed

    Ghazouani, Lakhdar; Abboud, Nesrine; Mtiraoui, Nabil; Zammiti, Walid; Addad, Faouzi; Amin, Haitham; Almawi, Wassim Y; Mahjoub, Touhami

    2009-02-01

    Elevation in homocysteine and methylenetetrahydrofolate reductase (MTHFR) gene variants, C677T and A1298C, have been linked with atherothrombosis. However their exact contribution to coronary artery disease (CAD) remains controversial. Moreover, data from Tunisian patients are scarse. We examined the association of MTHFR C677T and A1298C, and changes in plasma homocysteine in 352 Tunisian patients with angiographically-demonstrated CAD, and 390 age and gender-matched healthy subjects. Significantly higher frequency of 677T allele and homozygous 677T/T genotype were seen in patients vs. control subjects; the distribution of A1298C alleles and genotypes being comparable in the two groups. Specific MTHFR haplotypes comprising 677C/1298A (P < 0.001) and 677T/1298A (P < 0.001) were negatively and positively associated with CAD, respectively. Plasma homocysteine concentration was significantly higher in 677T/T genotype with respect to 677C/C and 677C/T genotypes in patients and controls, but homocysteine levels were generally comparable between both groups. Univariate analysis identified 677T/1298A (P = 0.033) haplotype to be positively associated with CAD, which remained significant by multivariate analysis after adjusting for a number of covariates (P = 0.038). MTHFR C677T, but not A1298C SNPs, is associated with CAD and with elevated homocysteine levels in a Tunisian population. The negative and positive association of the 1298A allele with CAD being indicative of a neutral (absent) effect of the A1298C SNP on disease pathogenesis. PMID:18204887

  11. Methylenetetrahydrofolate reductase (MTHFR) polymorphism (C677T) in relation to homocysteine concentration in overweight and obese Thais.

    PubMed

    Thawnashom, Kittisak; Tungtrongchitr, Rungsunn; Petmitr, Songsak; Pongpaew, Praneet; Phonrat, Benjaluck; Tungtrongchitr, Anchalee; Schelp, Frank Peter

    2005-03-01

    We analyzed the association between MTHFR (C677T) gene polymorphism with serum concentrations of homocysteine, folate, and vitamin B12 in 37 male and 112 female overweight/ obese Thai volunteers (BMI > or = 25.00 kg/m2), and compared them with 23 male and 90 female control subjects (BMI = 18.5-24.99 kg/m2). Statistically significant higher levels of serum homocysteine were found in the overweight/obese subjects than the control subjects (p < 0.05). Serum folic acid levels in the overweight/obese subjects were significantly lower than the control subjects (p < 0.05). When the data were grouped according to homocysteine concentration and MTHFR gene polymorphism, there were significantly higher homocysteine concentrations in the overweight/obese subjects than the control subjects in wild type gene polymorphism (CC) in the hyperhomocysteine group (homocysteine >10.0 mmol/l) (p < 0.05), but in genotype polymorphism (CC, CT, TT) there were lower folic acid and vitamin B12 concentrations in the overweight/obese subjects than in the control subjects. In the hyperhomocysteine groups, there was no significant difference in the frequencies of MTHFR (C677T) gene polymorphism between the overweight/obese subjects and the control subjects. Folic acid and gene polymorphism were found to be significantly related to the overweight/ obese and control groups in logistic regression analysis (p < 0.05). The results support the supposition that folic acid is more important than vitamin B12. PMID:15916056

  12. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and high plasma homocysteine in chronic hepatitis C (CHC) infected patients from the Northeast of Brazil

    PubMed Central

    2011-01-01

    Background/Aim Hyperhomocysteinemia due to Methylenetetrahydrofolate Reductase (MTHFR) gene, in particular the C677T (Ala222Val) polymorphism were recently associated to steatosis and fibrosis. We analyzed the frequency of MTHFR gene in a cross-sectional study of patients affected by Chronic Hepatitis C (CHC) from Northeast of Brazil. Method One hundred seven-four untreated patients with CHC were genotyped for the C677T MTHFR. Genomic DNA was extracted from peripheral blood cells and the C677T MTHFR polymorphism was identified by PCR-RFLP. The homocysteine (Hcy) levels were determined by chemiluminescence method. All patients were negative for markers of Wilson's disease, hemochromatosis and autoimmune diseases and have current and past daily alcohol intake less than 100 g/week. Results Among subjects infected with CHC genotype non-1 the frequency of MTHFR genotypes TT was 9.8% versus 4.4% genotype 1 (p = 0.01). Nevertheless, association was found between the MTHFR genotype TT CT/CC polymorphism and the degree of steatosis and fibrosis in both hepatitis C genotype (p < 0.05). A significant difference was found on plasma Hcy levels in patients with steatosis regardless of HCV genotype (p = 0.03). Conclusion Our results indicate that plasma Hcy levels is highly prevalent in subjects with chronic hepatits C with steatosis regardless of HCV genotype and vitamin deficiency. The presence of genotype TT of MTHFR C677T polymorphism was more common in CHC genotype non-1 infected patient regardless of histopathological classification and genotype TT+CT frequencies were significant in the presence of fibrosis grade 1+2 and of steatosis in CHC infected patients from the northeast of Brazil regardless of HCV genotype. The genetic susceptibility of MTHFR C677T polymorphism should be confirmed in a large population. PMID:21854603

  13. Role of Hyperhomocysteinemia and Methylene Tetrahydrofolate Reductase C677T Polymorphism in Idiopathic Portal Vein Thrombosis

    PubMed Central

    Ghaznavi, Habib; Soheili, Zahra; Samiei, Shahram; Soltanpour, Mohammad Soleiman

    2016-01-01

    Purpose: Portal vein thrombosis (PVT) is a rare and life-threatening vascular disorder characterized by obstruction or narrowing of the portal vein. Hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism has been studied in PVT patients with conflicting results. In the present study the association of hyperhomocysteinemia and MTHFR C677T polymorphism with PVT risk was investigated in Iranians. Materials and Methods: Our study population consisted of 10 idiopathic PVT patients and 80 healthy control subjects matched for age and sex. MTHFR C677T polymorphism was genotyped by the polymerase chain reaction technique combined with restriction enzyme fragment length polymorphism (PCR-RFLP) technique and plasma total homocysteine (tHcy) levels were determined by enzyme immunoassay method. Results: Mean plasma tHcy levels were significantly higher in PVT patients (20.2±6.8) than control subjects (10.9±4.7) (P=0.001). Moreover, plasma tHcy levels were significantly higher in 677T allele carriers relative to 677C allele carriers in both PVT patients (P=0.01) and control subjects (P=0.03). Neither homozygote nor heterozygote genotypes of MTHFR C677T polymorphism correlated significantly with PVT risk (P>0.05). Moreover, MTHFR C677T polymorphism didn’t increase the risk of PVT under dominant (CT+TT vs. CC) or recessive (TT vs. CC+CT) genetic models analyzed (P>0.05). The difference in frequency of minor 677T allele between PVT patients and control subjects was not statistically significant (P>0.05). Conclusion: Based on the current study, we suggest that hyperhomocysteinemia constitutes a significant and common risk factor for PVT. Also, MTHFR C677T polymorphism is not a risk factor for PVT but is a contributing factor for elevated plasma tHcy levels. PMID:27051654

  14. Total plasma homocysteine and methylenetetrahydrofolate reductase C677T polymorphism in patients with colorectal carcinoma

    PubMed Central

    Battistelli, Sandra; Vittoria, Aurelio; Stefanoni, Massimo; Bing, Camilla; Roviello, Franco

    2006-01-01

    AIM: To investigate the behaviour of total plasma homocysteine (tHcy) and its most common genetic determinant defect, the methylenetetrahydrofolate reductase C677T (C677TMTHFR) polymorphism in patients with early stage colorectal carcinoma. METHODS: tHcy was quantified by Abbott IMx immunoassay; screening for C677TMTHFR substitution was performed by PCR and restriction analysis. RESULTS: The frequency of the C/T and T/T genotypes of the C677TMTHFR gene polymorphism did not differ between the groups. The mean tHcy was statistically higher in cancer patients than in control subjects carrying the same C/C or C/T genotype, whereas there was no difference in the T/T homozygous carriers of the two groups. tHcy was significantly higher in the T/T homozygous carriers than in C/C and C/T genotype carriers. CONCLUSION: The statistically significant increase of tHcy observed in C/C and C/T genotype carriers among our cancer patients is related to substrate consumption dependent on the tumor cell proliferation rate, whereas the tHcy increase observed in T/T genotype carriers of both groups probably depends on the enzymatic deficit of the homocysteine conversion to methionine and/or on the folate deficiency. PMID:17036383

  15. The protective effect of methylenetetrahydrofolate reductase C677T polymorphism against prostate cancer risk: Evidence from 23 case-control studies.

    PubMed

    Guo, Shanqi; Jiang, Xingkang; Chen, Xiaobo; Chen, Liang; Li, Xiaojiang; Jia, Yingjie

    2015-07-01

    Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) were considered to have some influence on both folate metabolism and cancer risk. Previous studies on the relation between MTHFR C677T polymorphism and prostate cancer (PCa) risk remained controversial. To derive a more precise estimation of the relationship, we carried out an update comprehensive meta-analysis to assess the associations of the MTHFR C677T polymorphism with the susceptibility of PCa. Twenty-three trials with a total of 24,024 participants on the MTHFR C677T polymorphism that met inclusion criteria were analyzed in the current study. Overall, no statistical relationship was found with any MTHFR C677T genetic model associated with susceptibility to PCa (TT versus CC, OR=0.83, 95% CI 0.68-1.02, P=0.07; CT versus CC, OR=0.95, 95% CI 0.85-1.07, P=0.43; Dominant, OR=0.93, 95% CI 0.83-1.03, P=0.17; Recessive, OR=0.84, 95% CI 0.70-1.02, P=0.09.). Nevertheless, subgroup analysis found a reduced PCa risk associated with polymorphism in Asian population (TT versus CC, CT versus CC, dominant and recessive model). Moreover, the protective effect of polymorphism against PCa risk was also shown upon hospital-based studies (TT versus CC, and recessive model). When benign prostate hyperplasia was chosen as controls, both TT versus CC and recessive model showed significant difference. In addition, the protective effect of homozygote TT against high aggressive PCa was proved to have significant difference. Taken together, the existing evidence indicates the homozygote TT of MTHFR C677T should be viewed as a protective factor against PCa risk for clinical practice with the consideration of different gene background, study design as well as specific controls. PMID:25841988

  16. C677T and A1298C MTHFR polymorphisms, a challenge for antifolate and fluoropyrimidine-based therapy personalisation.

    PubMed

    De Mattia, Elena; Toffoli, Giuseppe

    2009-05-01

    Pharmacogenetics represents an exciting, new promising tool for the individualisation of therapy. Several genetic polymorphisms and haplotypes have been considered in an attempt to optimise therapy with specific drugs but, up to now, their clinical applications remain limited. 5,10-Methylenetetrahydrofolate reductase (MTHFR), a key enzyme of one-carbon metabolism, catalyses the irreversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. Two common non-synonymous variants, the C677T (Ala222Val) and A1298C (Glu429Ala), were described for the MTHFR gene and associated with a decreased enzymatic activity and an alteration of intracellular folate distribution. Other MTHFR polymorphisms with marginal impact on enzymatic activity were also reported. Several published clinical studies have investigated the potential predictive role of C677T and A1298C genetic variants on toxicity and efficacy of antifolate and fluoropyrimidine agents, such as methotrexate (MTX), 5-fluorouracil (5-FU) and raltitrexed. Many of these studies show significant associations with MTHFR variants, but others report neither association nor opposite results. A significant interaction between MTHFR polymorphisms and nutrient/environmental factors (i.e. folate status) as well as the ethnicity was reported. Finally, a haplotype approach and the combined analysis of multiple folate pathway gene variants seem to provide a more comprehensive strategy compared to single-locus investigations. The aim of this review is to critically analyse the available data on the importance of MTHFR polymorphisms in modulating the clinical outcome of antifolate and fluoropyrimidine therapies. PMID:19144510

  17. Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and gastric cancer susceptibility

    PubMed Central

    Xia, Lei-Zhou; Liu, Yi; Xu, Xiao-Zhou; Jiang, Peng-Cheng; Ma, Gui; Bu, Xue-Feng; Zhang, Yong-Jun; Yu, Feng; Xu, Ke-Sen; Li, Hua

    2014-01-01

    AIM: To identify the association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and gastric cancer (GC) susceptibility. METHODS: Systematic searches were performed on the electronic databases PubMed, ISI, Web of knowledge, CNKI and Wanfang, as well as manual searching of the references of the identified articles. A total of 26 papers were included in this meta-analysis. Overall and subgroup analyses were performed. Odds ratio (OR) and 95%CI were used to evaluate the associations between MTHFR polymorphisms and GC risk. The I2 statistics were used to evaluate between-study heterogeneity. Sensitivity analysis was also performed. RESULTS: Increased risk was found for the MTHFR C677T polymorphism under four genetic models (TT + CT vs CC: OR = 1.23, P = 0.002; T vs C: OR = 1.15, P = 0.001; TT vs CC: OR = 1.37, P = 0.0005; TT vs CT + CC: OR = 1.17, P = 0.0008). Subgroup analysis by ethnicity suggested that C677T polymorphism conferred a risk of GC in eastern but not in western populations. Stratification by tumor site showed an association between the C677T polymorphism and gastric cardia cancer and non-cardia GC in the worldwide population and in eastern populations. Regardless of comparisons with controls or diffuse-type GC, a positive association was found for the C677T polymorphism and an increased risk of intestinal-type GC in the whole population and in western populations. With regard to the A1298C polymorphism, we found that genotype CC was significantly decreased and conferred protection against GC in eastern populations (CC vs AA: OR = 0.44, P = 0.03; CC vs AC + AA: OR = 0.46, P = 0.04). CONCLUSION: MTHFR C677T polymorphism is a risk factor for GC, and the A1298C polymorphism may be a protective factor against GC in eastern populations. PMID:25170232

  18. The MTHFR C677T Variant is Associated with Responsiveness to Disulfiram Treatment for Cocaine Dependency

    PubMed Central

    Spellicy, Catherine J.; Kosten, Thomas R.; Hamon, Sara C.; Harding, Mark J.; Nielsen, David A.

    2013-01-01

    Objective: Disulfiram is a one of the few pharmacotherapies for cocaine addiction that shows promise. Since disulfiram and cocaine both affect levels of global methylation we hypothesized the MTHFR gene, whose product is involved in supplying methyl groups for DNA and protein methylation, may be associated with responsiveness to disulfiram in cocaine-dependent individuals. Methods: Sixty-seven cocaine-dependent patients were stabilized on methadone for 2 weeks and then randomized into disulfiram (250 mg/day, N = 32) and placebo groups (N = 35) for 10 weeks. Patients were genotyped for the MTHFR (rs1801133, also known as C677T) polymorphism and the data was evaluated for association with cocaine-free urines in the disulfiram or placebo groups. Data from patients that completed all 10 weeks of the study (N = 56) were analyzed using repeated measures analysis of variance (ANOVA), corrected for population structure. Results: The CT or TT MTHFR genotype group (N = 32) dropped from 73 to 52% cocaine-positive urines on disulfiram (p = 0.0001), while the placebo group showed no treatment effect. The CC MTHFR genotype group (N = 24) showed a smaller, but still significant, reduction in cocaine-positive urines on disulfiram compared to placebo; 81–69% (p = 0.007). Conclusion: This study indicates that a patient’s MTHFR genotype may be used to identify individuals who might show improved response to disulfiram treatment for cocaine dependence. Clinical Trial: Pharmacogenetics of Disulfiram for Cocaine, clinicaltrials.gov/ct2/show/NCT00149630, NIDA-18197-2, NCT00149630. PMID:23335901

  19. The impact of C677T and A1298C MTHFR polymorphisms on methotrexate therapeutic response in East Bohemian region rheumatoid arthritis patients.

    PubMed

    Soukup, Tomas; Dosedel, Martin; Pavek, Petr; Nekvindova, Jana; Barvik, Ivan; Bubancova, Iva; Bradna, Petr; Kubena, Ales Antonin; Carazo, Alejandro Fernández; Veleta, Tomas; Vlcek, Jiri

    2015-07-01

    Some single-nucleotide polymorphisms (SNPs) might be predictive of methotrexate (MTX) therapeutic outcome in rheumatoid arthritis (RA). The aim of this study was to determine whether SNPs in the methylenetetrahydrofolate reductase (MTHFR) gene are predictive of MTX response. Comparison was made using EULAR response criteria and according to the change of DAS28 (∆DAS28) after a 6-month MTX treatment in RA patient cohort. The two SNPs C677T (rs1801133) and A1298C (rs1801131) have been genotyped. A total of 120 patients were enrolled in the study, and all of them fulfilled the American College of Rheumatology 1987 RA criteria and are currently or previously taking MTX oral treatment, either as a monotherapy (n = 65) or in a combination with other disease-modifying antirheumatic drugs (n = 55). Genotyping was performed using qPCR allelic discrimination. We did not found any association of C677T and A1298C genotypes with MTX treatment inefficacy in dominant model (OR 1.23, 95 % CI 0.57-2.65, P = 0.697; and OR 0.98, 95 % CI 0.47-2.14, P = 1.0, respectively), or in recessive and codominant models. However, when ∆DAS28 after a 6-month therapy was used as a measure of treatment efficacy, the 677CT and 1298AC genotypes were found to be significantly associated with less favorable response to MTX (P = 0.025 and P = 0.043, respectively). In addition, even lower ∆DAS28 was determined for double-mutated 677CT-1298AC heterozygotes. It means that a synergistic effect of 677CT and 1298AC genotypes was observed. Nevertheless, the DAS28 baseline was lower here comparing to other genotypes. Unexpectedly, quite the opposite trend-i.e., better response to MTX-was found in genotypes 677CC-1298CC and 677TT-1298AA. It is an intriguing finding, because these double-mutated homozygotes are known for their low MTHFR-specific activity. Global significance was P = 0.013, η (2) = 0.160-i.e., large-size effect. Thus, our data show greater ability of 677CC-1298CC and 677TT-1298AA genotypes to respond to MTX treatment. PMID:25618758

  20. MTHFR C677T Polymorphism is Associated with Tumor Response to Preoperative Chemoradiotherapy: A Result Based on Previous Reports

    PubMed Central

    Zhao, Yue; Li, Xingde; Kong, Xiangjun

    2015-01-01

    Background Preoperative chemoradiotherapy (pRCT) followed by surgery has been widely practiced in locally advanced rectal cancer, esophageal cancer, gastric cancer and other cancers. However, the therapy also exerts some severe adverse effects and some of the patients show poor or no response. It is very important to develop biomarkers (e.g., gene polymorphisms) to identify patients who have a higher likelihood of responding to pRCT. Recently, a series of reports have investigated the association of the genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and epidermal growth factor receptor (EGFR) genes with the tumor response to pRCT; however, the results were inconsistent and inconclusive. Material/Methods A systematic review and meta-analysis was performed by searching relevant studies about the association of MTHFR and EGFR polymorphisms with the tumor regression grade (TRG) in response to pRCT in databases of PubMed, EMBAS, Web of science, Chinese National Knowledge Infrastructure, and Wanfang database up to March 30, 2015. The pooled odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs) were calculated to assess the strength of the association under 5 genetic models. Results A total of 11 eligible articles were included in the present meta-analysis, of which 8 studies were performed in rectal cancer and 3 studies were performed in esophageal cancer. We finally included 8 included studies containing 839 cases for MTHFR C677T, 5 studies involving 634 cases for MTHFR A1298C, 3 studies containing 340 cases for EGFR G497A, and 4 studies containing 396 cases for EGFR CA repeat. The pooled analysis results indicated that MTHFR C677T might be correlated with the tumor response to pRCT under the recessive model (CC vs. CTTT) in overall analysis (OR=1.426(1.074–1.894), P=0.014), rectal cancer (OR=1.483(1.102–1.996), P=0.009), and TRG 1–2 vs. 3–5 group (OR=1.423(1.046–1.936), P=0.025), while other polymorphism including MTHFR A1298C, EGFR G497A, and EGFR CA repeat polymorphisms exerted significant association under all genetic models in overall analysis or subgroup analysis. Conclusions MTHFR C677T might be correlated with the tumor response to pRCT. Further well-designed, larger-scale epidemiological studies are needed to validate our results. PMID:26456456

  1. MTHFR C677T polymorphism contributes to prostate cancer risk among Caucasians: A meta-analysis of 3511 cases and 2762 controls.

    PubMed

    Bai, Jian-Ling; Zheng, Ming-Hua; Xia, Xian; Ter-Minassian, Monica; Chen, Yong-Ping; Chen, Feng

    2009-05-01

    Published data regarding the association between 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and prostate cancer risk have been conflicting. To derive a more precise estimation of the relationship, a meta-analysis was performed. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association between MTHFR C677T and A1298C polymorphisms and prostate cancer risk. Six studies including 3511 cases and 2762 controls described C677T genotypes, among which four articles totalling 838 cases and 1121 controls described A1298C genotypes, were involved in this meta-analysis. Overall meta-analysis indicated that the 677T allele was more likely to exert a protective effect on prostate cancer risk (OR=0.81, 95% CI: 0.68-0.98) with a recessive genetic model. No association was found for the 677CT genotype and the 677TT mutant homozygote with prostate cancer risk compared with 677CC, with OR=1.13 (95% CI: 0.88-1.45) and OR=0.85 (95% CI: 0.71-1.03), respectively. No evidence of an association of MTHFR A1298C polymorphism with prostate cancer was found. This meta-analysis supports that the C677T of the MTHFR gene is a low-penetrance susceptibility gene for prostate cancer, and might provide protective effects against prostate cancer risk. PMID:19223177

  2. MTHFR C677T polymorphism interaction with heavy alcohol consumption increases head and neck carcinoma risk.

    PubMed

    Zhuo, Xianlu; Song, Jue; Li, Dairong; Wu, Yongzhong; Zhou, Qi

    2015-01-01

    MTHFR C677T polymorphism has been indicated to be a risk factor for cancers, but its association with head and neck cancer (HNC) risk remains inconclusive. In the present study, we aimed to get a more precise estimation by performing a quantitative meta-analysis. Published papers up to Jun 2014 was searched and screened. Necessary information was rigorously extracted for data pooling and analyzing, and then, subgroup analyses on ethnicity, source of controls, sample size, tumor type, smoking and drinking status were also carried out. As a result, twenty-three case-control studies including 14298 subjects were included. The overall data failed to reveal a significant association between MTHFR C677T polymorphism and HNC risk (homozygote comparison model: OR = 1.16; 95%CI = 0.93-1.45; dominant model: OR = 1.05; 95%CI =  .90-1.21; recessive model: OR = 1.14; 95%CI = 0.93-1.38). However, in the subgroup analysis about drinking status, increase risk was shown in the heavy drinking subgroup (TT vs CC: OR = 3.11; 95%CI = 1.52-3.02). In conclusion, the results of the present study suggest that Homozygous TT alleles of MTHFR C677T polymorphism might be a risk factor for HNC among individuals who have a heavy drinking history. Further studies are needed to get a more definitive conclusion. PMID:26035704

  3. The methylenetetrahydrofolate reductase C677T polymorphism influences risk of esophageal cancer in Chinese.

    PubMed

    Qu, Hong-Hong; Cui, Li-Hong; Wang, Ke; Wang, Peng; Song, Chun-Hua; Wang, Kai-Juan; Zhang, Jian-Ying; Dai, Li-Ping

    2013-01-01

    Methylenetetrahydrofolate reductase (MTHFR) plays a central role in folate metabolism. This study with 381 esophageal cancer patients and 432 healthy controls was conducted to examine the association of MTHFR C677T and A1298C polymorphisms with susceptibility to esophageal cancer (EC) in a Chinese population. Compared with the CC genotype of MTHFR C677T, subjects carrying homozygote TT and variant genotypes (CT+TT) demonstrated reduced risk of EC with adjusted ORs (95% CI) of 0.44 (0.28-0.71) and 0.57 (0.37-0.88), respectively. However, no association was found between the MTHFR A1298C polymorphism and the risk of EC. Comparing to haplotype CA, haplotypes TA and TC could reduce the susceptibility to EC with adjusted ORs (95% CI) of 0.61(0.47-0.79) and 0.06 (0.01-0.43), respectively. In conclusion, the present study suggested that the MTHFR C677T polymorphism can markedly influence the risk of EC in Chinese. PMID:23803097

  4. MTHFR C677T polymorphism interaction with heavy alcohol consumption increases head and neck carcinoma risk

    PubMed Central

    Zhuo, Xianlu; Song, Jue; Li, Dairong; Wu, Yongzhong; Zhou, Qi

    2015-01-01

    MTHFR C677T polymorphism has been indicated to be a risk factor for cancers, but its association with head and neck cancer (HNC) risk remains inconclusive. In the present study, we aimed to get a more precise estimation by performing a quantitative meta-analysis. Published papers up to Jun 2014 was searched and screened. Necessary information was rigorously extracted for data pooling and analyzing, and then, subgroup analyses on ethnicity, source of controls, sample size, tumor type, smoking and drinking status were also carried out. As a result, twenty-three case-control studies including 14298 subjects were included. The overall data failed to reveal a significant association between MTHFR C677T polymorphism and HNC risk (homozygote comparison model: OR = 1.16; 95%CI = 0.93-1.45; dominant model: OR = 1.05; 95%CI = 0.90-1.21; recessive model: OR = 1.14; 95%CI = 0.93-1.38). However, in the subgroup analysis about drinking status, increase risk was shown in the heavy drinking subgroup (TT vs CC: OR = 3.11; 95%CI = 1.52-3.02). In conclusion, the results of the present study suggest that Homozygous TT alleles of MTHFR C677T polymorphism might be a risk factor for HNC among individuals who have a heavy drinking history. Further studies are needed to get a more definitive conclusion. PMID:26035704

  5. Genetic interactions between MTHFR (C677T), methionine synthase (A2756G, C2758G) variants with vitamin B12 and folic acid determine susceptibility to premature coronary artery disease in Indian population

    PubMed Central

    Kanth, V. V. Ravi; Golla, Jaya Prakash; Sastry, B. K. S; Naik, Sudhir; Kabra, Nitin; Sujatha, Madireddi

    2011-01-01

    Background: Researchers have determined that Indians face a higher risk of heart disease, despite the fact that nearly half of them are vegetarians and lack many of the other traditional risk factors. In the below-30 age group, coronary artery disease mortality among Indians is three-fold higher than in the whites in United Kingdom and ten-fold higher than the Chinese in Singapore. High levels of homocysteine have been widely linked to the early onset of heart diseases in other populations, although a definite proof among Indians is lacking, which needs to be investigated by way of screening for factors responsible for high homocysteine levels. Objective: To screen for genetic factors responsible for hyperhomocysteinemia and the risk for premature coronary artery disease. Materials and Methods: A total of 100 individuals with proven premature coronary artery disease and 200 age-and-sex matched controls were screened for polymorphisms in Methylenetetrahydrofolate reductase (MTHFR) (C677T) Methionine synthase (MS) genes (A2756G, C2758G), and the B12 and Folate levels were estimated. Results: Results from the mutational analysis revealed that in the study group, seven individuals had a polymorphism for the C677T allele in the MTHFR gene (one homozygous and six heterozygous) (Fischer's Exact test P > 0.046) (OR: 0.2711 95% CI 0.0774 to 0.9491). Six were heterozygous for the A2756G polymorphism in the MS gene (Fischer's Exact test P > 0.0012). None showed a polymorphism at the C2758G allele in the MS gene. Four controls showed heterozygosity for the C677T polymorphism and none for the MS gene. The B12 and Folate levels were significantly lower in the study group as compared to the controls. Conclusions: It is important to know which factors determine the total homocysteine concentrations. In the general population, the most important modifiable determinants of tHcy are folate intake and coffee consumption. Smoking and alcohol consumption are also associated with the total homocysteine concentrations, but more research is necessary to elucidate whether these relations are not originating from residual confounding due to other lifestyle factors. PMID:22022143

  6. Significant impact of MTHFR C677T polymorphism on plasma homovanillic acid (HVA) levels among alcohol-dependent patients.

    PubMed

    Lutz, Ulrich C; Batra, Anil; Wiatr, Gerlinde; Machicao, Fausto; Kolb, Werner; Maurer, Sandra; Buchkremer, Gerhard; Khnke, Michael D

    2007-03-01

    The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) synthesizes 5-methyltetrahydrofolate. It plays a critical role in homocysteine metabolism. A high impact of MTHFR C677T polymorphism on plasma homocysteine levels has been observed among alcoholics. Recent studies indicate that homocysteine has toxic effects on dopaminergic neurons. Thus it lowers levels of homovanillic acid (HVA) in the striatal region in rats. Alcoholics had significantly lower plasma HVA concentrations compared with healthy controls. Aim of this study is to elucidate whether HVA plasma levels in alcoholics are influenced by MTHFR C677T polymorphism. A total of 142 alcohol-dependent patients and 101 healthy controls were examined regarding plasma HVA concentration and MTHFR C677T genotype. Blood samples of alcoholics were obtained after a minimum of 22 days of abstinence. Among alcohol-dependent patients MTHFR C677T polymorphism was significantly associated with plasma HVA levels: carriers of MTHFR C677T T-allele had significantly lower HVA plasma levels compared with homozygote carriers of C-allele: 11.9 ng/ml versus 14.4 ng/ml (chi2: 5.39; P = 0.02). In healthy control subjects plasma HVA levels did not differ significantly between MTHFR C677T T-allele carriers and homozygote carriers of C-allele: 15.1 ng/ml versus 15.3 ng/ml (chi2: 0.04; P = 0.82). The data suggest an influence of MTHFR C677T polymorphism on plasma HVA among alcohol-dependent patients. This might be due to neurotoxic effects of homocysteine on the dopaminergic system or direct impairment of monoamine metabolism. Future studies should try to elucidate whether this effect is reversible during alcohol abstinence. PMID:17407503

  7. [Methylenetetrahydrofolate reductase polymorphism C677T in patients with consolidated fractures and pseudarthrosis of long bones: relationship with homocystein and inflammatory mediators].

    PubMed

    Bezsmertnyĭ, Iu O

    2013-01-01

    In article described research the results of the prevalence of the genetic polymorphism of the gene Methylentetrahydrofolatereductase C677T (MTHFR) in 130 patients with pseudarthrosis of long bones and in those with consolidated fractures. The incidence of allele-T among patients with pseudarthrosis was 1.4 times higher than among those with consolidated fractures. Pathological genotype MTHFR 677-TT was associated with the development avital types of pseudarthrosis and increase the proportion of people with hyperhomocysteinemia, high content of inflammatory mediators and development refracture. PMID:24605633

  8. Methyltetrahydrofolate vs Folic Acid Supplementation in Idiopathic Recurrent Miscarriage with Respect to Methylenetetrahydrofolate Reductase C677T and A1298C Polymorphisms: A Randomized Controlled Trial

    PubMed Central

    Hekmatdoost, Azita; Vahid, Farhad; Yari, Zahra; Sadeghi, Mohammadreza; Eini-Zinab, Hassan; Lakpour, Niknam; Arefi, Soheila

    2015-01-01

    Purpose To determine whether 5-methylenetetrahydrofolate (MTHF) is more effective than folic acid supplementation in treatment of recurrent abortion in different MTHFR gene C677T and A1298C polymorphisms. Methods A randomized, double blind, placebo-controlled trial conducted April 2011-September 2014 in recurrent abortion clinics in Tehran, Iran. The participants were women with three or more idiopathic recurrent abortion, aged 20 to 45 years. Two hundred and twenty eligible women who consented to participate were randomly assigned to receive either folic acid or 5-MTHF according to the stratified blocked randomization by age and the number of previous abortions. Participants took daily 1 mg 5-methylentetrahydrofolate or 1 mg folic acid from at least 8 weeks before conception to the 20th week of the pregnancy. The primary outcome was ongoing pregnancy rate at 20th week of pregnancy, and the secondary outcomes were serum folate and homocysteine at the baseline, after 8 weeks, and at the gestational age of 4, 8, 12, and 20 weeks, MTHFR gene C677T and A1298C polymorphisms. Results There was no significant difference in abortion rate between two groups. Serum folate increased significantly in both groups over time; these changes were significantly higher in the group receiving 5-MTHF than the group receiving folic acid (value = 2.39, p<00.1) and the result was the same by considering the time (value = 1.24, p<0.01). Plasma tHcys decreased significantly in both groups over time; however these changes were not significantly different between the groups (value = 0.01, p = 0.47). Conclusion The results do not support any beneficial effect of 5-MTHF vs. folate supplementation in women with recurrent abortion with any MTHFR C677T and/or A1298C polymorphism. Trial Registration ClinicalTrials.gov NCT01976676 PMID:26630680

  9. Lack of association between MTHFR C677T polymorphism and breast cancer risk in Ahvaz, west south-Iran

    PubMed Central

    Mohammadzadeh, Ghorban; Karimi, Maryam; Bazyar, Mohammad; Hosseini, Seyed-Mohammad

    2016-01-01

    Background: Association between C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR), a key enzyme involved in folate metabolism and DNA methylation, and breast cancer risk are inconsistent. We investigated in a case-control study, possible effect of the common MTHFR C677T polymorphism on breast cancer risk in a sample of Iranian patients. Materials and Methods: The study subjects comprised of 123 breast cancer cases and 110 cancer-free control, who were matched for age and body mass index (BMI). C677T genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Lipid profile was measured in all subjects by standard method. Results: The genotypes distributions (CC, CT, and TT) were 55.3, 39, and 5.7% in breast cancer cases and 51.8, 44.5, and 3.6% in controls. Chi square analysis revealed that there was no significant association between breast cancer risk and MTHFR genotypes and alleles. Additionally, no significant association was observed between C677T genotypes and biochemistry parameters. A multinomial logistic regression model with MTHFR genotypes, lipid profiles, BMI and age as covariates revealed that there is no significant association between MTHFR genotypes and risk of breast cancer, but higher values of LDL and HDL significantly increase risk of breast cancer. Conclusions: Our findings do not support the hypothesis that genetic variation in the MTHFR C677T polymorphism is implicated in the breast cancer risk in a sample of Iranian patients. PMID:27014653

  10. Association between MTHFR C677T polymorphism and diabetic nephropathy in the Chinese population: An updated meta-analysis and review.

    PubMed

    Xiong, Xuan; Lin, Xiao-Kun; Xiao, Xiao; Qin, Dan-Ping; Zhou, Dao-Yuan; Hu, Jian-Guang; Liu, Yan; Zhong, Xiao-Shi

    2016-01-01

    To clarify the effects of MTHFR C677T polymorphism on the risk of diabetic nephropathy (DN) in the Chinese population, an updated meta-analysis was performed. Related studies were identified from PubMed, Springer Link, Ovid and Chinese Databases up to 24 February 2015. A total of 15 studies including 1227 DN cases, 586 healthy controls and 1277 diabetes mellitus (DM) controls were involved in this meta-analysis. Overall, a significantly elevated risk of DN was associated with all variants of MTHFR C677T when compared with the healthy group (T vs C, odds ratio (OR) = 2.22, 95% confidence interval (CI) = 1.88-2.61; TT vs CC, OR = 4.22, 95% CI = 3.02-5.90; TT + CT vs CC, OR = 2.62, 95% CI = 2.07-3.31; TT vs CC + CT, OR = 2.81, 95% CI = 2.08-3.81) or DM (T vs C, OR = 1.78, 95% CI = 1.59-2.00; TT vs CC, OR = 2.95, 95% CI = 2.33-3.73; TT + CT vs CC, OR = 1.93, 95% CI = 1.63-2.29; TT vs CC + CT, OR = 2.31, 95% CI = 1.87-2.84). In subgroup analyses stratified by ethnicity and geographic areas, it revealed the significant results in Chinese Han, in North and South China. The risk conferred by MTHFR C677T polymorphism is higher in North China than in South China. This meta-analysis showed that the MTHFR C677T variants may influence DN risk in Chinese, and further studies with gene-gene and gene-environment interactions are required for definite conclusions. PMID:26072975

  11. MTHFR C677T and A1298C polymorphisms and risk of lung cancer: a comprehensive evaluation.

    PubMed

    Yang, Y; Yang, L J; Deng, M Z; Luo, Y Y; Wu, S; Xiong, L; Wang, D; Liu, Y; Liu, H

    2016-01-01

    Results from previous studies on the association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms C677T and A1298C and lung cancer have been conflicting. The aim of this meta-analysis was to clarify the effect of MTHFR polymorphisms on the risk of lung cancer. An electronic search of PubMed, EMBASE, the Cochrane library, and the China Knowledge Resource Integrated Database for papers on C677T and A1298C and susceptibility to lung cancer was performed. The STATA software (Version 13.0) was used for statistical analysis. Statistical heterogeneity, tests of publication bias, and a sensitivity analysis were performed. Twenty-six studies on C677T (12,324 cases and 12,532 controls) and thirteen studies on A1298C (6773 cases and 8207 controls) were included in the meta-analysis. The MTHFR C677T polymorphism showed significant pooled ORs for the homozygote comparison (TT versus CC: OR = 1.518, 95%CI = 1.220-1.890), heterozygote comparison (CT versus CC: OR = 1.053, 95%CI = 0.940-1.179), dominant model (CT + TT versus CC: OR = 1.143, 95%CI = 1.013-1.291), recessive model (TT versus CT + CC: OR = 1.435, 95%CI = 1.190-1.730), and additive model (T versus C: OR = 1.176, 95%CI = 1.066-1.298). In summary, our meta-analysis showed that the MTHFR C677T polymorphism is associated with a significant increase in lung cancer risk in Asian and overall populations, but not in Caucasian populations. However, no significant association between the MTHFR A1298C polymorphism and lung cancer risk was found in either the Caucasian or Asian group with any genetic models. PMID:27173216

  12. Association of Methylenetetrahydrofolate Reductase C677T Polymorphism with Hyperhomocysteinemia and Deep Vein Thrombosis in the Iranian Population

    PubMed Central

    Ghaznavi, Habib; Soheili, Zahra; Samiei, Shahram; Soltanpour, Mohammad Soleiman

    2015-01-01

    Purpose: Deep venous thrombosis (DVT) is a common but elusive condition characterized by a high morbidity and mortality rate. The aim of the present study was to investigate the correlation between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with plasma total homocysteine (tHcy) levels and DVT risk in an Iranian population. Materials and Methods: Our study population consisted of 67 patients with a diagnosis of DVT and 67 healthy subjects as controls. Genotyping of MTHFR C677T polymorphism was performed by the polymerase chain reaction technique combined with restriction enzyme fragment length polymorphism (PCR-RFLP) and measurement of tHcy levels was done by enzyme immunoassay method. Results: Plasma tHcy levels were significantly higher in DVT patients than controls (18.09±7.6 vs. 10.5±4.3, P=0.001). Also, plasma tHcy levels were significantly higher in MTHFR 677TT genotypes compared to 677CC genotypes in both DVT patients (P=0.016) and controls (P=0.03). Neither heterozygote nor homozygote genotypes of MTHFR C677T polymorphism was significantly correlated with DVT (P>0.05). The distribution of MTHFR C677T genotypes was similar between men and women in both DVT patients and controls (P>0.05). Moreover, the frequency of mutant 677T allele did not differ significantly between the two groups (28.3% vs. 21.6%, P=0.15). Conclusion: Based on this study, we propose that hyperhomocysteinemia but not homozygosity for MTHFR C677T polymorphism is a significant risk factor for DVT in the Iranian population. Also, MTHFR 677TT genotype is a determinant of elevated plasma tHcy levels. PMID:26719836

  13. Search for correlations between genotypes and electrophysiological patterns in migraine: the MTHFR C677T polymorphism and visual evoked potentials.

    PubMed

    Magis, D; Allena, M; Coppola, G; Di Clemente, L; Gérard, P; Schoenen, J

    2007-10-01

    Interictally, migraineurs have on average a reduction in habituation of pattern-reversal visual evoked potentials (PR-VEP) and in mitochondrial energy reserve. 5,10-Methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism and its C677T polymorphism may be more prevalent in migraine. The aim of this study was to search in migraineurs for a correlation between the MTHFR C677T polymorphism and the PR-VEP profile. PR-VEP were recorded in 52 genotyped migraine patients: 40 female, 24 without (MoA), 28 with aura (MA). Among them 21 had a normal genotype (CC), 18 were heterozygous (CT) and 13 homozygous (TT) for the MTHFR C677T polymorphism. Mean PR-VEP N1-P1 amplitude was significantly lower in CT compared with CC, and tended to be lower in TT with increasing age. The habituation deficit was significantly greater in CC compared with TT subjects. The correlation between the cortical preactivation level, as reflected by the VEP amplitude in the first block of averages, and habituation was stronger in CC than in CT or TT. The MTHFR C677T polymorphism could thus have an ambiguous role in migraine. On one hand, the better VEP habituation which is associated with its homozygosity, and possibly mediated by homocysteine derivatives increasing serotoninergic transmission, may protect the brain against overstimulation. On the other hand, MTHFR C677T homozygosity is linked to a reduction of grand average VEP amplitude with illness duration, which has been attributed to brain damage. PMID:17711493

  14. Serum Folate and Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism Adjusted for Folate Intake

    PubMed Central

    Nishio, Kazuko; Goto, Yasuyuki; Kondo, Takaaki; Ito, Shimon; Ishida, Yoshiko; Kawai, Sayo; Naito, Mariko; Wakai, Kenji; Hamajima, Nobuyuki

    2008-01-01

    Background Serum folate concentration is lower in individuals with the methylenetetrahydrofolate reductase (MTHFR) 677TT genotype than in those with the MTHFR 677CC or 677CT genotypes. Since studies considering folate intake are limited, we examined the association between folate intake and serum folate levels, according to the genotype. Methods The subjects comprised 170 Japanese persons (74 males and 96 females) aged 20-75 years who visited a clinic to test for Helicobacter pylori infection. Folate intake was estimated using a semiquantitative food-frequency questionnaire, and serum folate was measured in the residual fasting blood samples of the subjects. MTHFR C677T was genotyped using polymerase chain reaction. Results The geometric means of serum folate level were 6.19, 6.20, and 5.17 ng/mL among the 60 participants with the 677CC genotype, 90 participants with the 677CT genotype, and 20 participants with the 677TT genotype, respectively. No difference was noted in the mean folate intake estimated using the food-frequency questionnaire. Regression analysis showed that loge(serum folate) adjusted for age, sex, and loge(folate intake) was significantly lower among those with the 677TT genotype than among those with the 677CT or 677CC genotypes (p = 0.01). The adjusted reduction in serum folate was 20.2% (95% confidence interval, 5.4-32.6%) in the case of the 677TT genotype relative to the levels in the case of the 677CC/677CT genotypes. When folate intake was adjusted for total energy intake, using the residual method, the slope of the regression line for 677TT was smaller than those of the regression lines for 677CC and 677CT. Conclusion Individuals with the 677TT genotype may need to consume more folate to maintain serum folate levels similar to those found in individuals with the 677CC/677CT genotypes. PMID:18480590

  15. Association of methylenetetrahydrofolate reductase C677T polymorphism and serum lipid levels in the Guangxi Bai Ku Yao and Han populations

    PubMed Central

    2010-01-01

    Background The association of methylenetetrahydrofolate reductase (MTHFR) gene polymorphism and serum lipid profiles is still controversial in diverse ethnics. Bai Ku Yao is an isolated subgroup of the Yao minority in China. The aim of the present study was to eveluate the association of MTHFR C677T polymorphism and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations. Methods A total of 780 subjects of Bai Ku Yao and 686 participants of Han Chinese were randomly selected from our previous stratified randomized cluster samples. Genotyping of the MTHFR C677T was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. Results The levels of serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein (Apo) AI and ApoB were lower in Bai Ku Yao than in Han (P < 0.05-0.001). The frequency of C and T alleles was 77.4% and 22.6% in Bai Ku Yao, and 60.9% and 39.1% in Han (P < 0.001); respectively. The frequency of CC, CT and TT genotypes was 58.7%, 37.3% and 4.0% in Bai Ku Yao, and 32.6%, 56.4% and 11.0% in Han (P < 0.001); respectively. The levels of TC and LDL-C in both ethnic groups were significant differences among the three genotypes (P < 0.05-0.01). The T allele carriers had higher serum TC and LDL-C levels than the T allele noncarriers. The levels of ApoB in Han were significant differences among the three genotypes (P < 0.05). The T allele carriers had higher serum ApoB levels as compared with the T allele noncarriers. The levels of TC, TG and LDL-C in Bai Ku Yao were correlated with genotypes (P < 0.05-0.001), whereas the levels of LDL-C in Han were associated with genotypes (P < 0.001). Serum lipid parameters were also correlated with sex, age, body mass index, alcohol consumption, cigarette smoking, and blood pressure in the both ethnic groups. Conclusions The differences in serum TC, TG, LDL-C and ApoB levels between the two ethnic groups might partly result from different genotypic and allelic frequencies of the MTHFR C677T or different MTHFR gene-enviromental interactions. PMID:20977771

  16. Association of MTHFR C677T Genotype With Ischemic Stroke Is Confined to Cerebral Small Vessel Disease Subtype

    PubMed Central

    Traylor, Matthew; Adib-Samii, Poneh; Thijs, Vincent; Sudlow, Cathie; Rothwell, Peter M.; Boncoraglio, Giorgio; Dichgans, Martin; Meschia, James; Maguire, Jane; Levi, Christopher; Rost, Natalia S.; Rosand, Jonathan; Hassan, Ahamad; Bevan, Steve; Markus, Hugh S.

    2016-01-01

    Background and Purpose— Elevated plasma homocysteine levels are associated with stroke. However, this might be a reflection of bias or confounding because trials have failed to demonstrate an effect from homocysteine lowering in stroke patients, although a possible benefit has been suggested in lacunar stroke. Genetic studies could potentially overcome these issues because genetic variants are inherited randomly and are fixed at conception. Therefore, we tested the homocysteine levels–associated genetic variant MTHFR C677T for association with magnetic resonance imaging–confirmed lacunar stroke and compared this with associations with large artery and cardioembolic stroke subtypes. Methods— We included 1359 magnetic resonance imaging–confirmed lacunar stroke cases, 1824 large artery stroke cases, 1970 cardioembolic stroke cases, and 14 448 controls, all of European ancestry. Furthermore, we studied 3670 ischemic stroke patients in whom white matter hyperintensities volume was measured. We tested MTHFR C677T for association with stroke subtypes and white matter hyperintensities volume. Because of the established association of homocysteine with hypertension, we additionally stratified for hypertension status. Results— MTHFR C677T was associated with lacunar stroke (P=0.0003) and white matter hyperintensity volume (P=0.04), but not with the other stroke subtypes. Stratifying the lacunar stroke cases for hypertension status confirmed this association in hypertensive individuals (P=0.0002), but not in normotensive individuals (P=0.30). Conclusions— MTHFR C677T was associated with magnetic resonance imaging–confirmed lacunar stroke, but not large artery or cardioembolic stroke. The association may act through increased susceptibility to, or interaction with, high blood pressure. This heterogeneity of association might explain the lack of effect of lowering homocysteine in secondary prevention trials which included all strokes. PMID:26839351

  17. Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls

    PubMed Central

    Simone, B; De Stefano, V; Leoncini, E; Zacho, J; Martinelli, I; Emmerich, J; Rossi, E; Folsom, AR; Almawi, WY; Scarabin, PY; den Heijer, M; Cushman, M; Penco, S; Vaya, A; Angchaisuksiri, P; Okumus, G; Gemmati, D; Cima, S; Akar, N; Oguzulgen, KI; Ducros, V; Lichy, C; Fernandez-Miranda, C; Szczeklik, A; Nieto, JA; Torres, JD; Le Cam-Duchez, V; Ivanov, P; Cantu, C; Shmeleva, VM; Stegnar, M; Ogunyemi, D; Eid, SS; Nicolotti, N; De Feo, E; Ricciardi, W; Boccia, S

    2014-01-01

    BACKGROUND Genetic and environmental factors interact in determining the risk of venous thromboembolism (VTE). The risk associated with the polymorphic variants G1691A of factor V (Factor V Leiden,FVL), G20210A of prothrombin (PT20210A) and C677T of methylentetrahydrofolate reductase (C677T MTHFR) genes has been investigated in many studies. METHODS We performed a pooled analysis of case-control and cohort studies investigating in adults the association between each variant and VTE, published on Pubmed, Embase or Google through January 2010. Authors of eligible papers, were invited to provide all available individual data for the pooling. The Odds Ratio (OR) for first VTE associated with each variant, individually and combined with the others, were calculated with a random effect model, in heterozygotes and homozygotes (dominant model for FVL and PT20210A; recessive for C677T MTHFR). RESULTS We analysed 31 databases, including 11,239 cases and 21,521 controls. No significant association with VTE was found for homozygous C677T MTHFR (OR: 1.38; 95% confidence intervals [CI]: 0.98–1.93), whereas the risk was increased in carriers of either heterozygous FVL or PT20210 (OR=4.22; 95% CI: 3.35–5.32; and OR=2.79;95% CI: 2.25–3.46, respectively), in double hterozygotes (OR=3.42; 95%CI 1.64-7.13), and in homozygous FVL or PT20210A (OR=11.45; 95%CI: 6.79-19.29; and OR: 2.79; 95%CI: 2.25 – 3.46, respectively). The stratified analyses showed a stronger effect of FVL on individuals ≤45 years (p-value for interaction = 0.036) and of PT20210A in women using oral contraceptives (p-value for interaction = 0.045). CONCLUSIONS In this large pooled analysis, inclusive of large studies like MEGA, no effect was found for C677T MTHFR on VTE; FVL and PT20210A were confirmed to be moderate risk factors. Notably, double carriers of the two genetic variants produced an impact on VTE risk significantly increased but weaker than previously thought. PMID:23900608

  18. Adaptive developmental plasticity in methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism limits its frequency in South Indians.

    PubMed

    Naushad, Shaik Mohammad; Krishnaprasad, Chintakindi; Devi, Akella Radha Rama

    2014-05-01

    Methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism shows considerable heterogeneity in its distribution in humans worldwide. The current study was conducted to investigate whether this polymorphism exhibited adaptive developmental plasticity in the control of the TT-genotype frequency. We screened 1,818 South Indian subjects (895 males and 923 females) for MTHFR C677T polymorphism using PCR-restriction fragment length polymorphism approach. MTHFR 677T-allele frequency in males and females was 9.1 and 11.0%, respectively. Compared to females, males had lower frequency of TT-genotype [odds ratio 0.31, 95% confidence interval (CI) 0.08-1.01]. The frequency of MTHFR 677T-allele was highest in the age group of 20-40 years and it gradually decreased from 40-60 to 60-80 years (P trend<0.0001). MTHFR 677TT-genotype was associated with 7.02-folds (95% CI: 2.12-25.63, P<0.0001) cumulative risk for recurrent pregnancy loss (RPL), neural tube defects (NTDs) and deep vein thrombosis (DVT). Linear regression model suggested that male gender exhibited increased homocysteine levels by 9.35 ?mol/L while each MTHFR 677T-allele contributed to 4.63 ?mol/L increase in homocysteine. Plasma homocysteine showed inverse correlation with dietary folate (r=-0.17, P<0.0001), B2 (r=-0.14, P<0.0001) and B6 (r=-0.07, P=0.03). Examination of the spontaneously aborted fetuses (n=35) showed no significant association of fetal genotype on its in utero viability. From the current study, it was concluded that C677T seemed to have acquired adaptive developmental plasticity among South Indians due to environmental influences thus contributing to hyperhomocysteinemia and its associated complications such as RPL, NTDs, DVT, etc. PMID:24449370

  19. Association between the MTHFR C677T polymorphism and risk of cancer: evidence from 446 case-control studies.

    PubMed

    Xie, Shu-Zhe; Liu, Zhi-Zhong; Yu, Jun-hua; Liu, Li; Wang, Wei; Xie, Dao-Lin; Qin, Jiang-Bo

    2015-11-01

    Many molecular epidemiological studies have been performed to explore the association between MTHFR C677T polymorphism and cancer risk in diverse populations. However, the results were inconsistent. Hence, we performed a meta-analysis to investigate the association between cancer risk and MTHFR C677T (150,086 cases and 200,699 controls from 446 studies) polymorphism. Overall, significantly increased cancer risk was found when all eligible studies were pooled into the meta-analysis. In the further stratified and sensitivity analyses, significantly increased breast cancer risk was found in Asians and Indians, significantly decreased colon cancer risk was found, significantly decreased colorectal cancer risk was found in male population, significantly increased gastric cancer risk was found in Caucasians and Asians, significantly increased hepatocellular cancer risk was found in Asians, significantly decreased adult acute lymphoblastic leukemia (AALL) risk was found in Caucasians, significantly decreased childhood acute lymphoblastic leukemia (CALL) risk was found in Asians, and significantly increased multiple myeloma and NHL risk was found in Caucasians. In summary, this meta-analysis suggests that MTHFR C677T polymorphism is associated with increased breast cancer, gastric cancer, and hepatocellular cancer risk in Asians, is associated with increased gastric cancer, multiple myeloma, and NHL risk in Caucasians, is associated with decreased AALL risk in Caucasians, is associated with decreased CALL risk in Asians, is associated with increased breast cancer risk in Asians, is associated with decreased colon cancer risk, and is associated with decreased colorectal cancer risk in male population. Moreover, this meta-analysis also points out the importance of new studies, such as Asians of HNC, Asians of lung cancer, and Indians of breast cancer, because they had high heterogeneity in this meta-analysis (I(2) > 75%). PMID:26081619

  20. Polymorphisms of MTHFR C677T and A1298C association with oral carcinoma risk: a meta-analysis.

    PubMed

    Zhuo, Xianlu; Ling, Junjun; Zhou, Yan; Zhao, Houyu; Song, Yufeng; Tan, Yinghui

    2012-07-01

    Investigations regarding association of MTHFR polymorphisms with oral carcinoma risk have yielded inconclusive results. Thus, meta-analyses were performed. Results showed that no associations of C677T polymorphisms with oral carcinoma were observed for the overall data. In subgroup analyses by drinking status, homozygous TT alleles exhibited elevated oral cancer susceptibility in heavy drinkers. For A1298C polymorphism, CC alleles presented a possible preventive role for oral cancer. Collectively, results suggest that MTHFR 677TT polymorphism might be a low-penetrant risk factor for oral carcinoma only in heavy drinkers. Conversely, 1298CC alleles might play a preventive role for oral cancer. PMID:22536935

  1. Association of a Methylene Tetrahydrofolate Reductase C677T Polymorphism with Several Blood Chemical Levels in a Chinese Population

    PubMed Central

    Wen, Can; Lv, Jiao-Feng; Wang, Ling; Zhu, Wei-Feng

    2015-01-01

    Background: The methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with hypertension in certain populations. This study investigated the relationship between the MTHFR polymorphism and hypertension and correlated blood lipid indexes, including homocysteine (HCY), lipoprotein (a) [Lp (a)], high-density lipoprotein (HDL), low-density lipoprotein (LDL), apolipoprotein A I (Apo AI), Apo B, glucose (GLU), total cholesterol (TC), and triglyceride (TG), in a Chinese population. Materials and Methods: A total of 174 patients with hypertension and 634 healthy control individuals from Jiangxi Province were recruited between June 2012 and September 2012 for genotyping of the MTHFR C677T polymorphism using polymerase chain reaction-restriction fragment length polymorphism. Biochemical parameters were also assessed in these subjects and statistically compared to the MTHFR C677T polymorphism and the risk for hypertension. Results: HCY and Lp (a) levels were significantly higher in subjects with a MTHFR 677TT genotype than in those with a CC/CT genotype, independent of hypertension. The frequency of the TT genotype and the T allele in hypertension patients was significantly higher than in the healthy controls. Furthermore, in the male hypertension patient group, the average levels of HCY, HDL, Apo AI, and TC were significantly different from those in female hypertension patients (pHCY=0.001, pHDL=0.004, pApo AI<0.001, pTC=0.012). In the male control group, the average levels of HCY, HDL, Apo AI, GLU, and TC were significantly different from those of female controls (pHCY<0.001, pHDL<0.001, pApo AI<0.001, pGLU=0.001, and pTC=0.004). Conclusion: Our data demonstrate that the MTHFR C677T polymorphism is positively correlated with an increased risk of hypertension through an increase in HCY levels. The blood lipid correlative index was different between male and female hypertension patients and controls. PMID:25489783

  2. Bladder exstrophy-epispadias complex and the role of methylenetetrahydrofolate reductase C677T polymorphism: A case control study

    PubMed Central

    Raman, Venkat Shankar; Bajpai, Minu; Ali, Abid

    2016-01-01

    Purpose: The Bladder Exstrophy-Epispadias Complex (BEEC) is the most serious form of midline abdominal malformation. The etiology of BEEC is unknown and is thought to be multifactorial. Methylenetetrahydrofolate reductase (MTHFR) polymorphism C677T is strongly associated with other midline abnormalities such as neural tube defects. No proper case-control study existed comparing MTHFR polymorphism with BEEC. We sought to find an association with MTHFR polymorphism and patients with bladder exstrophy (BE). Materials and Methods: The design of the study was a case-control study, involving 50 children with BEEC and 50 normal healthy school children. Genetic analysis for MTHFR 677 polymorphism was carried out after DNA extraction and polymerase chain reaction amplification. Epidemiological analysis was done by using the birth defect questionnaire on parents of BEEC. Results: Forty-two classical BE, two cloacal exstrophies (CE), four epispadias, and two exstrophy variant patients were a part of this study. Severe variety of BE had a significant association with C667T MTHFR polymorphism as compared to the normal control population (P = 0.01). Conclusion: C677T MTHFR polymorphism has a strong association with severe variety (CE) of BEEC occurrence. PMID:26862292

  3. Status of Vitamins B-12 and B-6 but Not of Folate, Homocysteine, and the Methylenetetrahydrofolate Reductase C677T Polymorphism Are Associated with Impaired Cognition and Depression in Adults123

    PubMed Central

    Moorthy, Denish; Peter, Inga; Scott, Tammy M.; Parnell, Laurence D.; Lai, Chao-Qiang; Crott, Jimmy W.; Ordovás, José M.; Selhub, Jacob; Griffith, John; Rosenberg, Irwin H.; Tucker, Katherine L.; Troen, Aron M.

    2012-01-01

    The C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene differs in frequency in various ethnic groups that have differing prevalence of age-related cognitive impairments. We used a series of neuro-psychological tests to examine the association of the MTHFR C677T polymorphism with cognition and depression and also to assess whether genotype modifies the association of folate and homocysteine with these outcomes. This study analyzed pooled cross-sectional data from 2 ethnically diverse cohorts of community-living adults: the Boston Puerto Rican Health Study (n = 939) and the Nutrition, Aging, and Memory in Elders study (n = 1017). Individuals in both cohorts underwent anthropometric and laboratory measurements and dietary and health assessments using validated questionnaires between the years 2003 and 2007. Cognitive outcomes included measures of global cognition [Mini-Mental Status Exam (MMSE)], depression (Center for Epidemiological Studies Depression Scale), and 3 factor scores for the domains of attention, executive function, and memory that were derived from a detailed set of neuropsychological tests. Low plasma vitamin B-12 concentrations were associated with poorer MMSE scores and higher depression scores, and low vitamin B-6 concentrations were associated with lower MMSE and worse attention and executive function in the multivariate analysis. In contrast, MTHFR genotype, folate, and homocysteine were not associated with cognition or depression in either ethnicity-pooled or stratified analysis. The current study did not find evidence of an association between the MTHFR C677T TT genotype and impaired cognition or depression in a population with adequate folate status and a high prevalence of cognitive impairment and depression. PMID:22739363

  4. Association of 5, 10- methylenetetrahydrofolate reductase C677T polymorphism in susceptibility to tropical chronic pancreatitis in north Indian population.

    PubMed

    Singh, S; Choudhuri, G; Kumar, R; Agarwal, S

    2012-01-01

    MTHFR is a key enzyme in folate metabolism that catalyzes the conversion of 5, 10—methlenetetrahydrofolate (5, 10— methylene THF) to 5—methyltetrahydrofolate (5—methyl THF), a predominant circulatory form of folate and methyl donor for the remethylation of homocysteine to methionine. Some studies have shown that C667T polymorphism increases the risk of pancreatic cancer. Since MTHFR is involved in methylation, inflammation and protection against oxidative stress, the processes especially important for pancreatic homeostasis. The altered enzyme activity could play a role in pancreatic injury. The role of MTHFR C677T polymorphism in chronic pancreatitis has been explored by conducting a hospital based; case—control study involving 100 patients radiologically confirmed chronic pancreatitis and 329 healthy controls. All samples were analyzed for MTHFR C677T polymorphism using PCR—RFLP method. Restriction enzyme Hinf I was used to digest the 198 bp amplified product. The frequency of the MTHFR was 57.3%, 34.1% and 8.5% among cases compared with 87.2%,11.2% and 1.5% of controls for CC, CT and TT genotypes, respectively. The T Allele frequency was found significantly higher in patients than in controls. A significant association with T allele was observed with p—value (< 0.0001) odds ratio 4.475 and (95% CI=2.961—7.046). It could be predisposing to the traditional risk factors such as diabetes, dietary, alcohal and smoking habit that are known to be associated with chronic pancreatitis. Additionally it was observed that smoking increases the risk of chronic pancreatitis by 4.1 times. The T allele frequency of MTHFR (C667T) was found to be a significant risk factor for chronic pancreatitis playing a crucial role in altered folate metabolsim. PMID:23273201

  5. Folate intake and the MTHFR C677T genotype influence choline status in young Mexican American women☆

    PubMed Central

    Abratte, Christian M.; Wang, Wei; Li, Rui; Moriarty, David J.; Caudill, Marie A.

    2009-01-01

    Numerous studies have reported a relationship between folate status, the methylenetetrahydrofolate reductase (MTHFR) 677C→T variant and disease risk. Although folate and choline metabolism are inter-related, only limited data are available on the relationship between choline and folate status in humans. This study sought to examine the influences of folate intake and the MTHFR 677C→T variant on choline status. Mexican-American women (n =43; 14 CC, 12 CT and 17 TT) consumed 135 μg/day as dietary folate equivalents (DFE) for 7 weeks followed by randomization to 400 or 800 μg DFE/day for 7 weeks. Throughout the study, total choline intake remained unchanged at ∼350 mg/day. Plasma concentrations of betaine, choline, glycerophosphocholine, phosphatidylcholine and sphingomyelin were measured via LC-MS/MS for Weeks 0, 7 and 14. Phosphatidylcholine and sphingomyelin declined ( P=.001, P=.009, respectively) in response to folate restriction and increased ( P=.08, P=.029, respectively) in response to folate treatment. The increase in phosphatidylcholine occurred in response to 800 ( P=.03) not 400 ( P=.85) μg DFE/day (week×folate interaction, P=.017). The response of phosphatidylcholine to folate intake appeared to be influenced by MTHFR C677T genotype. The decline in phosphatidylcholine during folate restriction occurred primarily in women with the CC or CT genotype and not in the TT genotype (week×genotype interaction, P=.089). Moreover, when examined independent of folate status, phosphatidylcholine was higher ( P <.05) in the TT genotype relative to the CT genotype. These data suggest that folate intake and the MTHFR C677T genotype influence choline status in humans. PMID:17588738

  6. Quantitative assessment of the associations between MTHFR C677T and A1298C polymorphisms and risk of fractures: a meta-analysis.

    PubMed

    Bai, Rui; Liu, Wanlin; Zhao, Aiqing; Zhao, Zhenqun; Jiang, Dianming

    2013-03-01

    Many studies have investigated the associations between methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and risk of fractures, but the impact of MTHFR polymorphisms on fractures risk is unclear owing to the obvious inconsistence among those studies. This study aims to quantify the strength of association between MTHFR C677T and A1298C polymorphisms and risk of fractures. We searched the PubMed, Embase and Wanfang databases for articles relating the association between MTHFR C677T and A1298C polymorphisms and risk of fractures in humans. We estimated summary odds ratios (ORs) with their confidence intervals (CIs) to assess the associations. Meta-analyses suggested MTHFR C677T polymorphism was associated with increased risk of any site fractures (for T vs. C, OR = 1.17, 95 % CI 1.03-1.32; for TT vs. CC, OR = 1. 31, 95 % CI 1.11-1.54; for TT vs. CT, OR = 1.22, 95 % CI 1.04-1.43; for TT vs. CT/CC, OR = 1.31, 95 % CI 1.13-1.51). Besides, MTHFR A1298C polymorphism was also associated with increased risk of any site fractures. Subgroup meta-analyses suggested MTHFR C677T polymorphism was associated with increased risk of vertebral fractures under three genetic contrast modes (for TT vs. CC, OR = 1.43, 95 % CI 1.05-1.95; for TT vs. CT, OR = 1.36, 95 % CI 1.01-1.85; for TT vs. CT/CC, OR = 1.50, 95 % CI 1.17-1.91), but there was no association between MTHFR C677T polymorphism and risk of hip fractures and non-vertebral fractures (all P values were more than 0.05). Thus, individuals with homozygote genotype TT of MTHFR C677T have obviously increased risk of vertebral fractures compared those with heterozygote genotype CT or homozygote genotype CC. There is no association between MTHFR C677T polymorphism and risk of hip fractures and non-vertebral fractures. PMID:23229495

  7. Role of genetic mutations in folate-related enzyme genes on Male Infertility

    PubMed Central

    Liu, Kang; Zhao, Ruizhe; Shen, Min; Ye, Jiaxin; Li, Xiao; Huang, Yuan; Hua, Lixin; Wang, Zengjun; Li, Jie

    2015-01-01

    Several studies showed that the genetic mutations in the folate-related enzyme genes might be associated with male infertility; however, the results were still inconsistent. We performed a meta-analysis with trial sequential analysis to investigate the associations between the MTHFR C677T, MTHFR A1298C, MTR A2756G, MTRR A66G mutations and the MTHFR haplotype with the risk of male infertility. Overall, a total of 37 studies were selected. Our meta-analysis showed that the MTHFR C677T mutation was a risk factor for male infertility in both azoospermia and oligoasthenoteratozoospermia patients, especially in Asian population. Men carrying the MTHFR TC haplotype were most liable to suffer infertility while those with CC haplotype had lowest risk. On the other hand, the MTHFR A1298C mutation was not related to male infertility. MTR A2756G and MTRR A66G were potential candidates in the pathogenesis of male infertility, but more case-control studies were required to avoid false-positive outcomes. All of these results were confirmed by the trial sequential analysis. Finally, our meta-analysis with trial sequential analysis proved that the genetic mutations in the folate-related enzyme genes played a significant role in male infertility. PMID:26549413

  8. Role of genetic mutations in folate-related enzyme genes on Male Infertility.

    PubMed

    Liu, Kang; Zhao, Ruizhe; Shen, Min; Ye, Jiaxin; Li, Xiao; Huang, Yuan; Hua, Lixin; Wang, Zengjun; Li, Jie

    2015-01-01

    Several studies showed that the genetic mutations in the folate-related enzyme genes might be associated with male infertility; however, the results were still inconsistent. We performed a meta-analysis with trial sequential analysis to investigate the associations between the MTHFR C677T, MTHFR A1298C, MTR A2756G, MTRR A66G mutations and the MTHFR haplotype with the risk of male infertility. Overall, a total of 37 studies were selected. Our meta-analysis showed that the MTHFR C677T mutation was a risk factor for male infertility in both azoospermia and oligoasthenoteratozoospermia patients, especially in Asian population. Men carrying the MTHFR TC haplotype were most liable to suffer infertility while those with CC haplotype had lowest risk. On the other hand, the MTHFR A1298C mutation was not related to male infertility. MTR A2756G and MTRR A66G were potential candidates in the pathogenesis of male infertility, but more case-control studies were required to avoid false-positive outcomes. All of these results were confirmed by the trial sequential analysis. Finally, our meta-analysis with trial sequential analysis proved that the genetic mutations in the folate-related enzyme genes played a significant role in male infertility. PMID:26549413

  9. Screening for C677T and A1298C MTHFR polymorphisms in patients with epilepsy and risk of hyperhomocysteinemia.

    PubMed

    Caccamo, D; Condello, S; Gorgone, G; Crisafulli, G; Belcastro, V; Gennaro, S; Striano, P; Pisani, F; Ientile, R

    2004-01-01

    Hyperhomocysteinemia can result from decreased methylenetetrahydrofolate reductase (MTHFR) enzyme activity, owing to genetic polymorphisms andor inadequate folate intake. This study was aimed at investigating the prevalence of C677T and A1298C MTHFR polymorphisms, and their impact on hyperhomocysteinemia in 95 epileptic patients and 98 controls. Double gradient-denaturing gradient gel electrophoresis screening revealed that the frequency of T677 polymorphic allele was similar between cases and controls (46.3% vs 42.3%), whereas that of C1298 allele was significantly higher in patients (30.5% vs 19.4%, p < 0.05). Significant differences between the two groups were also found for the frequencies of genotypes AA1298 (46.3% in cases vs 67.3% in controls, p < 0.01) and AC1298 (46.3% in cases vs 26.6% in controls, p < 0.01). Other genotype frequencies did not show any statistically significant differences. Haplotype frequencies significantly differed between the two groups. The CT677/AC1298 diplotype was significantly more frequent in epileptic patients than in controls (32.6% vs 18.4%, p < 0.05). Patients treated with enzyme-inducing antiepileptic drugs, having this diplotype and concomitant low folate concentration (i.e., < 3.4 nmol/L), exhibited plasma homocysteine levels significantly higher than normal values (27.1 +/- 2.44 micromol/L, p < 0.001). This increase, however, was lower than that observed in folate-deficient patients with diplotype TT677/AA1298 (41.3 +/- 3.41 micromol/L, p < 0.001). Indeed, these two diplotypes could be regarded as risk factors for hyperhomocysteinemia. Conversely, we found that the CC677/AA1298 diplotype was significantly more frequent in controls (p < 0.01), suggesting a protective role. Our study suggests that both C677T and A1298C MTHFR polymorphisms should be examined when assessing genetic risk factors of hyperhomocysteinemia in epilepsy. PMID:15970629

  10. Association between MTHFR C677T Polymorphism and Risk of Acute Lymphoblastic Leukemia: A Meta-Analysis Based on 51 Case-Control Studies

    PubMed Central

    Li, Su-yi; Ye, Jie-yu; Liang, En-yu; Zhou, Li-xia; Yang, Mo

    2015-01-01

    Background Studies and systematic reviews have reached inconsistent conclusions on the role of 5, 10-methylenetetrahydrofolate reductase (MTHFR) polymorphism C677T in acute lymphoblastic leukemia (ALL) risk. Material/Methods The present meta-analysis comprising of 51 case-control studies, including 7892 cases and 14 280 controls was performed to reevaluate the association between MTHFR C677T polymorphism and ALL risk. Results Statistical differences were found in the dominant model (TT+CT vs. CC, odd ratio (OR)=0.89, 95% CI, 0.79–1.00, P=0.04) and the CT vs. CC (OR=0.89, 95% CI, 0.80–1.00, P=0.05), but not in the allele contrast model (T vs. C, OR=0.92, 95% CI, 0.84–1.01, P=0.08), additive model (TT vs. CC, OR=0.87, 95% CI, 0.73–1.05, P=0.15), or recessive model (TT vs. CT+CC, OR=0.94, 95% CI, 0.81–1.10, P=0.44) in overall populations. In the subgroup analyses stratified by age (children and adults) and ethnicity (Asian and Caucasian), no significant associations between MTHFR C677T polymorphism and ALL risk were observed. Conclusions The current study found no sufficient evidence of a protective role of MTHFR C677T polymorphism in ALL susceptibility. PMID:25761797

  11. Meta-analyses of Blood Homocysteine Levels for Gender and Genetic Association Studies of the MTHFR C677T Polymorphism in Schizophrenia

    PubMed Central

    Nishi, Akira; Numata, Shusuke; Tajima, Atsushi; Kinoshita, Makoto; Kikuchi, Kumiko; Shimodera, Shinji; Tomotake, Masahito; Ohi, Kazutaka; Hashimoto, Ryota; Imoto, Issei; Takeda, Masatoshi; Ohmori, Tetsuro

    2014-01-01

    Previous studies suggest that elevated blood homocysteine levels and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism are risk factors for schizophrenia. However, the effects of gender and MTHFR C677T genotypes on blood homocysteine levels in schizophrenia have not been consistent. We first investigated whether plasma total homocysteine levels were higher in patients with schizophrenia than in controls with stratification by gender and by the MTHFR C677T genotypes in a large cohort (N = 1379). Second, we conducted a meta-analysis of association studies between blood homocysteine levels and schizophrenia separately by gender (N = 4714). Third, we performed a case-control association study between the MTHFR C677T polymorphism and schizophrenia (N = 4998) and conducted a meta-analysis of genetic association studies based on Japanese subjects (N = 10 378). Finally, we assessed the effect of plasma total homocysteine levels on schizophrenia by a mendelian randomization approach. The ANCOVA after adjustment for age demonstrated a significant effect of diagnosis on the plasma total homocysteine levels in all strata, and the subsequent meta-analysis for gender demonstrated elevated blood homocysteine levels in both male and female patients with schizophrenia although antipsychotic medication might influence the outcome. The meta-analysis of the Japanese genetic association studies demonstrated a significant association between the MTHFR C677T polymorphism and schizophrenia. The mendelian randomization analysis in the Japanese populations yielded an OR of 1.15 for schizophrenia per 1-SD increase in plasma total homocysteine. Our study suggests that increased plasma total homocysteine levels may be associated with an increased risk of schizophrenia. PMID:24535549

  12. Maternal Supplementary Folate Intake, Methylenetetrahydrofolate Reductase (MTHFR) C677T and A1298C Polymorphisms and the Risk of Orofacial Cleft in Iranian Children

    PubMed Central

    Ebadifar, Asghar; KhorramKhorshid, Hamid Reza; Kamali, Koorosh; Salehi Zeinabadi, Mehdi; Khoshbakht, Tayyebeh; Ameli, Nazila

    2015-01-01

    Background: The purpose of this study was to describe the association of MTHFR gene single nucleotide polymorphisms (C677T and A1298C) and maternal supplementary folate intake with orofacial clefts in the Iranian population. Methods: In this case-control study, peripheral venous blood was taken from 65 patients with orofacial clefts and 215 unaffected controls for DNA extraction and kept in EDTA for further analysis. The genotyping was carried out using Polymerase Chain Reaction (PCR) followed by Restriction Fragment Length Polymorphism (RFLP) and gel electrophoresis. Data were analyzed using Chi square test and logistic regression tests. Results: Genotype frequencies of 677TT were reported to be 13.5 and 36.1% in controls and CL/P patients, respectively, which showed a significant difference compared to CC as reference (OR=4.118; 95% CI=1.997–8.492; p=0.001). Conversely, 1298CC with frequencies of 10.8 and 12.7% in controls and patients, respectively, showed no significant difference compared to AA (OR=2.359; 95% CI=0.792–7.023; p=0.123). Comparing patients whose mothers did not report the folate supplement intake during pregnancy, to controls, it was observed that lack of folate intake was a predisposing factor for having a child with oral clefts (OR=5/718, p=0.000). Conclusion: Children carrying the 677TT variant of the MTHFR gene may have an increased risk of CL/P. In addition, the finding that the risk associated with this allele was obviously higher when the mothers didn’t use folic acid, supports the hypothesis that folic acid may play a role in the etiology of CL/P. PMID:26140186

  13. MTHFR C677T and A1298C variant genotypes and the risk of microsatellite instability among Iranian colorectal cancer patients.

    PubMed

    Naghibalhossaini, Fakhraddin; Mokarram, Pooneh; Khalili, Islam; Vasei, Mohammad; Hosseini, Seyed Vahid; Ashktorab, Hassan; Rasti, Mozhgan; Abdollahi, Kourosh

    2010-03-01

    Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the folate metabolic pathway. We aimed to test the hypothesis that C677T and A1298C variants of MTHFR predispose to microsatellite instable (MSI) colorectal cancer. We determined MTHFR genotypes in 175 sporadic colorectal cancer patients and a total of 231 normal controls in Shiraz, Southern Iran. Among the genotypes found in our samples, MTHFR CT and CT+TT were associated with increased risk for CRC incidence [odds ratio (OR)=2.4, 95% confidence interval (95%CI)=1.8-4.4; OR=2.4, 95%CI=1.6-3.6, respectively]. Double heterozygotes 677CT/1298AC and double homozygote 677TT/1298AA and 677CC/1298CC genotypes also showed a significantly increased risk of developing CRC compared with the wild-type 677CC/1298AA genotypes of the controls. Among the 151 tumors tested, 36 (23.8%) were MSI+. MSI was more common in proximal tumors (OR=10.4; 95%CI=3.9-27.8) and in smokers (OR=2.9; 95%CI=1.3-6.7). In a case-control comparison, the MTHFR 677CT+TT genotype was strongly associated with MSI (OR=2.6; 95%CI=1.3-5.3). Hypermethylation of mismatch repair genes was positively related with MSI incidence in these tumor series (P=0.00). Our data suggest that the MTHFR 677CT+TT variant genotype may be a risk factor for MSI+ cancer. PMID:20193847

  14. MTHFR C677T genotype influences the isotopic enrichment of one-carbon metabolites in folate-compromised men consuming d9-choline123

    PubMed Central

    Yan, Jian; Wang, Wei; Gregory, Jesse F; Malysheva, Olga; Brenna, J Thomas; Stabler, Sally P; Allen, Robert H; Caudill, Marie A

    2011-01-01

    Background: Homozygosity for the variant 677T allele in the methylenetetrahydrofolate reductase (MTHFR) gene increases the requirement for folate and may alter the metabolic use of choline. The choline adequate intake is 550 mg/d for men, although the metabolic consequences of consuming extra choline are unclear. Objective: Deuterium-labeled choline (d9-choline) as tracer was used to determine the differential effects of the MTHFR C677T genotype and the effect of various choline intakes on the isotopic enrichment of choline derivatives in folate-compromised men. Design: Mexican American men with the MTHFR 677CC or 677TT genotype consumed a diet providing 300 mg choline/d plus supplemental choline chloride for total choline intakes of 550 (n = 11; 4 with 677CC and 7 with 677TT) or 1100 (n = 12; 4 with 677CC and 8 with 677TT) mg/d for 12 wk. During the last 3 wk, 15% of the total choline intake was provided as d9-choline. Results: Low but measurable enrichments of the choline metabolites were achieved, including that of d3-phosphatidylcholine (d3-PtdCho)—a metabolite produced in the de novo pathway via choline-derived methyl groups. Men with the MTHFR 677TT genotype had a higher urinary enrichment ratio of betaine to choline (P = 0.041), a higher urinary enrichment of sarcosine (P = 0.041), and a greater plasma enrichment ratio of d9-betaine to d9-PtdCho with the 1100 mg choline/d intake (P = 0.033). Conclusion: These data show for the first time in humans that choline itself is a source of methyl groups for de novo PtdCho biosynthesis and indicate that the MTHFR 677TT genotype favors the use of choline as a methyl donor. PMID:21123458

  15. Association between the MTHFR C677T polymorphism and gastric cancer susceptibility: A meta-analysis of 5,757 cases and 8,501 controls

    PubMed Central

    CHEN, LONG; LU, NING; ZHANG, BAI-HONG; WENG, LI; LU, JUN

    2015-01-01

    Current data regarding the association between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and the risk of developing gastric cancer are insufficient to draw definite conclusions. Therefore, the present meta-analysis was conducted to achieve a more precise estimation of the association. MEDLINE, EMBASE and Wanfang database searches resulted in the identification of 28 eligible studies describing 5,757 cases and 8,501 controls. The strength of the association between the MTHFR C677T polymorphism and gastric cancer risk were evaluated using crude odds ratios (ORs), with 95% confidence intervals (CIs). The pooled ORs were determined using homozygous (TT vs. CC), heterozygous (CT vs. CC), dominant (TT+CT vs. CC) and recessive (TT vs. CC+CT) models. When all studies were pooled into the meta-analysis, significant associations were identified between the MTHFR C677T polymorphism and the risk of gastric cancer (homozygous model: OR, 1.39; 95% CI, 1.20–1.62; heterozygous model: OR, 1.18; 95% CI, 1.05–1.32; dominant model: OR, 1.23; 95% CI, 1.10–1.38; recessive model: OR, 1.26; 95% CI, 1.12–1.42). Stratification of the data by ethnicity identified a statistically significantly elevated risk of gastric cancer in Asian MTHFR C677T polymorphism populations (homozygous model: OR, 1.64; 95% CI, 1.43–1.90; heterozygous model: OR, 1.30; 95% CI, 1.16–1.45; dominant model: OR, 1.39; 95% CI, 1.25–1.54; recessive model: OR, 1.41; 95% CI, 1.25–1.51), but not in Caucasian populations (homozygous model: OR, 1.15; 95% CI, 0.89–1.48; heterozygous model: OR, 1.03; 95% CI, 0.84–1.25; dominant model: OR, 1.05; 95% CI, 0.86–1.28; recessive model: OR, 1.09; 95% CI, 0.91–1.31). Following adjustment for heterogeneity, the current meta-analysis demonstrated that the MTHFR C677T polymorphism was not associated with the risk of gastric cancer in Caucasian individuals. Furthermore, no evidence of publication bias was observed. Thus, the current meta-analysis indicates that the MTHFR C677T allele may be a low-penetrant risk factor for the development of gastric cancer in Asian populations. PMID:26622644

  16. Methylenetetrahydrofolate Reductase C677T Polymorphism and Type 2 Diabetes Mellitus in Chinese Population: A Meta-Analysis of 29 Case-Control Studies

    PubMed Central

    Zhu, Bo; Wu, Xiaomei; Zhi, Xueyuan; Liu, Lei; Zheng, Quanmei; Sun, Guifan

    2014-01-01

    Background Methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, had significant effects on the homocysteine levels. The common functional MTHFR C677T polymorphism had been extensively researched. Several studies had evaluated the relationship between MTHFR C677T polymorphism and type 2 diabetes mellitus (T2DM), but the results were still controversial in the Chinese Han population. This meta-analysis was conducted to evaluate the relationship between MTHFR C677T polymorphism and T2DM in the Chinese Han population. Methods We searched the relevant studies in multiple electronic databases, which published up to December 2013. We reviewed and extracted data from all the included studies on the relationship between MTHFR C677T polymorphism and T2DM in the Chinese Han population. The odds ratios (ORs) and their 95% confidence intervals (95%CIs) were used to evaluate the relationship. Fixed-effects and random-effects meta-analysis were used to pool ORs by the heterogeneity. Publication bias and sensitivity analysis were also examined. Results 29 studies were finally included in our meta-analysis, which contained 4656 individuals with T2DM and 2127 healthy controls. There was a significant relationship between MTHFR C677T polymorphism and T2DM under dominant (OR: 1.70, 95% CI: 1.42–2.02), recessive (OR: 1.48, 95% CI: 1.21–1.80), homozygous (OR: 1.89, 95% CI: 1.47–2.42), heterozygous (OR: 1.58, 95% CI: 1.33–1.87), and additive (OR: 1.46, 95% CI: 1.28–1.68) genetic model in a random-effects model. Subgroup analysis also reached similar results. Sensitivity analysis indicated that the overall result were dependable. Conclusions There was a significant relationship between MTHFR C677T polymorphism and T2DM in the Chinese Han population. The results of our meta-analysis suggested that MTHFR 677T allele might be a risk genetic factor of T2DM in the Chinese Han population. PMID:25047451

  17. Coronary heart disease among Circassians in Israel is not associated with mutations in thrombophilia genes.

    PubMed

    Falik-Zaccai, Tzipora C; Haron, Yafa; Eilat, Danny; Harash, Bakky; Golinker, Ekaterina; Hussein, Osamah; Eisikovits, Rivka; Borochowitz, Zvi; Linn, Shai

    2003-02-01

    The Muslim Circassian community in Israel represents a unique ethnic community that has never been genetically and medically studied. One hundred and fifty-three randomly selected individuals (91 men and 62 women, ages 35 and older), both healthy or with a history of cardiovascular disease (14 men and 7 women), were studied in a cross-sectional descriptive study for mutations in three genes known to be associated with hypercoagulation. Their medical records were reviewed for risk factors and history of cardiovascular disease (CVD) and thromboembolic events. The mutation FV 1691G --> A in the gene for factor V (FV 1691G --> A), the mutation MTHFR 677C --> T in the gene 5,10-methylenetetrahydrofolate reductase, and the allele G20210A in the gene for prothrombin (PT 20210G --> A) were studied. The mutation FV 1691G --> A was observed in a heterozygous form in 1.3% of 153 studied individuals, while the PT 20210G --> A allele was identified in a heterozygous form in 6.5%. No individual was found homozygous for either of these two mutations. The MTHFR C677T mutation was present in 42.8% of the studied population in a heterozygous form and in 8.6% in a homozygous form. Serum homocysteine, folate, and B12 levels were studied among individuals heterozygous and homozygous for the MTHFR C677T mutation. There was no significant difference in the prevalence of all three mutations between individuals affected with CVD or other forms of thromboembolic disease and healthy individuals. This is the first report of a medical condition and its genetic background among Circassians. The high prevalence of CVD among Circassians was found to be etiologically unrelated to the three mutations studied in the genes for factor V, MTHFR, and prothrombin. PMID:12713146

  18. MTHFR C677T and A1298C polymorphisms as predictors of radiotherapy response in head and neck squamous cell carcinoma.

    PubMed

    Anders, Q S; Stur, E; Agostini, L P; Garcia, F M; Reis, R S; Santos, J A; Mendes, S O; Maia, L L; Peterle, G T; Stange, V; Carvalho, M B; Tajara, E H; Santos, M; Silva-Conforti, A M A; Louro, I D

    2015-01-01

    The C677T and A1298C polymorphisms in methylene-tetrahydrofolate reductase (MTHFR), which regulates the release of active folate in the body, may have reduced activity. Given that folate participates in important intracellular pathways, such as nucleotide synthesis and biomolecule methylation, it seems plausible that patients with head and neck squamous cell carcinoma (HNSCC) may respond differently to radiotherapy treatments, based on genetic polymor-phisms. Therefore, this study sought to understand the role of these polymorphisms in HNSCC patient radiotherapy response. Genotypes were detected by PCR-RFLP after extraction of DNA from peripheral blood lymphocytes. Survival curves were analyzed by the Kaplan- Meier model, and significant differences were analyzed by the Wil-coxon test. Response to radiotherapy in patients with laryngeal SCC was significantly associated with the MTHFR C677T polymorphism (P = 0.030). Indeed, the presence of at least one T allele decreases the mortality rate up to 3-fold. Therefore, we propose that MTHFR C677T may represent a putative biomarker for radiotherapy prognosis in la-ryngeal SCC patients. PMID:26535623

  19. Common Mutations of the Methylenetetrahydrofolate Reductase (MTHFR) Gene in Non-Syndromic Cleft Lips and Palates Children in North-West of Iran

    PubMed Central

    Abdollahi-Fakhim, Shahin; Asghari Estiar, Mehrdad; Varghaei, Parizad; Alizadeh Sharafi, Mahdi; Sakhinia, Masoud; Sakhinia, Ebrahim

    2015-01-01

    Introduction: Cleft lips and cleft palates are common congenital abnormalities in children. Various chromosomal loci have been suggested to be responsible the development of these abnormalities. The present study was carried out to investigate the association between the suspected genes (methylenetetrahydrofolate reductase [MTHFR] A1298C and C677T) that might contribute into the etiology of these disorders through application of molecular methods. Materials and Methods: This cross-sectional and explanatory study was carried out on a study population of 65 affected children, 130 respective parents and 50 healthy individuals between 2009 and 2012 at Tabriz University of Medical Sciences, IR Iran. After DNA extraction, amplification refractory mutation systempolymerase chain reaction (ARMS-PCR) and restriction fragment length polymorphism (RFLP)-PCR were used respectively to investigate the C677T and A1298C mutations for the MTHFR gene. Results: There was a significant difference in the rates of the C677T mutation when affected patients and their fathers were compared with the control group (odds ratio [OR]=0.44) (OR=0.64). However, there was no significant difference observed in the rate of this mutation between the patients mothers and the control group (OR=1.35). In addition, the abnormality rate was higher in patients with the A1298C mutation and their parents, when compared with the control group. This abnormality rate was higher for the affected children and their fathers in comparison with their mothers (Fathers, OR=0.26; Mothers, OR=0.65; Children, OR=0.55). No significant difference was seen in the rate of the polymorphism C677T in its CC, when the affected children and their parents were compared with the control group. However, there was a significant difference in the A1298C mutation. Conclusion: An association was seen between the A1298C mutation and cleft lip and cleft palate abnormalities in Iran. However, there seems to be a stronger relationship between the C67TT mutation and these abnormalities in other countries, which could be explained by racial differences. Moreover, this association was more notable between the affected children and their fathers than their mothers. The findings in this study may be helpful in future studies and screening programs. PMID:25745606

  20. MTHFR C677T genotype as a risk factor for epilepsy including post-traumatic epilepsy in a representative military cohort.

    PubMed

    Scher, Ann I; Wu, Holly; Tsao, Jack W; Blom, Henk J; Feit, Preethy; Nevin, Remington L; Schwab, Karen A

    2011-09-01

    The well-studied C677T variant in the methylenetetrahydrofolate reductase (MTHFR) enzyme is a biologically plausible genetic risk factor for seizures or epilepsy. First, plasma/serum levels of homocysteine, a pro-convulsant, are moderately elevated in individuals with the homozygote TT genotype. Furthermore, the TT genotype has been previously linked with migraine with aura-a comorbid condition-and with alcohol withdrawal seizures. Finally, several small studies have suggested that the TT genotype may be overrepresented in epilepsy patients. In this study, we consider whether the MTHFR C677T or A1298C variants are associated with risk of epilepsy including post-traumatic epilepsy (PTE) in a representative military cohort. Study subjects were selected from the cohort of military personnel on active duty during the years 2003 through 2007 who had archived serum samples at the DoD Serum Repository, essentially all active duty personnel during this time frame. We randomly selected 800 epilepsy patients and 800 matched controls based on ICD-9-CM diagnostic codes. We were able to isolate sufficient genetic material from the archived sera to genotype approximately 85% of our study subjects. The odds of epilepsy were increased in subjects with the TT versus CC genotype (crude OR=1.52 [1.04-2.22], p=0.031; adjusted OR=1.57 [1.07-2.32], p=0.023). In our sensitivity analysis, risk was most evident for patients with repeated rather than single medical encounters for epilepsy (crude OR=1.85 [1.14-2.97], p=0.011, adjusted OR=1.95 [1.19-3.19], p=0.008), and particularly for PTE (crude OR=3.14 [1.41-6.99], p=0.005; adjusted OR=2.55 [1.12-5.80], p=0.026). Our early results suggest a role for the common MTHFR C677T variant as a predisposing factors for epilepsy including PTE. Further exploration of baseline homocysteine and folate levels as predictors of seizure risk following traumatic brain injury is warranted. PMID:21787169

  1. The role of methylenetetrahydrofolate reductase C677T polymorphism on the peripheral blood natural killer cell proportion in women with unexplained recurrent miscarriages

    PubMed Central

    Park, Chan Woo; Han, Ae Ra; Kwak-Kim, Joanne; Park, So Yeon; Han, Jung Yeol; Koong, Mi Kyoung; Song, In Ok

    2011-01-01

    Objective To examine the association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and hyperhomocysteinemia in women with unexplained recurrent miscarriages (RM) and to investigate the association between MTHFR genotype variants and alloimmune activation, proportion of peripheral blood natural killer (pbNK) cells. Methods A total of 39 patients with a history of two or more unexplained miscarriages were recruited to this study. The controls were women who had a live birth without a history of RM (n=50). The proportion of pbNK cells was measured by flow cytometry. Plasma homocysteine levels and the incidence of the MTHFR variant of the RM and control groups were compared. The proportion of pbNK cells was compared to the MTHFR variants in the RM group. Results No differences were found between the two groups' mean plasma homocysteine levels (7.61.5 mol/L vs. 7.12.1 mol/L) or incidence of the MTHFR genotype variant (CC, 35% vs. 33%; CT, 40% vs. 53%; and TT, 25% vs. 14%). In the RM group, individuals with the TT variant (7.71.1 mol/L) had higher homocysteine levels than those with the CC and CT variants (7.41.9 mol/L and 7.41.2 mol/L) and those with the CT variant (19.28.1%) had a higher proportion of CD3-/CD56+ pbNK cells than those with the CC and TT variants (17.76.6% and 17.97. 0%), but the results of both comparisons were statistically insignificant. Conclusion These preliminary results show no difference in plasma homocysteine levels between the RM and control groups or among MTHFR genotype variants in the RM group, which may suggest that the plasma homocysteine level is difficult to use as a predictive marker of RM in the Korean population. A study of a larger number of patients is needed. PMID:22384438

  2. Are MTHFR C677T and MTRR A66G Polymorphisms Associated with Overweight/Obesity Risk? From a Case-Control to a Meta-Analysis of 30,327 Subjects

    PubMed Central

    Fan, Shu-Jun; Yang, Bo-Yi; Zhi, Xue-Yuan; He, Miao; Wang, Da; Wang, Yan-Xun; Wang, Yi-Nuo; Wei, Jian; Zheng, Quan-Mei; Sun, Gui-Fan

    2015-01-01

    Several studies have examined the associations of methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G polymorphisms with being overweight/obesity. However, the results are still controversial. We therefore conducted a case-control study (517 cases and 741 controls) in a Chinese Han population and then performed a meta-analysis by combining previous studies (5431 cases and 24,896 controls). In our case-control study, the MTHFR C677T polymorphism was not significantly associated with being overweight/obesity when examining homozygous codominant, heterozygous codominant, dominant, recessive and allelic genetic models. The following meta-analysis confirmed our case-control results. Heterogeneity was minimal in the overall analysis, and sensitivity analyses and publication bias tests indicated that the meta-analytic results were reliable. Similarly, both the case-control study and meta-analysis found no significant association between the MTRR A66G polymorphism and being overweight/obesity. However, sensitivity analyses showed that the associations between the MTRR A66G polymorphism and being overweight/obesity became significant in the dominant, heterozygous codominant and allelic models after excluding our case-control study. The results from our case-control study and meta-analysis suggest that both of the two polymorphisms are not associated with being overweight/obesity. Further large-scale population-based studies, especially for the MTRR A66G polymorphism, are still needed to confirm or refute our findings. PMID:26016497

  3. A Lower Degree of PBMC L1 Methylation in Women with Lower Folate Status May Explain the MTHFR C677T Polymorphism Associated Higher Risk of CIN in the US Post Folic Acid Fortification Era

    PubMed Central

    Badiga, Suguna; Johanning, Gary L.; Macaluso, Maurizio; Azuero, Andres; Chambers, Michelle M.; Siddiqui, Nuzhat R.; Piyathilake, Chandrika J.

    2014-01-01

    Background Studies in populations unexposed to folic acid (FA) fortification have demonstrated that MTHFR C677T polymorphism is associated with increased risk of higher grades of cervical intraepithelial neoplasia (CIN 2+). However, it is unknown whether exposure to higher folate as a result of the FA fortification program has altered the association between MTHFR C677T and risk of CIN, or the mechanisms involved with such alterations. The current study investigated the following in a FA fortified population: 1) The association between MTHFR C677T polymorphism and risk of CIN 2+; 2) The modifying effects of plasma folate concentrations on this association; and 3) The modifying effects of plasma folate on the association between the polymorphism and degree of methylation of long interspersed nucleotide elements (L1s), in peripheral blood mononuclear cell (PBMC) DNA, a documented biomarker of CIN risk. Methods The study included 457 US women diagnosed with either CIN 2+ (cases) or ≤ CIN 1 (non-cases). Unconditional logistic regression models were used to test the associations after adjusting for relevant risk factors for CIN. Results The 677CT/TT MTHFR genotypes were not associated with the risk of CIN 2+. Women with CT/TT genotype with lower folate, however, were more likely to be diagnosed with CIN 2+ compared to women with CT/TT genotype with higher folate (OR = 2.41, P = 0.030). Women with CT/TT genotype with lower folate were less likely to have a higher degree of PBMC L1 methylation compared to women with CT/TT genotype with higher folate (OR = 0.28, P = 0.017). Conclusions This study provides the first evidence that the MTHFR 677CT/TT genotype-associated lower degree of PBMC L1 methylation increases the risk of CIN 2+ in women in the US post-FA fortification era. Thus, even in the post-FA fortification era, not all women have adequate folate status to overcome MTHFR 677CT/TT genotype-associated lower degree of L1 methylation. PMID:25302494

  4. Evaluation of Factor V G1691A, prothrombin G20210A, Factor XIII V34L, MTHFR A1298C, MTHFR C677T and PAI-1 4G/5G genotype frequencies of patients subjected to cardiovascular disease (CVD) panel in south-east region of Turkey.

    PubMed

    Oztuzcu, Serdar; Ergun, Sercan; Ula?l?, Mustafa; Nacarkahya, Glper; I?ci, Yusuf Ziya; I?ci, Mehri; Bayraktar, Recep; Tamer, Ali; akmak, Ecir Ali; Arslan, Ahmet

    2014-06-01

    Cardiovascular disease (CVD) risk factors, such as arterial hypertension, obesity, dyslipidemia or diabetes mellitus, as well as CVDs, including myocardial infarction, coronary artery disease or stroke, are the most prevalent diseases and account for the major causes of death worldwide. In the present study, 4,709 unrelated patients subjected to CVD panel in south-east part of Turkey between the years 2010 and 2013 were enrolled and DNA was isolated from the blood samples of these patients. Mutation analyses were conducted using the real-time polymerase chain reaction method to screen six common mutations (Factor V G1691A, PT G20210A, Factor XIII V34L, MTHFR A1298C and C677T and PAI-1 -675 4G/5G) found in CVD panel. The prevalence of these mutations were 0.57, 0.25, 2.61, 13.78, 9.34 and 24.27 % in homozygous form, respectively. Similarly, the mutation percent of them in heterozygous form were 7.43, 3.44, 24.91, 44.94, 41.09 and 45.66%, respectively. No mutation was detected in 92 (1.95%) patients in total. Because of the fact that this is the first study to screen six common mutations in CVD panel in south-east region of Turkey, it has a considerable value on the diagnosis and treatment of these diseases. Upon the results of the present and previous studied a careful examination for these genetic variants should be carried out in thrombophilia screening programs, particularly in Turkish population. PMID:24532105

  5. Massive pulmonary embolism associated with Factor V Leiden, prothrombin, and methylenetetrahydrofolate reductase gene mutations in a young patient on oral contraceptive pills: a case report.

    PubMed

    Charafeddine, Khalil M; Mahfouz, Rami A; Ibrahim, Georges Y; Taher, Ali T; Hoballah, Jamal J; Taha, Assad M

    2010-10-01

    Factor V Leiden (Factor V G1691A), prothrombin gene mutation G20210A, and homozygous C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene are known to predispose venous thromboembolism (VTE). We present herein a rare case of a young woman heterozygous for these mutations and taking oral contraceptive pills for less than 2 months, diagnosed to have massive deep venous thrombosis and bilateral pulmonary embolism. The patient was managed for 10 days in the hospital and discharged home on oral anticoagulants. This case suggests that screening for these factors in people with family history of thrombosis and in relatives of patients with these mutations is highly recommended to prevent fatal consequences. In addition, a new guideline for treatment and prophylaxis with anticoagulant for these patients and others who are at risk of developing VTE (American College of Chest Physicians [ACCP] guidelines-Chest 2008) has been published recently. Our recommendation is to promote for the internationally published algorithms through their application, where necessary, to prevent any future thrombotic morbidity or mortality incidents. PMID:19520679

  6. Methylenetetrahydrofolate reductase gene polymorphisms in 13 Chinese ethnic populations.

    PubMed

    Mao, Renfang; Fan, Yihui; Chen, Feng; Sun, Donglin; Bai, Jing; Fu, Songbin

    2008-04-01

    It has been shown that the polymorphisms of Methylenetetrahydrofolate reductase (MTHFR) gene are associated with susceptibility to several disorders including hyperhomocysteinemia, vascular disease, birth defect, and certain cancers, and exhibit great diversities among various populations. The aim of this study was to investigate the prevalence of two common non-synonymous single nucleotide polymorphisms (i.e., C677T and A1298C) at MTHFR gene in 13 Chinese populations. A total of 1015 healthy individuals from 13 populations distributed widely from north to south in China were studied. DNA samples were isolated from peripheral blood samples and genotyped using polymerase chain reaction-restriction fragment length polymorphism. For C677T polymorphism, the frequency in Chinese of CC homozygous was 42.4%; CT heterozygous was 49.8%; and TT homozygous was 7.9%. For A1298C, AA homozygous was 39.2%; AC heterozygous was 38.6%; and CC homozygous was 22.2%. The allelic frequency of 677T and 1298C was 32.8 and 41.5%, respectively, and each allele frequency had significant variance in 13 Chinese populations. The frequency of the 677T allele among southern populations was 30.7% compared to 38.0% among northeastern and 30.5% among northwestern populations. The difference was statistically significant (p < 0.01). The frequency of 1298C mutation in southerns was 58.9% whereas in northeasterns it was 24.0% and 37.6% in northwesterns. This was also statistically significant (p < 0.01). The MTHFR C677T and A1298C sites were in linkage disequilibrium in the Chinese population revealed by our data. PMID:18098118

  7. Congenital IL-12R1? receptor deficiency and thrombophilia in a girl homozygous for an IL12RB1 mutation and compound heterozygous for MTFHR mutations: A case report and literature review.

    PubMed

    Akar, H H; Kose, M; Ceylan, O; Patiroglu, T; Bustamante, J; Casanova, J L; Akyildiz, B N; Doganay, S

    2014-03-01

    Interleukin-12 (IL-12) plays an important role in the production of interferon gamma from T cells and natural killer cells and is essential for protection against intra-macrophagic pathogens such as Mycobacterium and Salmonella. Here, we describe a 16-year-old girl with homozygous mutation in exon 12 of the IL12RB1 gene, which causes complete IL-12R?1 deficiency in association with heterozygous mutation (C677T and A1298C) in the methylenetetrahydrofolate reductase gene. She presented with disseminated Mycobacterium tuberculosis complex infection, retroperitoneal fungal abscess and also thrombosis in the superior mesenteric-portal vein junction. This is the first case report of a primary immunodeficiency associated with a genetically determined venous thrombosis. PMID:24678409

  8. Recurrent pregnancy loss in a subject with heterozygote factor V Leiden mutation; a case report

    PubMed Central

    Ebrahimzadeh-Vesal, Reza; Azam, Roza; Ghazarian, Arvin; Hajesmaeili, Mogge; Ranji, Najmeh; Ezzati, Mohammad Reza; Sadri, Mehrdad; Mohammadi, Mohammad Ali; Khavandi, Siamak

    2014-01-01

    Recurrent pregnancy loss is usually defined as the loss of two or more consecutive pregnancies before 20 weeks of gestation, which occurs in approximately 5% of reproductive-aged women. It has been suggested that women with thrombophilia have an increased risk of pregnancy loss and other adverse pregnancy outcomes. Thrombophilia is an important predisposition to blood clot formation and is considered as a significant risk factor for recurrent pregnancy loss. The inherited predisposition to thrombophilia is most often associated with factor V Leiden mutation, prothrombin G20210A mutation, and methylenetetrahydrofolate reductase C677T and A1298C gene variants. The net effect is an increased cleavage of prothrombin to thrombin and excessive blood coagulation. PMID:26989729

  9. MTHFR gene polymorphisms in bladder cancer in the Turkish population.

    PubMed

    Izmirli, Muzeyyen; Inandiklioglu, Nihal; Abat, Deniz; Alptekin, Davut; Demirhan, Osman; Tansug, Zuhtu; Bayazit, Yildirim

    2011-01-01

    Bladder cancer is the 9th most common cancer and is responsible for malignancy related death all on the world. Folate and folate related enzyme polymorphisms related to the cancer risk. The methylene tethrahydrofolate reductase (MTHFR) enzyme is folate related and association of bladder cancer and MTHFR gene. Our purpose was to assess the prevalence of MTHFR gene 677 CT and 1298 AC polymorphisms and Bladder cancer in Turkey. We intended that bladder cancer patients and controls and we used the Polymerase Chain Reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP) methods. The MTHFR gene C677T and A1298C polymorphisms were associated with an increased risk of bladder cancer in our population (For the MTHFR gene C677T polymorphism and A1298C polymorphism; p=0.036<0.05; p=0.278>0.05 respectively). Consequently, the MTHFR gene C677T polymorphism augments the risk of bladder cancer in Turkey. PMID:22126575

  10. The Frequency of Some Thrombophilic Mutations in Eastern Turkey

    PubMed Central

    Ozturk, Nurinnisa; Bakan, Ebubekir; Gul, Mehmet Ali; Bakan, Nuri; Sebin, Engin; Kiziltunc, Ahmet

    2016-01-01

    Objective: Factor V / Factor II / Methylenetetrahydrofolate reductase, gene polymorphisms are closely associated with thrombophilia. Regional frequencies of these mutations may show a characteristic state. The aim of our study was to evaluate the frequency of commonly seen Factor V / Factor II / Methylenetetrahydrofolate reductase gene polymorphisms in Eastern Turkey. Materials and Methods: In 433 patients sent to the laboratory with the suspicion of thrombophilia, using whole blood samples, an automated Nucleic Acid Test was used for mutation determinations in Verigene System. The kit module was designed to detect the Factor V G1691A / Factor II G20210A / Methylenetetrahydrofolate reductase gene C677T single nucleotide polymorphisms. Results: In 433 patients, 8.7% for Factor V G1691A polymorphisms were heterozygous genotype, 3.9% for Factor II G20210A polymorphisms were heterozygous genotype, and 43.9% for methylenetetrahydrofolate reductase 677C>T polymorphisms were heterozygous genotype and 3.0% homozygous mutation genotype. Conclusion: Detection of these commonly seen Factor V / Factor II / Methylenetetrahydrofolate reductase single nucleotide polymorphisms can help to identify patients in high risk group and to evaluate the interaction of genetic and acquired risk factors. Our findings suggest that commonly seen thrombophilic allele mutation frequency in our region is the same as the data reported in the literature. PMID:27026755

  11. Correlation of Homocysteine Metabolic Enzymes Gene Polymorphism and Mild Cognitive Impairment in the Xinjiang Uygur Population

    PubMed Central

    Luo, Mei; Ji, Huihui; Zhou, Xiaohui; Liang, Jie; Zou, Ting

    2015-01-01

    Background The aim of this study was to investigate the genetic polymorphisms in the homocysteine (HCY) metabolic enzymes in the Xinjiang Uygur population who have mild cognitive impairment (MCI). Material/Methods Based on the epidemiological investigation, 129 cases of diagnosed Uygur MCI patients and a matched control group with 131 cases were enrolled for analyzing the association between the polymorphisms in the HCY metabolism related genes (C677T, A1298C, and G1968A polymorphisms in MTHFR, as well as the A2756G polymorphism in MS) and MCI by using the SNaPshot method. We then determined the homocysteine level in patients. Results In Xinjiang Uygur subjects, the A1298C polymorphisms in MTHFR and the A2756G polymorphisms in the MS gene in the MCI group were different from those in the control group. However, the C677T and G1968A polymorphisms in the MTHFR gene in MCI patients were not different from those in the control group. Multivariate logistic regression showed that, in addition to the well-known risk factors, such as low education level, high cholesterol level, high level of low-density lipoprotein, and high homocysteine levels, the A>G mutation in the MS gene at the rs1805087 locus was another independent risk factor for MCI in the Uyghur MCI population. The risk of MCI in G allele carriers was 2.265 times higher than that in matched control individuals (95% CI: 1.205~4.256, P<0.05). Conclusions The genetic polymorphism of HCY metabolizing enzymes is correlated to the occurrence of MCI in the Xinjiang Uygur population. The A2756G polymorphism in the MS gene could be an independent risk factor for MCI in the Xinjiang Uygur population. PMID:25625218

  12. Prevalence of thrombophilic mutations in patients with unprovoked thromboembolic disease. A comparative analysis regarding arterial and venous disease

    PubMed Central

    Mandala, E; Lafaras, C; Tsioni, C; Speletas, M; Papageorgiou, A; Kleta, D; Dardavessis, T; Ilonidis, G

    2012-01-01

    Background: Thromboembolic disease (TED) represents one of the main reasons of morbitity and mortality in Western World. Venous and arterial thrombotic disorders have long been viewed as separate pathophysiological entities. However, in recent times the separate nature of arterial and venous thrombotic events has been challenged. Although inherited thrombophilia’s predominant clinical manifestation is venous thrombosis, its contribution to arterial thrombosis remains controversial. Purpose  of  the  study  was  to  evaluate  the  prevalence  of  the  most common  thrombophilic  mutations, FV Leiden G1691A-FVL and FII G20210A-PTM and to assess  the  differences between venous, arterial and mixed thrombotic events. Testing  for polymorphism MTHFR C677T and  antithrombin,  protein  C  and  protein  S was also performed. Correlations with  dyslipidemia, smoking, obesity, homocysteine and antiphospholipid antibodies were made. Methods: 515 patients with unprovoked TED, 263 males, median age 44 years, were studied. Patients were divided into three groups: 258 with venous thrombosis (group A), 239 with arterial (group B) and 18 with mixed episodes (group C). All patients were interviewed regarding family history of TED, origin, smoking and dyslipidemia. Body mass index (BMI) had been calculated. Molecular assessment of the FVL, PTM and MTHFR C677T was performed. Antithrombin, protein C, protein S, APCR, homocysteine, antiphospholipid antibodies and lipid profile were also measured. Results: The population studied was homogenous among three groups as regards age (p=0.943), lipid profile (p=0.271), BMI (p=0.506), homocysteine (p=0.177), antiphospholipid antibodies (p=0.576), and positive family history (p=0.099). There was no difference in the prevalence of FVL between venous and arterial disease (p=0.440). Significant correlation of PTM with venous TED was found (p=0.001). The number of positive and negative for MTHFR presented statistically significant difference with a support in arterial disease (p=0.05). Moreover, a 2-fold increase in the risk of venous thrombosis in FVL positive patients (odds ratio: 2.153) and a positive correlation of homocysteine levels with MTHFR C677T (p<0.001) was found. Conclusions: Correlation of PTM with venous thrombosis was established. Analysis showed no difference in prevalence of FVL between venous and arterial thrombosis, indicating that FVL might be a predisposing factor for arterial disease. A significant increase in MTHFR C677T prevalence in arterial disease was found. In conclusion, young patients with unprovoked arterial disease should undergo evaluation for thrombophilic genes. Identification of these mutations is important in the overall assessment and management of patients at high risk. Findings will influence the decisions of stratified approaches for antithrombotic therapy either primary or secondary thromboprophylaxis, the duration of therapy, the potential for avoiding clinical thrombosis by risk factor modification and the genetic counselling of family members. However, further studies are needed to clarify the nature of the association regarding venous and arterial thrombotic events. PMID:23935293

  13. Association of deep venous thrombosis with prothrombotic gene polymorphism identified in lung cancer cases.

    PubMed

    Arslan, Sulhattin; Manduz, Sinasi; Epztrk, Kr?at; Karahan, O?uz; Akkurt, Ibrahim

    2011-04-01

    Venous thrombosis is a significant cause of morbidity and mortality in patients with malignancies. We aimed to investigate the association between prothrombotic gene polymorphisms detected in lung cancer cases and deep venous thrombosis (DVT). Totally 66 patients with an established diagnosis of lung cancer, of which 33 developed DVT, were enrolled. Multiplex PCR technique and reverse hybridization strip assay were performed on DNA extracted from peripheral blood, in order to analyze prothrombin G20210A, factor V G1691A, methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, angiotensin converting enzyme (ACE), plasminogen activator inhibitor-1 (PAI-1), and glycoprotein IIIa (Gp IIIa) gene mutations. Among prothrombotic gene polymorphisms investigated in this study, the commonest ones were PAI-1 4G/5G (56% heterozygous, 39% homozygous) and ACE gene mutations (58% heterozygous, 17% homozygous). The presence of homozygous MTHFR A1298C mutation was significantly associated with DVT (P=0.020). Comparing the lung cancer patients with and without DVT, only MTHFR A1298C gene polymorphism differed significantly (P=0.040). We determined a higher rate of prothrombotic gene mutations in lung cancer patients who developed DVT. However, statistical significance was achieved only for MTHFR A1298C gene mutation. Therefore, nongenetic factors for disturbance of hemostatic metabolism should also be considered in lung cancer patients. PMID:21080081

  14. Gene mutations in chronic lymphocytic leukemia.

    PubMed

    Amin, Nisar A; Malek, Sami N

    2016-04-01

    The recent discovery of genes mutated in chronic lymphocytic leukemia (CLL) has stimulated new research into the role of these genes in CLL pathogenesis. CLL cases carry approximately 5-20 mutated genes per exome, a lower number than detected in many human tumors. Of the recurrently mutated genes in CLL, all are mutated in 10% or less of patients when assayed in unselected CLL cohorts at diagnosis. Mutations in TP53 are of major clinical relevance, are often associated with del17p and gain in frequency over time. TP53 mutated and associated del17p states substantially lower response rates, remission duration, and survival in CLL. Mutations in NOTCH1 and SF3B1 are recurrent, often associated with progressive CLL that is also IgVH unmutated and ZAP70-positive and are under investigation as targets for novel therapies and as factors influencing CLL outcome. There are an estimated 20-50 additional mutated genes with frequencies of 1%-5% in CLL; more work is needed to identify these and to study their significance. Finally, of the major biological aberration categories influencing CLL as a disease, gene mutations will need to be placed into context with regard to their ultimate role and importance. Such calibrated appreciation necessitates studies incorporating multiple CLL driver aberrations into biological and clinical analyses. PMID:27040699

  15. Methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms in chronic myeloid leukemia: an Egyptian study.

    PubMed

    Khorshied, Mervat Mamdooh; Shaheen, Iman Abdel Mohsen; Abu Khalil, Reham E; Sheir, Rania Elsayed

    2014-01-01

    Methylenetetrahydrofolate reductase (MTHFR) gene plays a pivotal role in folate metabolism. Several genetic variations in MTHFR gene as MTHFR-C677T and MTHFR-A1298C result in decreased MTHFR activity, which could influence efficient DNA methylation and explain susceptibility to different cancers. The etiology of chronic myeloid leukemia (CML) is obscure and little is known about individual's susceptibility to CML. In order to assess the influence of these genetic polymorphisms on the susceptibility to CML and its effect on the course of the disease among Egyptians, we performed an age-gender-ethnic matched case-control study. The study included 97 CML patients and 130 healthy controls. Genotyping of MTHFR-C677T and -A1298C was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The results showed no statistical difference in the distribution of MTHFR-C677T and -A1298C polymorphic genotypes between CML patients and controls. The frequency of MTHFR 677-TT homozygous variant was significantly higher in patients with accelerated/blastic transformation phase when compared to those in the chronic phase of the disease. In conclusion, our study revealed that MTHFR-C677T and -A1298C polymorphisms could not be considered as genetic risk factors for CML in Egyptians. However, MTHFR 677-TT homozygous variant might be considered as a molecular predictor for disease progression. PMID:24338216

  16. Gene deletion speeds mutation rate.

    PubMed

    2014-07-01

    The APOBEC proteins fight off viruses by editing their genomes. A deletion that removes one of the proteins produces large numbers of mutations in the human genome, potentially leading to cancer. PMID:25002600

  17. Paraoxonase Gene Mutations in Amyotrophic Lateral Sclerosis

    PubMed Central

    Ticozzi, Nicola; LeClerc, Ashley Lyn; Keagle, Pamela; Glass, Jonathan D.; Wills, Anne-Marie; van Blitterswijk, Marka; Bosco, Daryl A.; Rodriguez-Leyva, Ildefonso; Gellera, Cinzia; Ratti, Antonia; Taroni, Franco; McKenna-Yasek, Diane M.; Sapp, Peter C.; Silani, Vincenzo; Furlong, Clement E.; Brown, Robert H.; Landers, John E.

    2010-01-01

    Three clustered, homologous paraoxonase genes (PON1, PON2 and PON3) have roles in preventing lipid oxidation and detoxifying organophosphates. Recent reports describe a genetic association between the PON genes and sporadic amyotrophic lateral sclerosis (ALS). We now report that in genomic DNA from individuals with familial and sporadic ALS we have identified at least seven PON gene mutations that are predicted to alter PON function. PMID:20582942

  18. Classification of Missense Mutations of Disease Genes

    PubMed Central

    Zhou, Xi; Iversen, Edwin S.; Parmigiani, Giovanni

    2008-01-01

    Clinical management of individuals found to harbor a mutation at a known disease-susceptibility gene depends on accurate assessment of mutation-specific disease risk. For missense mutations (MMs)mutations that lead to a single amino acid change in the protein coded by the genethis poses a particularly challenging problem. Because it is not possible to predict the structural and functional changes to the protein product for a given amino acid substitution, and because functional assays are often not available, disease association must be inferred from data on individuals with the mutation. Inference is complicated by small sample sizes and by sampling mechanisms that bias toward individuals at high familial risk of disease. We propose a Bayesian hierarchical model to classify the disease association of MMs given pedigree data collected in the high-risk setting. The models structure allows simultaneous characterization of multiple MMs. It uses a group of pedigrees identified through probands tested positive for known disease associated mutations and a group of test-negative pedigrees, both obtained from the same clinic, to calibrate classification and control for potential ascertainment bias. We apply this model to study MMs of breast-ovarian susceptibility genes BRCA1 and BRCA2, using data collected at the Duke University Medical Center in Durham, North Carolina. PMID:18418466

  19. Cerebral sinovenous thrombosis associated with MTHFR A1298C mutation in the newborn: a case report.

    PubMed

    Cizmeci, Mehmet Nevzat; Kanburoglu, Mehmet Kenan; Akelma, Ahmet Zulfikar; Donmez, Ahsen; Sonmez, Fatma Mujgan; Polat, Aziz; Kosehan, Dilek; Tatli, Mustafa Mansur

    2013-02-01

    Although cerebral sinovenous thrombosis (CSVT) is a rare condition in the neonatal period, high rates of morbidity and mortality necessitate the establishment of an early diagnosis. Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and mutations of MTHFR are associated with vascular disease. While the C677T common missense mutation is the most well-defined MTHFR polymorphism, another common missense mutation, A1298C also exists. There has been no reported case of CSVT associated with MTHFR A1298C mutation in the neonatal period. Herein, we report a neonate with CSVT who was found to have MTHFR A1298C homozygosity. PMID:22797907

  20. Retrospective Review of MET Gene Mutations.

    PubMed

    Zenali, Maryam; deKay, James; Liu, Zesheng; Hamilton, Stanley; Zuo, Zhuang; Lu, Xinyan; Bakkar, Rania; Mills, Gordon; Broaddus, Russell

    2015-01-01

    C-MET proto-oncogene is a tyrosine kinase situated on chromosome 7. C-MET and its ligand hepatocyte growth factor/scatter factor (HGF/SF) play a role in proliferation, differentiation and organ development. C-MET genetic aberrations are found associated with driving tumorigenesis. In this retrospective study, we reviewed molecular analysis data gathered from a cancer institute during a two-year period (2010-2012). Upon detection of tumors harboring c-MET mutations, we determined the status of the other mutations tested and evaluated c-MET expression by fluorescent in-situ hybridization (FISH). Our search resulted in identification of 134 c-MET mutations, 44% of which had mutations of at least one of the other genes tested. No c-MET expression aberrancy was detected in this subset by FISH. Survival amongst the patients with surgically resected metastatic colorectal cancers (CRC) was slightly better in those with only a c-MET mutation compared to those with no mutation detected, although the difference was not statistically significant. When c-MET inhibition becomes an integrated part of chemotherapy practice, our observed frequency of co-mutations will be an argument for utilizing c-MET targeted treatment in combination with other targeted drugs and therapeutic strategies. Larger studies can aid to further parse out c-MET prognostic and therapeutic significance. PMID:26097886

  1. Retrospective Review of MET Gene Mutations

    PubMed Central

    Zenali, Maryam; deKay, James; Liu, Zesheng; Hamilton, Stanley; Zuo, Zhuang; Lu, Xinyan; Bakkar, Rania; Mills, Gordon; Broaddus, Russell

    2015-01-01

    C-MET proto-oncogene is a tyrosine kinase situated on chromosome 7. C-MET and its ligand hepatocyte growth factor/scatter factor (HGF/SF) play a role in proliferation, differentiation and organ development. C-MET genetic aberrations are found associated with driving tumorigenesis. In this retrospective study, we reviewed molecular analysis data gathered from a cancer institute during a two-year period (2010-2012). Upon detection of tumors harboring c-MET mutations, we determined the status of the other mutations tested and evaluated c-MET expression by fluorescent in-situ hybridization (FISH). Our search resulted in identification of 134 c-MET mutations, 44% of which had mutations of at least one of the other genes tested. No c-MET expression aberrancy was detected in this subset by FISH. Survival amongst the patients with surgically resected metastatic colorectal cancers (CRC) was slightly better in those with only a c-MET mutation compared to those with no mutation detected, although the difference was not statistically significant. When c-MET inhibition becomes an integrated part of chemotherapy practice, our observed frequency of co-mutations will be an argument for utilizing c-MET targeted treatment in combination with other targeted drugs and therapeutic strategies. Larger studies can aid to further parse out c-MET prognostic and therapeutic significance. PMID:26097886

  2. From Gene Mutation to Protein Characterization

    ERIC Educational Resources Information Center

    Moffet, David A.

    2009-01-01

    A seven-week "gene to protein" laboratory sequence is described for an undergraduate biochemistry laboratory course. Student pairs were given the task of introducing a point mutation of their choosing into the well studied protein, enhanced green fluorescent protein (EGFP). After conducting literature searches, each student group chose the…

  3. From Gene Mutation to Protein Characterization

    ERIC Educational Resources Information Center

    Moffet, David A.

    2009-01-01

    A seven-week "gene to protein" laboratory sequence is described for an undergraduate biochemistry laboratory course. Student pairs were given the task of introducing a point mutation of their choosing into the well studied protein, enhanced green fluorescent protein (EGFP). After conducting literature searches, each student group chose the

  4. The Wilson disease gene: Haplotypes and mutations

    SciTech Connect

    Thomas, G.R.; Roberts, E.A.; Cox, D.W.; Walshe, J.M.

    1994-09-01

    Wilson disease (WND) is an autosomal recessive defect of copper transport. The gene involved in WND, located on chromosome 13, has recently been shown to be a putative copper transporting P-type ATPase, designated ATP7B. The gene is highly similar to ATP7A, located on the X chromosome, which is defective in Menkes disease, another disorder of copper transport. We have available for study WND families from Canada (34 families), the United Kingdom (32 families), Japan (4 families), Iceland (3 families) and Hong Kong (2 families). We have utilized four highly polymorphic CA repeat markers (D13S296, D13S301, D13S314 and D13S316) surrounding the ATP7B locus to construct haplotypes in these families. Analysis indicates that there are many unique WND haplotypes not present on normal chromosomes and that there may be a large number of different WND mutations. We have screened the WND patients for mutations in the ATP7B gene. Fifty six patients, representing all of the identified haplotypes, have been screened using single strand conformational polymorphism (SSCP), followed by selective sequencing. To date, 19 mutations and 12 polymorphisms have been identified. All of the changes are nucleotide substitutions or small insertions/deletions and there is no evidence for larger deletions as seen in the similar gene on the X chromosome, ATP7A. Haplotypes of close markers and the ability to detect some of the mutations present in the gene allow for more reliable molecular diagnosis of presymptomatic sibs of WND patients. A reassessment of individuals previously diagnosed in the presymptomatic phase is now required, as we have have identified some heterozygotes who are biochemically indistinguishable from affected homozygotes. The identification of specific mutations will soon allow direct diagnosis of WND patients with a high level of certainty.

  5. LEOPARD Syndrome: Clinical Features and Gene Mutations

    PubMed Central

    Martínez-Quintana, E.; Rodríguez-González, F.

    2012-01-01

    The RAS/MAPK pathway proteins with germline mutations in their respective genes are associated with some disorders such as Noonan, LEOPARD (LS), neurofibromatosis type 1, Costello and cardio-facio-cutaneous syndromes. LEOPARD is an acronym, mnemonic for the major manifestations of this disorder, characterized by multiple lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness. Though it is not included in the acronym, hypertrophic cardiomyopathy is the most frequent cardiac anomaly observed, representing a potentially life-threatening problem in these patients. PTPN11, RAF1 and BRAF are the genes known to be associated with LS, identifying molecular genetic testing of the 3 gene mutations in about 95% of affected individuals. PTPN11 mutations are the most frequently found. Eleven different missense PTPN11 mutations (Tyr279Cys/Ser, Ala461Thr, Gly464Ala, Thr468Met/Pro, Arg498Trp/Leu, Gln506Pro, and Gln510Glu/Pro) have been reported so far in LS, 2 of which (Tyr279Cys and Thr468Met) occur in about 65% of the cases. Here, we provide an overview of clinical aspects of this disorder, the molecular mechanisms underlying pathogenesis and major genotype-phenotype correlations. PMID:23239957

  6. Mutations and polymorphisms in gonadotropin genes.

    PubMed

    Huhtaniemi, I; Jiang, M; Nilsson, C; Pettersson, K

    1999-05-25

    Mutations in gonadotropin genes are extremely rare. Only one case of inactivating human luteinizing hormone (LH) beta mutation exists in the literature, a male with absence of Leydig cells, lack of spontaneous puberty and infertility. A total of four cases of inactivating mutation of the follicle-stimulating hormone beta (FSHbeta) gene (two female and two male) are known. The phenotype of the women was primary amenorrhea and absence of follicular maturation, the men were azoospermic. In addition, a common genetic variant (v) of LH was recently discovered. It is caused by two point mutations in the LH beta-subunit gene, resulting in amino acid alterations: Trp8 --> Arg and Ile15 --> Thr. In addition, the latter change introduces an extra glycosylation signal for oligosaccharide attachment to Asn13. The v-LHbeta allele has a carrier frequency ranging from 0 to > 50% in various populations. The variant LH molecule has increased intrinsic bioactivity in vitro, but decreased circulatory half-life in vivo, and the v-LHbeta promoter is about 50% more active in cell line transfections than that of wild-type (wt) LH. These differences in LH synthesis and action in individuals homo- or heterozygous for the v-LH allele are reflected by altered disposition to pathologies of pituitary-gonadal function, such as delayed puberty, polycystic ovarian syndrome and infertility. PMID:10411323

  7. Alecensa Approved for Lung Cancer Tied to Gene Mutation

    MedlinePlus

    ... Alecensa Approved for Lung Cancer Tied to Gene Mutation Drug to be used for ALK-positive non- ... according to the National Cancer Institute. ALK gene mutations are involved in about 5 percent of cases ...

  8. Exome Sequencing Identifies PDE4D Mutations as Another Cause of Acrodysostosis

    PubMed Central

    Michot, Caroline; Le Goff, Carine; Goldenberg, Alice; Abhyankar, Avinash; Klein, Céline; Kinning, Esther; Guerrot, Anne-Marie; Flahaut, Philippe; Duncombe, Alice; Baujat, Genevieve; Lyonnet, Stanislas; Thalassinos, Caroline; Nitschke, Patrick; Casanova, Jean-Laurent; Le Merrer, Martine; Munnich, Arnold; Cormier-Daire, Valérie

    2012-01-01

    Acrodysostosis is a rare autosomal-dominant condition characterized by facial dysostosis, severe brachydactyly with cone-shaped epiphyses, and short stature. Moderate intellectual disability and resistance to multiple hormones might also be present. Recently, a recurrent mutation (c.1102C>T [p.Arg368∗]) in PRKAR1A has been identified in three individuals with acrodysostosis and resistance to multiple hormones. After studying ten unrelated acrodysostosis cases, we report here de novo PRKAR1A mutations in five out of the ten individuals (we found c.1102C>T [p.Arg368∗] in four of the ten and c.1117T>C [p.Tyr373His] in one of the ten). We performed exome sequencing in two of the five remaining individuals and selected phosphodiesterase 4D (PDE4D) as a candidate gene. PDE4D encodes a class IV cyclic AMP (cAMP)-specific phosphodiesterase that regulates cAMP concentration. Exome analysis detected heterozygous PDE4D mutations (c.673C>A [p.Pro225Thr] and c.677T>C [p.Phe226Ser]) in these two individuals. Screening of PDE4D identified heterozygous mutations (c.568T>G [p.Ser190Ala] and c.1759A>C [p.Thr587Pro]) in two additional acrodysostosis cases. These mutations occurred de novo in all four cases. The four individuals with PDE4D mutations shared common clinical features, namely characteristic midface and nasal hypoplasia and moderate intellectual disability. Metabolic screening was normal in three of these four individuals. However, resistance to parathyroid hormone and thyrotropin was consistently observed in the five cases with PRKAR1A mutations. Finally, our study further supports the key role of the cAMP signaling pathway in skeletogenesis. PMID:22464250

  9. Collodion Baby with TGM1 gene mutation

    PubMed Central

    Sharma, Deepak; Gupta, Basudev; Shastri, Sweta; Pandita, Aakash; Pawar, Smita

    2015-01-01

    Collodion baby (CB) is normally diagnosed at the time of birth and refers to a newborn infant that is delivered with a lambskin-like membrane encompassing the total body surface. CB is not a specific disease entity, but is a common phenotype in conditions like harlequin ichthyosis, lamellar ichthyosis, nonbullous congenital ichthyosiform erythroderma, and trichothiodystrophy. We report a CB that was brought to our department and later diagnosed to have TGM1 gene c.984+1G>A mutation. However, it could not be ascertained whether the infant had lamellar ichthyosis or congenital ichthyosiform erythroderma (both having the same mutation). The infant was lost to follow-up. PMID:26451124

  10. Deafness gene mutations in newborns in Beijing.

    PubMed

    Han, Shujing; Yang, Xiaojian; Zhou, Yi; Hao, Jinsheng; Shen, Adong; Xu, Fang; Chu, Ping; Jin, Yaqiong; Lu, Jie; Guo, Yongli; Shi, Jin; Liu, Haihong; Ni, Xin

    2016-05-01

    Objective To determine the incidence of congenital hearing loss (HL) in newborns by the rate of deafness-related genetic mutations. Design Clinical study of consecutive newborns in Beijing using allele-specific polymerase chain reaction-based universal array. Study sample This study tested 37 573 newborns within 3 days after birth, including nine sites in four genes: GJB2 (35 del G, 176 del 16, 235 del C, 299 del AT), SLC26A4 (IVS7-2 A > G, 2168 A > G), MTRNR1 (1555 A > G, 1494 C > T), and GJB3 (538 C > T). The birth condition of infants was also recorded. Results Of 37 573 newborns, 1810 carried pathogenic mutations, or 4.817%. The carrier rates of GJB2 (35 del G, 176 del 16, 235 del C, 299 del AT), GJB3 (538 C > T), SLC26A4 (IVS7-2 A > G, 2168 A > G), and MTRNR1 (1555 A > G, 1494 C > T) mutations were 0.005%, 0.104%, 1.924%, 0.551%, 0.295%, 0.253%, 1.387%, 0.024%, and 0.274%, respectively. Logistic regression analysis indicated no statistically significant relationship between mutations and infant sex, premature delivery, twin status, or birth weight. Conclusions The 235delC GJB2 mutation was the most frequent deafness-related mutation in the Chinese population. Genetic screening for the deafness gene will help detect more cases of newborn congenital HL than current screening practices. PMID:26766211

  11. Mutated Genes in Schizophrenia Map to Brain Networks

    MedlinePlus

    ... Research Matters August 12, 2013 Mutated Genes in Schizophrenia Map to Brain Networks Schizophrenia networks in the prefrontal cortex area of the ... University of Washington Researchers found that people with schizophrenia have a high number of spontaneous mutations in ...

  12. Analysis of the sarcomere protein gene mutation on cardiomyopathy - Mutations in the cardiac troponin I gene.

    PubMed

    Murakami, Chikako; Nakamura, Shigeki; Kobayashi, Masamune; Maeda, Kazuho; Irie, Wataru; Wada, Bunta; Hayashi, Maiko; Sasaki, Chizuko; Nakamaru, Naomi; Furukawa, Masataka; Kurihara, Katsuyoshi

    2010-11-01

    Developments in the molecular genetic studies of cardiomyopathy (CM) have led to discovery of a large number of mutations in the genes encoding the sarcomeric proteins. In this study, comprehensive screening of TNNI3 was performed in 36 consented autopsy cases diagnosed as CM, in order to evaluate the prevalence of gene mutations in sudden death caused by CM. In DCM cases, a new missense mutation Pro16Thr was detected. A single nucleotide polymorphism at -8 position of intron 3 (IVS 3 -8 T>A) was identified, which had a significant difference in allele frequency between DCM and control cases. From these results, it was indicated that this study contribute to genetic based diagnosis, risk stratification and prevention of sudden death caused by CM. PMID:20817590

  13. Shared and unique mutational gene co-occurrences in cancers.

    PubMed

    Liu, Junqi; Zhao, Di; Fan, Ruitai

    2015-10-01

    Cancers are often associated with mutations in multiple genes; thus, studying the distributions of genes that harbor cancer-promoting mutations in cancer samples and their co-occurrences could provide insights into cancer diagnostics and treatment. Using data from the Catalogue of Somatic Mutations in Cancer (COSMIC), we found that mutated genes in cancer samples followed a power-law distribution. For instance, a few genes were mutated in a large number of samples (designated as high-frequent genes), while a large number of genes were only mutated in a few samples. This power-law distribution can be found in samples of all cancer types as well as individual cancers. In samples where two or more mutated genes are found, the high-frequent genes, i.e., those that were frequently mutated, often did not co-occur with other genes, while the other genes often tended to co-occur. Co-occurrences of mutated genes were often unique to a certain cancer; however, some co-occurrences were shared by multiple cancer types. Our results revealed distinct patterns of high-frequent genes and those that were less-frequently mutated in the cancer samples in co-occurring and anti-co-occurring networks. Our results indicated that distinct treatment strategies should be adopted for cancer patients with known high-frequent gene mutations and those without. The latter might be better treated with a combination of drugs targeting multiple genes. Our results also suggested that possible cross-cancer treatments, i.e., the use of the same drug combinations, may treat cancers of different histological origins. PMID:26315265

  14. Parkinson disease (PARK) genes are somatically mutated in cutaneous melanoma

    PubMed Central

    Samuels, Yardena; Azizi, Esther; Qutob, Nouar; Inzelberg, Lilah; Domany, Eytan; Schechtman, Edna; Friedman, Eitan

    2016-01-01

    Objective: To assess whether Parkinson disease (PD) genes are somatically mutated in cutaneous melanoma (CM) tissue, because CM occurs in patients with PD at higher rates than in the general population and PD is more common than expected in CM cohorts. Methods: We cross-referenced somatic mutations in metastatic CM detected by whole-exome sequencing with the 15 known PD (PARK) genes. We computed the empirical distribution of the sum of mutations in each gene (Smut) and of the number of tissue samples in which a given gene was mutated at least once (SSampl) for each of the analyzable genes, determined the 90th and 95th percentiles of the empirical distributions of these sums, and verified the location of PARK genes in these distributions. Identical analyses were applied to adenocarcinoma of lung (ADENOCA-LUNG) and squamous cell carcinoma of lung (SQUAMCA-LUNG). We also analyzed the distribution of the number of mutated PARK genes in CM samples vs the 2 lung cancers. Results: Somatic CM mutation analysis (n = 246) detected 315,914 mutations in 18,758 genes. Somatic CM mutations were found in 14 of 15 PARK genes. Forty-eight percent of CM samples carried ≥1 PARK mutation and 25% carried multiple PARK mutations. PARK8 mutations occurred above the 95th percentile of the empirical distribution for SMut and SSampl. Significantly more CM samples harbored multiple PARK gene mutations compared with SQUAMCA-LUNG (p = 0.0026) and with ADENOCA-LUNG (p < 0.0001). Conclusions: The overrepresentation of somatic PARK mutations in CM suggests shared dysregulated pathways for CM and PD. PMID:27123489

  15. Low frequency of beta-catenin gene mutations in pilomatricoma.

    PubMed

    Ha, Seog-Jun; Kim, Jung-Soo; Seo, Eun-Joo; Lee, Kyung-Ho; Lee, Hyun-Jeong; Kim, Jin-Wou

    2002-01-01

    We investigated beta-catenin and adenomatous polyposis coli (APC) gene abnormalities in human pilomatricoma, in which a high incidence of beta-catenin gene mutations has been reported. Nucleated tumour cells were microdissected from 20 paraffin-embedded pilomatricomas. Exon 3 of the beta-catenin gene was amplified using polymerase chain reaction and sequencing analysis was performed. Immunostaining for beta-catenin and lymphoid-enhancer factor-1 was performed using the avidin-biotin-peroxidase method. Dinucleotide repeat markers D5S409 and D5S299 were used for polymerase chain reaction-based microsatellite analysis of the APC gene. The mutation cluster region of the APC gene was amplified using polymerase chain reaction and sequenced. Sequencing analysis revealed beta-catenin gene mutations in 30%. All studied samples showed nuclear lymphoid-enhancer factor-1 and cytoplasmic/nuclear beta-catenin expression. Loss of heterozygosity was observed in the APC gene, but no mutations in the mutation cluster region were found in seven tumours without beta-catenin mutations. The frequency of beta-catenin gene mutations was remarkably low, thus suggesting (i) the presence of mutations in other than exon 3 of the beta-catenin gene, (ii) a possible role of APC gene abnormalities, or (iii) involvement of other components of the Wingless-type MMTV integration site family pathway. PMID:12575848

  16. Mutation analysis of the gene involved in adrenoleukodystrophy

    SciTech Connect

    Oost, B.A. van; Ligtenberg, M.J.L.; Kemp, S.; Bolhuis, P.A.

    1994-09-01

    A gene responsible for the X-linked genetic disorder adrenoleukodystrophy (ALD) that is characterized by demyelination of the nervous system and adrenocortical insufficiency has been identified by positional cloning. The gene encodes an ATP-binding transporter which is located in the peroxisomal membrane. Deficiency of the gene leads to accumulation of unsaturated very long chain fatty acids due to impaired peroxisomal {beta}-oxidation. A systematic analysis of the open reading frame of the ALD gene unraveled the mutations in 28 different families using reverse transcriptase-PCR followed by direct sequencing. No entire gene deletions or drastic promoter mutations have been detected. Only in one family did the mutation involved multiple exons. The remaining mutations were subtle alterations leading to missense (about 50%) or nonsense mutations, frameshifts or splice acceptor site defects. In one patient a single codon was missing. Mutations affecting a single amino acid were concentrated in the region between the third and fourth putative membrane spanning fragments and in the ATP-binding domain. This overview of mutations aids in the determination of structural and functional important regions and facilitates the screening for mutations in other ALD patients. The detection of mutations in virtually all ALD families tested indicates that the isolated gene is the only gene responsible for ALD located in Xq28.

  17. Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: a meta-analysis.

    PubMed

    Pu, Danhua; Shen, Yiping; Wu, Jie

    2013-10-01

    Methylenetetrahydrofolate reductase (MTHFR) is essential for DNA biosynthesis and the epigenetic process of DNA methylation, and its gene polymorphisms have been implicated as risk factors for birth defects, neurological disorders, and cancers. However, reports on the association of MTHFR polymorphisms with autism spectrum disorders (ASD) are inconclusive. Therefore, we investigated the relationship of the MTHFR polymorphisms (C677T and A1298C) and the risk of ASD by meta-analysis. Up to December 2012, eight case-control studies involving 1672 patients with ASD and 6760 controls were included for meta-analysis. The results showed that the C677T polymorphism was associated with significantly increased ASD risk in all the comparison models [T vs. C allele (frequency of allele): odds ratio (OR) = 1.42, 95% confidence interval (CI): 1.09-1.85; CT vs. CC (heterozygote): OR = 1.48, 95% CI: 1.09-2.00; TT vs. CC (homozygote): OR = 1.86, 95% CI: 1.08-3.20; CT+TT vs. CC (dominant model): OR = 1.56, 95% CI: 1.12-2.18; and TT vs. CC+CT (recessive model): OR = 1.51, 95% CI: 1.02-2.22], whereas the A1298C polymorphism was found to be significantly associated with reduced ASD risk but only in a recessive model (CC vs. AA+AC: OR = 0.73, 95% CI: 0.56-0.97). In addition, we stratified the patient population based on whether they were from a country with food fortification of folic acid or not. The meta-analysis showed that the C677T polymorphism was found to be associated with ASD only in children from countries without food fortification. Our study indicated that the MTHFR C677T polymorphism contributes to increased ASD risk, and periconceptional folic acid may reduce ASD risk in those with MTHFR 677C>T polymorphism. PMID:23653228

  18. Mutational analysis of STK11 gene in ovarian carcinomas.

    PubMed

    Nishioka, Y; Kobayashi, K; Sagae, S; Sugimura, M; Ishioka, S; Nagata, M; Terasawa, K; Tokino, T; Kudo, R

    1999-06-01

    Recently STK11, the causative gene of Peutz-Jeghers syndrome (PJS) was identified on chromosome 19p13.3. PJS is often accompanied by several malignancies, including breast tumor, adenoma malignum of the uterine cervix, and ovarian tumor. To investigate the involvement of STK11 gene in the development of ovarian carcinomas, we analyzed 30 ovarian carcinomas for loss of heterozygosity (LOH) and STK11 gene mutations. We found one missense mutation (codon 281, Pro to Leu) with heterozygous and somatic status. This mutation occurred at codon 281, which lies within the mutational hot spot (codon 279-281) of STK11 gene previously reported in PJS. We also detected LOH in 2 (11%) of 19 informative ovarian carcinomas. Our results suggest that mutations of the STK11 gene may play a limited role in the development of ovarian carcinomas. PMID:10429654

  19. Novel recurrently mutated genes and a prognostic mutation signature in colorectal cancer

    PubMed Central

    Yu, Jun; Wu, William K K; Li, Xiangchun; He, Jun; Li, Xiao-Xing; Ng, Simon S M; Yu, Chang; Gao, Zhibo; Yang, Jie; Li, Miao; Wang, Qiaoxiu; Liang, Qiaoyi; Pan, Yi; Tong, Joanna H; To, Ka F; Wong, Nathalie; Zhang, Ning; Chen, Jie; Lu, Youyong; Lai, Paul B S; Chan, Francis K L; Li, Yingrui; Kung, Hsiang-Fu; Yang, Huanming; Wang, Jun; Sung, Joseph J Y

    2015-01-01

    Background Characterisation of colorectal cancer (CRC) genomes by next-generation sequencing has led to the discovery of novel recurrently mutated genes. Nevertheless, genomic data has not yet been used for CRC prognostication. Objective To identify recurrent somatic mutations with prognostic significance in patients with CRC. Method Exome sequencing was performed to identify somatic mutations in tumour tissues of 22 patients with CRC, followed by validation of 187 recurrent and pathway-related genes using targeted capture sequencing in additional 160 cases. Results Seven significantly mutated genes, including four reported (APC, TP53, KRAS and SMAD4) and three novel recurrently mutated genes (CDH10, FAT4 and DOCK2), exhibited high mutation prevalence (614% for novel cancer genes) and higher-than-expected number of non-silent mutations in our CRC cohort. For prognostication, a five-gene-signature (CDH10, COL6A3, SMAD4, TMEM132D, VCAN) was devised, in which mutation(s) in one or more of these genes was significantly associated with better overall survival independent of tumor-node-metastasis (TNM) staging. The median survival time was 80.4?months in the mutant group versus 42.4?months in the wild type group (p=0.0051). The prognostic significance of this signature was successfully verified using the data set from the Cancer Genome Atlas study. Conclusions The application of next-generation sequencing has led to the identification of three novel significantly mutated genes in CRC and a mutation signature that predicts survival outcomes for stratifying patients with CRC independent of TNM staging. PMID:24951259

  20. Gene Expression in the Star Mutation of Petunia x Hybrida

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Differences in structural gene expression are responsible for a wide range of responses from human cancer to patterned flowers. Gene silencing is one of the ways in which gene expression is controlled. We have developed a model system to study anthocyanin gene silencing using a mutation in Petunia ...

  1. Influence of Nitrous Oxide Anesthesia, B-Vitamins, and MTHFR gene polymorphisms on Perioperative Cardiac Events: The Vitamins in Nitrous Oxide (VINO) Randomized Trial

    PubMed Central

    Nagele, Peter; Brown, Frank; Francis, Amber; Scott, Mitchell G.; Gage, Brian F.; Miller, J. Philip

    2013-01-01

    Background Nitrous oxide causes an acute increase in plasma homocysteine that is more pronounced in patients with the MTHFR C677T or A1298C gene variant. In this randomized controlled trial we sought to determine if patients carrying the MTHFR C677T or A1298C variant had a higher risk for perioperative cardiac events after nitrous oxide anesthesia and if this risk could be mitigated by B-vitamins. Methods We randomized adult patients with cardiac risk factors undergoing noncardiac surgery to receive nitrous oxide plus intravenous B-vitamins before and after surgery or to nitrous oxide and placebo. Serial cardiac biomarkers and 12-lead electrocardiograms were obtained. The primary study endpoint was the incidence of myocardial injury, as defined by cardiac troponin I elevation within the first 72 hours after surgery. Results A total of 500 patients completed the trial. Patients who were homozygous for either MTHFR C677T or A1298C gene variant (n= 98; 19.6%) had no increased rate of postoperative cardiac troponin I elevation compared to wild-type and heterozygous patients (11.2% vs. 14.0%; relative risk 0.96, 95% CI 0.85 to 1.07, p=0.48). B-vitamins blunted the rise in homocysteine, but had no effect on cardiac troponin I elevation compared to patients receiving placebo (13.2% vs. 13.6%; relative risk 1.02, 95% CI 0.78 to 1.32, p=0.91). Conclusions Neither MTHFR C677T and A1298C gene variant nor acute homocysteine increase are associated with perioperative cardiac troponin elevation after nitrousoxide anesthesia. B-vitamins blunt nitrous oxide-induced homocysteine increase but have no effect on cardiac troponin elevation. PMID:23856660

  2. Human beta-galactosidase gene mutations in morquio B disease.

    PubMed Central

    Oshima, A; Yoshida, K; Shimmoto, M; Fukuhara, Y; Sakuraba, H; Suzuki, Y

    1991-01-01

    Three different beta-galactosidase gene mutations--a 273Trp----Leu (mutation F) in both families, 482Arg----His (mutation G) in one family, and 509Trp----Cys (mutation H) in the other family--were identified in three patients with Morquio B disease who were from two unrelated families. Restriction-site analysis using StuI, Nsp(7524)I or RsaI confirmed these mutations. In human fibroblasts, mutation F expressed as much as 8% of the normal allele's enzyme activity, but the other mutations expressed no detectable enzyme activity. We conclude that the unique clinical manifestations are specifically associated with mutation F, a common two-base substitution, in this disease. Images Figure 1 PMID:1928092

  3. Modeling Autism by SHANK Gene Mutations in Mice

    PubMed Central

    Jiang, Yong-hui; Ehlers, Michael D.

    2013-01-01

    Summary Shank family proteins (Shank1, Shank2, and Shank3) are synaptic scaffolding proteins that organize an extensive protein complex at the postsynaptic density (PSD) of excitatory glutamatergic synapses. Recent human genetic studies indicate that SHANK family genes (SHANK1, SHANK2, and SHANK3) are causative genes for idiopathic autism spectrum disorders (ASD). Neurobiological studies of Shank mutations in mice support a general hypothesis of synaptic dysfunction in the pathophysiology of ASD. However, the molecular diversity of SHANK family gene products, as well as the heterogeneity in human and mouse phenotypes, pose challenges to modeling human SHANK mutations. Here, we review the molecular genetics of SHANK mutations in human ASD and discuss recent findings where such mutations have been modeled in mice. Conserved features of synaptic dysfunction and corresponding behaviors in Shank mouse mutants may help dissect the pathophysiology of ASD, but also highlight divergent phenotypes that arise from different mutations in the same gene. PMID:23583105

  4. Novel KRAS Gene Mutations in Sporadic Colorectal Cancer

    PubMed Central

    Naser, Walid M.; Shawarby, Mohamed A.; Al-Tamimi, Dalal M.; Seth, Arun; Al-Quorain, Abdulaziz; Nemer, Areej M. Al; Albagha, Omar M. E.

    2014-01-01

    Introduction In this article, we report 7 novel KRAS gene mutations discovered while retrospectively studying the prevalence and pattern of KRAS mutations in cancerous tissue obtained from 56 Saudi sporadic colorectal cancer patients from the Eastern Province. Methods Genomic DNA was extracted from formalin-fixed, paraffin-embedded cancerous and noncancerous colorectal tissues. Successful and specific PCR products were then bi-directionally sequenced to detect exon 4 mutations while Mutector II Detection Kits were used for identifying mutations in codons 12, 13 and 61. The functional impact of the novel mutations was assessed using bioinformatics tools and molecular modeling. Results KRAS gene mutations were detected in the cancer tissue of 24 cases (42.85%). Of these, 11 had exon 4 mutations (19.64%). They harbored 8 different mutations all of which except two altered the KRAS protein amino acid sequence and all except one were novel as revealed by COSMIC database. The detected novel mutations were found to be somatic. One mutation is predicted to be benign. The remaining mutations are predicted to cause substantial changes in the protein structure. Of these, the Q150X nonsense mutation is the second truncating mutation to be reported in colorectal cancer in the literature. Conclusions Our discovery of novel exon 4 KRAS mutations that are, so far, unique to Saudi colorectal cancer patients may be attributed to environmental factors and/or racial/ethnic variations due to genetic differences. Alternatively, it may be related to paucity of clinical studies on mutations other than those in codons 12, 13, 61 and 146. Further KRAS testing on a large number of patients of various ethnicities, particularly beyond the most common hotspot alleles in exons 2 and 3 is needed to assess the prevalence and explore the exact prognostic and predictive significance of the discovered novel mutations as well as their possible role in colorectal carcinogenesis. PMID:25412182

  5. DRUMS: a human disease related unique gene mutation search engine.

    PubMed

    Li, Zuofeng; Liu, Xingnan; Wen, Jingran; Xu, Ye; Zhao, Xin; Li, Xuan; Liu, Lei; Zhang, Xiaoyan

    2011-10-01

    With the completion of the human genome project and the development of new methods for gene variant detection, the integration of mutation data and its phenotypic consequences has become more important than ever. Among all available resources, locus-specific databases (LSDBs) curate one or more specific genes' mutation data along with high-quality phenotypes. Although some genotype-phenotype data from LSDB have been integrated into central databases little effort has been made to integrate all these data by a search engine approach. In this work, we have developed disease related unique gene mutation search engine (DRUMS), a search engine for human disease related unique gene mutation as a convenient tool for biologists or physicians to retrieve gene variant and related phenotype information. Gene variant and phenotype information were stored in a gene-centred relational database. Moreover, the relationships between mutations and diseases were indexed by the uniform resource identifier from LSDB, or another central database. By querying DRUMS, users can access the most popular mutation databases under one interface. DRUMS could be treated as a domain specific search engine. By using web crawling, indexing, and searching technologies, it provides a competitively efficient interface for searching and retrieving mutation data and their relationships to diseases. The present system is freely accessible at http://www.scbit.org/glif/new/drums/index.html. PMID:21913285

  6. CFTR gene mutations in isolated chronic obstructive pulmonary disease

    SciTech Connect

    Pignatti, P.F.; Bombien, C.; Marigo, C.

    1994-09-01

    In order to identify a possible hereditary predisposition to the development of chronic obstructive pulmonary disease (COPD), we have looked for the presence of cystic fibrosis transmembrane regulator (CFTR) gene DNA sequence modifications in 28 unrelated patients with no signs of cystic fibrosis. The known mutations in Italian CF patients, as well as the most frequent worldwide CF mutations, were investigated. In addition, a denaturing gradient gel electrophoresis analysis of about half of the coding sequence of the gene in 56 chromosomes from the patients and in 102 chromosomes from control individuals affected by other pulmonary diseases and from normal controls was performed. Nine different CFTR gene mutations and polymorphisms were found in seven patients, a highly significant increase over controls. Two of the patients were compound heterozygotes. Two frequent CF mutations were detected: deletion F508 and R117H; two rare CF mutations: R1066C and 3667ins4; and five CF sequence variants: R75Q (which was also described as a disease-causing mutation in male sterility cases due to the absence of the vasa deferentia), G576A, 2736 A{r_arrow}G, L997F, and 3271+18C{r_arrow}T. Seven (78%) of the mutations are localized in transmembrane domains. Six (86%) of the patients with defined mutations and polymorphisms had bronchiectasis. These results indicate that CFTR gene mutations and sequence alterations may be involved in the etiopathogenesis of some cases of COPD.

  7. Ferredoxin Gene Mutation in Iranian Trichomonas vaginalis Isolates

    PubMed Central

    HEIDARI, Soudabeh; BANDEHPOUR, Mojgan; SEYYED-TABAEI, Seyyed-Javad; VALADKHANI, Zarintaj; HAGHIGHI, Ali; ABADI, AliReza; KAZEMI, Bahram

    2013-01-01

    Background Trichomonas vaginalis causes trichomoniasis and metronidazole is its chosen drug for treatment. Ferredoxin has role in electron transport and carbohydrate metabolism and the conversion of an inactive form of metronidazole (CO) to its active form (CPR). Ferredoxin gene mutations reduce gene expression and increase its resistance to metronidazole. In this study, the frequency of ferredoxin gene mutations in clinical isolates of T.vaginalis in Tehran has been studied. Methods Forty six clinical T. vaginalis isolates of vaginal secretions and urine sediment were collected from Tehran Province since 2011 till 2012. DNA was extracted and ferredoxin gene was amplified by PCR technique. The ferredoxin gene PCR products were sequenced to determine gene mutations. Results In four isolates (8.69%) point mutation at nucleotide position -239 (the translation start codon) of the ferredoxin gene were detected in which adenosine were converted to thymine. Conclusion Mutation at nucleotide -239 ferredoxin gene reduces translational regulatory protein's binding affinity which concludes reduction of ferredoxin expression. For this reduction, decrease in activity and decrease in metronidazole drug delivery into the cells occur. Mutations in these four isolates may lead to resistance of them to metronidazole. PMID:24454433

  8. Amelogenesis Imperfecta and Screening of Mutation in Amelogenin Gene

    PubMed Central

    Oliveira, Fernanda Veronese; Gurgel, Carla Vecchione; Kobayashi, Tatiana Yuriko; Dionsio, Thiago Jos; Neves, Lucimara Teixeira; Santos, Carlos Ferreira; Machado, Maria Aparecida Andrade Moreira

    2014-01-01

    The aim of this study was to report the clinical findings and the screening of mutations of amelogenin gene of a 7-year-old boy with amelogenesis imperfecta (AI). The genomic DNA was extracted from saliva of patient and his family, followed by PCR and direct DNA sequencing. The c.261C>T mutation was found in samples of mother, father, and brother, but the mutation was not found in the sequence of the patient. This mutation is a silent mutation and a single-nucleotide polymorphism (rs2106416). Thus, it is suggested that the mutation found was not related to the clinical presence of AI. Further research is necessary to examine larger number of patients and genes related to AI. PMID:25045544

  9. Mutation hot spots in the canine herpesvirus thymidine kinase gene.

    PubMed

    Yamada, Shinya; Matsumoto, Yasunobu; Takashima, Yasuhiro; Otsuka, Haruki

    2005-08-01

    The guanine and cytosine content (GC-content) of alpha-herpesvirus genes are highly variable despite similar genome structures. It is known that drug resistant HSV, which has the genome with a high GC-content (approximately 70%), commonly includes frameshift mutations in homopolymer stretches of guanine (G) and cytosine (C) within the thymidine kinase (TK) gene. However, whether such mutation hotspots exist in the TK gene of canine herpesvirus (CHV) which has a low GC-content was unknown. In this study, we investigated mutations in the TK gene of CHV. CHV was passaged in the presence of iodo-deoxyuridine (IDU), and IDU-resistant clones were isolated. In all IDU-resistant virus clones, mutations in the TK gene were observed. The majority of these mutations were frameshift mutations of an adenine (A) insertion or deletion within either of 2 stretches of eight A's in the TK gene. It was demonstrated that CHV TK mutations frequently occur at a limited number of hot spots within long homopolymer nucleotide stretches. PMID:15965615

  10. Mutation screening of the ARX gene in patients with autism

    PubMed Central

    Chaste, Pauline; Nygren, Gudrun; Anckarsäter, Henrik; Råstam, Maria; Coleman, Mary; Leboyer, Marion; Gillberg, Christopher; Betancur, Catalina

    2007-01-01

    Mutations in the ARX gene are associated with a broad spectrum of disorders, including nonsyndromic X-linked mental retardation, sometimes associated with epilepsy, as well as syndromic forms with brain abnormalities and abnormal genitalia. Furthermore, ARX mutations have been described in a few patients with autism or autistic features. In this study, we screened the ARX gene in 226 male patients with autism spectrum disorders and mental retardation; 42 of the patients had epilepsy. The mutation analysis was performed by direct sequencing of all exons and flanking regions. No ARX mutations were identified in any of the patients tested. These findings indicate that mutations in the ARX gene are very rare in autism. PMID:17044103

  11. Four novel mutations of the coproporphyrinogen III oxidase gene.

    PubMed

    Aurizi, C; Lupia Palmieri, G; Barbieri, L; Macrì, A; Sorge, F; Usai, G; Biolcati, G

    2009-01-01

    Here we report the characterization of four novel mutations and a previously described one of the coproporphyrinogen III oxidase (CPO) gene in five Italian patients affected by Hereditary Coproporphyria (HCP). Three of the novel genetic variants are missense mutations (p.Gly242Cys; p.Leu398Pro; p.Ser245Phe) and one is a frameshift mutation (p.Gly188TrpfsX45). PMID:19267996

  12. Diverse growth hormone receptor gene mutations in Laron syndrome

    SciTech Connect

    Berg, M.A.; Francke, U. ); Gracia, R.; Rosenbloom, A.; Toledo, S.P.A. ); Chernausek, S. ); Guevara-Aguirre, J. ); Hopp, M. ); Rosenbloom, A.; Argente, J. ); Toledo, S.P.A. )

    1993-05-01

    To better understand the molecular genetic basis and genetic epidemiology of Laron syndrome (growth-hormone insensitivity syndrome), the authors analysed the growth-hormone receptor (GHR) genes of seven unrelated affected individuals from the United States, South America, Europe, and Africa. They amplified all nine GHR gene exons and splice junctions from these individuals by PCR and screened the products for mutations by using denaturing gradient gel electrophoresis (DGGE). They identified a single GHR gene fragment with abnormal DGGE results for each affected individual, sequenced this fragment, and, in each case, identified a mutation likely to cause Laron syndrome, including two nonsense mutations (R43X and R217X), two splice-junction mutations, (189-1 G to T and 71+1 G to A), and two frameshift mutations (46 del TT and 230 del TA or AT). Only one of these mutations, R43X, has been previously reported. Using haplotype analysis, they determined that this mutation, which involves a CpG dinucleotide hot spot, likely arose as a separate event in this case, relative to the two prior reports of R43X. Aside from R43X, the mutations identified are unique to patients from particular geographic regions. Ten GHR gene mutations have now been described in this disorder. The authors conclude that Laron syndrome is caused by diverse GHR gene mutations, including deletions, RNA processing defects, translational stop codons, and missense codons. All the identified mutations involve the extracellular domain of the receptor, and most are unique to particular families or geographic areas. 35 refs., 3 figs., 1 tab.

  13. Simulation of gene evolution under directional mutational pressure

    NASA Astrophysics Data System (ADS)

    Dudkiewicz, Małgorzata; Mackiewicz, Paweł; Kowalczuk, Maria; Mackiewicz, Dorota; Nowicka, Aleksandra; Polak, Natalia; Smolarczyk, Kamila; Banaszak, Joanna; R. Dudek, Mirosław; Cebrat, Stanisław

    2004-05-01

    The two main mechanisms generating the genetic diversity, mutation and recombination, have random character but they are biased which has an effect on the generation of asymmetry in the bacterial chromosome structure and in the protein coding sequences. Thus, like in a case of two chiral molecules-the two possible orientations of a gene in relation to the topology of a chromosome are not equivalent. Assuming that the sequence of a gene may oscillate only between certain limits of its structural composition means that the gene could be forced out of these limits by the directional mutation pressure, in the course of evolution. The probability of the event depends on the time the gene stays under the same mutation pressure. Inversion of the gene changes the directional mutational pressure to the reciprocal one and hence it changes the distance of the gene to its lower and upper bound of the structural tolerance. Using Monte Carlo methods we were able to simulate the evolution of genes under experimentally found mutational pressure, assuming simple mechanisms of selection. We found that the mutation and recombination should work in accordance to lower their negative effects on the function of the products of coding sequences.

  14. Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy

    PubMed Central

    Ceyhan-Birsoy, Ozge; Agrawal, Pankaj B.; Hidalgo, Carlos; Schmitz-Abe, Klaus; DeChene, Elizabeth T.; Swanson, Lindsay C.; Soemedi, Rachel; Vasli, Nasim; Iannaccone, Susan T.; Shieh, Perry B.; Shur, Natasha; Dennison, Jane M.; Lawlor, Michael W.; Laporte, Jocelyn; Markianos, Kyriacos; Fairbrother, William G.; Granzier, Henk

    2013-01-01

    Objective: To identify causative genes for centronuclear myopathies (CNM), a heterogeneous group of rare inherited muscle disorders that often present in infancy or early life with weakness and hypotonia, using next-generation sequencing of whole exomes and genomes. Methods: Whole-exome or -genome sequencing was performed in a cohort of 29 unrelated patients with clinicopathologic diagnoses of CNM or related myopathy depleted for cases with mutations of MTM1, DNM2, and BIN1. Immunofluorescence analyses on muscle biopsies, splicing assays, and gel electrophoresis of patient muscle proteins were performed to determine the molecular consequences of mutations of interest. Results: Autosomal recessive compound heterozygous truncating mutations of the titin gene, TTN, were identified in 5 individuals. Biochemical analyses demonstrated increased titin degradation and truncated titin proteins in patient muscles, establishing the impact of the mutations. Conclusions: Our study identifies truncating TTN mutations as a cause of congenital myopathy that is reported as CNM. Unlike the classic CNM genes that are all involved in excitation-contraction coupling at the triad, TTN encodes the giant sarcomeric protein titin, which forms a myofibrillar backbone for the components of the contractile machinery. This study expands the phenotypic spectrum associated with TTN mutations and indicates that TTN mutation analysis should be considered in cases of possible CNM without mutations in the classic CNM genes. PMID:23975875

  15. Phenotypic Involvement in Females with the FMR1 Gene Mutation.

    ERIC Educational Resources Information Center

    Riddle, J. E.; Cheema, A.; Sobesky, W. E.; Gardner, S. C.; Taylor, A. K.; Pennington, B. F.; Hagerman, R. J.

    1998-01-01

    A study investigated phenotypic effects seen in 114 females with premutation and 41 females (ages 18-58) with full Fragile X mental retardation gene mutation. Those with the full mutation had a greater incidence of hand-flapping, eye contact problems, special education help for reading and math, and grade retention. (Author/CR)

  16. MAMMALIAN CELL GENE MUTATION ASSAYS WORKING GROUP REPORT

    EPA Science Inventory

    Mammalian cell gene mutation assays have been used for many years and the diversity of the available systems attests to the varied methods found to grow mammalian dells and detect mutations. s part of the International Workshop on Standardization of Genotoxicity Test Procedures, ...

  17. [2% Haemophilia A patients without mutation in the FVIII gene].

    PubMed

    Uen, C; Oldenburg, J; Schröder, J; Brackmann, H-J; Schramm, W; Schwaab, R; Schneppenheim, R; Graw, J

    2003-02-01

    In Germany, approximately 6,000 patients are suffering from haemophilia A. Screening methods cover 97% of the mutations. For the other patients the coding sequences of the FVIII gene have to be sequenced in total. Out of 1,350 patients, no mutation was observed in 80 patients. In 5 patients, we observed an inversion in intron 1. Known mutations were detected in 16 patients, and in 19 cases novel mutations were characterized (14 in coding regions and 5 in flanking introns). The mutations are mainly base pair substitutions, small deletions or insertions (max. 4 bp) and predicted to cause amino acid exchanges or frameshifts leading to premature stop codons. Moreover, 5 polymorphisms were identified in exons 14 and 26 as well as in introns 7 and 19. Further studies are necessary to identify their causative effects. Surprisingly, in 23 patients out of this subgroup of 80, no mutation was identified in the FVIII gene. Therefore, mutations in non-coding areas or even in other genes have to be considered responsible for the haemophilia A like phenotype. One of them codes for the von Willebrand factor (vWF). We confirmed in two of our cases mutations in the vWF gene. PMID:12567191

  18. Variable expressivity and mutation databases: The androgen receptor gene mutations database.

    PubMed

    Gottlieb, B; Beitel, L K; Trifiro, M A

    2001-05-01

    For over 50 years genetics has presumed that variations in phenotypic expression have, for the most part, been the result of alterations in genotype. The importance and value of mutation databases has been based on the premise that the same gene or allelic variation in a specific gene that has been proven to determine a specific phenotype, will always produce the same phenotype. However, recent evidence has shown that so called "simple" Mendelian disorders or monogenic traits are often far from simple, exhibiting phenotypic variation (variable expressivity) that cannot be explained solely by a gene or allelic alteration. The AR gene mutations database now lists 25 cases where different degrees of androgen insensitivity are caused by identical mutations in the androgen receptor gene. In five of these cases the phenotypic variability is due to somatic mosaicism, that is, somatic mutations that occur in only certain cells of androgen-sensitive tissue. Recently, a number of other cases of variable expressivity have also been linked to somatic mosaicism. The impact of variable expressivity due to somatic mutations and mosaicism on mutation databases is discussed. In particular, the effect of an organism exhibiting genetic heterogeneity within its tissues, and the possibility of an organism's genotype changing over its lifetime, are considered to have important implications for mutation databases in the future. PMID:11317353

  19. Gene Mutations Linked to Rare Form of Female Infertility

    MedlinePlus

    ... identified the gene, the researchers used experiments with egg cells -- from mice and humans -- to prove that the TUBB8 mutations do halt egg maturation. "The practical implication of our discovery is ...

  20. A novel GBA2 gene missense mutation in spastic ataxia.

    PubMed

    Votsi, Christina; Zamba-Papanicolaou, Eleni; Middleton, Lefkos T; Pantzaris, Marios; Christodoulou, Kyproula

    2014-01-01

    Autosomal recessive cerebellar ataxias (ARCA) encompass a heterogeneous group of rare diseases that affect the cerebellum, the spinocerebellar tract and/or the sensory tracts of the spinal cord. We investigated a consanguineous Cypriot family with spastic ataxia, aiming towards identification of the causative mutation. Family members were clinically evaluated and studied at the genetic level. Linkage analysis at marker loci spanning known ARCA genes/loci revealed linkage to the APTX locus. Thorough investigation of the APTX gene excluded any possible mutation. Whole genome linkage screening using microsatellite markers and whole genome SNP homozygosity mapping using the Affymetrix Genome-Wide Human SNP Array 6.0 enabled mapping of the disease gene/mutation in this family to Chromosome 9p21.1-p13.2. Due to the large number of candidate genes within this region, whole-exome sequencing of the proband was performed and further analysis of the obtained data focused on the mapped interval. Further investigation of the candidate variants resulted in the identification of a novel missense mutation in the GBA2 gene. GBA2 mutations have recently been associated with hereditary spastic paraplegia and ARCA with spasticity. We hereby report a novel GBA2 mutation associated with spastic ataxia and suggest that GBA2 mutations may be a relatively frequent cause of ARCA. PMID:24252062

  1. Convergence in pigmentation at multiple levels: mutations, genes and function

    PubMed Central

    Manceau, Marie; Domingues, Vera S.; Linnen, Catherine R.; Rosenblum, Erica Bree; Hoekstra, Hopi E.

    2010-01-01

    Convergencethe independent evolution of the same trait by two or more taxahas long been of interest to evolutionary biologists, but only recently has the molecular basis of phenotypic convergence been identified. Here, we highlight studies of rapid evolution of cryptic coloration in vertebrates to demonstrate that phenotypic convergence can occur at multiple levels: mutations, genes and gene function. We first show that different genes can be responsible for convergent phenotypes even among closely related populations, for example, in the pale beach mice inhabiting Florida's Gulf and Atlantic coasts. By contrast, the exact same mutation can create similar phenotypes in distantly related species such as mice and mammoths. Next, we show that different mutations in the same gene need not be functionally equivalent to produce similar phenotypes. For example, separate mutations produce divergent protein function but convergent pale coloration in two lizard species. Similarly, mutations that alter the expression of a gene in different ways can, nevertheless, result in similar phenotypes, as demonstrated by sister species of deer mice. Together these studies underscore the importance of identifying not only the genes, but also the precise mutations and their effects on protein function, that contribute to adaptation and highlight how convergence can occur at different genetic levels. PMID:20643733

  2. DNA Methylation and Mutator Genes in Escherichia coli K-12

    PubMed Central

    Marinus, Martin G.

    2010-01-01

    Mutator strains of Escherichia coli have been used to define mechanisms that account for the high fidelity of chromosome duplication and chromosome stability. Mutant strains defective in post-replicative mismatch repair display a strong mutator phenotype consistent with a role for correction of mismatches arising from replication errors. Inactivation of the gene (dam) encoding DNA adenine methyltransferase results in a mutator phenotype consistent with a role for DNA methylation in strand discrimination during mismatch repair. This review gives a personal perspective on the discovery of dam mutants in E. coli and their relationship to mismatch repair and mutator phenotypes. PMID:20471491

  3. Novel mutations and the emergence of a common mutation in the SDHD gene causing familial paraganglioma.

    PubMed

    Milunsky, J M; Maher, T A; Michels, V V; Milunsky, A

    2001-05-15

    Familial paragangliomas (PGL) are slow-growing, highly vascular, generally benign neoplasms, usually of the head and neck, that arise from neural crest cells. This rare autosomal dominant disorder is highly penetrant and influenced by genomic imprinting through paternal transmission. Timely detection of these tumors may afford the affected individual the opportunity to avoid the potential serious morbidity associated with surgical removal and the mortality that may accompany local and distant metastases. Linkage to two distinct chromosomal loci, 11q13.1 and 11q23, has been previously reported. Recently, germline mutations in SDHD, a mitochondrial complex II gene on chromosome 11q23, have been demonstrated. We evaluated members of seven families with PGL, five previously studied and shown to have linkage to chromosome 11q23. The entire coding region of the SDHD gene was sequenced and yielded four novel mutations and one mutation shared in three of our unrelated families. Novel mutations found included a truncating mutation in exon 2, as well as a missense mutation, a deletion, and an insertion in exon 4. Three of our families had a common mutation in exon 3 (P81L) that has been reported and thought to be a founder mutation. A restriction enzyme assay was developed for initial screening of this mutation. Molecular analysis is now available and recommended for presymptomatic diagnosis in those at-risk individuals and for confirmatory diagnosis in those having PGL. PMID:11343322

  4. SAIVGeM: spreadsheet analysis of immunoglobulin VH gene mutations.

    PubMed

    Messmer, Bradley T

    2005-09-01

    The analysis of mutations in immunoglobulin heavy chain variable (IGHV) region genes is a tedious process when performed by hand on multiple sequences. This report describes a set of linked Microsoft Excel files that perform several common analyses on large numbers of IGHV sequences. The spreadsheet analysis of immunoglobulin VH gene mutations (SAIVGeM) package determines the distribution of mutations among each nucleotide, the nature of the mutation at both the nucleotide and amino acid level, the frequency of mutation in the A/G G C/T A/T (RGYW) hotspot motifs of both strand polarity, and the distribution of replacement and silent mutations among the complementarity determining regions (CDRs) and the framework regions (FRs) of the immunoglobulin gene as defined by either the Kabat or IMGT conventions. These parameters are summarized and graphically presented where appropriate. In addition, the SAIVGeM package analyzes those mutations that occur in third positions of redundant codons. Because any nucleotide change in these positions is inherently silent, these positions can be used to study the mutational spectra without biases from the selection of protein structure. PMID:16206907

  5. Protective protein gene mutations in galactosialidosis.

    PubMed Central

    Shimmoto, M; Fukuhara, Y; Itoh, K; Oshima, A; Sakuraba, H; Suzuki, Y

    1993-01-01

    Four different protective protein cDNA mutations, 146A-->G (Q49R), 193T-->C (W65R), 268-269TC-->CT (S90L), and 1184A-->G (Y395C), were identified in six Japanese galactosialidosis patients with various phenotypic manifestations, and another mutation, 746T-->A (Y249N), in a patient of French-German origin with an atypical clinical course. Y395C was a common mutation in four Japanese patients in infancy and childhood; two juvenile patients were compound heterozygotes of Y395C and another common mutation, SpDEx7, and the other two infants were compound heterozygotes of Y395C and mutant alleles other than SpDEx7. We confirmed these mutations in genomic DNA by direct-sequence analysis or restriction-site analysis. The mutant cDNA clones, transiently expressed in a transformed galactosialidosis cell line, did not restore the secondarily deficient beta-galactosidase or alpha-neuraminidase activity except for the Y249N mutation that expressed some carboxypeptidase activity and restored the two lysosomal enzyme activities. Pulse-chase analysis detected a small amount of the mature form, as well as the precursor, in the cells transfected with the Y249N cDNA. Only precursor proteins were detected, mature proteins not appearing for the other mutant cDNAs. Images PMID:8514852

  6. Molecular approaches to the estimation of germinal gene mutation rates

    SciTech Connect

    Mohrenweiser, H.W.; Perry, B.A.; Judd, S.A.

    1989-12-11

    Estimation of the induced germinal gene mutation rate in human populations is difficult because de novo mutations, especially of functional gene loci, are rare events and the sizes of the human populations that have been exposed to known mutagens are generally small. Thus, if statistically significant estimates of mutation rates are to be generated, it is critical that a significant body of data be obtained from each offspring included in a mutation screening study. Additionally, the assay(s) employed must be sufficiently robust to efficiently detect the spectrum of lesions that may be induced by different classes of mutagens. DNA-based techniques have the potential to overcome these problems because it may be possible to screen the entire genome for mutational events and the alterations in DNA structure can be analyzed directly. Two assay systems are being developed and tested for feasibility as germinal gene mutation screening strategies. One is based upon denaturing gradient gel electrophoresis to detect nucleotide substitutions while the second is a restriction enzyme site mapping strategy to identify DNA insertions, deletions and rearrangements. Cell lines derived by clonal expansion of cells following exposure to mutagens are being screened in an initial prototype experiment. Preliminary results indicate that is should be feasible to screen for germinal gene mutations in rodent test systems and in human populations in the near future with these two techniques. 51 refs., 4 figs.

  7. 21 CFR 866.5900 - Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation detection system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... regulator (CFTR) gene mutation detection system. 866.5900 Section 866.5900 Food and Drugs FOOD AND DRUG...) gene mutation detection system. (a) Identification. The CFTR gene mutation detection system is a device used to simultaneously detect and identify a panel of mutations and variants in the CFTR gene. It...

  8. 21 CFR 866.5900 - Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation detection system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... regulator (CFTR) gene mutation detection system. 866.5900 Section 866.5900 Food and Drugs FOOD AND DRUG...) gene mutation detection system. (a) Identification. The CFTR gene mutation detection system is a device used to simultaneously detect and identify a panel of mutations and variants in the CFTR gene. It...

  9. 21 CFR 866.5900 - Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation detection system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... regulator (CFTR) gene mutation detection system. 866.5900 Section 866.5900 Food and Drugs FOOD AND DRUG...) gene mutation detection system. (a) Identification. The CFTR gene mutation detection system is a device used to simultaneously detect and identify a panel of mutations and variants in the CFTR gene. It...

  10. AB125. Neonatal diabetes mellitus due to insulin gene mutation

    PubMed Central

    Can, Ngoc Thi Bich; Vu, Dung Chi; Bui, Thao Phuong; Nguyen, Khanh Ngoc; Nguyen, Dat Phu; Craig, Maria; Ellard, Sian; Nguyen, Hoan Thi

    2015-01-01

    Background and objective Insulin (INS) gene mutations that cause permanent neonatal diabetes mellitus change single protein building blocks (amino acids) in the protein sequence. These mutations are believed to disrupt the cleavage of the proinsulin chain or the binding of the A and B chains to form insulin, leading to impaired blood sugar control. At least ten mutations in the INS gene have been identified in people with permanent neonatal diabetes mellitus. To describe clinical features and laboratory manifestations of patients with INS gene mutation and to evaluate outcome of management. Methods Clinical features, biochemical finding, mutation analysis and management outcome of six cases from six unrelated families were study. All exons of INS gene were amplified from genomic DNA and directly sequenced. Results Six cases (three girls and three boys) onset at 129.2±128.8 days of age (median 101.5 days) with gestation age of 37.3±3.0 weeks, birth weight of 2,816.6±767.8 g. Five out of six patients admitted with the feature of diabetic ketoacidosis with pH of 7.04±0.22; plasma glucose levels were 34.3±12.7 mmoL/L, HbA1C of 9.75%±3.5%. Mutation analysis of the INS gene showed: heterozygous for a novel missense mutation (c.127T > A; C43S) in exon 2 in one case; heterozygous for a splicing mutation c.188-31G > A in intron 2 in two cases; heterozygous for a missense mutation c.286T > C in exon 3 in one case; heterozygous for a missense mutation c.265C > T [p.Arg89Cys (p.R89C)] in exon 3 in two cases. After 19.2±13.4 months of insulin treatment, 4/5 patients have normal development with DQ 80-100%, HbA1C of 6.85%±0.49%, quite normal blood glucose levels. The case with c.127T > A mutation treated with insulin for 14 years has physical development delay, poor blood glucose control with HbA1C of 11.4%. Conclusions It is important to perform screening gene mutation for patients with diabetes diagnosed before 6 months of age to control blood glucose and follow up the patients.

  11. From minisatellites and genes: When do germinal mutations occur

    SciTech Connect

    Mohrenweiser, H.

    1997-10-01

    Utilization of molecular techniques has provided insight into the molecular techniques has provided insight into the molecular techniques has provided insight into the molecular character and origins of spontaneous and induced germinal mutations. Review of the variants and disease loci suggests differences among loci in the frequency of nucleotide substitutions and more complex events. Mechanistic features associated with the alterations in DNA structure are observed in each variant class. The spectrum of mutations identified reflects the gene structure and the selective pressure generating disease phenotypes, and the techniques employed to screen for variation. Locus specificity in spectra has the potential to compromise estimates of increases in germinal gene mutation rates. Recent studies have identified mosaicism, rather than de novo mutation, as the explanation for the non-traditional pattern of inheritance of disease in some families. Mosaicism is a concern for studies of induced mutation rates as it reflects embryonic exposure of the parent of the proband. This is in contrast to the {open_quotes}normal expectation{close_quotes} that induced mutations result from parental exposure to genotoxins in the environment. Observations suggest that the germ cell stage sensitivity may reflect interaction of the mutagen and the loci screened. The mosaicism and germ cell stage issues, in conjunction with incomplete ascertainment of mutational events, increase the complexity of efforts to estimate induced germinal mutation rates and associated health consequences in populations exposed to genotoxic agents.

  12. Conditional lethal amber mutations in essential Escherichia coli genes.

    PubMed

    Herring, Christopher D; Blattner, Frederick R

    2004-05-01

    The essential genes of microorganisms encode biological functions important for survival and thus tend to be of high scientific interest. Drugs that interfere with essential functions are likely to be interesting candidates for antimicrobials. However, these genes are hard to study genetically because knockout mutations in them are by definition inviable. We recently described a conditional mutation system in Escherichia coli that uses a plasmid to produce an amber suppressor tRNA regulated by the arabinose promoter. This suppressor was used here in the construction of amber mutations in seven essential E. coli genes. Amber stop codons were introduced as "tagalong" mutations in the flanking DNA of a downstream antibiotic resistance marker by lambda red recombination. The drug marker was removed by expression of I-SceI meganuclease, leaving a markerless mutation. We demonstrate the method with the genes frr, gcpE, lpxC, map, murA, ppa, and rpsA. We were unable to isolate an amber mutation in ftsZ. Kinetics of cell death and morphological changes were measured following removal of arabinose. As expected given the wide range of cellular mechanisms represented, different mutants showed widely different death curves. All of the mutations were bactericidal except the mutation in gcpE, which was bacteriostatic. The strain carrying an amber mutation in murA was by far the most sensitive, showing rapid killing in nonpermissive medium. The MurA protein is critical for peptidoglycan synthesis and is the target for the antibiotic fosfomycin. Such experiments may inexpensively provide valuable information for the identification and prioritization of targets for antibiotic development. PMID:15090508

  13. Coincidence of mutations in different connexin genes in Hungarian patients.

    PubMed

    Tóth, Tímea; Kupka, Susan; Haack, Birgit; Fazakas, Ferenc; Muszbek, Laszló; Blin, Nikolaus; Pfister, Markus; Sziklai, István

    2007-09-01

    Mutations in the GJB2 gene are the most common cause of hereditary prelingual sensorineural hearing impairment in Europe. Several studies indicate that different members of the connexin protein family interact to form gap junctions in the inner ear. Mutations in different connexin genes may accumulate and, consequently lead to hearing impairment. Therefore, we screened 47 Hungarian GJB2- heterozygous (one mutation in coding exon of the GJB2 gene) patients with hearing impairment for DNA changes in two further connexin genes (GJB6 and GJB3) and in the 5' non-coding region of GJB2 including the splice sites. Eleven out of 47 GJB2-heterozygous patients analyzed carried the splice site mutation -3170G>A in the 5'UTR region of GJB2. One out of these 11 patients showed homozygous -3170G>A genotype in combination with p.R127H. Next to the GJB2 mutations we noted 2 cases of deletion in GJB6 [Delta(GJB6-D13S1830)] and 3 (2 new and 1 described) base substitutions in GJB3 [c.357C>T, c.798C>T and c.94C>T (p.R32W)] which are unlikely disease-causing. Our results suggest the importance of routine screening for the rather frequent -3170G>A mutation (in addition to c.35delG) in patients with hearing impairment. PMID:17671735

  14. Neurocognitive Profiles in Duchenne Muscular Dystrophy and Gene Mutation Site

    PubMed Central

    D’Angelo, Maria Grazia; Lorusso, Maria Luisa; Civati, Federica; Comi, Giacomo Pietro; Magri, Francesca; Del Bo, Roberto; Guglieri, Michela; Molteni, Massimo; Turconi, Anna Carla; Bresolin, Nereo

    2011-01-01

    The presence of nonprogressive cognitive impairment is recognized as a common feature in a substantial proportion of patients with Duchenne muscular dystrophy. To investigate the possible role of mutations along the dystrophin gene affecting different brain dystrophin isoforms and specific cognitive profiles, 42 school-age children affected with Duchenne muscular dystrophy, subdivided according to sites of mutations along the dystrophin gene, underwent a battery of tests tapping a wide range of intellectual, linguistic, and neuropsychologic functions. Full-scale intelligence quotient was approximately 1 S.D. below the population average in the whole group of dystrophic children. Patients with Duchenne muscular dystrophy and mutations located in the distal portion of the dystrophin gene (involving the 140-kDa brain protein isoform, called Dp140) were generally more severely affected and expressed different patterns of strengths and impairments, compared with patients with Duchenne muscular dystrophy and mutations located in the proximal portion of the dystrophin gene (not involving Dp140). Patients with Duchenne muscular dystrophy and distal mutations demonstrated specific impairments in visuospatial functions and visual memory (which seemed intact in proximally mutated patients) and greater impairment in syntactic processing. PMID:22000308

  15. A novel mutation of the fibrillin gene causing Ectopia lentis

    SciTech Connect

    Loennqvist, L.; Kainulainen, K.; Puhakka, L.; Peltonen, L. ); Child, A. ); Peltonen, L. )

    1994-02-01

    Ectopia lentis (EL), a dominantly inherited connective tissue disorder, has been genetically linked to the fibrillin gene on chromosome 15 (FBN1) in earlier studies. Here, the authors report the first EL mutation in the FBN1 gene confirming that EL is caused by mutations of this gene. So far, several mutations in the FBN1 gene have been reported in patients with Marfan syndrome (MFS). EL and MFS are clinically related but distinct conditions with typical manifestations in the ocular and skeletal systems, the fundamental difference between them being the absence of cardiovascular involvement in EL. They report a point mutation, cosegregating with the disease in the described family, that displays EL over four generations. The mutation changes a conserved glutamic acid residue in an EGF-like motif, which is the major structural component of the fibrillin and is repeated throughout the polypeptide. In vitro mutagenetic studies have demonstrated the necessity of an analogous glutamic acid residue for calcium binding in an EGF-like repeat of human factor IX. This provides a possible explanation for the role of this mutation in the disease pathogenesis. 32 refs., 2 figs., 1 tab.

  16. Mutation analysis of the Smad3 gene in human osteoarthritis.

    PubMed

    Yao, Jun-Yan; Wang, Yan; An, Jing; Mao, Chun-Ming; Hou, Ning; Lv, Ya-Xin; Wang, You-Liang; Cui, Fang; Huang, Min; Yang, Xiao

    2003-09-01

    Osteoarthritis (OA) is the most common joint disease worldwide. Recent studies have shown that targeted disruption of Smad3 in mouse results in OA. To reveal the possible association between the Smad3 gene mutation and human OA, we employed polymerase chain reaction-single strand conformation polymorphism and sequencing to screen mutations in all nine exons of the Smad3 gene in 32 patients with knee OA and 50 patients with only bone fracture. A missense mutation of the Smad3 gene was found in one patient. The single base mutation located in the linker region of the SMAD3 protein was A --> T change in the position 2 of codon 197 and resulted in an asparagine to isoleucine amino-acid substitution. The expressions of matrix metalloproteinase 2 (MMP-2) and MMP-9 in sera of the patient carrying the mutation were higher than other OA patients and controls. This is the first report showing that the Smad3 gene mutations could be associated with the pathogenesis of human OA. PMID:12939660

  17. Gene mutation-based and specific therapies in precision medicine.

    PubMed

    Wang, Xiangdong

    2016-04-01

    Precision medicine has been initiated and gains more and more attention from preclinical and clinical scientists. A number of key elements or critical parts in precision medicine have been described and emphasized to establish a systems understanding of precision medicine. The principle of precision medicine is to treat patients on the basis of genetic alterations after gene mutations are identified, although questions and challenges still remain before clinical application. Therapeutic strategies of precision medicine should be considered according to gene mutation, after biological and functional mechanisms of mutated gene expression or epigenetics, or the correspondent protein, are clearly validated. It is time to explore and develop a strategy to target and correct mutated genes by direct elimination, restoration, correction or repair of mutated sequences/genes. Nevertheless, there are still numerous challenges to integrating widespread genomic testing into individual cancer therapies and into decision making for one or another treatment. There are wide-ranging and complex issues to be solved before precision medicine becomes clinical reality. Thus, the precision medicine can be considered as an extension and part of clinical and translational medicine, a new alternative of clinical therapies and strategies, and have an important impact on disease cures and patient prognoses. PMID:26994883

  18. Legius Syndrome: two novel mutations in the SPRED1 gene

    PubMed Central

    Bianchi, Marika; Saletti, Veronica; Micheli, Roberto; Esposito, Silvia; Molinaro, Anna; Gagliardi, Stella; Orcesi, Simona; Cereda, Cristina

    2015-01-01

    The SPRED1 gene encodes a protein involved in the Ras/MAPK (mitogen-activated protein kinase) signaling pathway. Mutations in SPRED1 have been reported to cause Legius Syndrome, a rare developmental disorder that shares some clinical features with Neurofibromatosis-1. Direct sequencing was used to define SPRED1 mutations. We present two previously undescribed mutations: a frameshift mutation causing a stop codon, which was identified in an Italian family (p.Ile60Tyrfs*18) and a missense variation, which was identified in one sporadic Italian case (p.Pro422Arg). Our results led us to hypothesize that these modifications may contribute to the Legius Syndrome phenotype. Further studies will be needed to determine the roles of these mutations in the mechanisms of Legius Syndrome.

  19. Molecular evaluation of a novel missense mutation & an insertional truncating mutation in SUMF1 gene

    PubMed Central

    Kotecha, Udhaya H.; Movva, Sireesha; Sharma, Deepak; Verma, Jyotsna; Puri, Ratna Dua; Verma, Ishwar Chander

    2014-01-01

    Background & objectives: Multiple suphphatase deficiency (MSD) is an autosomal recessive disorder affecting the post translational activation of all enzymes of the sulphatase family. To date, approximately 30 different mutations have been identified in the causative gene, sulfatase modifying factor 1 (SUMF1). We describe here the mutation analysis of a case of MSD. Methods: The proband was a four year old boy with developmental delay followed by neuroregression. He had coarse facies, appendicular hypertonia, truncal ataxia and ichthyosis limited to both lower limbs. Radiographs showed dysostosis multiplex. Clinical suspicion of MSD was confirmed by enzyme analysis of four enzymes of the sulphatase group. Results: The patient was compound heterozygote for a c.451A>G (p.K151E) substitution in exon 3 and a single base insertion mutation (c.690_691 InsT) in exon 5 in the SUMF1 gene. The bioinformatic analysis of the missense mutation revealed no apparent effect on the overall structure. However, the mutated 151-amino acid residue was found to be adjacent to the substrate binding and the active site residues, thereby affecting the substrate binding and/or catalytic activity, resulting in almost complete loss of enzyme function. Conclusions: The two mutations identified in the present case were novel. This is perhaps the first report of an insertion mutation in SUMF1 causing premature truncation of the protein. PMID:25222778

  20. Plasma homocysteine levels correlated to interactions between folate status and methylene tetrahydrofolate reductase gene mutation in women with unexplained recurrent pregnancy loss.

    PubMed

    Kumar, K S D; Govindaiah, V; Naushad, S E; Devi, R R; Jyothy, A

    2003-01-01

    Hyperhomocysteinaemia, a risk factor for recurrent pregnancy loss, is related either to a hereditary defect within the methionine-homocysteine pathway or it might be acquired as a result of deficiencies of vitamin B(12) and folate (B(9)). Because hyperhomocysteinaemia seems to be determined by both genetic and environmental factors, the current study was undertaken to find out the interactions between folate status and MTHFR mutation on the homocysteine concentration in 24 women experiencing unexplained three or more consecutive recurrent pregnancy losses. The median fasting total plasma homocysteine concentration in the study group was 10.23 micro mol/l compared to 8.95 micro mol/l; P = 0.096 in the controls. Elevated homocysteine levels > 18 micro mol/l, which was considered to be a risk factor for recurrent early pregnancy loss, was found in four women in the study group and none among the controls. Lower red cell folate levels (normal range >/= 160 ng/ml) were observed in nine (37.5%) women among the study group, compared to five (20.84%) women among controls. The mean +/- SD red cell folate levels in the study group was found to be 154.37 +/- 37.07, while in the controls it was 159.0 +/- 28.97. In the present study six women in the study group and two among controls were found to be carriers for the C677T MTHFR mutation. None were homozygous for the mutant (TT) allele. The highest values of homocysteine concentration were found in women experiencing recurrent pregnancy loss with both the CT genotype and folate deficiency. Identification of hyperhomocysteinaemia in women with recurrent pregnancy loss may help in therapeutic normalisation and might permit a normal birth. PMID:12623486

  1. SERPINA1 Full-Gene Sequencing Identifies Rare Mutations Not Detected in Targeted Mutation Analysis.

    PubMed

    Graham, Rondell P; Dina, Michelle A; Howe, Sarah C; Butz, Malinda L; Willkomm, Kurt S; Murray, David L; Snyder, Melissa R; Rumilla, Kandelaria M; Halling, Kevin C; Highsmith, W Edward

    2015-11-01

    Genetic α-1 antitrypsin (AAT) deficiency is characterized by low serum AAT levels and the identification of causal mutations or an abnormal protein. It needs to be distinguished from deficiency because of nongenetic causes, and diagnostic delay may contribute to worse patient outcome. Current routine clinical testing assesses for only the most common mutations. We wanted to determine the proportion of unexplained cases of AAT deficiency that harbor causal mutations not identified through current standard allele-specific genotyping and isoelectric focusing (IEF). All prospective cases from December 1, 2013, to October 1, 2014, with a low serum AAT level not explained by allele-specific genotyping and IEF were assessed through full-gene sequencing with a direct sequencing method for pathogenic mutations. We reviewed the results using American Council of Medical Genetics criteria. Of 3523 cases, 42 (1.2%) met study inclusion criteria. Pathogenic or likely pathogenic mutations not identified through clinical testing were detected through full-gene sequencing in 16 (38%) of the 42 cases. Rare mutations not detected with current allele-specific testing and IEF underlie a substantial proportion of genetic AAT deficiency. Full-gene sequencing, therefore, has the ability to improve accuracy in the diagnosis of AAT deficiency. PMID:26321041

  2. Gene mutations and molecularly targeted therapies in acute myeloid leukemia

    PubMed Central

    Hatzimichael, Eleftheria; Georgiou, Georgios; Benetatos, Leonidas; Briasoulis, Evangelos

    2013-01-01

    Acute myelogenous leukemia (AML) can progress quickly and without treatment can become fatal in a short period of time. However, over the last 30 years fine-tuning of therapeutics have increased the rates of remission and cure. Cytogenetics and mutational gene profiling, combined with the option of allogeneic hematopoietic stem cell transplantation offered in selected patients have further optimized AML treatment on a risk stratification basis in younger adults. However there is still an unmet medical need for effective therapies in AML since disease relapses in almost half of adult patients becoming refractory to salvage therapy. Improvements in the understanding of molecular biology of cancer and identification of recurrent mutations in AML provide opportunities to develop targeted therapies and improve the clinical outcome. In the spectrum of identified gene mutations, primarily targetable lesions are gain of function mutations of tyrosine kinases FLT3, JAK2 and cKIT for which specific, dual and multi-targeted small molecule inhibitors have been developed. A number of targeted compounds such as sorafenib, quizartinib, lestaurtinib, midostaurin, pacritinib, PLX3397 and CCT137690 are in clinical development. For loss-of-function gene mutations, which are mostly biomarkers of favorable prognosis, combined therapeutic approaches can maximize the therapeutic efficacy of conventional therapy. Apart from mutated gene products, proteins aberrantly overexpressed in AML appear to be clinically significant therapeutic targets. Such a molecule for which targeted inhibitors are currently in clinical development is PLK1. We review characteristic gene mutations, discuss their biological functions and clinical significance and present small molecule compounds in clinical development, which are expected to have a role in treating AML subtypes with characteristic molecular alterations. PMID:23358589

  3. Gene mutations and molecularly targeted therapies in acute myeloid leukemia.

    PubMed

    Hatzimichael, Eleftheria; Georgiou, Georgios; Benetatos, Leonidas; Briasoulis, Evangelos

    2013-01-01

    Acute myelogenous leukemia (AML) can progress quickly and without treatment can become fatal in a short period of time. However, over the last 30 years fine-tuning of therapeutics have increased the rates of remission and cure. Cytogenetics and mutational gene profiling, combined with the option of allogeneic hematopoietic stem cell transplantation offered in selected patients have further optimized AML treatment on a risk stratification basis in younger adults. However there is still an unmet medical need for effective therapies in AML since disease relapses in almost half of adult patients becoming refractory to salvage therapy. Improvements in the understanding of molecular biology of cancer and identification of recurrent mutations in AML provide opportunities to develop targeted therapies and improve the clinical outcome. In the spectrum of identified gene mutations, primarily targetable lesions are gain of function mutations of tyrosine kinases FLT3, JAK2 and cKIT for which specific, dual and multi-targeted small molecule inhibitors have been developed. A number of targeted compounds such as sorafenib, quizartinib, lestaurtinib, midostaurin, pacritinib, PLX3397 and CCT137690 are in clinical development. For loss-of-function gene mutations, which are mostly biomarkers of favorable prognosis, combined therapeutic approaches can maximize the therapeutic efficacy of conventional therapy. Apart from mutated gene products, proteins aberrantly overexpressed in AML appear to be clinically significant therapeutic targets. Such a molecule for which targeted inhibitors are currently in clinical development is PLK1. We review characteristic gene mutations, discuss their biological functions and clinical significance and present small molecule compounds in clinical development, which are expected to have a role in treating AML subtypes with characteristic molecular alterations. PMID:23358589

  4. Mutational screening of NOTCH3 gene reveals two novel mutations: complexity of CADASIL diagnosis.

    PubMed

    Mosca, Lorena; Rivieri, Francesca; Tanel, Raffaella; Bonfante, Aldo; Burlina, Alessandro; Manfredini, Emanuela; Primignani, Paola; Gesu, Giovanni P; Marocchi, Alessandro; Penco, Silvana

    2014-12-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an adult onset hereditary vascular disease with neurological manifestations. The classical clinical course is relentlessly progressive with early transient ischaemic attacks (TIA) or strokes, dementia and finally death in the mid-1960s. The disorder is inherited in an autosomal dominant fashion, with high penetrance and broad variable clinical course even within family. It is caused by mutations in the NOTCH3 gene; all causative mutations result in gain or loss of a cysteine residue within the extracellular domain, with exons 3 and 4 reported as hot spot mutational sites. Mutation analysis of the NOTCH3 gene was performed through direct sequencing of the 2-23 exons containing all EGF-like domains. Patients underwent genetic counselling pre and post testing. Here, we report two novel mutations located in exons 6 and 15 of the NOTCH3 gene; clinical description for the probands and for available relatives is enclosed. No reliable data on incidence or prevalence rates of this disease are available: it is therefore essential that the diagnosis is obtained in all suspected cases through the extensive analysis of the NOTCH3 gene and that all cases are brought to the attention of the scientific community. PMID:24816653

  5. Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids.

    PubMed

    Fernandez-Cuesta, Lynnette; Peifer, Martin; Lu, Xin; Sun, Ruping; Ozretić, Luka; Seidel, Danila; Zander, Thomas; Leenders, Frauke; George, Julie; Müller, Christian; Dahmen, Ilona; Pinther, Berit; Bosco, Graziella; Konrad, Kathryn; Altmüller, Janine; Nürnberg, Peter; Achter, Viktor; Lang, Ulrich; Schneider, Peter M; Bogus, Magdalena; Soltermann, Alex; Brustugun, Odd Terje; Helland, Åslaug; Solberg, Steinar; Lund-Iversen, Marius; Ansén, Sascha; Stoelben, Erich; Wright, Gavin M; Russell, Prudence; Wainer, Zoe; Solomon, Benjamin; Field, John K; Hyde, Russell; Davies, Michael P A; Heukamp, Lukas C; Petersen, Iver; Perner, Sven; Lovly, Christine M; Cappuzzo, Federico; Travis, William D; Wolf, Jürgen; Vingron, Martin; Brambilla, Elisabeth; Haas, Stefan A; Buettner, Reinhard; Thomas, Roman K

    2014-01-01

    Pulmonary carcinoids are rare neuroendocrine tumours of the lung. The molecular alterations underlying the pathogenesis of these tumours have not been systematically studied so far. Here we perform gene copy number analysis (n=54), genome/exome (n=44) and transcriptome (n=69) sequencing of pulmonary carcinoids and observe frequent mutations in chromatin-remodelling genes. Covalent histone modifiers and subunits of the SWI/SNF complex are mutated in 40 and 22.2% of the cases, respectively, with MEN1, PSIP1 and ARID1A being recurrently affected. In contrast to small-cell lung cancer and large-cell neuroendocrine lung tumours, TP53 and RB1 mutations are rare events, suggesting that pulmonary carcinoids are not early progenitor lesions of the highly aggressive lung neuroendocrine tumours but arise through independent cellular mechanisms. These data also suggest that inactivation of chromatin-remodelling genes is sufficient to drive transformation in pulmonary carcinoids. PMID:24670920

  6. Mutations in many genes affect aggressive behavior in Drosophila melanogaster

    PubMed Central

    Edwards, Alexis C; Zwarts, Liesbeth; Yamamoto, Akihiko; Callaerts, Patrick; Mackay, Trudy FC

    2009-01-01

    Background Aggressive behavior in animals is important for survival and reproduction. Identifying the underlying genes and environmental contexts that affect aggressive behavior is important for understanding the evolutionary forces that maintain variation for aggressive behavior in natural populations, and to develop therapeutic interventions to modulate extreme levels of aggressive behavior in humans. While the role of neurotransmitters and a few other molecules in mediating and modulating levels of aggression is well established, it is likely that many additional genetic pathways remain undiscovered. Drosophila melanogaster has recently been established as an excellent model organism for studying the genetic basis of aggressive behavior. Here, we present the results of a screen of 170 Drosophila P-element insertional mutations for quantitative differences in aggressive behavior from their co-isogenic control line. Results We identified 59 mutations in 57 genes that affect aggressive behavior, none of which had been previously implicated to affect aggression. Thirty-two of these mutants exhibited increased aggression, while 27 lines were less aggressive than the control. Many of the genes affect the development and function of the nervous system, and are thus plausibly relevant to the execution of complex behaviors. Others affect basic cellular and metabolic processes, or are mutations in computationally predicted genes for which aggressive behavior is the first biological annotation. Most of the mutations had pleiotropic effects on other complex traits. We characterized nine of these mutations in greater detail by assessing transcript levels throughout development, morphological changes in the mushroom bodies, and restoration of control levels of aggression in revertant alleles. All of the P-element insertions affected the tagged genes, and had pleiotropic effects on brain morphology. Conclusion This study reveals that many more genes than previously suspected affect aggressive behavior, and that these genes have widespread pleiotropic effects. Given the conservation of aggressive behavior among different animal species, these are novel candidate genes for future study in other animals, including humans. PMID:19519879

  7. Novel mutations of the transglutaminase 1 gene in lamellar ichthyosis.

    PubMed

    Yang, J M; Ahn, K S; Cho, M O; Yoneda, K; Lee, C H; Lee, J H; Lee, E S; Candi, E; Melino, G; Ahvazi, B; Steinert, P M

    2001-08-01

    Lamellar ichthyosis, one form of congenital autosomal recessive ichthyosis, is caused by mutations in the gene (TGM1) encoding the transglutaminase 1 enzyme. Mutations, deletions, or insertion of TGM1 have been reported so far. Here we report that three novel mutations of TGM1, D101V, N288T, and R306W, cause lamellar ichthyosis in two different families. The patient in family LI-KD has N288T and R306W mutations, and the patient in family LI-LK has D101V and R306W mutations. The activity of the transglutaminase 1 enzyme of the patient in family LI-LK was only about 15% of normal. Also, three-dimensional structural prediction analyses revealed that the N288T and R306W mutations, and possibly the D101V mutation, cause misfolding in the central catalytic core domain of the transglutaminase 1 enzyme that would probably result in reduced enzyme activity. Our data suggest that the greatly reduced transglutaminase 1 activities are due to disruptions of the native folding of transglutaminase 1, and that these mutations may play a critical role in the pathology of lamellar ichthyosis. PMID:11511296

  8. Thick and thin filament gene mutations in striated muscle diseases.

    PubMed

    Tajsharghi, Homa

    2008-06-01

    The sarcomere is the fundamental unit of cardiac and skeletal muscle contraction. During the last ten years, there has been growing awareness of the etiology of skeletal and cardiac muscle diseases originating in the sarcomere, an important evolving field. Many sarcomeric diseases affect newborn children, i. e. are congenital myopathies. The discovery and characterization of several myopathies caused by mutations in myosin heavy chain genes, coding for the major component of skeletal muscle thick filaments, has led to the introduction of a new entity in the field of neuromuscular disorders: myosin myopathies. Recently, mutations in genes coding for skeletal muscle thin filaments, associated with various clinical features, have been identified. These mutations evoke distinct structural changes within the sarcomeric thin filament. Current knowledge regarding contractile protein dysfunction as it relates to disease pathogenesis has failed to decipher the mechanistic links between mutations identified in sarcomeric proteins and skeletal myopathies, which will no doubt require an integrated physiological approach. The discovery of additional genes associated with myopathies and the elucidation of the molecular mechanisms of pathogenesis will lead to improved and more accurate diagnosis, including prenatally, and to enhanced potential for prognosis, genetic counseling and developing possible treatments for these diseases. The goal of this review is to present recent progress in the identification of gene mutations from each of the major structural components of the sarcomere, the thick and thin filaments, related to skeletal muscle disease. The genetics and clinical manifestations of these disorders will be discussed. PMID:19325803

  9. Thick and Thin Filament Gene Mutations in Striated Muscle Diseases

    PubMed Central

    Tajsharghi, Homa

    2008-01-01

    The sarcomere is the fundamental unit of cardiac and skeletal muscle contraction. During the last ten years, there has been growing awareness of the etiology of skeletal and cardiac muscle diseases originating in the sarcomere, an important evolving field. Many sarcomeric diseases affect newborn children, i. e. are congenital myopathies. The discovery and characterization of several myopathies caused by mutations in myosin heavy chain genes, coding for the major component of skeletal muscle thick filaments, has led to the introduction of a new entity in the field of neuromuscular disorders: myosin myopathies. Recently, mutations in genes coding for skeletal muscle thin filaments, associated with various clinical features, have been identified. These mutations evoke distinct structural changes within the sarcomeric thin filament. Current knowledge regarding contractile protein dysfunction as it relates to disease pathogenesis has failed to decipher the mechanistic links between mutations identified in sarcomeric proteins and skeletal myopathies, which will no doubt require an integrated physiological approach. The discovery of additional genes associated with myopathies and the elucidation of the molecular mechanisms of pathogenesis will lead to improved and more accurate diagnosis, including prenatally, and to enhanced potential for prognosis, genetic counseling and developing possible treatments for these diseases. The goal of this review is to present recent progress in the identification of gene mutations from each of the major structural components of the sarcomere, the thick and thin filaments, related to skeletal muscle disease. The genetics and clinical manifestations of these disorders will be discussed. PMID:19325803

  10. TINF2 Gene Mutation in a Patient with Pulmonary Fibrosis

    PubMed Central

    Hoffman, T. W.; van der Vis, J. J.; van Oosterhout, M. F. M.; van Es, H. W.; van Kessel, D. A.; Grutters, J. C.; van Moorsel, C. H. M.

    2016-01-01

    Pulmonary fibrosis is a frequent manifestation of telomere syndromes. Telomere gene mutations are found in up to 25% and 3% of patients with familial disease and sporadic disease, respectively. The telomere gene TINF2 encodes an eponymous protein that is part of the shelterin complex, a complex involved in telomere protection and maintenance. A TINF2 gene mutation was recently reported in a family with pulmonary fibrosis. We identified a heterozygous Ser245Tyr mutation in the TINF2 gene of previously healthy female patient that presented with progressive cough due to pulmonary fibrosis as well as panhypogammaglobulinemia at age 52. Retrospective multidisciplinary evaluation classified her as a case of possible idiopathic pulmonary fibrosis. Telomere length-measurement indicated normal telomere length in the peripheral blood compartment. This is the first report of a TINF2 mutation in a patient with sporadic pulmonary fibrosis, which represents another association between TINF2 mutations and this disease. Furthermore, this case underlines the importance of telomere dysfunction and not telomere length alone in telomere syndromes and draws attention to hypogammaglobulinemia as a manifestation of telomere syndromes. PMID:27088026

  11. SPINK1 gene mutations and pancreatitis in Japan.

    PubMed

    Shimosegawa, Tooru; Kume, Kiyoshi; Masamune, Atsushi

    2006-10-01

    SPINK1 can inhibit up to 20% of trypsin activity, and may constitute one major mechanism to protect the pancreas from autodigestion. In 2000, Witt et al. first recognized the association between mutations in the SPINK1 gene and chronic pancreatitis (CP), but the significance of SPINK1 gene mutation in pancreatitis and its relation to alcohol consumption remains unclear in Japan. The aim of the present paper was to clarify the incidence of SPINK1 mutations in CP patients with various etiologies in Japan and, in addition, to examine the relationship between alcohol metabolism and the polymorphisms in the key enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase-2 (ALDH2). A total of 156 patients with CP, and 165 healthy volunteers, all Japanese, were examined for the SPINK1 mutations by polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. In Japan, the prevalence of [N34S; IVS1-37T > C] and [-215G > A; IVS3 + 2T > C] was significantly higher in patients with idiopathic CP (10.6% and 12.8%, respectively) than normal subjects (0.6% and 0%). The frequency of the [-215G > A; IVS3 + 2T > C] mutation in Japan was significantly higher than that reported in other populations. Concerning alcoholic CP, the [-215G > A; IVS3 + 2T > C] mutation was found in only a small number of patients (3.9%). On analysis of ADH2 and ALDH2 gene polymorphisms an association was found between ADH2*2 allele and alcoholic CP, and the ADH2*2/2*2 genotype had a tendency to increase the risk of developing pancreatic pseudocyst. In conclusion, in Japan the [-215G > A; IVS3 + 2T > C] mutation in the SPINK1 gene may form a unique genetic background for pancreatitis. PMID:16958672

  12. Law-medicine interfacing: patenting of human genes and mutations.

    PubMed

    Fialho, Arsenio M; Chakrabarty, Ananda M

    2011-08-01

    Mutations, Single Nucleotide Polymorphisms (SNPs), deletions and genetic rearrangements in specific genes in the human genome account for not only our physical characteristics and behavior, but can lead to many in-born and acquired diseases. Such changes in the genome can also predispose people to cancers, as well as significantly affect the metabolism and efficacy of many drugs, resulting in some cases in acute toxicity to the drug. The testing of the presence of such genetic mutations and rearrangements is of great practical and commercial value, leading many of these genes and their mutations/deletions and genetic rearrangements to be patented. A recent decision by a judge in the Federal District Court in the Southern District of New York, has created major uncertainties, based on the revocation of BRCA1 and BRCA2 gene patents, in the eligibility of all human and presumably other gene patents. This article argues that while patents on BRCA1 and BRCA2 genes could be challenged based on a lack of utility, the patenting of the mutations and genetic rearrangements is of great importance to further development and commercialization of genetic tests that can save human lives and prevent suffering, and should be allowed. PMID:21574951

  13. Mutator gene and hereditary non-polyposis colorectal cancer

    DOEpatents

    de la Chapelle, Albert; Vogelstein, Bert; Kinzler, Kenneth W.

    2008-02-05

    The human MSH2 gene, responsible for hereditary non-polyposis colorectal cancer, was identified by virtue of its homology to the MutS class of genes, which are involved in DNA mismatch repair. The sequence of cDNA clones of the human gene are provided, and the sequence of the gene can be used to demonstrate the existence of germ line mutations in hereditary non-polyposis colorectal cancer (HNPCC) kindreds, as well as in replication error.sup.+ (RER.sup.+) tumor cells.

  14. Mutation distributions and clinical correlations of PIK3CA gene mutations in breast cancer.

    PubMed

    Dirican, Ebubekir; Akkiprik, Mustafa; Özer, Ayşe

    2016-06-01

    Breast cancer (BCa) is the most common cancer and the second cause of death among women. Phosphoinositide 3-kinase (PI3K) signaling pathway has a crucial role in the cellular processes such as cell survival, growth, division, and motility. Moreover, oncogenic mutations in the PI3K pathway generally involve the activation phosphatidylinositol-4,5-bisphosphate 3-kinase-catalytic subunit alpha (PIK3CA) mutation which has been identified in numerous BCa subtypes. In this review, correlations between PIK3CA mutations and their clinicopathological parameters on BCa will be described. It is reported that PIK3CA mutations which have been localized mostly on exon 9 and 20 hot spots are detected 25-40 % in BCa. This relatively high frequency can offer an advantage for choosing the best treatment options for BCa. PIK3CA mutations may be used as biomarkers and have been major focus of drug development in cancer with the first clinical trials of PI3K pathway inhibitors currently in progress. Screening of PIK3CA gene mutations might be useful genetic tests for targeted therapeutics or diagnosis. Increasing data about PIK3CA mutations and its clinical correlations with BCa will help to introduce new clinical applications in the near future. PMID:26921096

  15. [Mutations of epigenetic regulator genes and myeloid malignancies].

    PubMed

    Muto, Tomoya; Sashida, Goro; Oshima, Motohiko; Iwama, Atsushi

    2015-11-01

    Recent genome studies have identified recurrent somatic mutations in various myeloid malignancies, including acute myeloid leukemia, myelodysplastic syndrome and myeloproliferative neoplasm. These mutations frequently occur in epigenetic regulator genes, and functions of the proteins encoded by these genes in hematopoietic cells have been extensively analyzed, as reported recently. It is noteworthy that several epigenetic regulator genes, such as DNMT3A, TET2 and ASXL1, have also been identified in pre-leukemic stem cells. As targeting pre-leukemic stem cells would be a promising therapeutic approach, further investigations of epigenetic abnormalities in hematopoietic cells are anticipated to lead to the development of novel epigenetic therapies. In this review, we discuss recent genetic and functional data regarding epigenetic regulator genes and the future landscape of this new research field. PMID:26666714

  16. Identification of 5 novel mutations in the AGXT gene.

    PubMed

    Basmaison, O; Rolland, M O; Cochat, P; Bozon, D

    2000-06-01

    In order to identify additional genotypes in primary hyperoxaluria type 1, we sequenced the AGXT genes of 9 patients. We report 5 new mutations. Three are splice-site mutations situated at the end of intron 4 and 8 (647-1G>A, 969-1G>C, 969-3C>G), one is a missense mutation in exon 5 (D183N), and one is a short duplication in exon 2 (349ins7). Their consequence is always a lack of enzymatic activity of the Alanine-Glyoxylate Aminotransferase (AGT); for 4 of them, we were able to deduce that they were associated to the absence of AGT protein. These mutations are rare, as they have been found on one allele in our study (except 969-3C>G present in 2 unrelated families), and have not been previously reported. PMID:10862087

  17. Genetic association analyses of nitric oxide synthase genes and neural tube defects vary by phenotype.

    PubMed

    Soldano, Karen L; Garrett, Melanie E; Cope, Heidi L; Rusnak, J Michael; Ellis, Nathen J; Dunlap, Kaitlyn L; Speer, Marcy C; Gregory, Simon G; Ashley-Koch, Allison E

    2013-10-01

    Neural tube defects (NTDs) are caused by improper neural tube closure during the early stages of embryonic development. NTDs are hypothesized to have a complex genetic origin and numerous candidate genes have been proposed. The nitric oxide synthase 3 (NOS3) G594T polymorphism has been implicated in risk for spina bifida, and interactions between that single nucleotide polymorphism (SNP) and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism have also been observed. To evaluate other genetic variation in the NO pathway in the development of NTDs, we examined all three NOS genes: NOS1, NOS2, and NOS3. Using 3109 Caucasian samples in 745 families, we evaluated association in the overall dataset and within specific phenotypic subsets. Haplotype tagging SNPs in the NOS genes were tested for genetic association with NTD subtypes, both for main effects as well as for the presence of interactions with the MTHFR C677T polymorphism. Nominal main effect associations were found with all subtypes, across all three NOS genes, and interactions were observed between SNPs in all three NOS genes and MTHFR C677T. Unlike the previous report, the most significant associations in our dataset were with cranial subtypes and the AG genotype of rs4795067 in NOS2 (p = 0.0014) and the interaction between the rs9658490 G allele in NOS1 and MTHFR 677TT genotype (p = 0.0014). Our data extend the previous findings by implicating a role for all three NOS genes, independently and through interactions with MTHFR, in risk not only for spina bifida, but all NTD subtypes. PMID:24323870

  18. Mutated Genes in Schizophrenia Map to Brain Networks

    MedlinePlus

    ... Mental Health (NIMH) and Fogarty International Center (FIC); Brain & Behavior Research Foundation; and a gift from Steve and Connie ... Standard Care Mutated Genes in Schizophrenia Map to Brain Networks Connect with Us Subscribe to get NIH Research Matters by email RSS Feed Facebook Email us ...

  19. Mutation Burden of Rare Variants in Schizophrenia Candidate Genes

    PubMed Central

    Girard, Simon L.; Dion, Patrick A.; Bourassa, Cynthia V.; Geoffroy, Steve; Lachance-Touchette, Pamela; Barhdadi, Amina; Langlois, Mathieu; Joober, Ridha; Krebs, Marie-Odile; Dubé, Marie-Pierre; Rouleau, Guy A.

    2015-01-01

    Background Schizophrenia (SCZ) is a very heterogeneous disease that affects approximately 1% of the general population. Recently, the genetic complexity thought to underlie this condition was further supported by three independent studies that identified an increased number of damaging de novo mutations DNM in different SCZ probands. While these three reports support the implication of DNM in the pathogenesis of SCZ, the absence of overlap in the genes identified suggests that the number of genes involved in SCZ is likely to be very large; a notion that has been supported by the moderate success of Genome-Wide Association Studies (GWAS). Methods To further examine the genetic heterogeneity of this disease, we resequenced 62 genes that were found to have a DNM in SCZ patients, and 40 genes that encode for proteins known to interact with the products of the genes with DNM, in a cohort of 235 SCZ cases and 233 controls. Results We found an enrichment of private nonsense mutations amongst schizophrenia patients. Using a kernel association method, we were able to assess for association for different sets. Although our power of detection was limited, we observed an increased mutation burden in the genes that have DNM. PMID:26039597

  20. Mutations of the tyrosinase gene produce autosomal recessive ocular albinism

    SciTech Connect

    King, R.A.; Summers, C.G.; Oetting, W.S.

    1994-09-01

    Albinism has historically been divided into ocular (OA) and oculocutaneous (OCA) types based on the presence or absence of clinically apparent skin and hair involvement in an individual with the ocular features of albinism. The major genes for OCA include the tyrosinase gene in OCA1 and the P gene in OCA2. X-linked and autosomal recessive OA have been described and the responsible genes have not been identified. We now present six Caucasian individuals who have the phenotype of autosomal recessive OA but who have OCA1 as shown by the presence of mutations of the tyrosinase. They had white or very light hair and white skin at birth, and cutaneous pigment developed in the first decade of life. At ages ranging from 1.5-23 years, hair color was dark blond to light brown. The skin had generalized pigment and well developed tan was present on the exposed arm and face skin of four. Iris pigment was present and iris translucency varied. Molecular analysis of the tyrosinase gene, using PCR amplification and direct di-deoxy sequencing showed the following mutations: E398Z/E398Q, P406S/g346a, R402E/T373K, ?/D383N, and H211N/T373K. The homozygous individual was not from a known consanguineous mating. T373K is the most common tyrosinase gene mutation in our laboratory. Three of these mutations are associated with a total loss of tyrosinase activity (g346a splice-site, T373K, and D383N), while four are associated with residual enzyme activity (H211N, R402E, E398Q, and P406S). These studies show that mutations of the tyrosinase gene can produce the phenotype of autosomal recessive OA in an individual who has normal amounts of cutaneous pigment and the ability to tan after birth. This extends the phenotypic range of OCA1 to normal cutaneous pigment after early childhood, and suggest that mutations of the tyrosinase gene account for a significant number of individuals with autosomal recessive OA.

  1. Mutation detection in tumor suppressor genes using archival tissue specimens.

    PubMed

    Astrinidis, Aristotelis; Henske, Elizabeth Petri

    2006-01-01

    Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome characterized by seizures, mental retardation, and benign tumors of many organs, including the brain, kidneys, skin, retina, and heart. TSC is caused by mutations in the TSC1 and TSC2 tumor suppressor genes. The genes follow the two-hit model for tumorigenesis, with germline mutations inactivating one allele and somatic mutations inactivating the remaining wild-type allele. Allelic loss (also called loss of heterozygosity [LOH]) in the 9q34 and 16p13 regions has been found in many tumor types from TSC patients. Cardiac rhabdomyomas are frequently found in infants with TSC. Because rhabdomyomas often spontaneously regress, access to fresh tissue is limited. In this chapter, we present methodology for detection of genetic inactivation of TSC1 and TSC2 in paraffin-embedded archival tissues. The template DNA is obtained either by direct scraping of tissue or after laser capture microdissection. LOH analysis is performed after polymerase chain reaction amplification of microsatellite markers in the 9q34 and 16p13 regions and denaturing polyacrylamide gel electrophoresis. Mutation detection is performed using single-strand conformation polymorphisms on mutation detection enhancement gels. Finally, variant bands are amplified and analyzed by direct sequencing. PMID:16930013

  2. [Ataxia-telangiectasia mutated gene and breast cancer susceptibility].

    PubMed

    Zhang, Nan; Che, Jian; Bai, Song; Wu, Zheng; Cui, Yuying; Zou, Wei

    2010-01-01

    Breast cancer is bound up with the environment. As a consequence of DNA damage induced by environmental carcinogens, a number of sophisticated sensing and transduction systems are initiated and the signal is conveyed simultaneously to multiple effectors. This process ultimately results in cancer. The protein kinase Ataxia-telangiectasia mutated (ATM) that encoded by ATM gene is the master regulator of DNA damage response. In this consecutive reaction, the protein kinase ATM responds to the DNA damage by phosphorylating a variety of downstream substrates, which plays an important role in the inhibition of the development of breast cancer. After ATM gene mutate, DNA damaged could not be accurately repaired and finally accelerates breast cancer transformation and proliferation. With the further research of ATM gene structure, function and breast cancer susceptibility, the extensive attention is paid to the relationship between ATM gene and breast cancer susceptibility. We reviewed the research advances in breast cancer susceptibility in several aspects of ATM gene, including mutation, polymorphism and methylation. PMID:20353086

  3. Epidermal growth factor receptor gene mutations in papillary thyroid carcinoma.

    PubMed

    Masago, Katsuhiro; Asato, Ryo; Fujita, Shiro; Hirano, Shigeru; Tamura, Yoshihiro; Kanda, Tomoko; Mio, Tadashi; Katakami, Nobuyuki; Mishima, Michiaki; Ito, Juichi

    2009-06-01

    Recent studies have indicated that somatic mutations in the epidermal growth factor receptor (EGFR) gene have been identified in a subset of patients with nonsmall-cell lung cancer (NSCLC) and are associated with sensitivity to the EGFR-tyrosine-kinase inhibitors. These mutations have been reported to be almost exclusively found in a pulmonary adenocarcinoma subgroup of NSCLC, with a low frequency in other solid tumors. We describe a patient with advanced-stage papillary thyroid carcinoma (PTC) whose disease had been diagnosed as pulmonary adenocarcinoma at first, and who had a marked response to the EGFR-tyrosine-kinase inhibitor, gefitinib. An in-frame deletion in exon 19 that eliminated 4 amino acids at positions 746 through 750, which is one of the common drug-sensitive mutations in pulmonary adenocarcinoma, and a serine-to-proline substitution at codon 752, were found in a tumor specimen of the patient. We subsequently searched for mutations in the EGFR tyrosine kinase domain in primary tumors from 23 patients with PTC, and drug-sensitive mutations commonly observed in pulmonary adenocarcinoma were found in 7 of these patients. Our observation of a high frequency of the EGFR-activating mutations in PTC suggests that the EGFR mutation may be an important event in the development of PTC. EGFR gene amplification, also considered to be a predictor of response to EGFR-tyrosine-kinase inhibitors, was evaluated by fluorescence in situ hybridization (FISH); however, only 1 FISH-positive tumor was detected. Our data suggest that EGFR-tyrosine-kinase inhibitors may deserve consideration in the treatment of a subset of patients with PTC, just as with pulmonary adenocarcinoma. PMID:19253367

  4. PDCD10 Gene Mutations in Multiple Cerebral Cavernous Malformations

    PubMed Central

    Cigoli, Maria Sole; Avemaria, Francesca; De Benedetti, Stefano; Gesu, Giovanni P.; Accorsi, Lucio Giordano; Parmigiani, Stefano; Corona, Maria Franca; Capra, Valeria; Mosca, Andrea; Giovannini, Simona; Notturno, Francesca; Ciccocioppo, Fausta; Volpi, Lilia; Estienne, Margherita; De Michele, Giuseppe; Antenora, Antonella; Bilo, Leda; Tavoni, Antonietta; Zamponi, Nelia; Alfei, Enrico; Baranello, Giovanni; Riva, Daria; Penco, Silvana

    2014-01-01

    Cerebral cavernous malformations (CCMs) are vascular abnormalities that may cause seizures, intracerebral haemorrhages, and focal neurological deficits. Familial form shows an autosomal dominant pattern of inheritance with incomplete penetrance and variable clinical expression. Three genes have been identified causing familial CCM: KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3. Aim of this study is to report additional PDCD10/CCM3 families poorly described so far which account for 10-15% of hereditary cerebral cavernous malformations. Our group investigated 87 consecutive Italian affected individuals (i.e. positive Magnetic Resonance Imaging) with multiple/familial CCM through direct sequencing and Multiplex Ligation-Dependent Probe Amplification (MLPA) analysis. We identified mutations in over 97.7% of cases, and PDCD10/CCM3 accounts for 13.1%. PDCD10/CCM3 molecular screening revealed four already known mutations and four novel ones. The mutated patients show an earlier onset of clinical manifestations as compared to CCM1/CCM2 mutated patients. The study of further families carrying mutations in PDCD10/CCM3 may help define a possible correlation between genotype and phenotype; an accurate clinical follow up of the subjects would help define more precisely whether mutations in PDCD10/CCM3 lead to a characteristic phenotype. PMID:25354366

  5. Mutational analysis of adrenoleukodystrophy (ALD) gene in Japanese ALD patients

    SciTech Connect

    Koike, R.; Onodera, O.; Tabe, H.

    1994-09-01

    Recently a putative ALD gene containing a striking homology with peroxisomal membrane protein (PMP70) has been identified. Besides childhood ALD, various clinical phenotypes have been identified with the onset in adolescence or adulthood (adrenomyeloneuropathy (AMN), adult cerebral ALD or cerebello-brainstem dominant type). The different clinical phenotypes occasionally coexist even in the same family. To investigate if there is a correlation between the clinical phenotypes and genotypes of the mutations in the ALD gene, we have analyzed 43 Japanese ALD patients. By Southern blot analysis, we identified non-overlapping deletions of 0.5 kb to 10.4 kb involving the ALD gene in 3 patients with adult onset cerebello-brainstem dominant type. By detailed direct sequence analysis, we found 4 patients who had point mutations in the coding region. An AMN patient had a point mutation leading to {sup 266}Gly{r_arrow}Arg change, and another patient with adult cerebral ALD had a 3 bp deletion resulting in the loss of glutamic acid at codon 291, which is a conserved amino acid both in ALD protein and PMP70. Two patients with childhood ALD had point mutations leading to {sup 507}Gly{r_arrow}Val, and {sup 518}Arg{r_arrow}Gln, respectively. Since amino acids from 507 to 520 are highly conserved as ATP-binding cassette transporter proteins, mutations in this region are expected to result in dramatic changes of the function of this protein. Although there is a tendancy for mutation in childhood ALD to be present within the ATP-binding site motif, we found two adult patients who had large deletions involving the region. Taken together, strong correlation between genotypes and clinical phenotypes is unlikely to exist, and some other modifying factors might well play an important role for the clinical manifestations of ALD.

  6. Recombinational and Mutational Hotspots within the Human Lipoprotein Lipase Gene

    PubMed Central

    Templeton, Alan R.; Clark, Andrew G.; Weiss, Kenneth M.; Nickerson, Deborah A.; Boerwinkle, Eric; Sing, Charles F.

    2000-01-01

    Summary Here an analysis is presented of the roles of recombination and mutation in shaping previously determined haplotype variation in 9.7 kb of genomic DNA sequence from the human lipoprotein lipase gene (LPL), scored in 71 individuals from three populations: 24 African Americans, 24 Finns, and 23 non-Hispanic whites. Recombination and gene-conversion events inferred from data on 88 haplotypes that were defined by 69 variable sites were tested. The analysis revealed 29 statistically significant recombination events and one gene-conversion event. The recombination events were concentrated in a 1.9-kb region, near the middle of the segment, that contains a microsatellite and a pair of tandem and complementary mononucleotide runs; both the microsatellite and the runs show length variation. An analysis of site variation revealed that 9.6% of the nucleotides at CpG sites were variable, as were 3% of the nucleotides found in mononucleotide runs of ?5 nucleotides, 3% of the nucleotides found ?3 bp from certain putative polymerase ?arrest sites, and 0.5% of the remaining nucleotides. This nonhomogeneous distribution of variation suggests that multiple mutational hits at certain sites are common, an observation that challenges the fundamental assumption of the infinite-sitesmutation model. The nonrandom patterns of recombination and mutation suggest that randomly chosen single-nucleotide polymorphisms may not be optimal for disequilibrium mapping of this gene. Overall, these results indicate that both recombinational and mutational hotspots have played significant roles in shaping the haplotype variation at the LPL locus. PMID:10631137

  7. Adjusting for background mutation frequency biases improves the identification of cancer driver genes

    PubMed Central

    Evans, Perry; Avey, Stefan; Kong, Yong; Krauthammer, Michael

    2013-01-01

    A common goal of tumor sequencing projects is finding genes whose mutations are selected for during tumor development. This is accomplished by choosing genes that have more non-synonymous mutations than expected from an estimated background mutation frequency. While this background frequency is unknown, it can be estimated using both the observed synonymous mutation frequency and the non-synonymous to synonymous mutation ratio. The synonymous mutation frequency can be determined across all genes or in a gene-specific manner. This choice introduces an interesting trade-off. A gene-specific frequency adjusts for an underlying mutation bias, but is difficult to estimate given missing synonymous mutation counts. Using a genome-wide synonymous frequency is more robust, but is less suited for adjusting biases. Studying four evaluation criteria for identifying genes with high non-synonymous mutation burden (reflecting preferential selection of expressed genes, genes with mutations in conserved bases, genes with many protein interactions, and genes that show loss of heterozygosity), we find that the gene-specific synonymous frequency is superior in the gene expression and protein interaction tests. In conclusion, the use of the gene-specific synonymous mutation frequency is well suited for assessing a gene’s non-synonymous mutation burden. PMID:23694700

  8. Transposon-induced nuclear mutations that alter chloroplast gene expression

    SciTech Connect

    Barkan, A.

    1992-01-01

    The goal of this project is to use mutant phenotypes as a guide to nuclear genes that determine the timing and localization of chloroplast development The immediate goals are to identify nuclear mutants with defects in chloroplast gene expression from maize lines harboring active Mu transposons; characterize their phenotypes to determine the precise defect in gene expression; clone several of the most interesting mutations by exploiting the transposon tag; and use the clones to further define the roles of these genes in modulating chloroplast gene expression. Three mutants were described earlier that had global defects in chloroplast gene expression. We have found that two of these mutations are allelic. Both alleles have global defects in chloroplast translation initiation, as revealed by the failure to assemble chloroplast mRNAs into polysomes. We have isolated and characterized three new mutants from Mu lines that have novel defects in chloroplast RNA metabolism. We are now ready to begin the task of cloning several of these genes, by using the Mu transposon tag.

  9. Screening for mutations in the PKD1 gene

    SciTech Connect

    Roelfsema, J.H.; Spruit, L.; Ommen, G.J.B. van

    1994-09-01

    With an estimated incidence of 1:1000, polycystic kidney disease is one of the most frequent single-gene disorders in the Caucasian population. The PKD1 gene, which is involved in approximately 85% of all cases, has recently been identified. The gene, which has a very large transcript, is partly situated within a duplicated area. This fact makes mutation screening a difficult task. Thus far, few deletions have been found. Therefore it seems likely that in a large number of patients the disease is caused by point mutations, possibly resulting in stop codons which lead to truncated proteins. A truncated protein can explain a putative dominant negative effect of the mutation. We are able to screen the patients which carry such stop codons with the protein truncation test (PTT). It is relatively easy to screen large stretches of the PKD1 gene with the PTT. The screening will be done on mRNA with the aid of RT-PCR. The reverse transcription reaction can give us the opportunity to specifically obtain the PKD1 transcript.

  10. Mutations of epigenetic regulatory genes are common in thymic carcinomas

    PubMed Central

    Wang, Yisong; Thomas, Anish; Lau, Christopher; Rajan, Arun; Zhu, Yuelin; Killian, J. Keith; Petrini, Iacopo; Pham, Trung; Morrow, Betsy; Zhong, Xiaogang; Meltzer, Paul S.; Giaccone, Giuseppe

    2014-01-01

    Genetic alterations and etiology of thymic epithelial tumors (TETs) are largely unknown, hampering the development of effective targeted therapies for patients with TETs. Here TETs of advanced-stage patients enrolled in a clinical trial of molecularly-guided targeted therapies were employed for targeted sequencing of 197 cancer-associated genes. Comparative sequence analysis of 78 TET/blood paired samples obtained from 47 thymic carcinoma (TC) and 31 thymoma patients revealed a total of 86 somatic non-synonymous sequence variations across 39 different genes in 33 (42%) TETs. TCs (62%; 29/47) showed higher incidence of somatic non-synonymous mutations than thymomas (13%; 4/31; p < 0.0001). TP53 was the most frequently mutated gene in TETs (n = 13; 17%), especially in TCs (26%), and was associated with a poorer overall survival (p < 0.0001). Genes in histone modification [BAP1 (n = 6; 13%), SETD2 (n = 5; 11%), ASXL1 (n = 2; 4%)], chromatin remodeling [SMARCA4 (n = 2; 4%)], and DNA methylation [DNMT3A (n = 3; 7%), TET2 (n = 2; 4%), WT1 (n = 2; 4%)] pathways were recurrently mutated in TCs, but not in thymomas. Our results suggest a potential disruption of epigenetic homeostasis in TCs, and a substantial difference in genetic makeup between TCs and thymomas. Further investigation is warranted into the roles of epigenetic dysregulation in TC development and its potential for targeted therapy. PMID:25482724

  11. Gestational diabetes mellitus and gene mutations which affect insulin secretion.

    PubMed

    Allan, C J; Argyropoulos, G; Bowker, M; Zhu, J; Lin, P M; Stiver, K; Golichowski, A; Garvey, W T

    1997-06-01

    We investigated whether genetic mutations known to impair insulin secretion and glucose tolerance are operative in a group of American women with gestational diabetes mellitus. Study groups were comprised of elderly non-diabetic controls (n = 55) with normal glucose tolerance and patients with gestational diabetes (n = 50), together with one family with maturity-onset diabetes of the young (three controls and three affected). No mutations were detected in any exon of the human glucokinase gene or the mitochondrial tRNA[Leu](UUR) gene by single strand conformational analysis and direct exon sequencing. Also, chi2 analysis showed no significant association with gestational diabetes for a polymorphism at position -30 (G --> A) of the beta-cell-specific glucokinase gene promoter. We have determined that glucokinase and mitochondrial tRNA[Leu](UUR) gene mutations, which are known to impair insulin secretion are relatively uncommon and do not constitute a large component of genetic risk for gestational diabetes in the study population. PMID:9237779

  12. Mutations of epigenetic regulatory genes are common in thymic carcinomas.

    PubMed

    Wang, Yisong; Thomas, Anish; Lau, Christopher; Rajan, Arun; Zhu, Yuelin; Killian, J Keith; Petrini, Iacopo; Pham, Trung; Morrow, Betsy; Zhong, Xiaogang; Meltzer, Paul S; Giaccone, Giuseppe

    2014-01-01

    Genetic alterations and etiology of thymic epithelial tumors (TETs) are largely unknown, hampering the development of effective targeted therapies for patients with TETs. Here TETs of advanced-stage patients enrolled in a clinical trial of molecularly-guided targeted therapies were employed for targeted sequencing of 197 cancer-associated genes. Comparative sequence analysis of 78 TET/blood paired samples obtained from 47 thymic carcinoma (TC) and 31 thymoma patients revealed a total of 86 somatic non-synonymous sequence variations across 39 different genes in 33 (42%) TETs. TCs (62%; 29/47) showed higher incidence of somatic non-synonymous mutations than thymomas (13%; 4/31; p < 0.0001). TP53 was the most frequently mutated gene in TETs (n = 13; 17%), especially in TCs (26%), and was associated with a poorer overall survival (p < 0.0001). Genes in histone modification [BAP1 (n = 6; 13%), SETD2 (n = 5; 11%), ASXL1 (n = 2; 4%)], chromatin remodeling [SMARCA4 (n = 2; 4%)], and DNA methylation [DNMT3A (n = 3; 7%), TET2 (n = 2; 4%), WT1 (n = 2; 4%)] pathways were recurrently mutated in TCs, but not in thymomas. Our results suggest a potential disruption of epigenetic homeostasis in TCs, and a substantial difference in genetic makeup between TCs and thymomas. Further investigation is warranted into the roles of epigenetic dysregulation in TC development and its potential for targeted therapy. PMID:25482724

  13. Polo-like kinase 2 (SNK/PLK2) is a novel epigenetically regulated gene in acute myeloid leukemia and myelodysplastic syndromes: genetic and epigenetic interactions.

    PubMed

    Benetatos, Leonidas; Dasoula, Aggeliki; Hatzimichael, Eleftheria; Syed, Nelofer; Voukelatou, Maria; Dranitsaris, George; Bourantas, Konstantinos L; Crook, Tim

    2011-09-01

    Polo-like kinase 2 (SNK/PLK2), a transcriptional target for wild-type p53 and is hypermethylated in a high percentage of multiple myeloma and B cell lymphomas patients. Given these data, we sought to study the methylation status of the specific gene in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), and to correlate it with clinical and genetic features. Using methylation-specific PCR MSP, we analyzed the methylation profile of 45 cases of AML and 43 cases of MDS. We also studied the distribution of MTHFR A1298C and MTHFR C677T polymorphisms and FLT3 mutations in AML patients and correlated the results with hypermethylation in the SNK/PLK2 CpG island. The SNK/PLK2 CpG island was hypermethylated in 68.9% and 88.4% of AML and MDS cases, respectively. Cases with hypermethylation had a trend towards more favorable overall survival (OS). There was no association between different MTHFR genotypes and susceptibility to develop AML. SNK/PLK2 hypermethylation combined with the MTHFR AA1298 genotype was associated with a tendency for a better OS. Similarly, patients with SNK/PLK2 hypermethylation combined with the MTHFR CT677 polymorphism had a better OS (HR = 0.34; p = 0.017). SNK/PLK2 methylation associated with unmutated FLT3 cases had a trend for better OS compared to patients with mutated FLT3 gene. SNK/PLK2 is a novel epigenetically regulated gene in AML and MDS, and methylation occurs at high frequency in both diseases. As such, SNK/PLK2 could represent a potential pathogenetic factor, although additional studies are necessary to verify its exact role in disease pathogenesis. PMID:21340720

  14. HFE gene: Structure, function, mutations, and associated iron abnormalities.

    PubMed

    Barton, James C; Edwards, Corwin Q; Acton, Ronald T

    2015-12-15

    The hemochromatosis gene HFE was discovered in 1996, more than a century after clinical and pathologic manifestations of hemochromatosis were reported. Linked to the major histocompatibility complex (MHC) on chromosome 6p, HFE encodes the MHC class I-like protein HFE that binds beta-2 microglobulin. HFE influences iron absorption by modulating the expression of hepcidin, the main controller of iron metabolism. Common HFE mutations account for ~90% of hemochromatosis phenotypes in whites of western European descent. We review HFE mapping and cloning, structure, promoters and controllers, and coding region mutations, HFE protein structure, cell and tissue expression and function, mouse Hfe knockouts and knockins, and HFE mutations in other mammals with iron overload. We describe the pertinence of HFE and HFE to mechanisms of iron homeostasis, the origin and fixation of HFE polymorphisms in European and other populations, and the genetic and biochemical basis of HFE hemochromatosis and iron overload. PMID:26456104

  15. De Novo Mutations in Ataxin-2 Gene and ALS Risk

    PubMed Central

    Laffita-Mesa, José Miguel; Rodríguez Pupo, Jorge Michel; Moreno Sera, Raciel; Vázquez Mojena, Yaimee; Kourí, Vivian; Laguna-Salvia, Leonides; Martínez-Godales, Michael; Valdevila Figueira, José A.; Bauer, Peter O.; Rodríguez-Labrada, Roberto; Zaldívar, Yanetza González; Paucar, Martin; Svenningsson, Per; Pérez, Luís Velázquez

    2013-01-01

    Pathogenic CAG repeat expansion in the ataxin-2 gene (ATXN2) is the genetic cause of spinocerebellar ataxia type 2 (SCA2). Recently, it has been associated with Parkinsonism and increased genetic risk for amyotrophic lateral sclerosis (ALS). Here we report the association of de novo mutations in ATXN2 with autosomal dominant ALS. These findings support our previous conjectures based on population studies on the role of large normal ATXN2 alleles as the source for new mutations being involved in neurodegenerative pathologies associated with CAG expansions. The de novo mutations expanded from ALS/SCA2 non-risk alleles as proven by meta-analysis method. The ALS risk was associated with SCA2 alleles as well as with intermediate CAG lengths in the ATXN2. Higher risk for ALS was associated with pathogenic CAG repeat as revealed by meta-analysis. PMID:23936447

  16. Heterogeneous AVPR2 gene mutations in congenital nephrogenic diabetes insipidus

    SciTech Connect

    Wildin, R.S.; Antush, M.J.; Bennett, R.L.; Schoof, J.M.; Scott, C.R. )

    1994-08-01

    Mutations in the AVPR2 gene encoding the receptor for arginine vasopressin in the kidney (V2 ADHR) have been reported in patients with congenital nephrogenic diabetes insipidus, a predominantly X-linked disorder of water homeostasis. The authors have used restriction-enzyme analysis and direct DNA sequencing of genomic PCR product to evaluate the AVPR2 gene in 11 unrelated affected males. Each patient has a different DNA sequence variation, and only one matches a previously reported mutation. Cosegregation of the variations with nephrogenic diabetes insipidus was demonstrated for two families, and a de novo mutation was accomplished in one family. All the variations predict frameshifts, truncations, or nonconservative amino acid substitutions in evolutionarily conserved positions in the V2 ADHR and related receptors. Of interest, a 28-bp deletion is found in one patient, while another, unrelated patient has a tandem duplication of the same 28-bp segment, suggesting that both resulted from the same unusual unequal crossing-over mechanism facilitated by 9-mer direct sequence repeats. Since the V2 ADHR is a member of the seven-transmembrane-domain, G-protein-coupled receptor superfamily, the loss-of-function mutations from this study and others provide important clues to the structure-function relationship of this and related receptors. 55 refs., 4 figs., 2 tabs.

  17. Heterogeneous AVPR2 gene mutations in congenital nephrogenic diabetes insipidus.

    PubMed Central

    Wildin, R. S.; Antush, M. J.; Bennett, R. L.; Schoof, J. M.; Scott, C. R.

    1994-01-01

    Mutations in the AVPR2 gene encoding the receptor for arginine vasopressin in the kidney (V2 ADHR) have been reported in patients with congenital nephrogenic diabetes insipidus, a predominantly X-linked disorder of water homeostasis. We have used restriction-enzyme analysis and direct DNA sequencing of genomic PCR product to evaluate the AVPR2 gene in 11 unrelated affected males. Each patient has a different DNA sequence variation, and only one matches a previously reported mutation. Cosegregation of the variations with nephrogenic diabetes insipidus was demonstrated for two families, and a de novo mutation was documented in two additional cases. Carrier detection was accomplished in one family. All the variations predict frameshifts, truncations, or nonconservative amino acid substitutions in evolutionarily conserved positions in the V2 ADHR and related receptors. Of interest, a 28-bp deletion is found in one patient, while another, unrelated patient has a tandem duplication of the same 28-bp segment, suggesting that both resulted from the same unusual unequal crossing-over mechanism facilitated by 9-mer direct sequence repeats. Since the V2 ADHR is a member of the seven-transmembrane-domain, G-protein-coupled receptor superfamily, the loss-of-function mutations from this study and others provide important clues to the structure-function relationship of this and related receptors. Images Figure 1 Figure 2 Figure 3 PMID:7913579

  18. Mutations in COL1A1 Gene Change Dentin Nanostructure.

    PubMed

    Duan, Xiaohong; Liu, Zhenxia; Gan, Yunna; Xia, Dan; Li, Qiang; Li, Yanling; Yang, Jiaji; Gao, Shan; Dong, Mingdong

    2016-04-01

    Although many studies have attempted to associate specific gene mutations with dentin phenotypic severity, it remains unknown how the mutations in COL1A1 gene influence the mechanical behavior of dentin collagen and matrix. Here, we reported one osteogenesis imperfecta (OI) pedigree caused by two new inserting mutations in exon 5 of COL1A1 (NM_000088.3:c.440_441insT;c.441_442insA), which resulted in the unstable expression of COL1A1 mRNA and half quantity of procollagen production. We investigated the morphological and mechanical features of proband's dentin using atomic force microscope (AFM), scanning electron microscope, and transmission electron microscope. Increased D-periodic spacing, variably enlarged collagen fibrils coating with fewer minerals were found in the mutated collagen. AFM analysis demonstrated rougher dentin surface and sparsely decreased Young's modulus in proband's dentin. We believe that our findings provide new insights into the genetic-/nano- mechanisms of dentin diseases, and may well explain OI dentin features with reduced mechanical strength and a lower crosslinked density. Anat Rec, 299:511-519, 2016. © 2015 Wiley Periodicals, Inc. PMID:26694865

  19. Spontaneous Mutation in the Escherichia Coli Laci Gene

    PubMed Central

    Schaaper, R. M.; Dunn, R. L.

    1991-01-01

    To gain more detailed insight into the nature and mechanisms of spontaneous mutations, we undertook a DNA sequence analysis of a large collection of spontaneous mutations in the N-terminal region of the Escherichia coli lacI gene. This region of circa 210 base pairs is the target for dominant lacI mutations (i(-d)) and is suitable for studies of mutational specificity since it contains a relatively high density of detectable mutable sites. Among 414 independent i(-d) mutants, 70.8% were base substitutions, 17.2% deletions, 7.7% additions and 4.3% single-base frameshifts. The base substitutions were both transitions (60%) and transversions (40%), the largest single group being G.C->A.T (47% of base substitutions). All four transversions were observed. Among the 71 deletions, a hotspot (37 mutants) was present: an 87-bp deletion presumably directed by an 8-bp repeated sequence at its endpoints. The remaining 34 deletions were distributed among 29 different mutations, either flanked (13/34) or not flanked (21/34) by repeated sequences. The 32 additions comprised 29 different events, with only two containing a direct repeat at the endpoints. The single-base frameshifts were the loss of a single base from either repeated (67%) or nonrepeated (33%) bases. A comparison with the spectrum obtained previously in strains defective in DNA mismatch correction (mutH, mutL, mutS strains) yielded information about the apparent efficiency of mismatch repair. The overall effect was 260-fold but varied substantially among different classes of mutations. An interesting asymmetry was uncovered for the two types of transitions, A.T->G.C and G.C->A.T being reduced by mismatch repair 1340- and 190-fold, respectively. Explanations for this asymmetry and its possible implications for the origins of spontaneous mutations are discussed. PMID:1660424

  20. Molecular screening of pituitary adenomas for gene mutations and rearrangements

    SciTech Connect

    Herman, V.; Drazin, N.Z.; Gonskey, R.; Melmed, S. )

    1993-07-01

    Although pituitary tumors arise as benign monoclonal neoplasms, genetic alterations have not readily been identified in these adenomas. The authors studied restriction fragment abnormalities involving the GH gene locus, and mutations in the p53 and H-, K-, and N-ras genes in 22 human GH cell adenomas. Twenty two nonsecretory adenomas were also examined for p53 and ras gene mutations. Seven prolactinoma DNA samples were tested for deletions in the multiple endocrine neoplasia-1 (MEN-1) locus, as well as for rearrangements in the hst gene, a member of the fibroblast growth factor family. In DNA from GH-cell adenomas, identical GH restriction patterns were detected in both pituitary and lymphocyte DNA in all patients and in one patient with a mixed GH-TSH cell adenoma. Using polymerase chain reaction (PCR)-single stranded conformation polymorphism analysis, no mutations were detected in exons 5, 6, 7 and 8 of the p53 gene in GH cell adenomas nor in 22 nonsecretory adenomas. Codons 12/13 and 61 of H-ras, K-ras, and N-ras genes were also intact on GH cell adenomas and in nonsecretory adenomas. Site-specific probes for chromosome 11q13 including, PYGM, D11S146, and INT2 were used in 7 sporadic PRL-secreting adenomas to detect deletions of the MEN-1 locus on chromosome 11. One patient was identified with a loss of 11p, and the remaining 6 patients did not demonstrate loss of heterozygosity in the pituitary 11q13 locus, compared to lymphocyte DNA. None of these patients demonstrated hst gene rearrangements which also maps to this locus. These results show that p53 and ras gene mutations are not common events in the pathogenesis of acromegaly and nonsecretory tumors. Although hst gene rearrangements and deletions of 11q13 are not associated with sporadic PRl-cell adenoma formation, a single patient was detected with a partial loss of chromosome 11, including the putative MEN-1 site. 31 refs., 5 figs., 2 tabs.

  1. Next generation sequencing in synovial sarcoma reveals novel gene mutations

    PubMed Central

    Vlenterie, Myrella; Hillebrandt-Roeffen, Melissa H.S.; Flucke, Uta E.; Groenen, Patricia J.T.A.; Tops, Bastiaan B.J.; Kamping, Eveline J.; Pfundt, Rolph; de Bruijn, Diederik R.H.; van Kessel, Ad H.M. Geurts; van Krieken, Han J.H.J.M.; van der Graaf, Winette T.A.; Versleijen-Jonkers, Yvonne M.H.

    2015-01-01

    Over 95% of all synovial sarcomas (SS) share a unique translocation, t(X;18), however, they show heterogeneous clinical behavior. We analyzed multiple SS to reveal additional genetic alterations besides the translocation. Twenty-six SS from 22 patients were sequenced for 409 cancer-related genes using the Comprehensive Cancer Panel (Life Technologies, USA) on an Ion Torrent platform. The detected variants were verified by Sanger sequencing and compared to matched normal DNAs. Copy number variation was assessed in six tumors using the Oncoscan array (Affymetrix, USA). In total, eight somatic mutations were detected in eight samples. These mutations have not been reported previously in SS. Two of these, in KRAS and CCND1, represent known oncogenic mutations in other malignancies. Additional mutations were detected in RNF213, SEPT9, KDR, CSMD3, MLH1 and ERBB4. DNA alterations occurred more often in adult tumors. A distinctive loss of 6q was found in a metastatic lesion progressing under pazopanib, but not in the responding lesion. Our results emphasize t(X;18) as a single initiating event in SS and as the main oncogenic driver. Our results also show the occurrence of additional genetic events, mutations or chromosomal aberrations, occurring more frequently in SS with an onset in adults. PMID:26415226

  2. Next generation sequencing in synovial sarcoma reveals novel gene mutations.

    PubMed

    Vlenterie, Myrella; Hillebrandt-Roeffen, Melissa H S; Flucke, Uta E; Groenen, Patricia J T A; Tops, Bastiaan B J; Kamping, Eveline J; Pfundt, Rolph; de Bruijn, Diederik R H; Geurts van Kessel, Ad H M; van Krieken, Han J H J M; van der Graaf, Winette T A; Versleijen-Jonkers, Yvonne M H

    2015-10-27

    Over 95% of all synovial sarcomas (SS) share a unique translocation, t(X;18), however, they show heterogeneous clinical behavior. We analyzed multiple SS to reveal additional genetic alterations besides the translocation. Twenty-six SS from 22 patients were sequenced for 409 cancer-related genes using the Comprehensive Cancer Panel (Life Technologies, USA) on an Ion Torrent platform. The detected variants were verified by Sanger sequencing and compared to matched normal DNAs. Copy number variation was assessed in six tumors using the Oncoscan array (Affymetrix, USA). In total, eight somatic mutations were detected in eight samples. These mutations have not been reported previously in SS. Two of these, in KRAS and CCND1, represent known oncogenic mutations in other malignancies. Additional mutations were detected in RNF213, SEPT9, KDR, CSMD3, MLH1 and ERBB4. DNA alterations occurred more often in adult tumors. A distinctive loss of 6q was found in a metastatic lesion progressing under pazopanib, but not in the responding lesion. Our results emphasize t(X;18) as a single initiating event in SS and as the main oncogenic driver. Our results also show the occurrence of additional genetic events, mutations or chromosomal aberrations, occurring more frequently in SS with an onset in adults. PMID:26415226

  3. Single molecule targeted sequencing for cancer gene mutation detection.

    PubMed

    Gao, Yan; Deng, Liwei; Yan, Qin; Gao, Yongqian; Wu, Zengding; Cai, Jinsen; Ji, Daorui; Li, Gailing; Wu, Ping; Jin, Huan; Zhao, Luyang; Liu, Song; Ge, Liangjin; Deem, Michael W; He, Jiankui

    2016-01-01

    With the rapid decline in cost of sequencing, it is now affordable to examine multiple genes in a single disease-targeted clinical test using next generation sequencing. Current targeted sequencing methods require a separate step of targeted capture enrichment during sample preparation before sequencing. Although there are fast sample preparation methods available in market, the library preparation process is still relatively complicated for physicians to use routinely. Here, we introduced an amplification-free Single Molecule Targeted Sequencing (SMTS) technology, which combined targeted capture and sequencing in one step. We demonstrated that this technology can detect low-frequency mutations using artificially synthesized DNA sample. SMTS has several potential advantages, including simple sample preparation thus no biases and errors are introduced by PCR reaction. SMTS has the potential to be an easy and quick sequencing technology for clinical diagnosis such as cancer gene mutation detection, infectious disease detection, inherited condition screening and noninvasive prenatal diagnosis. PMID:27193446

  4. A new spontaneous mouse mutation in the Kcne1 gene.

    PubMed

    Letts, V A; Valenzuela, A; Dunbar, C; Zheng, Q Y; Johnson, K R; Frankel, W N

    2000-10-01

    A new mouse mutant, punk rocker (allele symbol Kcne1(pkr)), arose spontaneously on a C57BL/10J inbred strain background and is characterized by a distinctive head-tossing, circling, and ataxic phenotype. It is also profoundly and bilaterally deaf. The mutation resides in the Kcne1 gene on Chromosome (Chr) 16 and has been identified as a single base change within the coding region of the third exon. The C to T nucleotide substitution causes an arginine to be altered to a termination codon at amino acid position 67, and predictably this will result in a significantly truncated protein product. The Kcne1(pkr) mutant represents the first spontaneous mouse model for the human disorder, Jervell and Lange-Nielsen syndrome, associated with mutations in the homologous KCNE1 gene on human Chr 21. PMID:11003695

  5. Optimization of gene sequences under constant mutational pressure and selection

    NASA Astrophysics Data System (ADS)

    Kowalczuk, M.; Gierlik, A.; Mackiewicz, P.; Cebrat, S.; Dudek, M. R.

    1999-12-01

    We have analyzed the influence of constant mutational pressure and selection on the nucleotide composition of DNA sequences of various size, which were represented by the genes of the Borrelia burgdorferi genome. With the help of MC simulations we have found that longer DNA sequences accumulate much less base substitutions per sequence length than short sequences. This leads us to the conclusion that the accuracy of replication may determine the size of genome.

  6. Combining gene mutation with gene expression data improves outcome prediction in myelodysplastic syndromes.

    PubMed

    Gerstung, Moritz; Pellagatti, Andrea; Malcovati, Luca; Giagounidis, Aristoteles; Porta, Matteo G Della; Jädersten, Martin; Dolatshad, Hamid; Verma, Amit; Cross, Nicholas C P; Vyas, Paresh; Killick, Sally; Hellström-Lindberg, Eva; Cazzola, Mario; Papaemmanuil, Elli; Campbell, Peter J; Boultwood, Jacqueline

    2015-01-01

    Cancer is a genetic disease, but two patients rarely have identical genotypes. Similarly, patients differ in their clinicopathological parameters, but how genotypic and phenotypic heterogeneity are interconnected is not well understood. Here we build statistical models to disentangle the effect of 12 recurrently mutated genes and 4 cytogenetic alterations on gene expression, diagnostic clinical variables and outcome in 124 patients with myelodysplastic syndromes. Overall, one or more genetic lesions correlate with expression levels of ~20% of all genes, explaining 20-65% of observed expression variability. Differential expression patterns vary between mutations and reflect the underlying biology, such as aberrant polycomb repression for ASXL1 and EZH2 mutations or perturbed gene dosage for copy-number changes. In predicting survival, genomic, transcriptomic and diagnostic clinical variables all have utility, with the largest contribution from the transcriptome. Similar observations are made on the TCGA acute myeloid leukaemia cohort, confirming the general trends reported here. PMID:25574665

  7. Combining gene mutation with gene expression data improves outcome prediction in myelodysplastic syndromes

    PubMed Central

    Gerstung, Moritz; Pellagatti, Andrea; Malcovati, Luca; Giagounidis, Aristoteles; Porta, Matteo G Della; Jädersten, Martin; Dolatshad, Hamid; Verma, Amit; Cross, Nicholas C. P.; Vyas, Paresh; Killick, Sally; Hellström-Lindberg, Eva; Cazzola, Mario; Papaemmanuil, Elli; Campbell, Peter J.; Boultwood, Jacqueline

    2015-01-01

    Cancer is a genetic disease, but two patients rarely have identical genotypes. Similarly, patients differ in their clinicopathological parameters, but how genotypic and phenotypic heterogeneity are interconnected is not well understood. Here we build statistical models to disentangle the effect of 12 recurrently mutated genes and 4 cytogenetic alterations on gene expression, diagnostic clinical variables and outcome in 124 patients with myelodysplastic syndromes. Overall, one or more genetic lesions correlate with expression levels of ~20% of all genes, explaining 20–65% of observed expression variability. Differential expression patterns vary between mutations and reflect the underlying biology, such as aberrant polycomb repression for ASXL1 and EZH2 mutations or perturbed gene dosage for copy-number changes. In predicting survival, genomic, transcriptomic and diagnostic clinical variables all have utility, with the largest contribution from the transcriptome. Similar observations are made on the TCGA acute myeloid leukaemia cohort, confirming the general trends reported here. PMID:25574665

  8. Mutations of the KISS1 Gene in Disorders of Puberty

    PubMed Central

    Silveira, L. G.; Noel, S. D.; Silveira-Neto, A. P.; Abreu, A. P.; Brito, V. N.; Santos, M. G.; Bianco, S. D. C.; Kuohung, W.; Xu, S.; Gryngarten, M.; Escobar, M. E.; Arnhold, I. J. P.; Mendonca, B. B.; Kaiser, U. B.; Latronico, A. C.

    2010-01-01

    Context: Kisspeptin, encoded by the KISS1 gene, is a key stimulatory factor of GnRH secretion and puberty onset. Inactivating mutations of its receptor (KISS1R) cause isolated hypogonadotropic hypogonadism (IHH). A unique KISS1R-activating mutation was described in central precocious puberty (CPP). Objective: Our objective was to investigate KISS1 mutations in patients with idiopathic CPP and normosmic IHH. Patients: Eighty-three children with CPP (77 girls) and 61 patients with IHH (40 men) were studied. The control group consisted of 200 individuals with normal pubertal development. Methods: The promoter region and the three exons of KISS1 were amplified and sequenced. Cells expressing KISS1R were stimulated with synthetic human wild-type or mutant kisspeptin-54 (kp54), and inositol phosphate accumulation was measured. In a second set of experiments, kp54 was preincubated in human serum before stimulation of the cells. Results: Two novel KISS1 missense mutations, p.P74S and p.H90D, were identified in three unrelated children with idiopathic CPP. Both mutations were absent in 400 control alleles. The p.P74S mutation was identified in the heterozygous state in a boy who developed CPP at 1 yr of age. The p.H90D mutation was identified in the homozygous state in two unrelated girls with CPP. In vitro studies revealed that the capacity of the P74S and H90D mutants to stimulate IP production was similar to the wild type. After preincubation of wild-type and mutant kp54 in human serum, the capacity to stimulate signal transduction was significantly greater for P74S compared with the wild type, suggesting that the p.P74S variant is more stable. Only polymorphisms were found in the IHH group. Conclusion: Two KISS1 mutations were identified in unrelated patients with idiopathic CPP. The p.P74S variant was associated with higher kisspeptin resistance to degradation in comparison with the wild type, suggesting a role for this mutation in the precocious puberty phenotype. PMID:20237166

  9. Sarcomeric gene mutations in sudden infant death syndrome (SIDS).

    PubMed

    Brion, Maria; Allegue, Catarina; Santori, Montserrat; Gil, Rocio; Blanco-Verea, Alejandro; Haas, Cordula; Bartsch, Christine; Poster, Simone; Madea, Burkhard; Campuzano, Oscar; Brugada, Ramon; Carracedo, Angel

    2012-06-10

    In developed countries, sudden infant death syndrome (SIDS) represents the most prevalent cause of death in children between 1 month and 1 year of age. SIDS is a diagnosis of exclusion, a negative autopsy which requires the absence of structural organ disease. Although investigators have confirmed that a significant percentage of SIDS cases are actually channelopathies, no data have been made available as to whether other sudden cardiac death-associated diseases, such as hypertrophic cardiomyopathy (HCM), could be responsible for some cases of SIDS. The presence of a genetic mutation in the sarcomeric protein usually affects the force of contraction of the myocyte, whose weakness is compensated with progressive hypertrophy and disarray. However, it is unclear whether in the most incipient forms, that is, first years of life, the lack of these phenotypes still confers a risk of arrhythmogenesis. The main goal of the present study is to wonder whether genetic defects in the sarcomeric proteins, previously associated with HCM, could be responsible for SIDS. We have analysed 286 SIDS cases for the most common genes implicated in HCM in adults. A total of 680 mutations localised in 16 genes were analysed by semi-automated matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDITOF-MS) using the Sequenom MassARRAY(®) System. Ten subjects with completely normal hearts showed mutated alleles at nine of the genetic variants analysed, and one additional novel mutation was detected by conventional sequencing. Therefore, a genetic mutation associated with HCM may cause sudden cardiac death in the absence of an identifiable phenotype. PMID:22361390

  10. Mutational analysis of genes coding for cell surface proteins in colorectal cancer cell lines reveal novel altered pathways, druggable mutations and mutated epitopes for targeted therapy

    PubMed Central

    Correa, Bruna R.; Bettoni, Fabiana; Koyama, Fernanda C.; Navarro, Fabio C.P.; Perez, Rodrigo O.; Mariadason, John; Sieber, Oliver M.; Strausberg, Robert L.; Simpson, Andrew J.G.; Jardim, Denis L.F.; Reis, Luiz Fernando L.; Parmigiani, Raphael B.; Galante, Pedro A.F.; Camargo, Anamaria A.

    2014-01-01

    We carried out a mutational analysis of 3,594 genes coding for cell surface proteins (Surfaceome) in 23 colorectal cancer cell lines, searching for new altered pathways, druggable mutations and mutated epitopes for targeted therapy in colorectal cancer. A total of 3,944 somatic non-synonymous substitutions and 595 InDels, occurring in 2,061 (57%) Surfaceome genes were catalogued. We identified 48 genes not previously described as mutated in colorectal tumors in the TCGA database, including genes that are mutated and expressed in >10% of the cell lines (SEMA4C, FGFRL1, PKD1, FAM38A, WDR81, TMEM136, SLC36A1, SLC26A6, IGFLR1). Analysis of these genes uncovered important roles for FGF and SEMA4 signaling in colorectal cancer with possible therapeutic implications. We also found that cell lines express on average 11 druggable mutations, including frequent mutations (>20%) in the receptor tyrosine kinases AXL and EPHA2, which have not been previously considered as potential targets for colorectal cancer. Finally, we identified 82 cell surface mutated epitopes, however expression of only 30% of these epitopes was detected in our cell lines. Notwithstanding, 92% of these epitopes were expressed in cell lines with the mutator phenotype, opening new venues for the use of “general” immune checkpoint drugs in this subset of patients. PMID:25193853

  11. Screening of sarcomere gene mutations in young athletes with abnormal findings in electrocardiography: identification of a MYH7 mutation and MYBPC3 mutations.

    PubMed

    Kadota, Chika; Arimura, Takuro; Hayashi, Takeharu; Naruse, Taeko K; Kawai, Sachio; Kimura, Akinori

    2015-10-01

    There is an overlap between the physiological cardiac remodeling associated with training in athletes, the so-called athlete's heart, and mild forms of hypertrophic cardiomyopathy (HCM), the most common hereditary cardiac disease. HCM is often accompanied by unfavorable outcomes including a sudden cardiac death in the adolescents. Because one of the initial signs of HCM is abnormality in electrocardiogram (ECG), athletes may need to monitor for ECG findings to prevent any unfavorable outcomes. HCM is caused by mutations in genes for sarcomere proteins, but there is no report on the systematic screening of gene mutations in athletes. One hundred and two genetically unrelated young Japanese athletes with abnormal ECG findings were the subjects for the analysis of four sarcomere genes, MYH7, MYBPC3, TNNT2 and TNNI3. We found that 5 out of 102 (4.9%) athletes carried mutations: a heterozygous MYH7 Glu935Lys mutation, a heterozygous MYBPC3 Arg160Trp mutation and another heterozygous MYBPC3 Thr1046Met mutation, all of which had been reported as HCM-associated mutations, in 1, 2 and 2 subjects, respectively. This is the first study of systematic screening of sarcomere gene mutations in a cohort of athletes with abnormal ECG, demonstrating the presence of sarcomere gene mutations in the athlete's heart. PMID:26178432

  12. Patient with FMF and Triple MEFV Gene Mutations

    PubMed Central

    Salehzadeh, Farhad; Fathi, Afshin

    2015-01-01

    Introduction: Familial Mediterranean fever (FMF) is the most common auto-inflammatory disease with monogenic (MEditerranean FeVer –MEFV- gene) inherited pattern. It mainly affects ethnic groups living along the eastern Mediterranean Sea: Turks, Sephardic Jews, Armenians, and Arabs [1]. Today FMF is not rare disease in other Mediterranean ethnicities, such as Greeks, Italians, and Iranians. Case report: Here we report a child with complex allele mutations E148Q/V726A/R761H, whilst, whose mother showed E148Q/V726A and his father had R761H/wt in analysis. The severity of the disease and genotype-phenotype correlation of patient showed no significant differences with his mother and other patients with the same two mutations, V726A/R761H, E148Q/V726A, and E148Q/R761H. Conclusion: This type of mutation is the first report of triple mutations in FMF patients with no specific phenotype correlation. PMID:26543317

  13. The clinical implications of gene mutations in chronic lymphocytic leukaemia.

    PubMed

    Rossi, Davide; Gaidano, Gianluca

    2016-04-12

    Chronic lymphocytic leukaemia (CLL) is a molecularly heterogeneous disease as revealed by recent genomic studies. Among genetic lesions that are recurrent in CLL, few clinically validated prognostic markers, such as TP53 mutations and 17p deletion, are available for the use in clinical practice to guide treatment decisions. Recently, several novel molecular markers have been identified in CLL. Though these mutations have not yet gained the qualification of predictive factors for treatment tailoring, they have shown to be promising to refine the prognostic stratification of patients. The introduction of targeted drugs is changing the genetics of CLL, and has disclosed the acquisition of previously unexpected drug resistant mutations in signalling pathway genes. Ultra-deep next generation sequencing has allowed to reach deep levels of resolution of the genetic portrait of CLL providing a precise definition of its subclonal genetic architecture. This approach has shown that small subclones harbouring drug resistant mutations anticipate the development of a chemorefractory phenotype. Here we review the recent advances in the definition of the genomic landscape of CLL and the ongoing research to characterise the clinical implications of old and new molecular lesions in the setting of both conventional chemo-immunotherapy and targeted drugs. PMID:27031852

  14. 40 CFR 799.9530 - TSCA in vitro mammalian cell gene mutation test.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 32 2014-07-01 2014-07-01 false TSCA in vitro mammalian cell gene... MIXTURE TESTING REQUIREMENTS Health Effects Test Guidelines § 799.9530 TSCA in vitro mammalian cell gene.... The in vitro mammalian cell gene mutation test can be used to detect gene mutations induced...

  15. 40 CFR 799.9530 - TSCA in vitro mammalian cell gene mutation test.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 33 2012-07-01 2012-07-01 false TSCA in vitro mammalian cell gene... MIXTURE TESTING REQUIREMENTS Health Effects Test Guidelines § 799.9530 TSCA in vitro mammalian cell gene.... The in vitro mammalian cell gene mutation test can be used to detect gene mutations induced...

  16. A magnetic nanoparticles-based method for DNA extraction from the saliva of stroke patients

    PubMed Central

    Yi, Li; Huang, Ying; Wu, Ting; Wu, Jun

    2013-01-01

    C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene is a risk factor for stroke, suggesting that widespread detection could help to prevent stroke. DNA from 70 stroke patients and 70 healthy controls was extracted from saliva using a magnetic nanoparticles-based method and from blood using conventional methods. Real-time PCR results revealed that the C677T polymorphism was genotyped by PCR using DNA extracted from both saliva and blood samples. The genotype results were confirmed by gene sequencing, and results for saliva and blood samples were consistent. The mutation TT genotype frequency was significantly higher in the stroke group than in controls. Homocysteine levels were significantly higher than controls in both TT genotype groups. Therefore, this noninvasive magnetic nanoparticles-based method using saliva samples could be used to screen for the MTHFR C677T polymorphism in target populations. PMID:25206624

  17. Thyroglobulin gene mutations in Chinese patients with congenital hypothyroidism.

    PubMed

    Hu, Xuyun; Chen, Rongyu; Fu, Chunyun; Fan, Xin; Wang, Jin; Qian, Jiale; Yi, Shang; Li, Chuan; Luo, Jingsi; Su, Jiasun; Zhang, Shujie; Xie, Bobo; Zheng, Haiyang; Lai, Yunli; Chen, Yun; Li, Hongdou; Gu, Xuefan; Chen, Shaoke; Shen, Yiping

    2016-03-01

    Mutations in Thyroglobulin (TG) are common genetic causes of congenital hypothyroidism (CH). But the TG mutation spectrum and its frequency in Chinese CH patients have not been investigated. Here we conducted a genetic screening of TG gene in a cohort of 382 Chinese CH patients. We identified 22 rare non-polymorphic variants including six truncating variants and 16 missense variants of unknown significance (VUS). Seven patients carried homozygous pathogenic variants, and three patients carried homozygous or compound heterozygous VUS. 48 out of 382 patients carried one of 18 heterozygous VUS which is significantly more often than their occurrences in control cohort (P < 0.0001). Unique to Asian population, the c.274+2T>G variant is the most common pathogenic variant with an allele frequency of 0.021. The prevalence of CH due to TG gene defect in Chinese population was estimated to be approximately 1/101,000. Our study uncovered ethnicity specific TG mutation spectrum and frequency. PMID:26777470

  18. Mutations and a polymorphism in the tuberin gene

    SciTech Connect

    Northup, H.; Rodriguez, J.A.; Au, K.S.; Rodriguez, E.

    1994-09-01

    Two deletions and a polymorphism have been identified in the recently described tuberin gene. The tuberin gene (designated TSC2) when mutated causes tuberous sclerosis complex (TSC). Fifty-three affected individuals (30 from families with multiple affected and 23 isolated cases) were screened with the tuberin cDNA for gross deletions or rearrangements. Both deletions were found in families with multiple affected members (family designations: HOU-5 and HOU-22). The approximate size of the deletion in HOU-5 is ten kilobases and eliminates a BamHI restriction site. The deletion includes a portion of the 5{prime} half of the tuberin cDNA. The deletion in HOU-22 occurs in the 3{prime} half of the gene. The deletions are being further characterized. A HindIII restriction site polymorphism was detected by a 0.5 kilobase probe from the 5{prime} coding region of the tuberin gene in an individual from a family linked to chromosome 9 (posterior probability of linkage 93%). The polymorphism did not segregate with TSC in the family. The family had previously been shown to give negative results with multiple markers on chromosome 16. The polymorphism was also seen in one individual among a panel of 20 randomly selected unaffected individuals. Thirty-five additional affected probands (five from families and 30 isolated cases) are being tested with the tuberin cDNA. Testing for subtle mutations is our panel of 80 affected probands is underway utilizing SSCP. Additional mutations or polymorphisms detected will be reported. The tuberin cDNA was a kind gift of The European Chromosome 16 Tuberous Sclerosis Consortium.

  19. Sarcomere gene mutations in hypertrophy and heart failure.

    PubMed

    Morita, Hiroyuki; Nagai, Ryozo; Seidman, J G; Seidman, Christine E

    2010-08-01

    Despite considerable progress in identifying and modifying risk factors that cause cardiovascular disease, heart failure has emerged as an important medical and socioeconomic problem. Hypertrophic remodeling, a common response to many cardiovascular disorders, increases the risk of heart failure. Discovery of the genetic basis of hypertrophic cardiomyopathy has allowed consideration of whether these genes also contribute to pathologic remodeling that occurs in the context of common acquired cardiovascular disorders. Evidence supporting a shared etiology has emerged from the recent identification of sarcomere protein mutations and sequence variants in community-based populations with hypertrophy and heart failure. These findings imply that harnessing genetic testing for hypertrophic mutations may help define patients at risk for heart failure. In the future, mechanistic insights into hypertrophic remodeling, combined with strategies to prevent this pathology, are expected to reduce the burden of heart failure. PMID:20559778

  20. Cohesin gene mutations in tumorigenesis: from discovery to clinical significance

    PubMed Central

    Solomon, David A.; Kim, Jung-Sik; Waldman, Todd

    2014-01-01

    Cohesin is a multi-protein complex composed of four core subunits (SMC1A, SMC3, RAD21, and either STAG1 or STAG2) that is responsible for the cohesion of sister chromatids following DNA replication until its cleavage during mitosis thereby enabling faithful segregation of sister chromatids into two daughter cells. Recent cancer genomics analyses have discovered a high frequency of somatic mutations in the genes encoding the core cohesin subunits as well as cohesin regulatory factors (e.g. NIPBL, PDS5B, ESPL1) in a select subset of human tumors including glioblastoma, Ewing sarcoma, urothelial carcinoma, acute myeloid leukemia, and acute megakaryoblastic leukemia. Herein we review these studies including discussion of the functional significance of cohesin inactivation in tumorigenesis and potential therapeutic mechanisms to selectively target cancers harboring cohesin mutations. [BMB Reports 2014; 47(6): 299-310] PMID:24856830

  1. Polymorphisms in MTHFR, MS and CBS Genes and Homocysteine Levels in a Pakistani Population

    PubMed Central

    Yakub, Mohsin; Moti, Naushad; Parveen, Siddiqa; Chaudhry, Bushra; Azam, Iqbal; Iqbal, Mohammad Perwaiz

    2012-01-01

    Background Hyperhomocysteinemia (>15 mol/L) is highly prevalent in South Asian populations including Pakistan. In order to investigate the genetic determinants of this condition, we studied 6 polymorphisms in genes of 3 enzymes - methylenetetrahydrofolate reductase (MTHFR; C677T; A1298C), methionine synthase (MS; A2756G), cystathionine-?-synthase (CBS; T833C/844ins68, G919A) involved in homocysteine metabolism and investigated their interactions with nutritional and environmental factors in a Pakistani population. Methodology/Principal Findings In a cross-sectional survey, 872 healthy adults (355 males and 517 females; age 1860 years) were recruited from a low-income urban population in Karachi. Fasting venous blood was obtained and assessed for plasma/serum homocysteine; folate, vitamin B12, pyridoxal phosphate and blood lead. DNA was isolated and genotyping was performed by PCR-RFLP (restriction-fragment-length- polymorphism) based assays. The average changes in homocysteine levels for MTHFR 677CT and TT genotypes were positive [?(SE ?), 2.01(0.63) and 16.19(1.8) mol/L, respectively]. Contrary to MTHFR C677T polymorphism, the average changes in plasma homocysteine levels for MS 2756AG and GG variants were negative [?(SE ?), ?0.56(0.58) and ?0.83(0.99) mol/L, respectively]. The average change occurring for CBS 844ins68 heterozygous genotype (ancestral/insertion) was ?1.88(0.81) mol/L. The combined effect of MTHFR C677T, MS A2756G and CBS 844ins68 genotypes for plasma homocysteine levels was additive (p value <0.001). Odds of having hyperhomocysteinemia with MTHFR 677TT genotype was 10-fold compared to MTHFR 677CC genotype [OR (95%CI); 10.17(3.628.67)]. Protective effect towards hyperhomocysteinemia was observed with heterozygous (ancestral/insertion) genotype of CBS 844ins68 compared to homozygous ancestral type [OR (95% CI); 0.58 (0.340.99)]. Individuals with MTHFR 677CT or TT genotypes were at a greater risk of hyperhomocysteinemia in folate and vitamin B12 deficiencies and high blood lead (p value <0.05) level. Conclusions Gene polymorphism (especially MTHFR C677T transition), folate and vitamin B12 deficiencies, male gender and high blood lead level appear to be contributing towards the development of hyperhomocysteinemia in a Pakistani population. PMID:22470444

  2. Mutations in the caveolin-3 gene: When are they pathogenic?

    PubMed

    de Paula, F; Vainzof, M; Bernardino, A L; McNally, E; Kunkel, L M; Zatz, M

    2001-04-01

    Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetic disorders usually with autosomal recessive (AR) inheritance and, less often, displaying autosomal dominant (AD) inheritance. Mutations in the caveolin-3 gene (CAV-3) associated with a reduction of protein expression cause AD-LGMD1C muscular dystrophy. Based on a previous study in the American and Brazilian population, it has been suggested that CAV-3 mutations might also cause AR-LGMD. Here we report the analysis of the CAV-3 gene in 61 additional Brazilian LGMD patients and 100 additional Brazilian normal controls. Two rare G55S and C71W missense changes previously detected only in LGMD patients (and not detected in 100 normal controls from the American population) were now found in normal Brazilian controls. In addition, we have identified a novel R125H missense change in one LGMD female patient that was also found in two of her unaffected siblings. These observations, together with the normal immunofluorescence caveolin pattern in the muscle biopsy from two patients with the G55W and R125H changes in the CAV-3 gene suggest that the G55S, C71W, and R125H polymorphisms, on their own, are not sufficient to produce the pathology. PMID:11251997

  3. Short Communication: Lack of association between MTHFR gene polymorphisms and response to methotrexate treatment in Pakistani patients with rheumatoid arthritis.

    PubMed

    Iqbal, Mohammad Perwaiz; Ali, Azra Arif; Mehboobali, Naseema; Iqbal, Khalida

    2015-09-01

    Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms have been reported to be associated with response to methotrexate (MTX) in certain populations of patients with rheumatoid arthritis (RA). This study aims at investigating any relationship of two single nucleotide polymorphisms (SNPs) in MTHFR gene, C677T and A1298C with response to therapy with MTX in Pakistani RA patients. Allelic frequencies of the two polymorphisms (C677T and A1298C) were determined in 67 RA patients (9 males and 58 females; mean age 42.87 ± 13.5 years) who had previously participated in a prospective clinical trial. Fifty-one patients had received MTX and were followed up for response up to 6 months. Genotyping of the two MTHFR polymorphisms was carried out using PCR-RFLP, while fasting concentration of plasma homocysteine was determined using a kit method. Twenty-eight patients were found to be "good responders", while twenty-three were "poor responders". MTHFR 1298C and MTHFR 677T alleles' frequencies in "good responders" were not different from frequencies in "poor responders" (0.574 vs. 0.521; p=0.6 and 0.197 vs. 0.196; p=0.75, respectively). Plasma homocysteine levels in female RA patients were significantly higher compared to general population in Karachi (13.1 ± 6.7 µmol/l vs. 11.4 ± 5.3 µmol/l; p<0.001). MTHFR C677T and A1298C polymorphisms are not associated with response to MTX in a population of Pakistani RA patients. PMID:26408898

  4. Systematic analysis of somatic mutations impacting gene expression in 12 tumour types

    PubMed Central

    Ding, Jiarui; McConechy, Melissa K.; Horlings, Hugo M.; Ha, Gavin; Chun Chan, Fong; Funnell, Tyler; Mullaly, Sarah C.; Reimand, Jüri; Bashashati, Ali; Bader, Gary D.; Huntsman, David; Aparicio, Samuel; Condon, Anne; Shah, Sohrab P.

    2015-01-01

    We present a novel hierarchical Bayes statistical model, xseq, to systematically quantify the impact of somatic mutations on expression profiles. We establish the theoretical framework and robust inference characteristics of the method using computational benchmarking. We then use xseq to analyse thousands of tumour data sets available through The Cancer Genome Atlas, to systematically quantify somatic mutations impacting expression profiles. We identify 30 novel cis-effect tumour suppressor gene candidates, enriched in loss-of-function mutations and biallelic inactivation. Analysis of trans-effects of mutations and copy number alterations with xseq identifies mutations in 150 genes impacting expression networks, with 89 novel predictions. We reveal two important novel characteristics of mutation impact on expression: (1) patients harbouring known driver mutations exhibit different downstream gene expression consequences; (2) expression patterns for some mutations are stable across tumour types. These results have critical implications for identification and interpretation of mutations with consequent impact on transcription in cancer. PMID:26436532

  5. Adaptation to an automated platform of algorithmic combinations of advantageous mutations in genes generated using amino acid scanning mutational strategy.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Recent mutational strategies for generating and screening of genes for optimized traits, including directed evolution, domain shuffling, random mutagenesis, and site-directed mutagenesis, have been adapted for automated platforms. Here we discuss the amino acid scanning mutational strategy and its ...

  6. 40 CFR 799.9530 - TSCA in vitro mammalian cell gene mutation test.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... several base pairs in the DNA. Forward mutation is a gene mutation from the parental type to the mutant... multiple base pairs in the DNA molecule. Mutant frequency is the number of mutant cells observed divided...

  7. Analysis of p16 gene deletion and point mutation in breast carcinoma.

    PubMed Central

    Quesnel, B.; Fenaux, P.; Philippe, N.; Fournier, J.; Bonneterre, J.; Preudhomme, C.; Peyrat, J. P.

    1995-01-01

    We looked for p16 gene deletion by Southern analysis and p16 gene point mutation by single-stranded conformation polymorphism (SSCP) analysis and direct sequencing of DNA from fresh tumour samples of 35 and 33 breast carcinomas respectively. No homozygous p16 gene deletion was found in any case. A missense point mutation of the p16 gene was found in only one patient. This point mutation was absent from the patient's lymphocytes, ruling out a polymorphism or a germline mutation. These findings suggest that p16 gene alterations are rarely observed in breast carcinoma. Images Figure 1 PMID:7640217

  8. Four novel MSH2 / MLH1 gene mutations in portuguese HNPCC families.

    PubMed

    Isidro, G; Veiga, I; Matos, P; Almeida, S; Bizarro, S; Marshall, B; Baptista, M; Leite, J; Regateiro, F; Soares, J; Castedo, S; Boavida, M G

    2000-01-01

    Hereditary non-polyposis colorectal cancer (HNPCC) is considered to be determined by germline mutations in the mismatch repair (MMR) genes, especially MSH2 and MLH1. While screening for mutations in these two genes in HNPCC portuguese families, 3 previously unreported MSH2 and 1 MLH1 mutations have been identified in families meeting strict Amsterdam criteria. Hum Mutat 15:116, 2000. PMID:10612836

  9. Single-gene mutations and healthy ageing in mammals

    PubMed Central

    Bartke, Andrzej

    2011-01-01

    Studies of the effects of single-gene mutations on longevity in Caenorhabditis elegans, Drosophila melanogaster and Mus musculus identified homologous, highly conserved signalling pathways that influence ageing. In each of these very distantly related species, single mutations which leaddirectly or indirectlyto reduced insulin, insulin-like growth factor (IGF) or insulin/IGF-like signalling (IIS) can produce significant increases in both average and maximal lifespan. In mice, most of the life-extending mutations described to date reduce somatotropic (growth hormone (GH) and IGF-1) signalling. The reported extensions of longevity are most robust in GH-deficient and GH-resistant mice, while suppression of somatotropic signalling downstream of the GH receptor produces effects that are generally smaller and often limited to female animals. This could be due to GH influencing ageing by both IGF-1-mediated and IGF-1-independent mechanisms. In mutants that have been examined in some detail, increased longevity is associated with various indices of delayed ageing and extended healthspan. The mechanisms that probably underlie the extension of both lifespan and healthspan of these animals include increased stress resistance, improved antioxidant defences, alterations in insulin signalling (e.g. hypoinsulinaemia combined with improved insulin sensitivity in some mutants and insulin resistance in others), a shift from pro- to anti-inflammatory profile of circulating adipokines, reduced mammalian target of rapamycin-mediated translation and altered mitochondrial function including greater utilization of lipids when compared with carbohydrates. PMID:21115527

  10. Mutations of the prion protein gene phenotypic spectrum.

    PubMed

    Kovács, Gábor G; Trabattoni, Gianriccardo; Hainfellner, Johannes A; Ironside, James W; Knight, Richard S G; Budka, Herbert

    2002-11-01

    Prion diseases are inherited in 5-15 % of cases. They are classified according to changes in the prion protein gene ( PRNP) or conventionally according to phenotype as Gerstmann-Sträussler-Scheinker disease (GSS), fatal familial insomnia (FFI), or familial Creutzfeldt-Jakob disease (fCJD). Point mutations and insertions within PRNP form the genetic background. We report the results of a systematic analysis of over 500 case reports of patients with PRNP abnormalities. We compare clinical, neuropathological and molecular data in five groups, namely GSS, FFI, fCJD, base pair insertion (BPI), and all cases collectively. Clinical presentation overlaps between mutations, but some have characteristic features (e. g. P105L, D178N-129M, T183A). Some mutations, especially in the lack of sufficient family history, in earlier phases tend to resemble other neurodegenerative disorders like multiple system atrophy, corticobasal degeneration or familial diseases such as late-onset spinocerebellar ataxia, spastic paraparesis, frontotemporal dementia, or Alzheimer's disease. The codon 129 polymorphism has a phenotypic influence in inherited prion diseases, as in non-genetic forms, but additional factors might be considered as background for phenotypic variability. PMID:12420099

  11. Human beta-galactosidase gene mutations in GM1-gangliosidosis: a common mutation among Japanese adult/chronic cases.

    PubMed Central

    Yoshida, K; Oshima, A; Shimmoto, M; Fukuhara, Y; Sakuraba, H; Yanagisawa, N; Suzuki, Y

    1991-01-01

    Molecular analysis of the human beta-galactosidase gene revealed six different mutations in 10 of 11 Japanese GM1-gangliosidosis patients. They were the only abnormalities in each allele examined in this study. A 165-nucleotide duplication (positions 1103-1267) was found in two infantile patients, producing an abnormally large mRNA; one patient was probably a homozygote, and the other was a heterozygote of this mutation. The other two infantile patients had different mutations; a 123 Gly(GGG)----Arg(AGG) mutation in one patient and a 316 Tyr(TAT)----Cys(TGT) mutation in the other. A 201 Arg(CGC)----Cys(TGC) mutation, eliminating a BspMI site, was detected in a late-infantile/juvenile patient; the restriction-site analysis of amplified genomic DNA confirmed his heterozygosity for this mutation. A 51 Ile(ATC)----Thr(ACC) mutation was found in all five adult/chronic patients examined in this study. It created a SauI site, and restriction-site analysis confirmed that four patients were homozygous mutants. The other was a compound heterozygote for this mutation and another 457 Arg(CGA)----Gln(CAA) mutation. These mutant genes expressed markedly decreased or completely deficient enzyme activities in beta-galactosidase-deficient human fibroblasts transformed by adenovirus-SV40 recombinants. We conclude that gene mutations are heterogeneous in GM1-gangliosidosis but that the 51 Ile(ATC)----Thr(ACC) mutation is common among the Japanese adult/chronic cases. Genotype-phenotype correlations in GM1-gangliosidosis are briefly discussed. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:1907800

  12. The association between methylene-tetrahydrofolate reductase gene polymorphism and lung cancer risk.

    PubMed

    Arslan, Sulhattin; Karadayi, Sule; Yildirim, Malik Ejder; Ozdemir, Ozturk; Akkurt, Ibrahim

    2011-02-01

    This study aimed to determine the relation between methylene-tetrahydrofolate reductase (MTHFR) gene polymorphism and lung cancer risk and the frequency of this polymorphism. The study involved 64 lung cancer patients (the study group) with definitive diagnosis and 61 noncancerous subjects (the control group). MTHFR C677T and A1298C mutation analysis was made using DNA isolated from peripheric blood and multiplex PCR and reverse hybridization strip test. Eighty-four percent of the patients were male. The age, gender, and history of alcohol use of the patients and control group were statistically similar. While MTHFR 677T and 677C allele frequency was 0.33 and 0.67 in the patients respectively, it was 0.29 and 0.71 in the control group. The frequencies of MTHFR 1298C and 1298A were 0.33 and 0.67 in the patients, and it was 0.31 and 0.69 in the control group respectively. When MTHFR 677TT and 677CT genotypes were compared with 677CC genotype, lung cancer risk was 2.4 times higher in the 677TT genotype. When MTHFR 1298AC and 1298CC genotypes were compared with 1298AA genotype, lung cancer risk was 1.5 times higher in 1298CC genotype. According to the results, allele frequency of homozygote T and C was high in lung cancer patients. It was 3.05 and 1.29 times higher in smokers than in non-smokers, and 3.05 and 1.64 times higher in males than in females; 3.0 and 2.44 times higher in those with non-small cell lung cancer than in those with small-cell lung cancer. PMID:20532637

  13. Barth syndrome: TAZ gene mutations, mRNAs, and evolution.

    PubMed

    Gonzalez, Iris L

    2005-05-01

    Barth syndrome (MIM 302060) is an X-linked condition that includes dilated cardiomyopathy, neutropenia, failure to thrive, abnormal mitochondria, and 3-methylglutaconic aciduria. The mutated gene, TAZ, first described in 1996, appeared to produce a large set of alternatively spliced mRNAs with initiations of transcription upstream of exons 1 and 3. Since then, disease-causing mutations have been found in all exons including, most recently, a missense mutation in the controversial exon 5. Because of the initially described second initiation of transcription in intron 2, with in-frame initiation of translation in exon 3, we hypothesized that subjects with mutations in exons 1 and 2 would produce more normal "short product" that might attenuate their phenotype. Moreover, it was of interest to determine which splice variants were potentially functional as exon 5 is not present in yeast and rodents, and the variant lacking this exon is the most abundant. Using RT-PCR, we characterized TAZ mRNAs in cultured lymphocytes from nine subjects with Barth syndrome and two healthy controls. The TAZ genes and mRNAs of primates were also included. We found the following: (1) there is only one site for initiation of transcription, and the normal alternatively spliced assortment is limited to full-length, delta5, delta7, delta5delta7; (2) there are two alternative splice sites within introns 1 and 2 that could potentially produce an in-frame product; (3) exon 5 evolved into "exonhood" in the primate lineage after the split between Old World monkeys and hominoid primates; and (4) our results suggest that only two functional protein variants exist in lymphocytes: delta5 and full-length. Although exon 5 does not appear to be required for TAZ function in yeast and monkeys, its evolution to a highly conserved spliced exon in hominoid primates and the recent finding of an exon 5 mutation in a patient with Barth syndrome suggest that the full-length variant is important to TAZ function. PMID:15793838

  14. Melanocortin 3 receptor gene and melanocortin 4 receptor gene mutations: the Asian Perspective.

    PubMed

    Lee, Yung Seng

    2012-12-01

    Melanocortin 4 receptor (MC4R) deficiency resulting from disruption of one or both MC4R alleles represents the commonest monogenic form of human obesity to date. Human MC4R deficiency was reported to affect 4 and 5.8% of severely obese French and British populations respectively. However, studies elsewhere reported low incidence of MC4R mutations in their obese populations. The significance of MC4R mutations in Asian obese populations has not been adequately examined, though small studies in Japan, China, and Singapore reported few or no pathogenic mutations, suggesting a low prevalence in this part of the world. There were also few common mutations described across populations, suggesting a relative lack of founder effect. The pathogenic role of melanocortin 3 receptor gene (MC3R) mutations in human obesity is not as well described and accepted as MC4R mutations, though it is gradually gaining ground. Two common single nucleotide polymorphisms Thr6Lys and Val81Ile within the coding region were associated with higher body fat and leptin levels in obese children, supported by impaired signaling activity in vitro. There were also reports of missense mutations enriched in obese populations. While MC3R mutations are unlikely to result in an autosomal dominant form of monogenic obesity given the lack of strong co-segregation in family studies, the studies so far provided evidence that MC3R can be one of the genes which contributes to increased adiposity, and exert an effect on the human phenotype. PMID:23280863

  15. GNAS gene mutation may be present only transiently during colorectal tumorigenesis

    PubMed Central

    Zauber, Peter; Marotta, Stephen P; Sabbath-Solitare, Marlene

    2016-01-01

    Mutations of the gene GNAS have been shown to activate the adenylate cyclase gene and lead to constitutive cAMP signaling. Several preliminary reports have suggested a role for GNAS gene mutations during colorectal carcinogenesis, particularly mucinous carcinomas. The aim of this study was to clarify the incidence of GNAS mutations in adenomas (tubular, tubulovillous, and villous), carcinomas with residual adenoma, and carcinomas, and to relate these findings to mutations of the KRAS gene and to the mucinous status of the tumors. We used standard PCR techniques and direct gene sequencing to evaluate tumors for gene mutations. No GNAS mutations were identified in 25 tubular adenomas, but were present in 6.4% of tubulovillous adenomas and 11.2% of villous adenomas. A GNAS mutation was found in 9.7% of the benign portion of carcinoma with residual adenoma, but in none of 86 carcinomas. A similar trend was seen for KRAS mutation across the five groups of tumors. GNAS mutations may function as an important driver mutation during certain phases of colorectal carcinogenesis, but may then be lost once the biological advantage gained by the mutated gene is no longer necessary to sustain or advance tumor development. PMID:27186325

  16. Mutation analysis of the Fanconi Anemia Gene FACC

    SciTech Connect

    Verlander, P.C.; Lin, J.D.; Udono, M.U.; Zhang, Q.; Auerbach, A.D. ); Gibson, R.A.; Mathew, C.G. )

    1994-04-01

    Fanconi anemia (FA) is a genetically heterogeneous autosomal recessive disorder characterized by a unique hypersensitivity of cells to DNA cross-linking agents; a gene for complementation group C (FACC) has recently been cloned. The authors have amplified FACC exons with their flanking intron sequences from genomic DNA from 174 racially and ethnically diverse families in the International Fanconi Anemia Registry and have screened for mutations by using SSCP analysis. They have identified eight different variants in 32 families; three were detected in exon 1, one in exon 4, one in intron 4, two in exon 6, and one in exon 14. Two of the eight variants, in seven families, did not segregate with the disease allele in multiplex families, suggesting that these variants represented benign polymorphisms. Disease-associated mutations in FACC were detected in a total of 25 (14.4%) of 174 families screened. The most frequent mutations were IVS4 + 4 A [yields] T (intron 4; 12 families) and 322delG (exon 1; 9 families). Other, less common mutations include Q13X in exon 1, R185X and D195V in exon 6, and L554P in exon 14. The polymorphisms were S26F in exon 1 and G139E in exon 4. All patients in the study with 322delG, Q13X, R185X, and D195V are of northern or eastern European or southern Italian ancestry, and 18 of 19 have a mild form of the disease, while the 2 patients with L554P, both from the same family, have a severe phenotype. All 19 patients with IVS4 + 4 A [yields] T have Jewish ancestry and have a severe phenotype. 19 refs., 1 fig., 3 tabs.

  17. Three faces of recombination activating gene 1 (RAG1) mutations.

    PubMed

    Patiroglu, Turkan; Akar, Himmet Haluk; Van Der Burg, Mirjam

    2015-12-01

    Severe combined immune deficiency (SCID) is a group of genetic disorder associated with development of T- and/or B-lymphocytes. Recombination-activating genes (RAG1/2) play a critical role on VDJ recombination process that leads to the production of a broad T-cell receptor (TCR) and B-cell receptor (BCR) repertoire in the development of T and B cells. RAG1/2 genes mutations result in various forms of primary immunodeficiency, ranging from classic SCID to Omenn syndrome (OS) to atypical SCID with such as granuloma formation and autoimmunity. Herein, we reported 4 patients with RAG1 deficiency: classic SCID was seen in two patients who presented with recurrent pneumonia and chronic diarrhoea, and failure to thrive. OS was observed in one patient who presented with chronic diarrhoea, skin rash, recurrent lower respiratory infections, and atypical SCID was seen in one patient who presented with Pyoderma gangrenosum (PG) and had novel RAG1 mutation. PMID:26689875

  18. Clinical potential of gene mutations in lung cancer.

    PubMed

    Carper, Miranda B; Claudio, Pier Paolo

    2015-12-01

    Lung cancer is the most common cancer type worldwide and the leading cause of cancer related deaths in the United States. The majority of newly diagnosed patients present with late stage metastatic lung cancer that is inoperable and resistant to therapies. High-throughput genomic technologies have made the identification of genetic mutations that promote lung cancer progression possible. Identification of the mutations that drive lung cancer provided new targets for non-small cell lung cancer (NSCLC) treatment and led to the development of targeted therapies such as tyrosine kinase inhibitors that can be used to combat the molecular changes that promote cancer progression. Development of targeted therapies is not the only clinical benefit of gene analysis studies. Biomarkers identified from gene analysis can be used for early lung cancer detection, determine patient's prognosis and response to therapy, and monitor disease progression. Biomarkers can be used to identify the NSCLC patient population that would most benefit from treatment (targeted therapies or chemotherapies), providing clinicians tools that can be used to develop a personalized treatment plan. This review explores the clinical potential of NSCLC genetic studies on diagnosing and treating NSCLC. PMID:26603430

  19. Mutation analysis of the RPGR gene reveals novel mutations in south European patients with X-linked retinitis pigmentosa.

    PubMed

    Miano, M G; Testa, F; Strazzullo, M; Trujillo, M; De Bernardo, C; Grammatico, B; Simonelli, F; Mangino, M; Torrente, I; Ruberto, G; Beneyto, M; Antinolo, G; Rinaldi, E; Danesino, C; Ventruto, V; D'Urso, M; Ayuso, C; Baiget, M; Ciccodicola, A

    1999-09-01

    The RPGR (retinitis pigmentosa GTPase regulator) gene has been shown to be mutated in 10-20% of patients with X-linked retinitis pigmentosa (XLRP), a severe form of inherited progressive retinal degeneration. A total of 29 different RPGR mutations have been identified in northern European and United States patients. We have performed mutation analysis of the RPGR gene in a cohort of 49 southern European males affected with XLRP. By multiplex SSCA and automatic direct sequencing of all 19 RPGR exons, seven different and novel mutations were identified in eight of the 49 families; these include three splice site mutations, two microdeletions, and two missense mutations. RNA analysis showed that the three splice site defects resulted in the generation of aberrant RPGR transcripts. Six of these mutations were detected in the conserved amino-terminal region of RPGR protein, containing tandem repeats homologous to the RCC1 protein, a guanine nucleotide-exchange factor for Ran-GTPase. Several exonic and intronic sequence variations were also detected. None of the RPGR mutations reported in other populations were identified in our series. Our results are consistent with the notions of heterogeneity and minority causation of XLRP by mutations in RPGR in Caucasian populations. PMID:10482958

  20. First-Step Mutations during Adaptation Restore the Expression of Hundreds of Genes.

    PubMed

    Rodríguez-Verdugo, Alejandra; Tenaillon, Olivier; Gaut, Brandon S

    2016-01-01

    The temporal change of phenotypes during the adaptive process remains largely unexplored, as do the genetic changes that affect these phenotypic changes. Here we focused on three mutations that rose to high frequency in the early stages of adaptation within 12 Escherichia coli populations subjected to thermal stress (42 °C). All the mutations were in the rpoB gene, which encodes the RNA polymerase beta subunit. For each mutation, we measured the growth curves and gene expression (mRNAseq) of clones at 42 °C. We also compared growth and gene expression with their ancestor under unstressed (37 °C) and stressed conditions (42 °C). Each of the three mutations changed the expression of hundreds of genes and conferred large fitness advantages, apparently through the restoration of global gene expression from the stressed toward the prestressed state. These three mutations had a similar effect on gene expression as another single mutation in a distinct domain of the rpoB protein. Finally, we compared the phenotypic characteristics of one mutant, I572L, with two high-temperature adapted clones that have this mutation plus additional background mutations. The background mutations increased fitness, but they did not substantially change gene expression. We conclude that early mutations in a global transcriptional regulator cause extensive changes in gene expression, many of which are likely under positive selection for their effect in restoring the prestress physiology. PMID:26500250

  1. AB158. Report of a Gardner’s syndrome case with an APC gene mutation

    PubMed Central

    Ngo, Phuoc; Nguyen, Suong; Bui, Lam; Nguyen, Tron; Huynh, Khai; Bui, Minh; Do, Thuy

    2015-01-01

    Background Gardner’s syndrome is an autosomal dominant disorder with complete penetrance, caused by mutations in the adenomatous polyposis coli gene(APC gene). Gardner’s syndrome is characterized by intestinal polyposis, osteomas and dental abnormalities. APC mutations are mostly point mutations, causing a truncated and dysfunctional APC protein. Detection of mutations in APC gene from a patient with Gardner’s syndrome. Methods A 19-year-old female patient with typical symptoms of Gardner’s syndrome was sent from the Hospital of Odonto-Stomatology, Ho Chi Minh City for detection of APC gene mutations. We performed APC gene sequencing and used bioinformatics tools to detect APC gene mutations and predict the effects of mutations. Results We detected the p.Gln1517ArgfsX6 mutation in APC gene and analyzed the effects of this mutation on functions of the APC protein. Conclusions We reported a p.Gln1517ArgfsX6 mutation in APC gene from a patient with Gardner’s syndrome.

  2. First-Step Mutations during Adaptation Restore the Expression of Hundreds of Genes

    PubMed Central

    Rodríguez-Verdugo, Alejandra; Tenaillon, Olivier; Gaut, Brandon S.

    2016-01-01

    The temporal change of phenotypes during the adaptive process remains largely unexplored, as do the genetic changes that affect these phenotypic changes. Here we focused on three mutations that rose to high frequency in the early stages of adaptation within 12 Escherichia coli populations subjected to thermal stress (42 °C). All the mutations were in the rpoB gene, which encodes the RNA polymerase beta subunit. For each mutation, we measured the growth curves and gene expression (mRNAseq) of clones at 42 °C. We also compared growth and gene expression with their ancestor under unstressed (37 °C) and stressed conditions (42 °C). Each of the three mutations changed the expression of hundreds of genes and conferred large fitness advantages, apparently through the restoration of global gene expression from the stressed toward the prestressed state. These three mutations had a similar effect on gene expression as another single mutation in a distinct domain of the rpoB protein. Finally, we compared the phenotypic characteristics of one mutant, I572L, with two high-temperature adapted clones that have this mutation plus additional background mutations. The background mutations increased fitness, but they did not substantially change gene expression. We conclude that early mutations in a global transcriptional regulator cause extensive changes in gene expression, many of which are likely under positive selection for their effect in restoring the prestress physiology. PMID:26500250

  3. Polymorphisms in methylenetetrahydrofolate reductase gene and risk of non-Hodgkin lymphoma in a multi-ethnic population.

    PubMed

    Suthandiram, Sujatha; Gan, Gin Gin; Zain, Shamsul Mohd; Haerian, Batoul Sadat; Bee, Ping Chong; Lian, Lay Hoong; Chang, Kian Meng; Ong, Tee Chuan; Mohamed, Zahurin

    2014-05-01

    An imbalance in folate metabolism can adversely affect DNA synthesis and methylation systems which can lead to susceptibility to non-Hodgkin lymphoma (NHL). Whether single nucleotide polymorphisms (SNPs) and their haplotypes in the methylenetetrahydrofolate reductase (MTHFR) are associated with NHL, remain inconclusive. We investigated the association between MTHFR C677T and A1298C SNPs and NHL risk in a population which is made up of Malay, Chinese and Indian ethnic subgroups. A total of 372 NHL patients and 722 controls were genotyped using the Sequenom MassARRAY platform. Our results of the pooled subjects failed to demonstrate significant association between the MTHFR C677T and A1298C SNPs with NHL and its subtypes. The results were in agreement with the previous meta-analyses. In the Indian ethnic subgroup however, single locus analysis of MTHFR A1298C appears to confer risk to NHL (Odds ratio (OR) 1.91, 95% confidence interval (95% CI) 1.22-3.00, P=0.006). The risk is almost doubled in homozygous carrier of MTHFR 1298CC (OR 4.03, 95% CI 1.56-10.43, P=0.004). Haplotype analysis revealed higher frequency of CC in the Indian NHL patients compared with controls (OR 1.86, 95% CI 1.18-2.93, P=0.007). There is lack of evidence to suggest an association between MTHFR C677T and A1298C with the risk of NHL in the Malays and Chinese. In the Indians however, the MTHFR A1298C confers risk to NHL. This study suggests ethnicity modifies the relationship between polymorphisms in the folate-metabolizing gene and NHL. PMID:24646728

  4. A Common Mutation and a Novel Mutation in the HPGD Gene in Nine Patients with Primary Hypertrophic Osteoarthropathy.

    PubMed

    Yuan, Lu; Chen, Ling; Liao, Ruo-xi; Lin, Yuan-yuan; Jiang, Yan; Wang, Ou; Li, Mei; Xing, Xiao-Ping; Pang, Qian-Qian; Jiajue, Ruizhi; Xia, Wei-bo

    2015-10-01

    Primary hypertrophic osteoarthropathy (PHO) is a hereditary bone disease characterized by digital clubbing, periostosis, and pachydermia. The HPGD gene encoding 15-prostaglandin dehydrogenase and SLCO2A1 encoding one type of prostaglandin transporter were found to be responsible for PHO. Mutations of either gene would lead to increased level of prostaglandin E2 (PGE2), which might contribute to the constellation of the symptoms. The aim of the study was to analyze the HPGD gene and the clinical characteristics in nine patients with the diagnosis of PHO. Nine patients, (eight males and one female) including two siblings and seven sporadic cases, were enrolled in the study. Clinical features were summarized, and blood and urine samples were collected. Sanger method was used to sequence the HPGD gene to detect mutations. Urinary PGE2 and prostaglandin metabolite (PGE-M) levels for each patient were measured and compared to the healthy controls. A recurrent c.310_311delCT mutation was identified in all patients, of which six were homozygous, two were heterozygous, and one was compound heterozygous with this mutation and a novel heterozygous missense mutation c.488G>A (p.R163H). The levels of PGE2 in urine were much higher than normal in all patients, along with lower PGE-M levels. In conclusion, nine PHO patients were characterized by typical clinical manifestations including digital clubbing, periostosis, and pachydermia. A common mutation and a novel mutation in HPGD gene were identified to be responsible for the disease, and c.310_311delCT mutation is likely to be a hot-spot mutation site for Asian PHO patients. PMID:26135126

  5. Ten-Eleven Translocation-2 gene mutations: A potential new molecular marker in malignant gliomas (Review).

    PubMed

    Yu, Lei; Qi, Songtao

    2012-01-01

    Alterations of the Ten-Eleven Translocation-2 (TET2) gene in myeloid malignancies and isocitrate dehydrogenase (IDH) gene mutations in gliomas and myeloid malignancies have recently been identified using molecular, comparative genomic hybridization and single nucleotide polymorphism array techniques. The mutations of the TET2 gene have been shown to be mutually exclusive with IDH1/2 mutations in acute myeloid leukemia (AML) and evidence has been found to provide a biochemical basis for the mutual exclusivity of IDH1/2 and TET2 gene mutations. Based on mounting evidence, we aimed to investigate whether TET2 mutations may be identified as novel mutations in malignant gliomas without IDH1/2 mutations, and indicate their possible significance in gliomas. PMID:22740846

  6. Mutation Analysis of IDH1/2 Genes in Unselected De novo Acute Myeloid Leukaemia Patients in India - Identification of A Novel IDH2 Mutation.

    PubMed

    Raveendran, Sureshkumar; Sarojam, Santhi; Vijay, Sangeetha; Geetha, Aswathy Chandran; Sreedharan, Jayadevan; Narayanan, Geetha; Sreedharan, Hariharan

    2015-01-01

    IDH1/2 mutations which result in alternation in DNA methylation pattern are one of the most common methylation associated mutations in Acute myeloid leukaemia. IDH1/2 mutations frequently associated with higher platelet level, normal cytogentics and NPM1 mutations. Here we analyzed IDH1/2 mutations in 200 newly diagnosed unselected Indian adult AML patients and investigated their correlation with clinical, cytogenetic parameters along with cooperating NPM1 mutation. We detected 5.5% and 4% mutations in IDH1/2 genes, respectively. Except IDH2 c.515_516GG>AA mutation, all the other identified mutations were reported mutations. Similar to reported c.515G>A mutation, the novel c.515_516GG>AA mutation replaces 172nd arginine to lysine in the active site of the enzyme. Even though there was a preponderance of IDH1/2 mutations in NK-AML, cytogenetically abnormal patients also harboured IDH1/2 mutations. IDH1 mutations showed significant higher platelet count and NPM1 mutations. IDH2 mutated patients displayed infrequent NPM1 mutations and lower WBC count. All the NPM1 mutations in the IDH1/2 mutated cases showed type A mutation. The present data suggest that IDH1/2 mutations are associated with normal cytogenetics and type A NPM1 mutations in adult Indian AML patients. PMID:25987093

  7. Recurrent mutation, gene conversion, or recombination at the human phenylalanine hydroxylase locus: evidence in French-Canadians and a catalog of mutations.

    PubMed Central

    John, S W; Rozen, R; Scriver, C R; Laframboise, R; Laberge, C

    1990-01-01

    The codon 408 mutation (CGG----TGG, Arg----Trp) in exon 12 of the phenylalanine hydroxylase (PAH) gene occurs on haplotype 1 in French-Canadians; elsewhere this mutation (R408W) occurs on haplotype 2. A CpG dinucleotide is involved. The finding is compatible with a recurrent mutation, gene conversion, or a single recombination between haplotypes 2 and 1. A tabulation of 20 known mutations at the PAH locus reveals three instances of putative recurrent mutation. PMID:1971147

  8. Combined Complement Gene Mutations in Atypical Hemolytic Uremic Syndrome Influence Clinical Phenotype

    PubMed Central

    Bresin, Elena; Rurali, Erica; Caprioli, Jessica; Sanchez-Corral, Pilar; Fremeaux-Bacchi, Veronique; Rodriguez de Cordoba, Santiago; Pinto, Sheila; Goodship, Timothy H.J.; Alberti, Marta; Ribes, David; Valoti, Elisabetta; Remuzzi, Giuseppe

    2013-01-01

    Several abnormalities in complement genes reportedly contribute to atypical hemolytic uremic syndrome (aHUS), but incomplete penetrance suggests that additional factors are necessary for the disease to manifest. Here, we sought to describe genotypephenotype correlations among patients with combined mutations, defined as mutations in more than one complement gene. We screened 795 patients with aHUS and identified single mutations in 41% and combined mutations in 3%. Only 8%10% of patients with mutations in CFH, C3, or CFB had combined mutations, whereas approximately 25% of patients with mutations in MCP or CFI had combined mutations. The concomitant presence of CFH and MCP risk haplotypes significantly increased disease penetrance in combined mutated carriers, with 73% penetrance among carriers with two risk haplotypes compared with 36% penetrance among carriers with zero or one risk haplotype. Among patients with CFH or CFI mutations, the presence of mutations in other genes did not modify prognosis; in contrast, 50% of patients with combined MCP mutation developed end stage renal failure within 3 years from onset compared with 19% of patients with an isolated MCP mutation. Patients with combined mutations achieved remission with plasma treatment similar to patients with single mutations. Kidney transplant outcomes were worse, however, for patients with combined MCP mutation compared with an isolated MCP mutation. In summary, these data suggest that genotyping for the risk haplotypes in CFH and MCP may help predict the risk of developing aHUS in unaffected carriers of mutations. Furthermore, screening patients with aHUS for all known disease-associated genes may inform decisions about kidney transplantation. PMID:23431077

  9. A single gene mutation that increases maize seed weight

    SciTech Connect

    Giroux, M.J.; Shaw, J.; Hannah, L.C.

    1996-06-11

    The maize endosperm-specific gene shrunken2 (Sh2) encodes the large subunit of the heterotetrameric starch synthetic enzyme adenosine diphosphoglucose pyrophosphorylase (AGP; EC 2.7.7.27). Here we exploit an in vivo, site-specific mutagenesis system to create short insertion mutations in a region of the gene known to be involved in the allosteric regulation of AGP. The site-specific mutagen is the transposable element dissociation (Ds). Approximately one-third (8 of 23) of the germinal revertants sequenced restored the wild-type sequence, whereas the remaining revertants contained insertions of 3 or 6 bp. All revertants retained the original reading frame 3 feet to the insertion site and involved the addition of tyrosine and/or serine. Each insertion revertant reduced total AGP activity and the amount of the SH2 protein. The revertant containing additional tyrosine and serine residues increased seed weight 11-18% without increasing or decreasing the percentage of starch. Other insertion revertants lacking an additional serine reduced seed weight. Reduced sensitivity to phosphate, a long-known inhibitor of AGP, was found in the high seed-weight revertant. This alteration is likely universally important since insertion of tyrosine and serine in the potato large subunit of AGP at the comparable position and expression in Escherichia coli also led to a phosphate-insensitive enzyme. These results show that single gene mutations giving rise to increased seed weight, and therefore perhaps yield, are clearly possible in a plant with a long history of intensive and successful breeding efforts. 20 refs., 5 figs., 5 tabs.

  10. Is methylenetetrahydrofolate reductase (MTHFR) gene A1298C polymorphism related with varicocele risk?

    PubMed

    Ucar, V B; Nami, B; Acar, H; Kilinç, M

    2015-02-01

    Varicocele is one of the main reasons for male infertility the exact aetiology of which remains unclear. Methylenetetrahydrofolate reductase (MTHFR) is important for DNA synthesis and methylation, which has a key role during spermatogenesis. Numerous literature suggests that the MTHFR polymorphism may be genetic risk factors for male infertility. In this study, we evaluated C677T and A1298C MTHFR gene polymorphism frequency in patients with varicocele and normal men. A total of 107 varicocele patients and 109 fertile healthy individuals were included. Genotyping of the MTHFR gene in C677T and A1298C base pairs carried out by using real-time PCR technique and afterwards, the statistical analysis accomplished. There is a statistical difference for the frequency of 1298AA genotype in patients with varicocele compared with normal controls (P = 0.0051, OR = 2.2750). Instead, subsequently, 1298/A allel frequency in patient group was significantly higher in comparison with control group (P = 0.0174). According to our results, 1298AA genotype in MTHFR gene raises the risk of varicocele approximately 2.3 times more compared with men carrying other genotypes. The results show that genetic factors have an important role in the molecular basis of varicocele. PMID:24456105

  11. Mutational analysis of PKD1 gene in a Chinese family with autosomal dominant polycystic kidney disease

    PubMed Central

    Liu, Jingyan; Li, Lanrong; Liu, Qingmin

    2015-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disease and common renal disease. Mutations of PKD genes are responsible for this disease. We analyzed a large Chinese family with ADPKD using Sanger sequencing to identify the mutation responsible for this disease. The family comprised 27 individuals including 10 ADPKD patients. These ADPKD patients had severe renal disease and most of them died very young. We analyzed 6 survival patients gene and found they all had C10529T mutation in exon 35 of PKD1 gene. We did not found gene mutation in any unaffected relatives or 300 unrelated controls. These findings suggested that the C10529T mutation in PKD1 gene might be the pathogenic mutation responsible for the disease in this family. PMID:26722532

  12. Exploring preferred amino acid mutations in cancer genes: Applications to identify potential drug targets.

    PubMed

    Anoosha, P; Sakthivel, R; Michael Gromiha, M

    2016-02-01

    Somatic mutations developed with missense, silent, insertions and deletions have varying effects on the resulting protein and are one of the important reasons for cancer development. In this study, we have systematically analysed the effect of these mutations at protein level in 41 different cancer types from COSMIC database on different perspectives: (i) Preference of residues at the mutant positions, (ii) probability of substitutions, (iii) influence of neighbouring residues in driver and passenger mutations, (iv) distribution of driver and passenger mutations around hotspot site in five typical genes and (v) distribution of silent and missense substitutions. We observed that R→H substitution is dominant in drivers followed by R→Q and R→C whereas E→K has the highest preference in passenger mutations. A set of 17 mutations including R→Y, W→A and V→R are specific to driver mutations and 31 preferred substitutions are observed only in passenger mutations. These frequencies of driver mutations vary across different cancer types and are selective to specific tissues. Further, driver missense mutations are mainly surrounded with silent driver mutations whereas the passenger missense mutations are surrounded with silent passenger mutations. This study reveals the variation of mutations at protein level in different cancer types and their preferences in cancer genes and provides new insights for understanding cancer mutations and drug development. PMID:26581171

  13. Combination of factor V Leiden and MTHFR mutations in myocardial infarction.

    PubMed

    Fekih-Mrissa, Najiba; Berredjeb-Benslama, Dhouha; Haggui, Abdeddayem; Haouala, Habib; Gritli, Nasreddine

    2013-01-01

    Identifying patients who are at high risk of suffering myocardial infarction can be done by determining risk factors or by the adoption of molecular genetic testing for inherited thrombophilia. We report a case of myocardial infarction at a young age. The patient complained of dyspnea (stage III) and a burning pain of severe intensity that radiated to the left retrosternal side, but was not associated with palpitations or diaphoresis. A number of biochemical parameters were normal except for an elevated creatinine phosphokinase (CPK) level. Genetic testing revealed the subject to be heterozygous for both the factor V leiden and MTHFR C677T polymorphisms. The combination of these two mutations may be a high risk factor for myocardial infarction. Genetic screening for inherited thrombophilia in young patients, especially in the presence of a common risk factor, may be useful for primary thrombopro.phylaxis and in asymptomatic relatives of patients. PMID:22750768

  14. Superoxide dismutase gene mutations in Italian patients with familial and sporadic amyotrophic lateral sclerosis: identification of three novel missense mutations.

    PubMed

    Gellera, C; Castellotti, B; Riggio, M C; Silani, V; Morandi, L; Testa, D; Casali, C; Taroni, F; Di Donato, S; Zeviani, M; Mariotti, C

    2001-05-01

    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons. The majority of the patients are sporadic cases (SALS), while 5-10% of the patients have a family history of ALS (familial ALS or FALS). Mutations in the gene coding for cytoplasmic Cu/Zn superoxide dismutase (SOD1) have been identified in about 20% of FALS cases. We found SOD1-gene mutations in five of 34 unrelated FALS, and in two of 44 SALS patients. Three FALS patients carried the previously described A4V (two cases) and L84F mutations (one case), while two FALS patients carried new missense mutations: a G12R substitution in exon 1, and a F45C substitution in exon 2, respectively. The newly identified mutations were both associated with a slowly progressive disease course. Two SALS patients carried the homozygous D90A and the heterozygous I113T mutation, respectively. In addition, in one SALS patient we identified an A95T amino acid substitution, that is apparently a non-pathogenic SOD1 variant. Our study increases the number of ALS-associated SOD1 gene mutations. PMID:11369193

  15. Systematic analysis of mutation distribution in three dimensional protein structures identifies cancer driver genes.

    PubMed

    Fujimoto, Akihiro; Okada, Yukinori; Boroevich, Keith A; Tsunoda, Tatsuhiko; Taniguchi, Hiroaki; Nakagawa, Hidewaki

    2016-01-01

    Protein tertiary structure determines molecular function, interaction, and stability of the protein, therefore distribution of mutation in the tertiary structure can facilitate the identification of new driver genes in cancer. To analyze mutation distribution in protein tertiary structures, we applied a novel three dimensional permutation test to the mutation positions. We analyzed somatic mutation datasets of 21 types of cancers obtained from exome sequencing conducted by the TCGA project. Of the 3,622 genes that had ≥3 mutations in the regions with tertiary structure data, 106 genes showed significant skew in mutation distribution. Known tumor suppressors and oncogenes were significantly enriched in these identified cancer gene sets. Physical distances between mutations in known oncogenes were significantly smaller than those of tumor suppressors. Twenty-three genes were detected in multiple cancers. Candidate genes with significant skew of the 3D mutation distribution included kinases (MAPK1, EPHA5, ERBB3, and ERBB4), an apoptosis related gene (APP), an RNA splicing factor (SF1), a miRNA processing factor (DICER1), an E3 ubiquitin ligase (CUL1) and transcription factors (KLF5 and EEF1B2). Our study suggests that systematic analysis of mutation distribution in the tertiary protein structure can help identify cancer driver genes. PMID:27225414

  16. Malignant pheochromocytomas/paragangliomas harbor mutations in transport and cell adhesion genes.

    PubMed

    Wilzén, Annica; Rehammar, Anna; Muth, Andreas; Nilsson, Ola; Tešan Tomić, Tajana; Wängberg, Bo; Kristiansson, Erik; Abel, Frida

    2016-05-01

    One out of ten patients with pheochromocytoma (PCC) and paraganglioma (PGL) develop malignant disease. Today there are no reliable pathological methods to predict malignancy at the time of diagnosis. Tumors harboring mutations in the succinate dehydrogenase subunit B (SDHB) gene often metastasize but the sequential genetic events resulting in malignant progression are not fully understood. The aim of this study was to identify somatic mutations that contribute to the malignant transformation of PCC/PGL. We performed pair-wise (tumor-normal) whole-exome sequencing to analyze the somatic mutational landscape in five malignant and four benign primary PCC/sympathetic PGL (sPGL), including two biological replicates from each specimen. In total, 225 unique somatic mutations were identified in 215 genes, with an average mutation rate of 0.54 mutations/megabase. Malignant tumors had a significantly higher number of mutations compared to benign tumors (p < 0.001). Three novel genes were identified as recurrently mutated; MYCN, MYO5B and VCL, and mutations in these genes were exclusively found in malignant sPGL tumors. Mutations in the MYO5B gene could be verified in two publicly available data sets. A gene ontology analysis of mutated genes showed enrichment of cellular functions related to cytoskeletal protein binding, myosin complex and motor activity, many of which had functions in Rab and Rac/Rho GTPase pathways. In conclusion, we have identified recurrent mutations in genes related to intracellular transport and cell adhesion, and we have confirmed MYO5B to be recurrently mutated in PCC/PGL cases with malignant potential. Our study suggests that deregulated Rab and Rac/Rho pathways may be important in PCC/PGL tumorigenesis. PMID:26650627

  17. Identifying sarcomere gene mutations in hypertrophic cardiomyopathy: a personal history.

    PubMed

    Seidman, Christine E; Seidman, J G

    2011-03-18

    This review provides an historical and personal perspective on the discovery of genetic causes for hypertrophic cardiomyopathy (HCM). Extraordinary insights by physicians who initially detailed remarkable and varied manifestations of the disorder, collaboration among multidisciplinary teams with skills in clinical diagnostics and molecular genetics, and hard work by scores of trainees solved the etiologic riddle of HCM and unexpectedly demonstrated mutations in sarcomere protein genes as the cause of disease. In addition to celebrating 20 years of genetic research in HCM, this article serves as an introductory overview to a thematic review series that will present contemporary advances in the field of hypertrophic heart disease. Through the continued application of advances in genetic methodologies, combined with biochemical and biophysical analyses of the consequences of human mutations, fundamental knowledge about HCM and sarcomere biology has emerged. Expanding research to elucidate the mechanisms by which subtle genetic variation in contractile proteins remodel the human heart remains an exciting opportunity, one with considerable promise to provide new strategies to limit or even prevent HCM pathogenesis. PMID:21415408

  18. Identifying Sarcomere Gene Mutations in HCM: A Personal History

    PubMed Central

    Seidman, Christine E.; Seidman, J.G.

    2011-01-01

    This article provides an historical and personal perspective on the discovery of genetic causes for hypertrophic cardiomyopathy (HCM). Extraordinary insights of physicians who initially detailed remarkable and varied manifestations of the disorder, collaboration among multidisciplinary teams with skills in clinical diagnostics and molecular genetics, and hard work by scores of trainees, solved the etiologic riddle of HCM, and unexpectedly demonstrated mutations in sarcomere protein genes as the cause of disease. In addition to celebrating 20 years of genetic research in HCM, this article serves as an introductory overview to a thematic review series that will present contemporary advances in the field of hypertrophic heart disease. Through the continued application of advances in genetic methodologies, combined with biochemical and biophysical analyses of the consequences of human mutations, fundamental knowledge about HCM and sarcomere biology has emerged. Expanding research to elucidate the mechanisms by which subtle genetic variation in contractile proteins remodel the human heart remains an exciting opportunity, one with considerable promise to provide new strategies to limit or even prevent HCM pathogenesis. PMID:21415408

  19. Low load for disruptive mutations in autism genes and their biased transmission

    PubMed Central

    Iossifov, Ivan; Levy, Dan; Allen, Jeremy; Ye, Kenny; Ronemus, Michael; Lee, Yoon-ha; Yamrom, Boris; Wigler, Michael

    2015-01-01

    We previously computed that genes with de novo (DN) likely gene-disruptive (LGD) mutations in children with autism spectrum disorders (ASD) have high vulnerability: disruptive mutations in many of these genes, the vulnerable autism genes, will have a high likelihood of resulting in ASD. Because individuals with ASD have lower fecundity, such mutations in autism genes would be under strong negative selection pressure. An immediate prediction is that these genes will have a lower LGD load than typical genes in the human gene pool. We confirm this hypothesis in an explicit test by measuring the load of disruptive mutations in whole-exome sequence databases from two cohorts. We use information about mutational load to show that lower and higher intelligence quotients (IQ) affected individuals can be distinguished by the mutational load in their respective gene targets, as well as to help prioritize gene targets by their likelihood of being autism genes. Moreover, we demonstrate that transmission of rare disruptions in genes with a lower LGD load occurs more often to affected offspring; we show transmission originates most often from the mother, and transmission of such variants is seen more often in offspring with lower IQ. A surprising proportion of transmission of these rare events comes from genes expressed in the embryonic brain that show sharply reduced expression shortly after birth. PMID:26401017

  20. Moderate malnutrition in rats induces somatic gene mutations.

    PubMed

    Pacheco-Martínez, M Monserrat; Cortés-Barberena, Edith; Cervantes-Ríos, Elsa; Del Carmen García-Rodríguez, María; Rodríguez-Cruz, Leonor; Ortiz-Muñiz, Rocío

    2016-07-01

    The relationship between malnutrition and genetic damage has been widely studied in human and animal models, leading to the observation that interactions between genotoxic exposure and micronutrient status appear to affect genomic stability. A new assay has been developed that uses the phosphatidylinositol glycan class A gene (Pig-a) as a reporter for measuring in vivo gene mutation. The Pig-a assay can be employed to evaluate mutant frequencies (MFs) in peripheral blood reticulocytes (RETs) and erythrocytes (RBCs) using flow cytometry. In the present study, we assessed the effects of malnutrition on mutagenic susceptibility by exposing undernourished (UN) and well-nourished (WN) rats to N-ethyl-N-nitrosourea (ENU) and measuring Pig-a MFs. Two week-old UN and WN male Han-Wistar rats were treated daily with 0, 20, or 40mg/kg ENU for 3 consecutive days. Blood was collected from the tail vein one day before ENU treatment (Day-1) and after ENU administration on Days 7, 14, 21, 28, 35, 42, 49, 56 and 63. Pig-a MFs were measured in RETs and RBCs as the RET(CD59-) and RBC(CD59-) frequencies. In the vehicle control groups, the frequencies of mutant RETs and RBCs were significantly higher in UN rats compared with WN rats at all sampling times. The ENU treatments increased RET and RBC MFs starting at Day 7. Although ENU-induced Pig-a MFs were consistently lower in UN rats than in WN rats, these differences were not significant. To understand these responses, further studies should use other mutagens and nucleated surrogate cells and examine the types of mutations induced in UN and WN rats. PMID:26994962

  1. A novel large deletion mutation of FERMT1 gene in a Chinese patient with Kindler syndrome

    PubMed Central

    GAO, Ying; BAI, Jin-li; LIU, Xiao-yan; QU, Yu-jin; CAO, Yan-yan; WANG, Jian-cai; JIN, Yu-wei; WANG, Hong; SONG, Fang

    2015-01-01

    Kindler syndrome (KS; OMIM 173650) is a rare autosomal recessive skin disorder, which results in symptoms including blistering, epidermal atrophy, increased risk of cancer, and poor wound healing. The majority of mutations of the disease-determining gene (FERMT1 gene) are single nucleotide substitutions, including missense mutations, nonsense mutations, etc. Large deletion mutations are seldom reported. To determine the mutation in the FERMT1 gene associated with a 7-year-old Chinese patient who presented clinical manifestation of KS, we performed direct sequencing of all the exons of FERMT1 gene. For the exons 2–6 without amplicons, we analyzed the copy numbers using quantitative real-time polymerase chain reaction (qRT-PCR) with specific primers. The deletion breakpoints were sublocalized and the range of deletion was confirmed by PCR and direct sequencing. In this study, we identified a new 17-kb deletion mutation spanning the introns 1–6 of FERMT1 gene in a Chinese patient with severe KS phenotypes. Her parents were carriers of the same mutation. Our study reported a newly identified large deletion mutation of FERMT1 gene involved in KS, which further enriched the mutation spectrum of the FERMT1 gene. PMID:26537214

  2. Muscle imaging in muscle dystrophies produced by mutations in the EMD and LMNA genes.

    PubMed

    Díaz-Manera, Jordi; Alejaldre, Aida; González, Laura; Olivé, Montse; Gómez-Andrés, David; Muelas, Nuria; Vílchez, Juan José; Llauger, Jaume; Carbonell, Pilar; Márquez-Infante, Celedonio; Fernández-Torrón, Roberto; Poza, Juan José; López de Munáin, Adolfo; González-Quereda, Lidia; Mirabet, Sonia; Clarimon, Jordi; Gallano, Pía; Rojas-García, Ricard; Gallardo, Eduard; Illa, Isabel

    2016-01-01

    Identifying the mutated gene that produces a particular muscle dystrophy is difficult because different genotypes may share a phenotype and vice versa. Muscle MRI is a useful tool to recognize patterns of muscle involvement in patients with muscle dystrophies and to guide the diagnosis process. The radiologic pattern of muscle involvement in patients with mutations in the EMD and LMNA genes has not been completely established. Our objective is to describe the pattern of muscle fatty infiltration in patients with mutations in the EMD and in the LMNA genes and to search for differences between the two genotypes that could be helpful to guide the genetic tests. We conducted a national multicenter study in 42 patients, 10 with mutations in the EMD gene and 32 with mutations in the LMNA gene. MRI or CT was used to study the muscles from trunk to legs. Patients had a similar pattern of fatty infiltration regardless of whether they had the mutation in the EMD or LMNA gene. The main muscles involved were the paravertebral, glutei, quadriceps, biceps, semitendinosus, semimembranosus, adductor major, soleus, and gastrocnemius. Involvement of peroneus muscle, which was more frequently affected in patients with mutations in the EMD gene, was useful to differentiate between the two genotypes. Muscle MRI/CT identifies a similar pattern of muscle fatty infiltration in patients with mutations in the EMD or the LMNA genes. The involvement of peroneus muscles could be useful to conduct genetic analysis in patients with an EDMD phenotype. PMID:26573435

  3. An infrequent point mutation of the p53 gene in human nasopharyngeal carcinoma.

    PubMed Central

    Sun, Y; Hegamyer, G; Cheng, Y J; Hildesheim, A; Chen, J Y; Chen, I H; Cao, Y; Yao, K T; Colburn, N H

    1992-01-01

    Point mutations in the p53 gene have been detected in a variety of human cancers; the mutations are clustered in four "hot-spots" located in the coding region of exons 5, 7, and 8, which coincide with the four most highly conserved regions of the gene. We report the finding of a heterozygous G----C mutation at codon 280 (exon 8), position 2, of the p53 gene in a nasopharyngeal carcinoma (NPC) cell line, originating from Guangdong, a province in the People's Republic of China that leads the world in NPC incidence. A survey of nasopharyngeal tissues and NPC biopsies revealed that 1 out of 12 NPC samples from Hunan, another province in the People's Republic of China with high NPC incidence, had the same heterozygous mutation at codon 280 of p53, and none of 10 biopsies from Taiwan showed a mutation within exons 5-8 of the p53 gene. No other alteration of gene structure, including gross rearrangement or loss of heterozygosity or abnormality of gene expression was detected in NPC cell lines or NPC biopsies. We conclude from this study that mutational or other alterations of the p53 gene are not common in nasopharyngeal carcinogenesis and that a codon-280 mutation of p53 may be involved in less than 10% of NPC cases. This result contrasts with the relatively high frequency of p53 mutations associated with several other human carcinomas and suggests the importance of other genes in NPC genesis. Images PMID:1631151

  4. mutation3D: Cancer Gene Prediction Through Atomic Clustering of Coding Variants in the Structural Proteome.

    PubMed

    Meyer, Michael J; Lapcevic, Ryan; Romero, Alfonso E; Yoon, Mark; Das, Jishnu; Beltrán, Juan Felipe; Mort, Matthew; Stenson, Peter D; Cooper, David N; Paccanaro, Alberto; Yu, Haiyuan

    2016-05-01

    A new algorithm and Web server, mutation3D (http://mutation3d.org), proposes driver genes in cancer by identifying clusters of amino acid substitutions within tertiary protein structures. We demonstrate the feasibility of using a 3D clustering approach to implicate proteins in cancer based on explorations of single proteins using the mutation3D Web interface. On a large scale, we show that clustering with mutation3D is able to separate functional from nonfunctional mutations by analyzing a combination of 8,869 known inherited disease mutations and 2,004 SNPs overlaid together upon the same sets of crystal structures and homology models. Further, we present a systematic analysis of whole-genome and whole-exome cancer datasets to demonstrate that mutation3D identifies many known cancer genes as well as previously underexplored target genes. The mutation3D Web interface allows users to analyze their own mutation data in a variety of popular formats and provides seamless access to explore mutation clusters derived from over 975,000 somatic mutations reported by 6,811 cancer sequencing studies. The mutation3D Web interface is freely available with all major browsers supported. PMID:26841357

  5. Mutational screening of the USH2A gene in Spanish USH patients reveals 23 novel pathogenic mutations

    PubMed Central

    2011-01-01

    Background Usher Syndrome type II (USH2) is an autosomal recessive disorder, characterized by moderate to severe hearing impairment and retinitis pigmentosa (RP). Among the three genes implicated, mutations in the USH2A gene account for 74-90% of the USH2 cases. Methods To identify the genetic cause of the disease and determine the frequency of USH2A mutations in a cohort of 88 unrelated USH Spanish patients, we carried out a mutation screening of the 72 coding exons of this gene by direct sequencing. Moreover, we performed functional minigene studies for those changes that were predicted to affect splicing. Results As a result, a total of 144 DNA sequence variants were identified. Based upon previous studies, allele frequencies, segregation analysis, bioinformatics' predictions and in vitro experiments, 37 variants (23 of them novel) were classified as pathogenic mutations. Conclusions This report provide a wide spectrum of USH2A mutations and clinical features, including atypical Usher syndrome phenotypes resembling Usher syndrome type I. Considering only the patients clearly diagnosed with Usher syndrome type II, and results obtained in this and previous studies, we can state that mutations in USH2A are responsible for 76.1% of USH2 disease in patients of Spanish origin. PMID:22004887

  6. Extensive Variation in the Mutation Rate Between and Within Human Genes Associated with Mendelian Disease.

    PubMed

    Smith, Thomas; Ho, Gladys; Christodoulou, John; Price, Elizabeth Ann; Onadim, Zerrin; Gauthier-Villars, Marion; Dehainault, Catherine; Houdayer, Claude; Parfait, Beatrice; van Minkelen, Rick; Lohman, Dietmar; Eyre-Walker, Adam

    2016-05-01

    We have investigated whether the mutation rate varies between genes and sites using de novo mutations (DNMs) from three genes associated with Mendelian diseases (RB1, NF1, and MECP2). We show that the relative frequency of mutations at CpG dinucleotides relative to non-CpG sites varies between genes and relative to the genomic average. In particular we show that the rate of transition mutation at CpG sites relative to the rate of non-CpG transversion is substantially higher in our disease genes than amongst DNMs in general; the rate of CpG transition can be several hundred-fold greater than the rate of non-CpG transversion. We also show that the mutation rate varies significantly between sites of a particular mutational type, such as non-CpG transversion, within a gene. We estimate that for all categories of sites, except CpG transitions, there is at least a 30-fold difference in the mutation rate between the 10% of sites with the highest and lowest mutation rates. However, our best estimate is that the mutation rate varies by several hundred-fold variation. We suggest that the presence of hypermutable sites may be one reason certain genes are associated with disease. PMID:26857394

  7. UNSTABLE MUTATIONS IN THE FMR1 GENE AND THE PHENOTYPES

    PubMed Central

    Loesch, Danuta; Hagerman, Randi

    2014-01-01

    Fragile X syndrome (FXS), a severe neurodevelopmental anomaly, and one of the earliest disorders linked to an unstable (‘dynamic’) mutation, is caused by the large (>200) CGG repeat expansions in the noncoding portion of the FMR1 (Fragile X Mental Retardation-1) gene. These expansions, termed full mutations, normally silence this gene's promoter through methylation, leading to a gross deficit of the Fragile X Mental Retardation Protein (FMRP) that is essential for normal brain development. Rare individuals with the expansion but with an unmethylated promoter (and thus, FMRP production), present a much less severe form of FXS. However, a unique feature of the relationship between the different sizes of CGG expanded tract and phenotypic changes is that smaller expansions (<200) generate a series of different clinical manifestations and/or neuropsychological changes. The major part of this chapter is devoted to those FMR1 alleles with small (55-200) CGG expansions, termed ‘premutations’, which have the potential for generating the full mutation alleles on mother-offspring transmission, on the one hand, and are associated with some phenotypic changes, on the other. Thus, the role of several factors known to determine the rate of CGG expansion in the premutation alleles is discussed first. Then, an account of various neurodevelopmental, congnitive, behavioural and physical changes reported in carriers of these small expansions is given, and possible association of these conditions with a toxicity of the elevated FMR1 gene's transcript (mRNA) is discussed. The next two sections are devoted to major and well defined clinical conditions associated with the premutation alleles. The first one is the late onset neurodegenerative disorder termed fragile X-associated tremor ataxia syndrome (FXTAS). The wide range of clinical and neuropsychological manifestations of this syndrome, and their relevance to elevated levels of the FMR1 mRNA, are described. Another distinct disorder linked to the CGG repeat expansions within the premutation range is fragile X-associated primary ovarian insufficiency (FXPOI) in females, and an account of the spectrum of manifestations of this disorder, together with the latest findings suggesting an early onset of the ovarian changes, is given. In the following section, the most recent findings concerning the possible contribution of FMR1 ‘grey zone’ alleles (those with the smallest repeat expansions overlapping with the normal range i.e., 41-54 CGGs), to the psychological and clinical manifestations, already associated with premutation alleles, are discussed. Special emphasis has been placed on the possibility that the modest elevation of ‘toxic’ FMR1 mRNA in the carriers of grey zone alleles may present an additional risk for some neurodegenerative diseases, such as those associated with parkinsonism, by synergizing with either other susceptibility genes or environmental poisons. The present status of the treatment of fragile X-related disorders, especially FXS, is presented in the last section of this chapter. Pharmacological interventions in this syndrome have recently extended beyond stimulants and antipsychotic medications, and the latest trials involving a group of GluR5 antagonists aim to ascertain if these substances have the potential to reverse some of the neurobiological abnormalities of FXS. PMID:23560306

  8. Association of PAX2 and Other Gene Mutations with the Clinical Manifestations of Renal Coloboma Syndrome

    PubMed Central

    Higashide, Tomomi; Sakurai, Mayumi; Hashimoto, Shin-ichi; Shinozaki, Yasuyuki; Hara, Akinori; Iwata, Yasunori; Sakai, Norihiko; Sugiyama, Kazuhisa; Kaneko, Shuichi; Wada, Takashi

    2015-01-01

    Background Renal coloboma syndrome (RCS) is characterized by renal anomalies and optic nerve colobomas. PAX2 mutations contribute to RCS. However, approximately half of the patients with RCS have no mutation in PAX2 gene. Methods To investigate the incidence and effects of mutations of PAX2 and 25 candidate genes, patient genes were screened using next-generation sequence analysis, and candidate mutations were confirmed using Sanger sequencing. The correlation between mutations and clinical manifestation was evaluated. Result Thirty patients, including 26 patients (two families of five and two, 19 sporadic cases) with RCS, and 4 optic nerve coloboma only control cases were evaluated in the present study. Six PAX2 mutations in 21 probands [28%; two in family cohorts (n = 5 and n = 2) and in 4 out of 19 patients with sporadic disease] including four novel mutations were confirmed using Sanger sequencing. Moreover, four other sequence variants (CHD7, SALL4, KIF26B, and SIX4) were also confirmed, including a potentially pathogenic novel KIF26B mutation. Kidney function and proteinuria were more severe in patients with PAX2 mutations than in those without the mutation. Moreover, the coloboma score was significantly higher in patients with PAX2 gene mutations. Three out of five patients with PAX2 mutations had focal segmental glomerulosclerosis (FSGS) diagnosed from kidney biopsies. Conclusion The results of this study identify several new mutations of PAX2, and sequence variants in four additional genes, including a novel potentially pathogenic mutation in KIF26B, which may play a role in the pathogenesis of RCS. PMID:26571382

  9. Detecting recurrent gene mutation in interaction network context using multi-scale graph diffusion

    PubMed Central

    2013-01-01

    Background Delineating the molecular drivers of cancer, i.e. determining cancer genes and the pathways which they deregulate, is an important challenge in cancer research. In this study, we aim to identify pathways of frequently mutated genes by exploiting their network neighborhood encoded in the protein-protein interaction network. To this end, we introduce a multi-scale diffusion kernel and apply it to a large collection of murine retroviral insertional mutagenesis data. The diffusion strength plays the role of scale parameter, determining the size of the network neighborhood that is taken into account. As a result, in addition to detecting genes with frequent mutations in their genomic vicinity, we find genes that harbor frequent mutations in their interaction network context. Results We identify densely connected components of known and putatively novel cancer genes and demonstrate that they are strongly enriched for cancer related pathways across the diffusion scales. Moreover, the mutations in the clusters exhibit a significant pattern of mutual exclusion, supporting the conjecture that such genes are functionally linked. Using multi-scale diffusion kernel, various infrequently mutated genes are found to harbor significant numbers of mutations in their interaction network neighborhood. Many of them are well-known cancer genes. Conclusions The results demonstrate the importance of defining recurrent mutations while taking into account the interaction network context. Importantly, the putative cancer genes and networks detected in this study are found to be significant at different diffusion scales, confirming the necessity of a multi-scale analysis. PMID:23343428

  10. Identification of a novel mutation in the presenilin 1 gene in a Chinese Alzheimer's disease family.

    PubMed

    Deng, Bo; Lian, Yan; Wang, Xin; Zeng, Fan; Jiao, Bin; Wang, Ye-Ran; Liang, Chun-Rong; Liu, Yu-Hui; Bu, Xian-Le; Yao, Xiu-Qing; Zhu, Chi; Shen, Lu; Zhou, Hua-Dong; Zhang, Tao; Wang, Yan-Jiang

    2014-10-01

    This study has identified a gene mutation in a Chinese family with Alzheimer's disease (AD). Family members were screened by a set of medical examinations and neuropsychological tests. Their DNA was extracted from blood cells and sequenced for gene mutation in the amyloid precursor protein (APP), the presenilin 1 (PS1) and the presenilin 2 (PS2) genes. Genetic analysis showed that the AD patients in the family harbored a T to G missense mutation at the position 314 in exon 4 of the PS1 gene, resulting in a change of F105C in amino acid sequence. Clinical manifestation of these patients included memory loss, counting difficulty, personality change, disorientation, dyscalculia, agnosia, aphasia, and apraxia, which was similar to that of the familial AD (FAD) patients harboring other PS1 mutations. We intend to add a novel mutation F105C of the PS1 gene to the pool of FAD mutations. With the current available genetic data, mutations of the PS1 gene account for the majority of gene mutations in Chinese FAD. PMID:24737487

  11. A novel nonsense mutation in the WFS1 gene causes the Wolfram syndrome.

    PubMed

    Noorian, Shahab; Savad, Shahram; Mohammadi, Davood Shah

    2016-05-01

    Wolfram syndrome is a rare autosomal recessive neurodegenerative disorder, which is mostly caused by mutations in the WFS1 gene. The WFS1 gene product, which is called wolframin, is thought to regulate the function of endoplasmic reticulum. The endoplasmic reticulum has a critical role in protein folding and material transportation within the cell or to the surface of the cell. Identification of new mutations in WFS1 gene will unravel the molecular pathology of WS. The aim of this case report study is to describe a novel mutation in exon 4 of the WFS1 gene (c.330C>A) in a 9-year-old boy with WS. PMID:26943604

  12. Targeting cancer-specific mutations by T cell receptor gene therapy

    PubMed Central

    Blankenstein, Thomas; Leisegang, Matthias; Uckert, Wolfgang; Schreiber, Hans

    2015-01-01

    The ease of sequencing the cancer genome, identifying all somatic mutations and grafting mutation-specific T cell receptor (TCR) genes into T cells for adoptive transfer allow, for the first time, a truly tumor-specific and effective therapy. Mutation-specific TCR gene therapy might achieve optimal efficacy with least possible toxicity. Recent clinical data confirm the long-standing evidence from experimental cancer models that antigens encoded by the tumor-specific somatic mutations are potentially the best targets for adoptive T cell therapy. Open questions are, how many somatic mutations create suitable epitopes, whether only individual-specific or also recurrent somatic mutations qualify as suitable epitopes and how neoantigen-specific TCRs are most efficiently obtained. Tumor heterogeneity needs to be considered; therefore, it will be important to identify immunogenic driver mutations that occurred early, are essential for cancer cell survival and present in all cancer cells. PMID:25728991

  13. Spliceosomal gene mutations in myelodysplasia: molecular links to clonal abnormalities of hematopoiesis

    PubMed Central

    Inoue, Daichi; Bradley, Robert K.; Abdel-Wahab, Omar

    2016-01-01

    Genomic analyses of the myeloid malignancies and clonal disorders of hematopoiesis that may give rise to these disorders have identified that mutations in genes encoding core spliceosomal proteins and accessory regulatory splicing factors are among the most common targets of somatic mutations. These spliceosomal mutations often occur in a mutually exclusive manner with one another and, in aggregate, account for the most frequent class of mutations in patients with myelodysplastic syndromes (MDSs) in particular. Although substantial progress has been made in understanding the effects of several of these mutations on splicing and splice site recognition, functional connections linking the mechanistic changes in splicing induced by these mutations to the phenotypic consequences of clonal and aberrant hematopoiesis are not yet well defined. This review describes our current understanding of the mechanistic and biological effects of spliceosomal gene mutations in MDSs as well as the regulation of splicing throughout normal hematopoiesis. PMID:27151974

  14. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance.

    PubMed

    Rossi, A; Superti-Furga, A

    2001-03-01

    Mutations in the DTDST gene can result in a family of skeletal dysplasia conditions which comprise two lethal disorders, achondrogenesis type 1B (ACG1B) and atelosteogenesis type 2 (AO2); and two non-lethal disorders, diastrophic dysplasia (DTD) and recessive multiple epiphyseal dysplasia (rMED). The gene product is a sulfate-chloride exchanger of the cell membrane. Inactivation of the sulfate exchanger leads to intracellular sulfate depletion and to the synthesis of undersulfated proteoglycans in susceptible cells such as chondrocytes and fibroblasts. Genotype-phenotype correlations are recognizable, with mutations predicting a truncated protein or a non-conservative amino acid substitution in a transmembrane domain giving the severe phenotypes, and non-transmembrane amino acid substitutions and splice site mutations giving the milder phenotypes. The clinical phenotype is modulated strictly by the degree of residual activity. Over 30 mutations have been observed, including 22 novel mutations reported here. The most frequent mutation, 862C>T (R279W), is a mild mutation giving the rMED phenotype when homozygous and mostly DTD when compounded; occurrence at a CpG dinucleotide and its panethnic distribution suggest independent recurrence. Mutation IVS1+2T>C is the second most common mutation, but is very frequent in Finland. It produces low levels of correctly spliced mRNA, and results in DTD when homozygous. Two other mutations, 1045-1047delGTT (V340del) and 558C>T (R178X), are associated with severe phenotypes and have been observed in multiple patients. Most other mutations are rare. Heterozygotes are clinically unaffected. When clinical samples are screened for radiologic and histologic features compatible with the ACG1B/AO2/DTD/rMED spectrum prior to analysis, the mutation detection rate is high (over 90% of alleles), and appropriate genetic counseling can be given. The sulfate uptake or sulfate incorporation assays in cultured fibroblasts have largely been replaced by mutation analysis, but may still be useful in cases where mutation analysis is not informative. Although supplementation of patients' cultured cells with thiols may bypass the transporter defect and enhance sulfation of proteoglycans, therapeutic approaches are not yet available. Mouse models for this and other disorders of sulfate metabolism are being developed to help in developing therapeutic treatments. PMID:11241838

  15. Glucocerebrosidase gene L444P mutation is a risk factor for Parkinson's disease in Chinese population.

    PubMed

    Sun, Qi-Ying; Guo, Ji-Feng; Wang, Lei; Yu, Ren-He; Zuo, Xing; Yao, Ling-Yan; Pan, Qian; Xia, Kun; Tang, Bei-Sha

    2010-06-15

    An association between mutations in the glucocerebrosidase (GBA) gene and Parkinson's disease (PD) has been reported in several populations. We searched for four common GBA mutations (L444P, F213I, R353W, and N370S) in 402 Chinese PD patients and 413 age- and sex-matched controls. In the PD cohort, 11 patients were found carrying a heterozygous GBA mutation and all of them had the L444P mutation. Heterozygous GBA mutations were detected none in controls. The GBA gene L444P mutation was detected at a significantly higher frequency among PD patients (11/402 = 2.74%), when compared with the control group (0/413): P = 0.0007. To evaluate the possible role of the GBA gene L444P mutation in PD in Ashkenazi Jewish and non-Jewish populations, we conducted a meta-analysis on the topic. In the Chinese population, the GBA gene L444P mutation was detected at a significantly higher frequency among PD patients, when compared with the control group: Z = 3.83, P = 0.0001, OR = 8.42, confidence interval = 95%, 2.83-25.06. In the non-Jewish populations, the difference was obviously significant: Z = 5.76, P < 0.00001, OR = 8.82, confidence interval = 95%, 4.21-18.48. The results suggest that the GBA gene L444P mutation appears to be a risk factor for PD in Chinese population. PMID:20131388

  16. Compound EGFR mutation is frequently detected with co-mutations of actionable genes and associated with poor clinical outcome in lung adenocarcinoma.

    PubMed

    Kim, Eun Young; Cho, Eun Na; Park, Heae Surng; Hong, Ji Young; Lim, Seri; Youn, Jong Pil; Hwang, Seung Yong; Chang, Yoon Soo

    2016-03-01

    Compound EGFR mutations, defined as double or multiple mutations in the EGFR tyrosine kinase domain, are frequently detected with advances in sequencing technology but its clinical significance is unclear. This study analyzed 61 cases of EGFR mutation positive lung adenocarcinoma using next-generation sequencing (NGS) based repeated deep sequencing panel of 16 genes that contain actionable mutations and investigated clinical implication of compound EGFR mutations. Compound EGFR mutation was detected in 15 (24.6%) of 61 cases of EGFR mutation-positive lung adenocarcinoma. The majority (12/15) of compound mutations are combination of the atypical mutation and typical mutations such as exon19 deletion, L858R or G719X substitutions, or exon 20 insertion whereas 3 were combinations of rare atypical mutations. The patients with compound mutation showed shorter overall survival than those with simple mutations (83.7 vs. 72.8 mo; P = 0.020, Breslow test). Among the 115 missense mutations discovered in the tested genes, a few number of actionable mutations were detected irrelevant to the subtype of EGFR mutations, including ALK rearrangement, BCL2L11 intron 2 deletion, KRAS c.35G>A, PIK3CA c.1633G>A which are possible target of crizotinib, BH3 mimetics, MEK inhibitors, and PI3K-tyrosine kinase inhibitors, respectively. 31 missense mutations were detected in the cases with simple mutations whereas 84 in those with compound mutation, showing that the cases with compound missense mutation have higher burden of missense mutations (P = 0.001, independent sample t-test). Compound EGFR mutations are detected at a high frequency using NGS-based repeated deep sequencing. Because patients with compound EGFR mutations showed poor clinical outcomes, they should be closely monitored during follow-up. PMID:26785607

  17. Compound EGFR mutation is frequently detected with co-mutations of actionable genes and associated with poor clinical outcome in lung adenocarcinoma

    PubMed Central

    Kim, Eun Young; Cho, Eun Na; Park, Heae Surng; Hong, Ji Young; Lim, Seri; Youn, Jong Pil; Hwang, Seung Yong; Chang, Yoon Soo

    2016-01-01

    Compound EGFR mutations, defined as double or multiple mutations in the EGFR tyrosine kinase domain, are frequently detected with advances in sequencing technology but its clinical significance is unclear. This study analyzed 61 cases of EGFR mutation positive lung adenocarcinoma using next-generation sequencing (NGS) based repeated deep sequencing panel of 16 genes that contain actionable mutations and investigated clinical implication of compound EGFR mutations. Compound EGFR mutation was detected in 15 (24.6%) of 61 cases of EGFR mutation-positive lung adenocarcinoma. The majority (12/15) of compound mutations are combination of the atypical mutation and typical mutations such as exon19 deletion, L858R or G719X substitutions, or exon 20 insertion whereas 3 were combinations of rare atypical mutations. The patients with compound mutation showed shorter overall survival than those with simple mutations (83.7 vs. 72.8 mo; P = 0.020, Breslow test). Among the 115 missense mutations discovered in the tested genes, a few number of actionable mutations were detected irrelevant to the subtype of EGFR mutations, including ALK rearrangement, BCL2L11 intron 2 deletion, KRAS c.35G>A, PIK3CA c.1633G>A which are possible target of crizotinib, BH3 mimetics, MEK inhibitors, and PI3K-tyrosine kinase inhibitors, respectively. 31 missense mutations were detected in the cases with simple mutations whereas 84 in those with compound mutation, showing that the cases with compound missense mutation have higher burden of missense mutations (P = 0.001, independent sample t-test). Compound EGFR mutations are detected at a high frequency using NGS-based repeated deep sequencing. Because patients with compound EGFR mutations showed poor clinical outcomes, they should be closely monitored during follow-up. PMID:26785607

  18. Polymorphisms in the methylene tetrahydrofolate reductase and methionine synthase reductase genes and their correlation with unexplained recurrent spontaneous abortion susceptibility.

    PubMed

    Zhu, L

    2015-01-01

    We aimed to explore the correlation between unexplained recurrent spontaneous abortion and polymorphisms in the methylene tetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) genes. A case control study was conducted in 118 patients with unexplained recurrent spontaneous abortion (abortion group) and 174 healthy women (control group). The genetic material was extracted from the oral mucosal epithelial cells obtained from all subjects. The samples were subjected to fluorescence quantitative PCR to detect the single nucleotide polymorphisms (SNPs) in the MTHFR (C677T and A1298C) and MTRR (A66G) gene loci. The distribution frequency (18/118, 15.3%) of the MTHFR 677TT genotype was significantly higher in the abortion group (χ2 = 11.006, P = 0.004) than in the control group (2/174, 1.1%); on the other hand, the distribution frequency of the MTHFR A1298C genotype did not significantly differ between the abortion and control groups (χ(2) = 0.441, P = 0.507). The distribution frequency of the MTRR A66G genotype was also significantly higher in the abortion group (14/118, 11.9%; χ(2) = 10.503, P = 0.005) than in the control group (8/174, 4.6%). The MTHFR C677T and MTRR A66G polymorphisms are significantly correlated with the occurrence of spontaneous abortion. PMID:26345779

  19. Stability of p53 tumor suppressor gene mutations during the process of metastasis and during chemotherapy.

    PubMed

    Taniguchi, Y; Gemma, A; Takeda, Y; Takenaka, K; Niitani, H; Kudoh, S; Shimada, T

    1996-06-01

    We analyzed 29 pairs of primary and metastatic lung carcinomas obtained at autopsy for mutations in the p53 gene, using the polymerase chain reaction-single strand conformation polymorphism method (PCR-SSCP). We examined the relationship between p53 gene mutations and the development of metastasis, and the stability of p53 gene mutations during chemotherapy. The tumors consisted of six small cell carcinomas, 13 adenocarcinomas, eight squamous cell carcinomas, one large cell carcinoma, and one adeno-squamous cell carcinoma. PCR-SSCP analysis showed that three small cell carcinomas (50%), three adenocarcinomas (23%), two squamous cell carcinomas (25%), and one large cell carcinoma (100%) had p53 gene mutations. All these abnormalities were found between exon five and exon eight. The mutations in the primary tumors and the metastatic tumors were identical. These results suggest that p53 gene mutations occur before distant metastases develop, and that they may be stable during the process of metastasis. There were nine metastatic tumor samples that existed before the patients received chemotherapy. These samples showed identical p53 mutations as the corresponding primary tumor. This suggests that anticancer drugs rarely induce p53 gene mutations. PMID:8794405

  20. A proportion of patients with lymphoma may harbor mutations of the perforin gene.

    PubMed

    Clementi, Rita; Locatelli, Franco; Dupré, Loïc; Garaventa, Alberto; Emmi, Lorenzo; Bregni, Marco; Cefalo, Graziella; Moretta, Antonia; Danesino, Cesare; Comis, Margherita; Pession, Andrea; Ramenghi, Ugo; Maccario, Rita; Aricò, Maurizio; Roncarolo, Maria Grazia

    2005-06-01

    Perforin mutations have been demonstrated in a proportion of patients diagnosed with the familial form of hemophagocytic lymphohistiocytosis (HLH). In the present study, we evaluated whether some patients with lymphoma sharing clinical characteristics with HLH might harbor mutations of the perforin gene. We analyzed 29 patients and found that 4 patients, who developed either Hodgkin or non-Hodgkin lymphoma, had biallelic mutations of the perforin gene. One of these 4 patients, a 19-year-old female with T-cell lymphoma, had a brother carrying the same mutations who developed HLH. In 2 of the 4 patients with biallelic mutations of the perforin gene, we evaluated perforin expression by flow cytometry and natural killer (NK) activity and both were found to be absent. Moreover, we documented the presence of monoallelic mutations of the perforin gene in 4 more patients. One of these 4 latter patients also carried a mutation of the Fas gene. These data indicate that perforin deficiency, either alone or in combination with other mutations of genes involved in lymphocyte survival or functional activity, may be present in patients with lymphoma. These findings suggest that perforin also plays a key role in the mechanisms of immune surveillance that prevent tumor growth and/or development. PMID:15728124

  1. Polymorphism analysis and new JAG1 gene mutations of Alagille syndrome in Mexican population☆

    PubMed Central

    Vázquez-Martínez, Edgar Ricardo; Varela-Fascinetto, Gustavo; García-Delgado, Constanza; Rodríguez-Espino, Benjamín Antonio; Sánchez-Boiso, Adriana; Valencia-Mayoral, Pedro; Heller-Rosseau, Solange; Pelcastre-Luna, Erika Lisselly; Zenteno, Juan C.; Cerbón, Marco; Morán-Barroso, Verónica Fabiola

    2013-01-01

    Alagille syndrome is a multisystem disorder with an autosomic dominant pattern of inheritance that affects the liver, heart, eyes, kidneys, skeletal system and presents characteristic facial features. Mutations of the JAG1 gene have been identified in 20–89% of the patients with Alagille syndrome, this gene encodes for a ligand that activates the Notch signaling pathway. In the present study we analyzed 9 Mexican patients with Alagille syndrome who presented the clinical criteria for the classical presentation of the disease. By using the denaturing high performance liquid chromatography mutation analysis we were able to identify different mutations in 7 of the patients (77.77%), importantly, we found 5 novel mutations in JAG1 gene. The allelic frequency distribution of 13 polymorphisms in Mexican population is also reported. The overall results demonstrated an expanding mutational spectrum of JAG1 gene in the Mexican population. PMID:25606387

  2. Mutations in origin recognition complex gene ORC4 cause Meier-Gorlin syndrome.

    PubMed

    Guernsey, Duane L; Matsuoka, Makoto; Jiang, Haiyan; Evans, Susan; Macgillivray, Christine; Nightingale, Mathew; Perry, Scott; Ferguson, Meghan; LeBlanc, Marissa; Paquette, Jean; Patry, Lysanne; Rideout, Andrea L; Thomas, Aidan; Orr, Andrew; McMaster, Chris R; Michaud, Jacques L; Deal, Cheri; Langlois, Sylvie; Superneau, Duane W; Parkash, Sandhya; Ludman, Mark; Skidmore, David L; Samuels, Mark E

    2011-04-01

    Meier-Gorlin syndrome is a rare autosomal recessive genetic condition whose primary clinical hallmarks include small stature, small external ears and small or absent patellae. Using marker-assisted mapping in multiple families from a founder population and traditional coding exon sequencing of positional candidate genes, we identified three different mutations in the gene encoding ORC4, a component of the eukaryotic origin recognition complex, in five individuals with Meier-Gorlin syndrome. In two such individuals that were negative for mutations in ORC4, we found potential mutations in ORC1 and CDT1, two other genes involved in origin recognition. ORC4 is well conserved in eukaryotes, and the yeast equivalent of the human ORC4 missense mutation was shown to be pathogenic in functional assays of cell growth. This is the first report, to our knowledge, of a germline mutation in any gene of the origin recognition complex in a vertebrate organism. PMID:21358631

  3. Polymorphism analysis and new JAG1 gene mutations of Alagille syndrome in Mexican population.

    PubMed

    Vzquez-Martnez, Edgar Ricardo; Varela-Fascinetto, Gustavo; Garca-Delgado, Constanza; Rodrguez-Espino, Benjamn Antonio; Snchez-Boiso, Adriana; Valencia-Mayoral, Pedro; Heller-Rosseau, Solange; Pelcastre-Luna, Erika Lisselly; Zenteno, Juan C; Cerbn, Marco; Morn-Barroso, Vernica Fabiola

    2014-12-01

    Alagille syndrome is a multisystem disorder with an autosomic dominant pattern of inheritance that affects the liver, heart, eyes, kidneys, skeletal system and presents characteristic facial features. Mutations of the JAG1 gene have been identified in 20-89% of the patients with Alagille syndrome, this gene encodes for a ligand that activates the Notch signaling pathway. In the present study we analyzed 9 Mexican patients with Alagille syndrome who presented the clinical criteria for the classical presentation of the disease. By using the denaturing high performance liquid chromatography mutation analysis we were able to identify different mutations in 7 of the patients (77.77%), importantly, we found 5 novel mutations in JAG1 gene. The allelic frequency distribution of 13 polymorphisms in Mexican population is also reported. The overall results demonstrated an expanding mutational spectrum of JAG1 gene in the Mexican population. PMID:25606387

  4. Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities

    PubMed Central

    Gao, Yang; Liu, Xiaoyan; Gao, Kai; Xie, Han; Wu, Ye; Zhang, Yuehua; Wang, Jingmin; Gao, Feng; Wu, Xiru; Jiang, Yuwu

    2015-01-01

    Objective Epilepsy and intellectual/developmental disabilities (ID/DD) have a high rate of co-occurrence. Here, we investigated gene mutations in Chinese children with unexplained epilepsy and ID/DD. Methods We used targeted next-generation sequencing to detect mutations within 300 genes related to epilepsy and ID/DD in 253 Chinese children with unexplained epilepsy and ID/DD. A series of filtering criteria was used to find the possible pathogenic variations. Validation and parental origin analyses were performed by Sanger sequencing. We reviewed the phenotypes of patients with each mutated gene. Results We identified 32 novel and 16 reported mutations within 24 genes in 46 patients. The detection rate was 18% (46/253) in the whole group and 26% (17/65) in the early-onset (before three months after birth) epilepsy group. To our knowledge, we are the first to report KCNAB1 is a disease-causing gene of epilepsy by identifying a novel de novo mutation (c.1062dupCA p.Leu355HisfsTer5) within this gene in one patient with early infantile epileptic encephalopathy (EIEE). Patients with an SCN1A mutation accounted for the largest proportion, 17% (8/46). A total of 38% (9/24) of the mutated genes re-occurred at least 2 times and 63% (15/24) occurred only one time. Ion channel genes are the most common (8/24) and genes related to synapse are the next most common to occur (5/24). Significance We have established genetic diagnosis for 46 patients of our cohort. Early-onset epilepsy had the highest detection rate. KCNAB1 mutation was first identified in EIEE patient. We expanded the phenotype and mutation spectrum of the genes we identified. The mutated genes in this cohort are mostly isolated. This suggests that epilepsy and ID/DD phenotypes occur as a consequence of brain dysfunction caused by a highly diverse population of mutated genes. Ion channel genes and genes related to synapse were more common mutated in this patient cohort. PMID:26544041

  5. Analysis of catechol-O-methyltransferase gene mutation and identification of new pathogenic gene for paroxysmal kinesigenic dyskinesia.

    PubMed

    Gu, Chengzhi; Li, Jia; Zhu, Lianhai; Lu, Zhenhui; Huang, Huaiyu

    2016-03-01

    We aimed to analyze the mutation site and frequency of catechol-O-methyltransferase (COMT) gene, to explore the relationship between COMT genotype and phenotype, and to find new pathogenic genes for paroxysmal kinesigenic dyskinesia (PKD). PKD patients who were treated from December 2011 to January 2014 were selected and subjected to genetic testing in the exon region of COMT. Two patients and one intrafamilial healthy control were subjected to exome sequencing using whole exome capture in combination with high-throughput sequencing to find candidate pathogenic gene sites. The results were verified by Sanger sequencing. A total of 11 familial PKD patients from 4 families and 9 sporadic patients without family history were included. Pathogenic c.634dupC(p.P220fsX7) mutation of COMT gene was found in 7 familial PKD patients and3 sporadic patients. Mutated COMT gene carriers suffered from PKD earlier (average age of onset: 11.61 ± 2.33 vs 16.21 ± 2.58, P = 0.001) with symmetric symptoms in most cases, while the mutation-negative group only showed unilateral symptoms (P = 0.001). The mutation-positive group also had more daily attacks (P = 0.038). Carbamazepine worked for all mutation-positive patients (10/10, 100 %), but only for a part of mutation-negative patients (3/10, 30.0 %). About 90000 single nucleotide polymorphisms and 2000 insertion-deletion polymorphisms were detected in each of the three samples. c.737C → T(p.T246 M) mutation of POC1B gene was a new pathogenic site for a selected family. COMT gene mutation, which was the pathogenesis of most familial PKD patients and a part of sporadic patients, predicted the response to carbamazepine. POC1B may be a novel pathogenic gene for PKD. PMID:26650803

  6. EpilepsyGene: a genetic resource for genes and mutations related to epilepsy

    PubMed Central

    Ran, Xia; Li, Jinchen; Shao, Qianzhi; Chen, Huiqian; Lin, Zhongdong; Sun, Zhong Sheng; Wu, Jinyu

    2015-01-01

    Epilepsy is one of the most prevalent chronic neurological disorders, afflicting about 3.5–6.5 per 1000 children and 10.8 per 1000 elderly people. With intensive effort made during the last two decades, numerous genes and mutations have been published to be associated with the disease. An organized resource integrating and annotating the ever-increasing genetic data will be imperative to acquire a global view of the cutting-edge in epilepsy research. Herein, we developed EpilepsyGene (http://61.152.91.49/EpilepsyGene). It contains cumulative to date 499 genes and 3931 variants associated with 331 clinical phenotypes collected from 818 publications. Furthermore, in-depth data mining was performed to gain insights into the understanding of the data, including functional annotation, gene prioritization, functional analysis of prioritized genes and overlap analysis focusing on the comorbidity. An intuitive web interface to search and browse the diversified genetic data was also developed to facilitate access to the data of interest. In general, EpilepsyGene is designed to be a central genetic database to provide the research community substantial convenience to uncover the genetic basis of epilepsy. PMID:25324312

  7. EpilepsyGene: a genetic resource for genes and mutations related to epilepsy.

    PubMed

    Ran, Xia; Li, Jinchen; Shao, Qianzhi; Chen, Huiqian; Lin, Zhongdong; Sun, Zhong Sheng; Wu, Jinyu

    2015-01-01

    Epilepsy is one of the most prevalent chronic neurological disorders, afflicting about 3.5-6.5 per 1000 children and 10.8 per 1000 elderly people. With intensive effort made during the last two decades, numerous genes and mutations have been published to be associated with the disease. An organized resource integrating and annotating the ever-increasing genetic data will be imperative to acquire a global view of the cutting-edge in epilepsy research. Herein, we developed EpilepsyGene (http://61.152.91.49/EpilepsyGene). It contains cumulative to date 499 genes and 3931 variants associated with 331 clinical phenotypes collected from 818 publications. Furthermore, in-depth data mining was performed to gain insights into the understanding of the data, including functional annotation, gene prioritization, functional analysis of prioritized genes and overlap analysis focusing on the comorbidity. An intuitive web interface to search and browse the diversified genetic data was also developed to facilitate access to the data of interest. In general, EpilepsyGene is designed to be a central genetic database to provide the research community substantial convenience to uncover the genetic basis of epilepsy. PMID:25324312

  8. Phenylalanine hydroxylase gene mutations in the United States: report from the Maternal PKU Collaborative Study.

    PubMed Central

    Guldberg, P.; Levy, H. L.; Hanley, W. B.; Koch, R.; Matalon, R.; Rouse, B. M.; Trefz, F.; de la Cruz, F.; Henriksen, K. F.; Güttler, F.

    1996-01-01

    The major cause of hyperphenylalaninemia is mutations in the gene encoding phenylalanine hydroxylase (PAH). The known mutations have been identified primarily in European patients. The purpose of this study was to determine the spectrum of mutations responsible for PAH deficiency in the United States. One hundred forty-nine patients enrolled in the Maternal PKU Collaborative Study were subjects for clinical and molecular investigations. PAH gene mutations associated with phenylketonuria (PKU) or mild hyperphenylalaninemia (MHP) were identified on 279 of 294 independent mutant chromosomes, a diagnostic efficiency of 95%. The spectrum is composed of 71 different mutations, including 47 missense mutations, 11 splice mutations, 5 nonsense mutations, and 8 microdeletions. Sixteen previously unreported mutations were identified. Among the novel mutations, five were found in patients with MHP, and the remainder were found in patients with PKU. The most common mutations were R408W, IVS12nt1g-->a, and Y414C, accounting for 18.7%, 7.8%, and 5.4% of the mutant chromosomes, respectively. Thirteen mutations had relative frequencies of 1%-5%, and 55 mutations each had frequencies < or = 1%. The mutational spectrum corresponded to that observed for the European ancestry of the U.S. population. To evaluate the extent of allelic variation at the PAH locus within the United States in comparison with other populations, we used allele frequencies to calculate the homozygosity for 11 populations where >90% ascertainment of mutations has been obtained. The United States was shown to contain one of the most heterogeneous populations, with homozygosity values similar to Sicily and ethnically mixed sample populations in Europe. The extent of allelic heterogeneity must be a major determining factor in the choice of mutation-detection methodology for molecular diagnosis in PAH deficiency. Images Figure 1 PMID:8659548

  9. Novel mutations in the USH1C gene in Usher syndrome patients

    PubMed Central

    Aparisi, María José; García-García, Gema; Jaijo, Teresa; Rodrigo, Regina; Graziano, Claudio; Seri, Marco; Simsek, Tulay; Simsek, Enver; Bernal, Sara; Baiget, Montserrat; Pérez-Garrigues, Herminio; Millán, José María

    2010-01-01

    Purpose Usher syndrome type I (USH1) is an autosomal recessive disorder characterized by severe-profound sensorineural hearing loss, retinitis pigmentosa, and vestibular areflexia. To date, five USH1 genes have been identified. One of these genes is Usher syndrome 1C (USH1C), which encodes a protein, harmonin, containing PDZ domains. The aim of the present work was the mutation screening of the USH1C gene in a cohort of 33 Usher syndrome patients, to identify the genetic cause of the disease and to determine the relative involvement of this gene in USH1 pathogenesis in the Spanish population. Methods Thirty-three patients were screened for mutations in the USH1C gene by direct sequencing. Some had already been screened for mutations in the other known USH1 genes (myosin VIIA [MYO7A], cadherin-related 23 [CDH23], protocadherin-related 15 [PCDH15], and Usher syndrome 1G [USH1G]), but no mutation was found. Results Two novel mutations were found in the USH1C gene: a non-sense mutation (p.C224X) and a frame-shift mutation (p.D124TfsX7). These mutations were found in a homozygous state in two unrelated USH1 patients. Conclusions In the present study, we detected two novel pathogenic mutations in the USH1C gene. Our results suggest that mutations in USH1C are responsible for 1.5% of USH1 disease in patients of Spanish origin (considering the total cohort of 65 Spanish USH1 patients since 2005), indicating that USH1C is a rare form of USH in this population. PMID:21203349

  10. Mutation analysis of 13 driver genes of colorectal cancer-related pathways in Taiwanese patients

    PubMed Central

    Chang, Yuli Christine; Chang, Jan-Gowth; Liu, Ta-Chih; Lin, Chien-Yu; Yang, Shu-Fen; Ho, Cheng-Mao; Chen, William Tzu-Liang; Chang, Ya-Sian

    2016-01-01

    AIM: To investigate the driver gene mutations associated with colorectal cancer (CRC) in the Taiwanese population. METHODS: In this study, 103 patients with CRC were evaluated. The samples consisted of 66 men and 37 women with a median age of 59 years and an age range of 26-86 years. We used high-resolution melting analysis (HRM) and direct DNA sequencing to characterize the mutations in 13 driver genes of CRC-related pathways. The HRM assays were conducted using the LightCycler® 480 Instrument provided with the software LightCycler® 480 Gene Scanning Software Version 1.5. We also compared the clinicopathological data of CRC patients with the driver gene mutation status. RESULTS: Of the 103 patients evaluated, 73.79% had mutations in one of the 13 driver genes. We discovered 18 novel mutations in APC, MLH1, MSH2, PMS2, SMAD4 and TP53 that have not been previously reported. Additionally, we found 16 de novo mutations in APC, BMPR1A, MLH1, MSH2, MSH6, MUTYH and PMS2 in cancerous tissues previously reported in the dbSNP database; however, these mutations could not be detected in peripheral blood cells. The APC mutation correlates with lymph node metastasis (34.69% vs 12.96%, P = 0.009) and cancer stage (34.78% vs 14.04%, P = 0.013). No association was observed between other driver gene mutations and clinicopathological features. Furthermore, having two or more driver gene mutations correlates with the degree of lymph node metastasis (42.86% vs 24.07%, P = 0.043). CONCLUSION: Our findings confirm the importance of 13 CRC-related pathway driver genes in the development of CRC in Taiwanese patients. PMID:26900293

  11. Somatic frameshift mutations in the Bloom syndrome BLM gene are frequent in sporadic gastric carcinomas with microsatellite mutator phenotype

    PubMed Central

    Calin, George; Ranzani, Guglielmina N; Amadori, Dino; Herlea, Vlad; Matei, Irina; Barbanti-Brodano, Giuseppe; Negrini, Massimo

    2001-01-01

    Background Genomic instability has been reported at microsatellite tracts in few coding sequences. We have shown that the Bloom syndrome BLM gene may be a target of microsatelliteinstability (MSI) in a short poly-adenine repeat located in its coding region. To further characterize the involvement of BLM in tumorigenesis, we have investigated mutations in nine genes containing coding microsatellites in microsatellite mutator phenotype (MMP) positive and negative gastric carcinomas (GCs). Methods We analyzed 50 gastric carcinomas (GCs) for mutations in the BLM poly(A) tract aswell as in the coding microsatellites of the TGFβ1-RII, IGFIIR, hMSH3, hMSH6, BAX, WRN, RECQL and CBL genes. Results BLM mutations were found in 27% of MMP+ GCs (4/15 cases) but not in any of the MMP negative GCs (0/35 cases). The frequency of mutations in the other eight coding regions microsatellite was the following: TGFβ1-RII (60 %), BAX (27%), hMSH6 (20%),hMSH3 (13%), CBL (13%), IGFIIR (7%), RECQL (0%) and WRN (0%). Mutations in BLM appear to be more frequently associated with frameshifts in BAX and in hMSH6and/or hMSH3. Tumors with BLM alterations present a higher frequency of unstable mono- and trinucleotide repeats located in coding regions as compared with mutator phenotype tumors without BLM frameshifts. Conclusions BLM frameshifts are frequent alterations in GCs specifically associated with MMP+tumors. We suggest that BLM loss of function by MSI may increase the genetic instability of a pre-existent unstable genotype in gastric tumors. PMID:11532193

  12. Next-generation sequencing identifies novel CACNA1A gene mutations in episodic ataxia type 2.

    PubMed

    Maksemous, Neven; Roy, Bishakha; Smith, Robert A; Griffiths, Lyn R

    2016-03-01

    Episodic Ataxia type 2 (EA2) is a rare autosomal dominantly inherited neurological disorder characterized by recurrent disabling imbalance, vertigo, and episodes of ataxia lasting minutes to hours. EA2 is caused most often by loss of function mutations of the calcium channel gene CACNA1A. In addition to EA2, mutations in CACNA1A are responsible for two other allelic disorders: familial hemiplegic migraine type 1 (FHM1) and spinocerebellar ataxia type 6 (SCA6). Herein, we have utilized next-generation sequencing (NGS) to screen the coding sequence, exon-intron boundaries, and Untranslated Regions (UTRs) of five genes where mutation is known to produce symptoms related to EA2, including CACNA1A. We performed this screening in a group of 31 unrelated patients with EA2 symptoms. Both novel and known mutations were detected through NGS technology, and confirmed through Sanger sequencing. Genetic testing showed in total 15 mutation bearing patients (48%), of which nine were novel mutations (6 missense and 3 small frameshift deletion mutations) and six known mutations (4 missense and 2 nonsense).These results demonstrate the efficiency of our NGS-panel for detecting known and novel mutations for EA2 in the CACNA1A gene, also identifying a novel missense mutation in ATP1A2 which is not a normal target for EA2 screening. PMID:27066515

  13. Investigation of the gene mutations in two Chinese families with X-linked infantile nystagmus

    PubMed Central

    Li, Ningdong; Wang, Xiaojuan; Wang, Yuchuan; Wang, Liming; Ying, Ming; Han, Ruifang; Liu, Yuyan

    2011-01-01

    Purpose To identify the gene mutations causing X-linked infantile nystagmus in two Chinese families (NYS003 and NYS008), of which the NYS003 family was assigned to the FERM domain–containing 7 (FRMD7) gene linked region in our previous study, and no mutations were found by direct sequencing. Methods Two microsatellites, DXS1047 and DXS1001, were amplified using a PCR reaction for the linkage study in the NYS008 family. FRMD7 was sequenced and mutations were analyzed. Multiplex ligation-dependent probe amplification (MLPA) was used to detect FRMD7 mutations in the NYS003 family. Results The NYS008 family yielded a maximum logarithm of odds (LOD) score of 1.91 at θ=0 with DXS1001. FRMD7 sequencing showed a nucleotide change of c. 623A>G in exon7 of the patients’ FRMD7 gene, which was predicted to result in an H208R amino acid change. This novel mutation was absent in 100 normal Han Chinese controls. No FRMD7 gene mutations were detected by MLPA in the NYS003 family. Conclusions We identified a novel mutation, c. 623A>G (p. H208R), in a Han Chinese family with infantile nystagmus. This mutation expands the mutation spectrum of FRMD7 and contributes to the research on the molecular pathogenesis of FRMD7. PMID:21365021

  14. Congenital nephrogenic diabetes insipidus with a novel mutation in the aquaporin 2 gene

    PubMed Central

    PARK, YOUN JONG; BAIK, HAING WOON; CHEONG, HAE IL; KANG, JU HYUNG

    2014-01-01

    Congenital nephrogenic diabetes insipidus (CNDI) is a rare disorder caused by mutations of the arginine vasopressin (AVP) V2 receptor or aquaporin 2 (AQP2) genes. The current study presented the case of CNDI in a 1-month-old male with a novel mutation in the AQP2 gene. The patient was referred due to the occurrence of hypernatremia and mild-intermittent fever since birth. An AVP stimulation test was compatible with CNDI as there was no significant response to desmopressin. Molecular genetic analysis demonstrated two mutations in exon 1 of the AQP2 gene: C to T transition, which resulted in a missense mutation of 108Thr (ACG) to Met (ATG); and a 127, 128 delCA, which resulted in a deletion mutation of glutamine in position 43 at codon CAG as the first affected amino acid, with the new reading frame endign in a termination codon at position 62. The molecular genetic analysis of the parents showed that the missense mutation was inherited maternally and the deletion mutation was inherited paternally. The parents showed no signs or symptoms of CNDI, indicating autosomal recessive inheritance. The 108Thr (ACG) to Met (ATG) mutation was confirmed as a novel mutation. Therefore, the molecular identification of the AQP2 gene has clinical significance, as early recognition of CNDI in infants that show only non-specific symptoms, can be facilitated. Thus, repeated episodes of dehydration, which may cause physical and mental retardation can be avoided. PMID:24944815

  15. Congenital nephrogenic diabetes insipidus with a novel mutation in the aquaporin 2 gene.

    PubMed

    Park, Youn Jong; Baik, Haing Woon; Cheong, Hae Il; Kang, Ju Hyung

    2014-07-01

    Congenital nephrogenic diabetes insipidus (CNDI) is a rare disorder caused by mutations of the arginine vasopressin (AVP) V2 receptor or aquaporin 2 (AQP2) genes. The current study presented the case of CNDI in a 1-month-old male with a novel mutation in the AQP2 gene. The patient was referred due to the occurrence of hypernatremia and mild-intermittent fever since birth. An AVP stimulation test was compatible with CNDI as there was no significant response to desmopressin. Molecular genetic analysis demonstrated two mutations in exon 1 of the AQP2 gene: C to T transition, which resulted in a missense mutation of (108)Thr (ACG) to Met (ATG); and a 127, 128 delCA, which resulted in a deletion mutation of glutamine in position 43 at codon CAG as the first affected amino acid, with the new reading frame endign in a termination codon at position 62. The molecular genetic analysis of the parents showed that the missense mutation was inherited maternally and the deletion mutation was inherited paternally. The parents showed no signs or symptoms of CNDI, indicating autosomal recessive inheritance. The (108)Thr (ACG) to Met (ATG) mutation was confirmed as a novel mutation. Therefore, the molecular identification of the AQP2 gene has clinical significance, as early recognition of CNDI in infants that show only non-specific symptoms, can be facilitated. Thus, repeated episodes of dehydration, which may cause physical and mental retardation can be avoided. PMID:24944815

  16. TET2 gene mutation is unfavorable prognostic factor in cytogenetically normal acute myeloid leukemia patients with NPM1+ and FLT3-ITD - mutations.

    PubMed

    Tian, Xiaopeng; Xu, Yang; Yin, Jia; Tian, Hong; Chen, Suning; Wu, Depei; Sun, Aining

    2014-07-01

    Cytogenetically normal acute myeloid leukemia (cn-AML) is a group of heterogeneous diseases. Gene mutations are increasingly used to assess the prognosis of cn-AML patients and guide risk-adapted treatment. In the present study, we analyzed the molecular genetics characteristics of 373 adult cn-AML patients and explored the relationship between TET2 gene mutations or different genetic mutation patterns and prognosis. We found that 16.1 % of patients had TET2 mutations, 31.6 % had FLT3 internal tandem duplications (ITDs), 6.2 % had FLT3 tyrosine kinase domain mutations, 2.4 % had c-KIT mutations, 37.8 % had NPM1 mutations, 11.3 % had WT1 mutations, 5.9 % had RUNX1 mutations, 11.5 % had ASXL1 mutations, 3.8 % had MLL-PTDs, 7.8 % had IDH1 mutations, 7.8 % had NRAS mutations, 12.3 % had IDH2 mutations, 1.6 % had EZH2 mutations, and 14.7 % had DNMT3A mutations, while none had CBL mutations. Gene mutations were detected in 76.94 % (287/373) of all patients. In the NPM1m(+) patients, those with TET2 mutations were associated with a shorter median overall survival (OS) as compared to TET2 wild-type (wt) patients (9.9 vs. 27.0 months, respectively; P = 0.023); Interestingly, the TET2 mutation was identified as an unfavorable prognostic factor and was closely associated with a shorter median OS as compared to TET2-wt (9.5 vs. 32.2 months, respectively; P = 0.013) in the NPM1m(+)/FLT3-ITDm(-) patient group. Thus, identification of TET2 combined with classic NPM1 and FLT3-ITD mutations allowed us to stratify cn-AML into distinct subtypes. PMID:24859829

  17. Mutation and polymorphism spectrum of the GALNS gene in mucopolysaccharidosis IVA (Morquio A).

    PubMed

    Tomatsu, Shunji; Montaño, Adriana M; Nishioka, Tatsuo; Gutierrez, Monica A; Peña, Olga M; Tranda Firescu, Georgeta G; Lopez, Patricia; Yamaguchi, Seiji; Noguchi, Akihiko; Orii, Tadao

    2005-12-01

    Mucopolysaccharidosis IVA (MPS IVA; Morquio A disease) is an autosomal-recessive disorder caused by a deficiency of lysosomal N-acetylgalactosamine-6-sulfate sulfatase (GALNS; E.C.3.1.6.4). GALNS is required to degrade glycosaminoglycans, keratan sulfate (KS), and chondroitin-6-sulfate. Accumulation of undegraded substrates in lysosomes of the affected tissues leads to a systemic bone dysplasia. We summarize information on 148 unique mutations determined to date in the GALNS gene, including 26 novel mutations (19 missense, four small deletions, one splice-site, and two insertions). This heterogeneity in GALNS gene mutations accounts for an extensive clinical variability within MPS IVA. Seven polymorphisms that cause an amino acid change, and nine silent variants in the coding region are also described. Of the analyzed mutant alleles, missense mutations accounted for 78.4%; small deletions, 9.2%; nonsense mutation, 5.0%; large deletion, 2.4%; and insertions, 1.6%. Transitional mutations at CpG dinucleotides accounted for 26.4% of all the described mutations. The importance of the relationship between methylation status and distribution of transitional mutations at CpG sites at the GALNS gene locus was elucidated. The three most frequent mutations (over 5% of all mutations) were represented by missense mutations (p.R386C, p.G301C, and p.I113F). A genotype/phenotype correlation was defined in some mutations. Missense mutations associated with a certain phenotype were studied for their effects on enzyme activity and stability, the levels of blood and urine KS, the location of mutations with regard to the tertiary structure, and the loci of the altered amino acid residues among sulfatase proteins. PMID:16287098

  18. Tumor-specific mutations in low-frequency genes affect their functional properties.

    PubMed

    Erdem-Eraslan, Lale; Heijsman, Daphne; de Wit, Maurice; Kremer, Andreas; Sacchetti, Andrea; van der Spek, Peter J; Sillevis Smitt, Peter A E; French, Pim J

    2015-05-01

    Causal genetic changes in oligodendrogliomas (OD) with 1p/19q co-deletion include mutations in IDH1, IDH2, CIC, FUBP1, TERT promoter and NOTCH1. However, it is generally assumed that more somatic mutations are required for tumorigenesis. This study aimed to establish whether genes mutated at low frequency can be involved in OD initiation and/or progression. We performed whole-genome sequencing on three anaplastic ODs with 1p/19q co-deletion. To estimate mutation frequency, we performed targeted resequencing on an additional 39 ODs. Whole-genome sequencing identified a total of 55 coding mutations (range 8-32 mutations per tumor), including known abnormalities in IDH1, IDH2, CIC and FUBP1. We also identified mutations in genes, most of which were previously not implicated in ODs. Targeted resequencing on 39 additional ODs confirmed that these genes are mutated at low frequency. Most of the mutations identified were predicted to have a deleterious functional effect. Functional analysis on a subset of these genes (e.g. NTN4 and MAGEH1) showed that the mutation affects the subcellular localization of the protein (n = 2/12). In addition, HOG cells stably expressing mutant GDI1 or XPO7 showed altered cell proliferation compared to those expressing wildtype constructs. Similarly, HOG cells expressing mutant SASH3 or GDI1 showed altered migration. The significantly higher rate of predicted deleterious mutations, the changes in subcellular localization and the effects on proliferation and/or migration indicate that many of these genes functionally may contribute to gliomagenesis and/or progression. These low-frequency genes and their affected pathways may provide new treatment targets for this tumor type. PMID:25694352

  19. Blue genes: An integrative laboratory to differentiate genetic transformation from gene mutation for underclassmen.

    PubMed

    Militello, Kevin T; Chang, Ming-Mei; Simon, Robert D; Lazatin, Justine C

    2016-01-01

    The ability of students to understand the relationship between genotype and phenotype, and the mechanisms by which genotypes and phenotypes can change is essential for students studying genetics. To this end, we have developed a four-week laboratory called Blue Genes, which is designed to help novice students discriminate between two mechanisms by which the genetic material can be altered: genetic transformation and gene mutation. In the first week of the laboratory, students incubate a plasmid DNA with calcium chloride-treated Escherichia coli JM109 cells and observe a phenotype change from ampicillin sensitive to ampicillin resistant and from white color to blue color on plates containing 5-bromo-4-chloro-3-indolyl-?-D-galactopyranoside (X-gal) and isopropyl ?-D-thiogalactopyranoside (IPTG). Over the course of the next three weeks, students use a battery of approaches including plasmid DNA isolation experiments, restriction maps, and PCR to differentiate between mutation and transformation. The students ultimately come to the conclusion that the changes in phenotypes are due to genetic transformation and not mutation based on the evidence generated over the four-week period. Pre-laboratory tests and post-laboratory tests indicate that this set of exercises is successful in helping students differentiate between transformation and mutation. The laboratory is designed for underclassmen and is a good prerequisite for an apprentice-based research opportunity, although it is not designed as a class based research experience. Potential modifications and future directions of the laboratory based upon student experiences and assessment are presented. 2015 by The International Union of Biochemistry and Molecular Biology, 44:55-62, 2016. PMID:26525488

  20. A spectrum of mutations in the second gene for autosomal dominant polycystic kidney disease (PKD2).

    PubMed Central

    Veldhuisen, B; Saris, J J; de Haij, S; Hayashi, T; Reynolds, D M; Mochizuki, T; Elles, R; Fossdal, R; Bogdanova, N; van Dijk, M A; Coto, E; Ravine, D; Nørby, S; Verellen-Dumoulin, C; Breuning, M H; Somlo, S; Peters, D J

    1997-01-01

    Recently the second gene for autosomal dominant polycystic kidney disease (ADPKD), located on chromosome 4q21-q22, has been cloned and characterized. The gene encodes an integral membrane protein, polycystin-2, that shows amino acid similarity to the PKD1 gene product and to the family of voltage-activated calcium (and sodium) channels. We have systematically screened the gene for mutations by single-strand conformation-polymorphism analysis in 35 families with the second type of ADPKD and have identified 20 mutations. So far, most mutations found seem to be unique and occur throughout the gene, without any evidence of clustering. In addition to small deletions, insertions, and substitutions leading to premature translation stops, one amino acid substitution and five possible splice-site mutations have been found. These findings suggest that the first step toward cyst formation in PKD2 patients is the loss of one functional copy of polycystin-2. Images Figure 2 PMID:9326320

  1. Mutations in Ehrlichia chaffeensis Causing Polar Effects in Gene Expression and Differential Host Specificities

    PubMed Central

    Cheng, Chuanmin; Nair, Arathy D. S.; Jaworski, Deborah C.; Ganta, Roman R.

    2015-01-01

    Ehrlichia chaffeensis, a tick-borne rickettsial, is responsible for human monocytic ehrlichiosis. In this study, we assessed E. chaffeensis insertion mutations impacting the transcription of genes near the insertion sites. We presented evidence that the mutations within the E. chaffeensis genome at four genomic locations cause polar effects in altering gene expressions. We also reported mutations causing attenuated growth in deer (the pathogen’s reservoir host) and in dog (an incidental host), but not in its tick vector, Amblyomma americanum. This is the first study documenting insertion mutations in E. chaffeensis that cause polar effects in altering gene expression from the genes located upstream and downstream to insertion sites and the differential requirements of functionally active genes of the pathogen for its persistence in vertebrate and tick hosts. This study is important in furthering our knowledge on E. chaffeensis pathogenesis. PMID:26186429

  2. A Novel Mutation in SLC3A1 Gene in Patients With Cystinuria.

    PubMed

    Markazi, Samaneh; Kheirollahi, Majid; Doosti, Abbas; Mohammadi, Mehrdad; Koulivand, Leila

    2016-01-01

    Cystinuria is an inherited disease characterized by the formation of cystine calculi in the kidneys, ureters,  and bladder. Cystinuria is associated with mutation in the SLC3A1 and SLC7A9 genes. These defects prevent appropriate reabsorption of dibasic amino acids lysine, ornithine, and arginine. Cystinuria is classified as type I (silent heterozygotes) and non-type I (heterozygotes with urinary hyperexcretion of cystine). In molecular term, cystinuria is classified as type A (mutations on SLC3A1 gene) and type B (mutations on SLC7A9 gene). This report describes 7 patients with early onset of cystine calculus formation. We are report a new mutation in SLC3A1 gene in exon 1. A novel nucleotide substitution c.-29A>G was found in exon 1 of the SLC3A1 gene, which had not been reported elsewhere previously. PMID:26837681

  3. Mutation spectrum of the rhodopsin gene among patients with autosomal dominant retinitis pigmentosa

    SciTech Connect

    Dryja, T.P.; Han, L.B.; Cowley, G.S.; McGee, T.L.; Berson, E.L. )

    1991-10-15

    The authors searched for point mutations in every exon of the rhodopsin gene in 150 patients from separate families with autosomal dominant retinitis pigmentosa. Including the 4 mutations the authors reported previously, they found a total of 17 different mutations that correlate with the disease. Each of these mutations is a single-base substitution corresponding to a single amino acid substitution. Based on current models for the structure of rhodopsin, 3 of the 17 mutant amino acids are normally located on the cytoplasmic side of the protein, 6 in transmembrane domains, and 8 on the intradiscal side. Forty-three of the 150 patients (29%) carry 1 of these mutations, and no patient has more than 1 mutation. In every family with a mutation so far analyzed, the mutation cosegregates with the disease. They found one instance of a mutation in an affected patient that was absent in both unaffected parents (i.e., a new germ-line mutation), indicating that some isolate cases of retinitis pigmentosa carry a mutation of the rhodopsin gene.

  4. [Identification of novel pathogenic gene mutations in pediatric acute myeloid leukemia by whole-exome resequencing].

    PubMed

    Shiba, Norio

    2015-12-01

    A new class of gene mutations, identified in the pathogenesis of adult acute myeloid leukemia (AML), includes DNMT3A, IDH1/2, TET2 and EZH2. However, these mutations are rare in pediatric AML cases, indicating that pathogeneses differ between adult and pediatric forms of AML. Meanwhile, the recent development of massively parallel sequencing technologies has provided a new opportunity to discover genetic changes across entire genomes or proteincoding sequences. In order to reveal a complete registry of gene mutations, we performed whole exome resequencing of paired tumor-normal specimens from 19 pediatric AML cases using Illumina HiSeq 2000. In total, 80 somatic mutations or 4.2 mutations per sample were identified. Many of the recurrent mutations identified in this study involved previously reported targets in AML, such as FLT3, CEBPA, KIT, CBL, NRAS, WT1 and EZH2. On the other hand, several genes were newly identified in the current study, including BCORL1 and major cohesin components such as SMC3 and RAD21. Whole exome resequencing revealed a complex array of gene mutations in pediatric AML genomes. Our results indicate that a subset of pediatric AML represents a discrete entity that could be discriminated from its adult counterpart, in terms of the spectrum of gene mutations. PMID:26725349

  5. Clinical significance of a point mutation in DNA polymerase beta (POLB) gene in gastric cancer.

    PubMed

    Tan, Xiaohui; Wang, Hongyi; Luo, Guangbin; Ren, Shuyang; Li, Wenmei; Cui, Jiantao; Gill, Harindarpal S; Fu, Sidney W; Lu, Youyong

    2015-01-01

    Gastric cancer (GC) is a major cause of global cancer mortality. Genetic variations in DNA repair genes can modulate DNA repair capability and, consequently, have been associated with risk of developing cancer. We have previously identified a T to C point mutation at nucleotide 889 (T889C) in DNA polymerase beta (POLB) gene, a key enzyme involved in base excision repair in primary GCs. The purpose of this study was to evaluate the mutation and expression of POLB in a larger cohort and to identify possible prognostic roles of the POLB alterations in GC. Primary GC specimens and their matched normal adjacent tissues were collected at the time of surgery. DNA, RNA and protein samples were isolated from GC specimens and cell lines. Mutations were detected by PCR-RFLP/DHPLC and sequencing analysis. POLB gene expression was examined by RT-PCR, tissue microarray, Western blotting and immunofluorescence assays. The function of the mutation was evaluated by chemosensitivity, MTT, Transwell matrigel invasion and host cell reactivation assays. The T889C mutation was detected in 18 (10.17%) of 177 GC patients. And the T889C mutation was associated with POLB overexpression, lymph nodes metastases and poor tumor differentiation. In addition, patients with- the mutation had significantly shorter survival time than those without-, following postoperative chemotherapy. Furthermore, cell lines with T889C mutation in POLB gene were more resistant to the treatment of 5-fluorouracil, cisplatin and epirubicin than those with wild type POLB. Forced expression of POLB gene with T889C mutation resulted in enhanced cell proliferation, invasion and resistance to anticancer drugs, along with increased DNA repair capability. These results suggest that POLB gene with T889C mutation in surgically resected primary gastric tissues may be clinically useful for predicting responsiveness to chemotherapy in patients with GC. The POLB gene alteration may serve as a prognostic biomarker for GC. PMID:25561897

  6. Clinical Significance of a Point Mutation in DNA Polymerase Beta (POLB) Gene in Gastric Cancer

    PubMed Central

    Tan, Xiaohui; Wang, Hongyi; Luo, Guangbin; Ren, Shuyang; Li, Wenmei; Cui, Jiantao; Gill, Harindarpal S.; Fu, Sidney W.; Lu, Youyong

    2015-01-01

    Gastric cancer (GC) is a major cause of global cancer mortality. Genetic variations in DNA repair genes can modulate DNA repair capability and, consequently, have been associated with risk of developing cancer. We have previously identified a T to C point mutation at nucleotide 889 (T889C) in DNA polymerase beta (POLB) gene, a key enzyme involved in base excision repair in primary GCs. The purpose of this study was to evaluate the mutation and expression of POLB in a larger cohort and to identify possible prognostic roles of the POLB alterations in GC. Primary GC specimens and their matched normal adjacent tissues were collected at the time of surgery. DNA, RNA and protein samples were isolated from GC specimens and cell lines. Mutations were detected by PCR-RFLP/DHPLC and sequencing analysis. POLB gene expression was examined by RT-PCR, tissue microarray, Western blotting and immunofluorescence assays. The function of the mutation was evaluated by chemosensitivity, MTT, Transwell matrigel invasion and host cell reactivation assays. The T889C mutation was detected in 18 (10.17%) of 177 GC patients. And the T889C mutation was associated with POLB overexpression, lymph nodes metastases and poor tumor differentiation. In addition, patients with- the mutation had significantly shorter survival time than those without-, following postoperative chemotherapy. Furthermore, cell lines with T889C mutation in POLB gene were more resistant to the treatment of 5-fluorouracil, cisplatin and epirubicin than those with wild type POLB. Forced expression of POLB gene with T889C mutation resulted in enhanced cell proliferation, invasion and resistance to anticancer drugs, along with increased DNA repair capability. These results suggest that POLB gene with T889C mutation in surgically resected primary gastric tissues may be clinically useful for predicting responsiveness to chemotherapy in patients with GC. The POLB gene alteration may serve as a prognostic biomarker for GC. PMID:25561897

  7. Software and database for the analysis of mutations in the human LDL receptor gene.

    PubMed Central

    Varret, M; Rabès, J P; Collod-Béroud, G; Junien, C; Boileau, C; Béroud, C

    1997-01-01

    The low-density lipoprotein receptor (LDLr) plays a pivotal role in cholesterol homeostasis. Mutations in the LDLr gene (LDLR), which is located on chromosome 19, cause familial hypercholesterolemia (FH), an autosomal dominant disorder characterized by severe hypercholesterolemia associated with premature coronary atherosclerosis. To date almost 300 mutations have been identified in the LDLR gene. To facilitate the mutational analysis of the LDLR gene, and promote the analysis of the relationship between genotype and phenotype, a software package along with a computerized database (currently listing 210 entries) have been created. PMID:9016531

  8. Mutations in the peripheral myelin genes and associated genes in inherited peripheral neuropathies.

    PubMed

    Nelis, E; Haites, N; Van Broeckhoven, C

    1999-01-01

    The peripheral myelin protein 22 gene (PMP22), the myelin protein zero gene (MPZ, P0), and the connexin 32 gene (Cx32, GJB1) code for membrane proteins expressed in Schwann cells of the peripheral nervous system (PNS). The early growth response 2 gene (EGR2) encodes a transcription factor that may control myelination in the PNS. Mutations in the respective genes, located on human chromosomes 17p11.2, 1q22-q23, Xq13.1, and 10q21.1-q22.1, are associated with several inherited peripheral neuropathies. To date, a genetic defect in one of these genes has been identified in over 1,000 unrelated patients manifesting a wide range of phenotypes, i.e., Charcot-Marie-Tooth disease type 1 (CMT1) and type 2 (CMT2), Dejerine-Sottas syndrome (DSS), hereditary neuropathy with liability to pressure palsies (HNPP), and congenital hypomyelination (CH). This large number of genetically defined patients provides an exceptional opportunity to examine the correlation between phenotype and genotype. PMID:9888385

  9. Phenylalanine hydroxylase gene mutations in the United States: Report from the maternal PKU collaborative study

    SciTech Connect

    Guldberg, P.; Henriksen, K.F.; Guettler, F.

    1996-07-01

    The major cause of hyperphenylalaninemia is mutations in the gene encoding phenylalanine hydroxylase (PAH). The known mutations have been identified primarily in European patients. The purpose of this study was to determine the spectrum of mutations responsible for PAH deficiency in the United States. One hundred forty-nine patients enrolled in the Maternal PKU Collaborative Study were subjects for clinical and molecular investigations. PAH gene mutations associated with phenylketonuria (PKU) or mild hyperphenylalaninemia (MHP) were identified on 279 of 294 independent mutant chromosomes, a diagnostic efficiency of 95%. The spectrum is composed of 71 different mutations, including 47 missense mutations, 11 splice mutations, 5 nonsense mutations, and 8 microdeletions. Sixteen previously unreported mutations were identified. Among the novel mutations, five were found in patients with MHP, and the remainder were found in patients with PKU. The most common mutations were R408W, IVS12nt1g{r_arrow}a, and Y414C, accounting for 18.7%, 7.8% and 5.4% of the mutant chromosomes, respectively. Thirteen mutations had relative frequencies of 1%-5%, and 55 mutations each had frequencies {le}1%. The mutational spectrum corresponded to that observed for the European ancestry of the U.S. population. To evaluate the extent of allelic variation at the PAH locus within the United States in comparison with other populations, we used allele frequencies to calculate the homozygosity for 11 populations where >90% ascertainment has been obtained. The United States was shown to contain one of the most heterogeneous populations, with homozygosity values similar to Sicily and ethnically mixed sample populations in Europe. The extent of allelic heterogeneity must be a major determining factor in the choice of mutation-detection methodology for molecular diagnosis in PAH deficiency. 47 refs., 1 fig., 5 tabs.

  10. Association between SNPs in genes involved in folate metabolism and preterm birth risk.

    PubMed

    Wang, B J; Liu, M J; Wang, Y; Dai, J R; Tao, J Y; Wang, S N; Zhong, N; Chen, Y

    2015-01-01

    We investigated the association between 12 single nucleotide polymorphisms (SNPs) in 11 genes involved in folate metabolic and preterm birth. A subset of SNPs selected from 11 genes/loci involved in the folic acid metabolism pathway were subjected to SNaPshot analysis in a case-control study. Twelve SNPs (CBS-C699T, DHFR-c594+59del19, GST01-C428T, MTHFD-G1958A, MTHFR-C677T, MTHFR-A1298C, MTR-A2756G, MTRR-A66G, NFE2L2-ins1+C11108T, RFC1-G80A, TCN2-C776G, and TYMS-1494del6) in 503 DNA samples were simultaneously tested, and included 315 preterm births and 188 controls. None of the 12 SNP genotype distributions related to the folic acid metabolism pathway showed a significant difference between preterm and term babies. The frequency of the compound mutation genotype of MTHFD-G1958A, MTR-A2756G and RFC1-G80A in preterm babies was 7.3%, which was significantly higher than the 2.7% in term babies. Seven babies carried the compound mutation genotype of MTHFD-G1958A, MTR-A2756G, and CBS-C699T, but this was not observed in term babies. The frequency of the combined wild-type genotype of MTHFD-G1958A, MTR-A2756G, MTRR-A66G, MTHFR-A1298C, NFE2L2-ins1+C11108T, and RFC1- G80A in preterm babies was 3.17%, which was significantly lower than the 7.4% in term babies. The 12 SNPs screened in this study were not independent risk factors of preterm birth. Compound mutation genotypes, including MTHFD-G1958A, MTR-A2756G, and RFC1- G80A and MTHFD-G1958A, MTR-A2756G, and CBS-C699T, may increase the risk of preterm birth. The combined wild-type genotype MTHFD-G1958A, MTR-A2756G, MTRR-A66G, MTHFR-A1298C, NFE2L2-ins1+C11108T, and RFC1-G80A may decrease the risk of preterm birth. PMID:25730024

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

    PubMed Central

    Kao, Hsiao-Wen; Liang, Der-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

    2015-01-01

    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. PMID:26375248

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

    PubMed

    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. PMID:26375248

  13. Phosphatidylinositol-3-kinase α catalytic subunit gene somatic mutations in bronchopulmonary neuroendocrine tumours

    PubMed Central

    CAPODANNO, ALESSANDRA; BOLDRINI, LAURA; ALÌ, GRETA; PELLICCIONI, SERENA; MUSSI, ALFREDO; FONTANINI, GABRIELLA

    2012-01-01

    Bronchopulmonary neuroendocrine tumours (BP-NETs) comprise a large spectrum of tumours including typical carcinoids (TCs), atypical carcinoids (ACs), large-cell neuroendocrine carcinomas (LCNECs) and small-cell lung carcinomas (SCLCs) that exhibit considerably different biological aggressiveness and clinical behaviours. The phosphatidylinositol-3-kinase α catalytic subunit (PIK3CA) gene is known to be involved in the pathogenesis of several types of human cancers through gene amplification, deletions or somatic missense mutations within the helical and catalytic domains. However, the PIK3CA gene status in BP-NETs has yet to be explored. This study aimed to investigate the PIK3CA gene status in a large series of BP-NETs by direct gene sequencing and to analyse its correlation with the main clinicopathological parameters. To the best of our knowledge, we demonstrated for the first time a high frequency of somatic missense mutations (23.2%) in the PIK3CA gene in a series of 190 BP-NETs, including 75 TCs, 23 ACs, 17 LCNECs and 75 SCLCs. The frequency of the PIK3CA gene mutation in the kinase domain was higher (17.9%) than that in the helical domain (5.3%). When the mutational status of the PIK3CA gene was compared with the main clinical and pathological characteristics of the BP-NET patients, we found a significant association between PIK3CA gene mutations and BP-NET histology (P=0.011). Interestingly, the frequency of PIK3CA gene mutations increased with the biological aggressiveness of all BP-NETs, except LCNECs. In conclusion, our results suggest that PIK3CA gene mutations may play a key role in tumourigenesis and aggressiveness of BP-NETs. The PIK3CA gene may represent a favourable candidate for an effective therapeutic strategy in the treatment of patients with BP-NETs. PMID:22949056

  14. Prevalence of Mutations in eyeGENE Probands With a Diagnosis of Autosomal Dominant Retinitis Pigmentosa

    PubMed Central

    Sullivan, Lori S.; Bowne, Sara J.; Reeves, Melissa J.; Blain, Delphine; Goetz, Kerry; NDifor, Vida; Vitez, Sally; Wang, Xinjing; Tumminia, Santa J.; Daiger, Stephen P.

    2013-01-01

    Purpose. To screen samples from patients with presumed autosomal dominant retinitis pigmentosa (adRP) for mutations in 12 disease genes as a contribution to the research and treatment goals of the National Ophthalmic Disease Genotyping and Phenotyping Network (eyeGENE). Methods. DNA samples were obtained from eyeGENE. A total of 170 probands with an intake diagnosis of adRP were tested through enrollment in eyeGENE. The 10 most common genes causing adRP (IMPDH1, KLHL7, NR2E3, PRPF3/RP18, PRPF31/RP11, PRPF8/RP13, PRPH2/RDS, RHO, RP1, and TOPORS) were chosen for PCR-based dideoxy sequencing, along with the two X-linked RP genes, RPGR and RP2. RHO, PRPH2, PRPF31, RPGR, and RP2 were completely sequenced, while only mutation hotspots in the other genes were analyzed. Results. Disease-causing mutations were identified in 52% of the probands. The frequencies of disease-causing mutations in the 12 genes were consistent with previous studies. Conclusions. The Laboratory for Molecular Diagnosis of Inherited Eye Disease at the University of Texas in Houston has thus far received DNA samples from 170 families with a diagnosis of adRP from the eyeGENE Network. Disease-causing mutations in autosomal genes were identified in 48% (81/170) of these families while mutations in X-linked genes accounted for an additional 4% (7/170). Of the 55 distinct mutations detected, 19 (33%) have not been previously reported. All diagnostic results were returned by eyeGENE to participating patients via their referring clinician. These genotyped samples along with their corresponding phenotypic information are also available to researchers who may request access to them for further study of these ophthalmic disorders. (ClinicalTrials.gov number, NCT00378742.) PMID:23950152

  15. Nemaline myopathy caused by mutations in the nebulin gene may present as a distal myopathy.

    PubMed

    Lehtokari, Vilma-Lotta; Pelin, Katarina; Herczegfalvi, Agnes; Karcagi, Veronika; Pouget, Jean; Franques, Jerôme; Pellissier, Jean François; Figarella-Branger, Dominique; von der Hagen, Maja; Huebner, Angela; Schoser, Benedikt; Lochmüller, Hanns; Wallgren-Pettersson, Carina

    2011-08-01

    Mutations in the nebulin gene are the main cause of autosomal recessive nemaline myopathy, with clinical presentations ranging from mild to severe disease. We have previously reported a nonspecific distal myopathy caused by homozygous missense mutations in the nebulin gene in six Finnish patients from four different families. Here we describe three non-Finnish patients in two unrelated families with distal nemaline myopathy caused by four different compound heterozygous nebulin mutations, only one of which is a missense mutation. One of the mutations has previously been identified in one family with the severe form of nemaline myopathy. We conclude that nemaline myopathy and distal myopathy caused by nebulin mutations form a clinical and histological continuum. Nemaline myopathy should be considered as a differential diagnosis in patients presenting with an early-onset predominantly distal myopathy. PMID:21724397

  16. Recurrent de novo mutations implicate novel genes underlying simplex autism risk

    PubMed Central

    O'Roak, B. J.; Stessman, H. A.; Boyle, E. A.; Witherspoon, K. T.; Martin, B.; Lee, C.; Vives, L.; Baker, C.; Hiatt, J. B.; Nickerson, D. A.; Bernier, R.; Shendure, J.; Eichler, E. E.

    2014-01-01

    Autism spectrum disorder (ASD) has a strong but complex genetic component. Here we report on the resequencing of 64 candidate neurodevelopmental disorder risk genes in 5,979 individuals: 3,486 probands and 2,493 unaffected siblings. We find a strong burden of de novo point mutations for these genes and specifically implicate nine genes. These include CHD2 and SYNGAP1, genes previously reported in related disorders, and novel genes TRIP12 and PAX5. We also show that mutation carriers generally have lower IQs and enrichment for seizures. These data begin to distinguish genetically distinct subtypes of autism important for etiological classification and future therapeutics. PMID:25418537

  17. Prevalence of Pathogenic Mutations in Cancer Predisposition Genes among Pancreatic Cancer Patients.

    PubMed

    Hu, Chunling; Hart, Steven N; Bamlet, William R; Moore, Raymond M; Nandakumar, Kannabiran; Eckloff, Bruce W; Lee, Yean K; Petersen, Gloria M; McWilliams, Robert R; Couch, Fergus J

    2016-01-01

    The prevalence of germline pathogenic mutations in a comprehensive panel of cancer predisposition genes is not well-defined for patients with pancreatic ductal adenocarcinoma (PDAC). To estimate the frequency of mutations in a panel of 22 cancer predisposition genes, 96 patients unselected for a family history of cancer who were recruited to the Mayo Clinic Pancreatic Cancer patient registry over a 12-month period were screened by next-generation sequencing. Fourteen pathogenic mutations in 13 patients (13.5%) were identified in eight genes: four in ATM, two in BRCA2, CHEK2, and MSH6, and one in BARD1, BRCA1, FANCM, and NBN. These included nine mutations (9.4%) in established pancreatic cancer genes. Three mutations were found in patients with a first-degree relative with PDAC, and 10 mutations were found in patients with first- or second-degree relatives with breast, pancreas, colorectal, ovarian, or endometrial cancers. These results suggest that a substantial proportion of patients with PDAC carry germline mutations in predisposition genes associated with other cancers and that a better understanding of pancreatic cancer risk will depend on evaluation of families with broad constellations of tumors. These findings highlight the need for recommendations governing germline gene-panel testing of patients with pancreatic cancer. PMID:26483394

  18. Prevalence of pathogenic mutations in cancer predisposition genes among pancreatic cancer patients

    PubMed Central

    Hu, Chunling; Hart, Steven N.; Bamlet, William R.; Moore, Raymond M.; Nandakumar, Kannabiran; Eckloff, Bruce W.; Lee, Yean K.; Petersen, Gloria M.; McWilliams, Robert R.; Couch, Fergus J.

    2016-01-01

    The prevalence of germline pathogenic mutations in a comprehensive panel of cancer predisposition genes is not well defined for patients with pancreatic ductal adenocarcinoma (PDAC). To estimate the frequency of mutations in a panel of 22 cancer predisposition genes, 96 patients unselected for a family history of cancer who were recruited to the Mayo Clinic Pancreatic Cancer patient registry over a 12 month period were screened by next-generation sequencing. Fourteen pathogenic mutations in 13 patients (13.5%) were identified in eight genes: four in ATM, two in BRCA2, CHEK2, and MSH6, and one in BARD1, BRCA1, FANCM, and NBN. These included nine mutations (9.4%) in established pancreatic cancer genes. Three mutations were found in patients with a first degree relative with PDAC, and 10 mutations were found in patients with first or second-degree relatives with breast, pancreas, colorectal, ovarian, or endometrial cancer. These results suggest that a substantial proportion of patients with PDAC carry germline mutations in predisposition genes associated with other cancers, and that a better understanding of pancreatic cancer risk will depend on evaluation of families with broad constellations of tumors. These findings highlight the need for recommendations governing germline gene-panel testing of pancreatic cancer patients. PMID:26483394

  19. DNA repair genes are selectively mutated in diffuse large B cell lymphomas

    PubMed Central

    de Miranda, Noel FCC; Peng, Roujun; Georgiou, Konstantinos; Wu, Chenglin; Srqvist, Elin Falk; Berglund, Mattias; Chen, Longyun; Gao, Zhibo; Lagerstedt, Kristina; Lisboa, Susana; Roos, Fredrik; van Wezel, Tom; Teixeira, Manuel R.; Rosenquist, Richard; Sundstrm, Christer; Enblad, Gunilla; Nilsson, Mats; Zeng, Yixin; Kipling, David

    2013-01-01

    DNA repair mechanisms are fundamental for B cell development, which relies on the somatic diversification of the immunoglobulin genes by V(D)J recombination, somatic hypermutation, and class switch recombination. Their failure is postulated to promote genomic instability and malignant transformation in B cells. By performing targeted sequencing of 73 key DNA repair genes in 29 B cell lymphoma samples, somatic and germline mutations were identified in various DNA repair pathways, mainly in diffuse large B cell lymphomas (DLBCLs). Mutations in mismatch repair genes (EXO1, MSH2, and MSH6) were associated with microsatellite instability, increased number of somatic insertions/deletions, and altered mutation signatures in tumors. Somatic mutations in nonhomologous end-joining (NHEJ) genes (DCLRE1C/ARTEMIS, PRKDC/DNA-PKcs, XRCC5/KU80, and XRCC6/KU70) were identified in four DLBCL tumors and cytogenetic analyses revealed that translocations involving the immunoglobulin-heavy chain locus occurred exclusively in NHEJ-mutated samples. The novel mutation targets, CHEK2 and PARP1, were further screened in expanded DLBCL cohorts, and somatic as well as novel and rare germline mutations were identified in 8 and 5% of analyzed tumors, respectively. By correlating defects in a subset of DNA damage response and repair genes with genomic instability events in tumors, we propose that these genes play a role in DLBCL lymphomagenesis. PMID:23960188

  20. Mutations in the SLC3A1 Transporter Gene in Cystinuria

    PubMed Central

    Pras, Elon; Raben, Nina; Golomb, Eliahu; Arber, Nadir; Aksentijevich, Ivona; Schapiro, Jonathan M.; Harel, Daniela; Katz, Giora; Liberman, Uri; Pras, Mordechai; Kastner, Daniel L.

    1995-01-01

    Cystinuria is an autosomal recessive disease characterized by the development of kidney stones. Guided by the identification of the SLC3A1 amino acid–transport gene on chromosome 2, we recently established genetic linkage of cystinuria to chromosome 2p in 17 families, without evidence for locus heterogeneity. Other authors have independently identified missense mutations in SLC3A1 in cystinuria patients. In this report we describe four additional cystinuria-associated mutations in this gene: a frameshift, a deletion, a transversion inducing a critical amino acid change, and a nonsense mutation. The latter stop codon was found in all of eight Ashkenazi Jewish carrier chromosomes examined. This report brings the number of disease-associated mutations in this gene to 10. We also assess the frequency of these mutations in our 17 cystinuria families. ImagesFigure 2Figure 3Figure 4 PMID:7539209

  1. Genomic analyses of gynaecologic carcinosarcomas reveal frequent mutations in chromatin remodelling genes

    PubMed Central

    Jones, Siân; Stransky, Nicolas; McCord, Christine L.; Cerami, Ethan; Lagowski, James; Kelly, Devon; Angiuoli, Samuel V.; Sausen, Mark; Kann, Lisa; Shukla, Manish; Makar, Rosemary; Wood, Laura D.; Diaz, Luis A.; Lengauer, Christoph; Velculescu, Victor E.

    2014-01-01

    Malignant mixed Müllerian tumours, also known as carcinosarcomas, are rare tumours of gynaecological origin. Here we perform whole-exome analyses of 22 tumours using massively parallel sequencing to determine the mutational landscape of this tumour type. On average, we identify 43 mutations per tumour, excluding four cases with a mutator phenotype that harboured inactivating mutations in mismatch repair genes. In addition to mutations in TP53 and KRAS, we identify genetic alterations in chromatin remodelling genes, ARID1A and ARID1B, in histone methyltransferase MLL3, in histone deacetylase modifier SPOP and in chromatin assembly factor BAZ1A, in nearly two thirds of cases. Alterations in genes with potential clinical utility are observed in more than three quarters of the cases and included members of the PI3-kinase and homologous DNA repair pathways. These findings highlight the importance of the dysregulation of chromatin remodelling in carcinosarcoma tumorigenesis and suggest new avenues for personalized therapy. PMID:25233892

  2. Mutations in the SLC3A1 transporter gene in cystinuria

    SciTech Connect

    Pras, E.; Raben, N.; Aksentijevich, I.

    1995-06-01

    Cystinuria is an autosomal recessive disease characterized by the development of kidney stones. Guided by the identification of the SLC3A1 amino acid-transport gene on chromosome 2, we recently established genetic linkage of cystinuria to chromosome 2p in 17 families, without evidence for locus heterogeneity. Other authors have independently identified missense mutations in SLC3A1 in cystinuria patients. In this report we describe four additional cystinuria-associated mutations in this gene: a frameshift, a deletion, a transversion inducing a critical amino acid change, and a nonsense mutation. The latter stop codon was found in all of eight Ashkenazi Jewish carrier chromosomes examined. This report brings the number of disease-associated mutations in this gene to 10. We also assess the frequency of these mutations in our 17 cystinuria families. 24 refs., 4 figs., 1 tab.

  3. Detection of nucleophosmin and FMS-like tyrosine kinase-3 gene mutations in acute myeloid leukemia

    PubMed Central

    Pazhakh, Vahid; Zaker, Farhad; Alimoghaddam, Kamran; Atashrazm, Farzaneh

    2011-01-01

    BACKGROUND AND OBJECTIVES: Nucleophosmin gene mutations are frequently reported in acute myeloid leukemia (AML) patients with normal karyotype, which is also frequently associated with internal tandem duplication mutations in the FMS-like tyrosine kinase-3 gene. We sought to detect the nucleophosmin and FMS-like tyrosine kinase-3 (FLT3) internal tandem duplication (ITD) mutations among Iranian patients with AML and to assess the relationship between these mutations and the subtypes of the disease. DESIGN AND SETTING: Cross-sectional study of patients referred during 2007 through 2009. PATIENTS AND METHODS: Bone marrow and peripheral blood samples of 131 AML patients were randomly collected at the time of diagnosis and prior to treatment and the DNA extracted. After amplifying the nucleophosmin and FLT3 gene regions, positive cases were screened by conformation-sensitive gel electrophoresis and agarose gel electrophoresis techniques. RESULTS: Of 131 patients, 23 (17.5%) (0.95% CI=0.107-0.244) had nucleophosmin gene mutations. The highest frequency of such mutations was found among the subtypes of M4 (30.4%), M3 (21.7%) and M5 (17.4%). There was a high frequency of these mutations in the M3 subtype as well as a high frequency of allele D in all subtypes. Also, 21 (16.0%) samples (0.95% CI=0.092-0.229) had FLT3/ITD mutation, of which 8 samples had mutant nucleophosmin (8 of 23, 35%), and another 13 samples had wild-type nucleophosmin gene (13 of 108, 12%). There was a high degree of association between the occurrence of nucleophosmin and FLT3/ITD mutations (P=.012). CONCLUSION: Our data showed a high frequency of NPM1 mutations in the monocytic subtypes of AML, as well as a high degree of association between the occurrence of NPM1 and FLT3/ITD mutations. PMID:21245599

  4. Consequences of Marfan mutations to expression of fibrillin gene and to the structure of microfibrils

    SciTech Connect

    Peltonen, L.; Karttunen, L.; Rantamaeki, T.

    1994-09-01

    Marfan syndrome (MFS) is a dominantly inherited connective tissue disorder which is caused by mutations in the fibrillin-1 gene (FBN1). Over 40 family-specific FBN1 mutations have been identified. We have characterized 18 different heterozygous mutations including amino acid substitutions, premature stop, and splicing defects leading to deletions or one insertion, and one compound heterozygote with two differently mutated FBN1 alleles inherited from his affected parents. To unravel the consequences of FBN1 mutations to the transcription of FBN1 gene, we have measured the steady state levels of mRNA transcribed from the normal and mutated alleles. The missense mutations do not affect the transcription of the allele while the nonsense mutation leads to lower steady state amount of mutated allele. For the dissection of molecular pathogenesis of FBN1 mutations we have performed rotary shadowing of the microfibrils produced by the cell cultures from MFS patients. The cells from the neonatal patients with established mutations produced only disorganized fibrillin aggregates but no clearly defined microfibrils could be detected, suggesting a major role of this gene region coding for exons 24-26 in stabilization and organization of the bead structure of microfibrils. From the cells of a rare compound heterozygote case carrying two different mutations, no detectable microfibrils could be detected whereas the cells of his parents with heterozygous mutations were able to form identifiable but disorganized microfibrils. In the cells of an MFS case caused by a premature stop removing the C-terminus of fibrillin, the microfibril assembly takes place but the appropriate packing of the microfibrils is disturbed suggesting that C-terminae are actually located within the interbead domain of the microfibrils.

  5. An Undergraduate Laboratory Class Using CRISPR/Cas9 Technology to Mutate Drosophila Genes

    ERIC Educational Resources Information Center

    Adame, Vanesa; Chapapas, Holly; Cisneros, Marilyn; Deaton, Carol; Deichmann, Sophia; Gadek, Chauncey; Lovato, TyAnna L.; Chechenova, Maria B.; Guerin, Paul; Cripps, Richard M.

    2016-01-01

    CRISPR/Cas9 genome editing technology is used in the manipulation of genome sequences and gene expression. Because of the ease and rapidity with which genes can be mutated using CRISPR/Cas9, we sought to determine if a single-semester undergraduate class could be successfully taught, wherein students isolate mutants for specific genes using…

  6. Free-floating thrombus of the carotid artery with a homozygous methylenetetrahydrofolate reductase gene mutation: a case report.

    PubMed

    Colak, Necmettin; Nazli, Yunus; Kosehan, Dilek; Alpay, Mehmet Fatih; Cakir, Omer

    2013-02-01

    Free-floating thrombus (FFT) of the carotid artery is a rare condition of currently unknown etiology. We describe a symptomatic patient with an FFT in the left common carotid artery. A duplex ultrasonography scan showed the presence of a mobile floating thrombus moving in cyclical motion with the cardiac cycles in the left common carotid artery. During emergency surgery, an FFT was seen at this location and removed. No underlying wall defect was seen at the time of surgery. In a genetic screening test, TT homozygous for the methylenetetrahydrofolate reductase (MTHFR) C677T genetic polymorphisms was detected. The patient recovered uneventfully, with no neurogical events. Lifelong anticoagulant therapy was recommended. An aggressive surgical approach is recommended in the patient to prevent embolic episodes. PMID:22101856

  7. Extending the mutation spectrum for Galloway-Mowat syndrome to include homozygous missense mutations in the WDR73 gene.

    PubMed

    Rosti, Rasim O; Dikoglu, Esra; Zaki, Maha S; Abdel-Salam, Ghada; Makhseed, Nawal; Sese, Jordan C; Musaev, Damir; Rosti, Basak; Harbert, Mary J; Jones, Marilyn C; Vaux, Keith K; Gleeson, Joseph G

    2016-04-01

    Galloway-Mowat syndrome is a rare autosomal-recessive disorder classically described as the combination of microcephaly and nephrotic syndrome. Recently, homozygous truncating mutations in WDR73 (WD repeat domain 73) were described in two of 31 unrelated families with Galloway-Mowat syndrome which was followed by a report of two sibs in an Egyptian consanguineous family. In this report, seven affecteds from four families showing biallelic missense mutations in WDR73 were identified by exome sequencing and confirmed to follow a recessive model of inheritance. Three-dimensional modeling predicted conformational alterations as a result of the mutation, supporting pathogenicity. An additional 13 families with microcephaly and renal phenotype were negative for WDR73 mutations. Missense mutations in the WDR73 gene are reported for the first time in Galloway-Mowat syndrome. A detailed phenotypic comparison of all reported WDR73-linked Galloway-Mowat syndrome patients with WDR73 negative patients showed that WDR73 mutations are limited to those with classical Galloway-Mowat syndrome features, in addition to cerebellar atrophy, thin corpus callosum, brain stem hypoplasia, occasional coarse face, late-onset and mostly slow progressive nephrotic syndrome, and frequent epilepsy. © 2016 Wiley Periodicals, Inc. PMID:27001912

  8. Characterisation of germline mutations in the neurofibromatosis type 1 (NF1) gene.

    PubMed Central

    Upadhyaya, M; Maynard, J; Osborn, M; Huson, S M; Ponder, M; Ponder, B A; Harper, P S

    1995-01-01

    Neurofibromatosis type 1 is one of the most common inherited disorders with an incidence of 1 in 3000. The search for NF1 mutations has been hampered by the overall size of the gene, the large number of exons, and the high mutation rate. To date, fewer than 90 mutations have been reported to the NF1 mutation analysis consortium and the details on 76 mutations have been published. We have identified five new mutations using single strand conformation polymorphism (SSCP) and heteroduplex analysis (HA) and three intragenic deletions with the microsatellite markers. Of the five new mutations, two were in exon 27a, two in exon 45, and one in exon 49 and these include 4630delA, 4572delC, R7846X, T7828A, and one in the 3' untranslated region (3' UTR). The two nucleotide alterations in exon 27a and the one in exon 45 are predicted to produce a truncated protein. Images PMID:8544190

  9. Characterization of phenylalanine hydroxylase gene mutations in phenylketonuria in Xinjiang of China

    PubMed Central

    Yu, Wuzhong; He, Jiang; Yang, Xi; Zou, Hongyun; Gui, Junhao; Wang, Rui; Yang, Liu; Wang, Zheng; Lei, Quan

    2014-01-01

    To investigate the spectrum and frequency of phenylalanine hydroxylase (PAH) gene mutations in phenylketonuria (PKU) patients in Xinjiang, China. Polymerase chain reaction (PCR), in combination with single-strand conformation polymorphism (SSCP) and DNA sequencing analyses were performed, to screen potential mutations in the PAH gene in 46 individual PKU patients. Direct DNA sequencing was used to analyze the all of the exons in the PAH gene, including the promoter and flanking intron regions, in another 15 PKU patients. Our results indicated that, 30 different mutation types were identified in all 122 PAH alleles, with the mutation detection rate of 78.7% (96/122). Four novel mutations, i.e., 5’-Flanking -626G>A, 5’-Flanking -480DelACT, S196fsX4, and IVS8+1G>C, were identified for the first time. Similar to other regions in North China, R243Q, EX6-96A>G, IVS4-1A>G, R111X, and Y356X were the most prevalent PAH mutations in PKU patients from Xinjiang. Additionally, common mutations showed different frequencies in Xinjiang, when compared to other areas. Furthermore, sixteen different PAH gene mutation types were identified for the first time in the minorities in Xinjiang. Distinctive mutation spectrum of PAH gene in PKU patients from Xinjiang were characterized, which may promote the construction of PAH gene mutation database and serve as valuable tools for genetic diagnosis and counseling, and prognostic evaluation for PKU cases in the local area. PMID:25550961

  10. The Mutator Gene Swi8 Effects Specific Mutations in the Mating-Type Region of Schizosaccharomyces Pombe

    PubMed Central

    Fleck, O.; Rudolph, C.; Albrecht, A.; Lorentz, A.; Schar, P.; Schmidt, H.

    1994-01-01

    The swi8(+) gene of Schizosaccharomyces pombe appears to be involved in the termination step of copy synthesis during mating-type (MT) switching. Mutations in swi8 confer a general mutator phenotype and, in particular, generate specific mutations in the MT region. Sequencing of the MT cassettes of the h(90) swi8-137 mutant revealed three altered sites. One is situated at the switching (smt) signal adjacent to the H1 homology box of the expression locus mat1:1. It reduces the rate of MT switching. The alteration at the smt signal arose frequently in other h(90) swi8 strains and is probably caused by gene conversion in which the sequence adjacent to the H1 box of mat2:2 is used as template. This change might be generated during the process of MT switching when hybrid DNA formation is anomalously extended into the more heterologous region flanking the H1 homology box. In addition to the gene conversion at mat1:1, two mutations were found in the H3 homology boxes of the silent cassettes mat2:2 and mat3:3. PMID:7851760

  11. Further evidence of mutational heterogeneity of the XPC gene in Tunisian families: a spectrum of private and ethnic specific mutations.

    PubMed

    Ben Rekaya, Mariem; Jerbi, Manel; Messaoud, Olfa; Ben Brick, Ahlem Sabrine; Zghal, Mohamed; Mbarek, Chiraz; Chadli-Debbiche, Ashraf; Jones, Meriem; Mokni, Mourad; Boussen, Hamouda; Boubaker, Mohamed Samir; Fazaa, Becima; Yacoub-Youssef, Houda; Abdelhak, Sonia

    2013-01-01

    Xeroderma Pigmentosum (XP) is a rare recessive autosomal cancer prone disease, characterized by UV hypersensitivity and early appearance of cutaneous and ocular malignancies. We investigated four unrelated patients suspected to be XP-C. To confirm linkage to XPC gene, genotyping and direct sequencing of XPC gene were performed. Pathogenic effect of novel mutations was confirmed by reverse Transciptase PCR. Mutation screening revealed the presence of two novel mutations g.18246G>A and g.18810G>T in the XPC gene (NG_011763.1). The first is present in one patient XP50NEF, but the second is present in three unrelated patients (XP16KEB, XP28SFA, and XP45GB). These 3 patients are from three different cities of Southern Tunisia and bear the same haplotype, suggesting a founder effect. Reverse Transciptase PCR revealed the absence of the XPC mRNA. In Tunisia, as observed in an other severe genodermatosis, the mutational spectrum of XP-C group seems to be homogeneous with some clusters of heterogeneity that should be taken into account to improve molecular diagnosis of this disease. PMID:23984341

  12. Further Evidence of Mutational Heterogeneity of the XPC Gene in Tunisian Families: A Spectrum of Private and Ethnic Specific Mutations

    PubMed Central

    Ben Rekaya, Mariem; Jerbi, Manel; Messaoud, Olfa; Ben Brick, Ahlem Sabrine; Zghal, Mohamed; Mbarek, Chiraz; Chadli-Debbiche, Ashraf; Mokni, Mourad; Boussen, Hamouda; Boubaker, Mohamed Samir; Fazaa, Becima; Yacoub-Youssef, Houda; Abdelhak, Sonia

    2013-01-01

    Xeroderma Pigmentosum (XP) is a rare recessive autosomal cancer prone disease, characterized by UV hypersensitivity and early appearance of cutaneous and ocular malignancies. We investigated four unrelated patients suspected to be XP-C. To confirm linkage to XPC gene, genotyping and direct sequencing of XPC gene were performed. Pathogenic effect of novel mutations was confirmed by reverse Transciptase PCR. Mutation screening revealed the presence of two novel mutations g.18246G>A and g.18810G>T in the XPC gene (NG_011763.1). The first is present in one patient XP50NEF, but the second is present in three unrelated patients (XP16KEB, XP28SFA, and XP45GB). These 3 patients are from three different cities of Southern Tunisia and bear the same haplotype, suggesting a founder effect. Reverse Transciptase PCR revealed the absence of the XPC mRNA. In Tunisia, as observed in an other severe genodermatosis, the mutational spectrum of XP-C group seems to be homogeneous with some clusters of heterogeneity that should be taken into account to improve molecular diagnosis of this disease. PMID:23984341

  13. Mutated human androgen receptor gene detected in a prostatic cancer patient is also activated by estradiol

    SciTech Connect

    Elo, J.P.; Kvist, L.; Leinonen, K.; Isomaa, V.

    1995-12-01

    Androgens are necessary for the development of prostatic cancer. The mechanisms by which the originally androgen-dependent prostatic cancer cells are relieved of the requirement to use androgen for their growth are largely unknown. The human prostatic cancer cell line LNCaP has been shown to contain a point mutation in the human androgen receptor gene (hAR), suggesting that changes in the hAR may contribute to the abnormal hormone response of prostatic cells. To search for point mutations in the hAR, we used single strand conformation polymorphism analysis and a polymerase chain reaction direct sequencing method to screen 23 prostatic cancer specimens from untreated patients, 6 prostatic cancer specimens from treated patients, and 11 benign prostatic hyperplasia specimens. One mutation was identified in DNA isolated from prostatic cancer tissue, and the mutation was also detected in the leukocyte DNA of the patient and his offspring. The mutation changed codon 726 in exon E from arginine to leucine and was a germ line mutation. The mutation we found in exon E of the hAR gene does not alter the ligand binding specificity of the AR, but the mutated receptor was activated by estradiol to a significantly greater extent than the wild-type receptor. The AR gene mutation described in this study might be one explanation for the altered biological activity of prostatic cancer. 36 refs., 4 figs.

  14. An analysis of substitution, deletion and insertion mutations in cancer genes

    PubMed Central

    Iengar, Prathima

    2012-01-01

    Cancer-associated mutations in cancer genes constitute a diverse set of mutations associated with the disease. To gain insight into features of the set, substitution, deletion and insertion mutations were analysed at the nucleotide level, from the COSMIC database. The most frequent substitutions were c→t, g→a, g→t, and the most frequent codon changes were to termination codons. Deletions more than insertions, FS (frameshift) indels more than I-F (in-frame) ones, and single-nucleotide indels, were frequent. FS indels cause loss of significant fractions of proteins. The 5′-cut in FS deletions, and 5′-ligation in FS insertions, often occur between pairs of identical bases. Interestingly, the cut-site and 3′-ligation in insertions, and 3′-cut and join-pair in deletions, were each found to be the same significantly often (p < 0.001). It is suggested that these features aid the incorporation of indel mutations. Tumor suppressors undergo larger numbers of mutations, especially disruptive ones, over the entire protein length, to inactivate two alleles. Proto-oncogenes undergo fewer, less-disruptive mutations, in selected protein regions, to activate a single allele. Finally, catalogues, in ranked order, of genes mutated in each cancer, and cancers in which each gene is mutated, were created. The study highlights the nucleotide level preferences and disruptive nature of cancer mutations. PMID:22492711

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

    PubMed

    Lei, Yunping; Zhu, Huiping; Duhon, Cody; Yang, Wei; Ross, M Elizabeth; Shaw, Gary M; Finnell, Richard H

    2013-01-01

    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. PMID:23922697

  16. Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis

    PubMed Central

    Garin, Intza; Edghill, Emma L.; Akerman, Ildem; Rubio-Cabezas, Oscar; Rica, Itxaso; Locke, Jonathan M.; Maestro, Miguel Angel; Alshaikh, Adnan; Bundak, Ruveyde; del Castillo, Gabriel; Deeb, Asma; Deiss, Dorothee; Fernandez, Juan M.; Godbole, Koumudi; Hussain, Khalid; O’Connell, Michele; Klupa, Thomasz; Kolouskova, Stanislava; Mohsin, Fauzia; Perlman, Kusiel; Sumnik, Zdenek; Rial, Jose M.; Ugarte, Estibaliz; Vasanthi, Thiruvengadam; Johnstone, Karen; Flanagan, Sarah E.; Martínez, Rosa; Castaño, Carlos; Patch, Ann-Marie; Fernández-Rebollo, Eduardo; Raile, Klemens; Morgan, Noel; Harries, Lorna W.; Castaño, Luis; Ellard, Sian; Ferrer, Jorge; de Nanclares, Guiomar Perez; Hattersley, Andrew T.

    2010-01-01

    Heterozygous coding mutations in the INS gene that encodes preproinsulin were recently shown to be an important cause of permanent neonatal diabetes. These dominantly acting mutations prevent normal folding of proinsulin, which leads to beta-cell death through endoplasmic reticulum stress and apoptosis. We now report 10 different recessive INS mutations in 15 probands with neonatal diabetes. Functional studies showed that recessive mutations resulted in diabetes because of decreased insulin biosynthesis through distinct mechanisms, including gene deletion, lack of the translation initiation signal, and altered mRNA stability because of the disruption of a polyadenylation signal. A subset of recessive mutations caused abnormal INS transcription, including the deletion of the C1 and E1 cis regulatory elements, or three different single base-pair substitutions in a CC dinucleotide sequence located between E1 and A1 elements. In keeping with an earlier and more severe beta-cell defect, patients with recessive INS mutations had a lower birth weight (−3.2 SD score vs. −2.0 SD score) and were diagnosed earlier (median 1 week vs. 10 weeks) compared to those with dominant INS mutations. Mutations in the insulin gene can therefore result in neonatal diabetes as a result of two contrasting pathogenic mechanisms. Moreover, the recessively inherited mutations provide a genetic demonstration of the essential role of multiple sequence elements that regulate the biosynthesis of insulin in man. PMID:20133622

  17. Osteogenesis imperfecta without features of type V caused by a mutation in the IFITM5 gene

    PubMed Central

    Grover, Monica; Campeau, Philippe M.; Lietman, Caressa Dee; Lu, James T.; Gibbs, Richard A.; Schlesinger, Alan E.; Lee, Brendan H.

    2013-01-01

    Osteogenesis imperfecta (OI) is typically caused by mutations in type 1 collagen genes, but in recent years new recessive and dominant forms caused by mutations in a plethora of different genes have been characterized. OI type V is a dominant form caused by the recurrent (c.-14C>T) mutation in the 5′UTR of the IFITM5 gene. The mutation adds 5 residues to the N-terminus of the IFITM5 but the pathophysiology of the disease still remains to be elucidated. Typical clinical features present in the majority of OI type V patients include interosseous membrane calcification between the radius and ulna, and the tibia and fibula, radial head dislocation and significant hyperplastic callus formation at the site of fractures. We report a 5 year-old child with clinical features of OI type III or severe OI type IV (characteristic facies, grey sclerae, typical fractures) and absence of classical features of OI type V with a de novo recurrent IFITM5 mutation (c.-14C>T), now typical of OI type V. This highlights the variability of OI caused by IFITM5 mutations and suggests screening for mutations in this gene in most cases of OI where type 1 collagen mutations are absent. PMID:23674381

  18. A novel elastin gene mutation in a Vietnamese patient with cutis laxa.

    PubMed

    Siefring, Mark L; Lawrence, Elizabeth C; Nguyen, Tom C; Lu, Doanh; Pham, Giang; Lorenchick, Christa; Levine, Kara L; Urban, Zsolt

    2014-01-01

    We report a 3-year-old girl from Vietnam with severe congenital cutis laxa; no cardiovascular, pulmonary, neurologic, or visceral involvement; and no family history of cutis laxa. Mutational analysis of the elastin gene identified heterozygosity for a previously unreported de novo c.2184delT mutation in exon 30 not present in either parent. PMID:24758204

  19. A NATURALLY OCCURRING EPIGENETIC MUTATION IN AN SBP-BOX GENE INHIBITS TOMATO FRUIT RIPENING

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A major player in the regulatory network controlling fruit ripening is likely to be the gene at the tomato Colorless non-ripening (Cnr) locus 1,2. The Cnr mutation results in colorless fruits with a significant loss of cell to cell adhesion. The nature of the mutation and the identity of the Cnr g...

  20. Low frequency of VHL gene mutations in young individuals with polycythemia and high serum erythropoietin.

    PubMed

    Randi, Maria Luigia; Murgia, Alessandra; Putti, Maria Caterina; Martella, Maddalena; Casarin, Alberto; Opocher, Giuseppe; Fabris, Fabrizio

    2005-05-01

    In one out of six young individuals with polycythemia and high erythropoietin levels we found a heterozygous VHL gene mutation (430G->A;Gly144Arg). The man's unaffected mother and sister carry the same mutation. No other VHL genomic or expression alterations were found. In one other patient different genetic conditions were found. PMID:15921386

  1. Novel Mutations in K13 Propeller Gene of Artemisinin-Resistant Plasmodium falciparum

    PubMed Central

    Uemura, Haruki; Kimata, Isao; Ichinose, Yoshio; Logedi, John; Omar, Ahmeddin H.; Kaneko, Akira

    2015-01-01

    We looked for mutations in the Plasmodium falciparum K13 propeller gene of an artemisinin-resistant parasite on islands in Lake Victoria, Kenya, where transmission in 2012–2013 was high. The 4 new types of nonsynonymous, and 5 of synonymous, mutations we detected among 539 samples analyzed provide clues to understanding artemisinin-resistant parasites. PMID:25695257

  2. Novel mutations in K13 propeller gene of artemisinin-resistant Plasmodium falciparum.

    PubMed

    Isozumi, Rie; Uemura, Haruki; Kimata, Isao; Ichinose, Yoshio; Logedi, John; Omar, Ahmeddin H; Kaneko, Akira

    2015-03-01

    We looked for mutations in the Plasmodium falciparum K13 propeller gene of an artemisinin-resistant parasite on islands in Lake Victoria, Kenya, where transmission in 2012-2013 was high. The 4 new types of nonsynonymous, and 5 of synonymous, mutations we detected among 539 samples analyzed provide clues to understanding artemisinin-resistant parasites. PMID:25695257

  3. GPR143 Gene Mutations in Five Chinese Families with X-linked Congenital Nystagmus

    PubMed Central

    Han, Ruifang; Wang, Xiaojuan; Wang, Dongjie; Wang, Liming; Yuan, Zhongfang; Ying, Ming; Li, Ningdong

    2015-01-01

    The ocular albinism type I (OA1) is clinically characterized by impaired visual acuity, nystagmus, iris hypopigmentation with translucency, albinotic fundus, and macular hypoplasia together with normally pigmented skin and hair. However, it is easily misdiagnosed as congenital idiopathic nystagmus in some Chinese patients with OA1 caused by the G-protein coupled receptor 143 (GPR143) gene mutations. Mutations in the FERM domaincontaining 7 (FRMD7) gene are responsible for the X-linked congenital idiopathic nystagmus. In this study, five Chinese families initially diagnosed as X-linked congenital nystagmus were recruited and patients underwent ophthalmological examinations. After direct sequencing of the FRMD7 and GPR143 genes, five mutations in GPR143 gene were detected in each of the five families, including a novel nonsense mutation of c.333G>A (p.W111X), two novel splicing mutations of c.360+1G>C and c.659-1G>A, a novel small deletion mutation of c.43_50dupGACGCAGC (p.L20PfsX25), and a previously reported missense mutation of c.703G>A (p.E235K). Optical coherence tomography (OCT) examination showed foveal hypoplasia in all the affected patients with nystagmus. Our study further expands the GPR143 mutation spectrum and contributes to the study of GPR143 molecular pathogenesis. Molecular diagnosis and optical coherence tomography (OCT) are two useful tools for differential diagnosis. PMID:26160353

  4. Mutations and a polymorphism in the factor VIII gene discovered by denaturing gradient gel electrophoresis

    SciTech Connect

    Kogan, S.; Gitschier, J. )

    1990-03-01

    Hemophilia A results from mutations in the gene coding for coagulation factor VIII. The authors gradient gel electrophoresis to screen for mutations in the region of the factor VIII gene coding for the first acidic domain. Amplification primers were designed employing the MELTMAP computer program to optimize the ability to detect mutations. Screening of amplified DNA from 228 unselected hemophilia A patients revealed two mutations and one polymorphism. Rescreening the same population by making heteroduplexes between amplified patient and control samples prior to electrophoresis revealed one additional mutation. The mutations include two missense and one 4-base-pair deletion, and each mutation was found in patients with severe hemophilia. The polymorphism, located adjacent to the adenine branch site in intron 7, is useful for genetic prediction in some cases where the Bcl I and Xba I polymorphisms are uninformative. These results suggest that DNA amplification and denaturing gradient gel electrophoresis should be an excellent strategy for identifying mutations and polymorphisms in defined regions of the factor VIII gene and other large genes.

  5. Spectrum of factor X gene mutations in Iranian patients with congenital factor X deficiency.

    PubMed

    Dorgalaleh, Akbar; Zaker, Farhad; Tabibian, Shadi; Alizadeh, Shaban; Dorgalele, Saeed; Hosseini, Soudabeh; Shamsizadeh, Morteza

    2016-04-01

    Congenital factor X deficiency is one of the most severe forms of rare bleeding disorders transmitted in autosomal recessive manner. According to the World Federation of Hemophilia survey, 153 patients with factor X deficiency (FXD) live in Iran, but a few studies have been performed to determine the precise distribution of FXD in different parts of the country and to assess molecular basis of this disorder in Iranian patients. This study was conducted to assess the spectrum of factor X gene mutation in Iranian patients with congenital FXD. All relevant English and Persian-language publications were searched (until 2015). Clinical presentations or molecular basis of nearly 90 Iranian patients were reported in different studies. Most of these studies focused on clinical presentations of patients, whereas molecular analyses were rarely performed. Most molecular studies found a diversity in factor X disease causing mutations in Iranian patients. Like other parts of the world, the majority of mutations in Iranian patients were missense mutations, but splice-site mutations were relatively common. Three extremely rare cases of combined factor X and factor VII deficiencies were observed in two cases of which this disorder resulted from different missense mutations in respective factor genes. A wide spectrum of factor X gene mutations was observed in Iranian patients with congenital FXD that revealed diversity in FXD gene mutations. PMID:26891460

  6. GPR143 Gene Mutations in Five Chinese Families with X-linked Congenital Nystagmus.

    PubMed

    Han, Ruifang; Wang, Xiaojuan; Wang, Dongjie; Wang, Liming; Yuan, Zhongfang; Ying, Ming; Li, Ningdong

    2015-01-01

    The ocular albinism type I (OA1) is clinically characterized by impaired visual acuity, nystagmus, iris hypopigmentation with translucency, albinotic fundus, and macular hypoplasia together with normally pigmented skin and hair. However, it is easily misdiagnosed as congenital idiopathic nystagmus in some Chinese patients with OA1 caused by the G-protein coupled receptor 143 (GPR143) gene mutations. Mutations in the FERM domain-containing 7 (FRMD7) gene are responsible for the X-linked congenital idiopathic nystagmus. In this study, five Chinese families initially diagnosed as X-linked congenital nystagmus were recruited and patients underwent ophthalmological examinations. After direct sequencing of the FRMD7 and GPR143 genes, five mutations in GPR143 gene were detected in each of the five families, including a novel nonsense mutation of c.333G>A (p.W111X), two novel splicing mutations of c.360+1G>C and c.659-1G>A, a novel small deletion mutation of c.43_50dupGACGCAGC (p.L20PfsX25), and a previously reported missense mutation of c.703G>A (p.E235K). Optical coherence tomography (OCT) examination showed foveal hypoplasia in all the affected patients with nystagmus. Our study further expands the GPR143 mutation spectrum and contributes to the study of GPR143 molecular pathogenesis. Molecular diagnosis and optical coherence tomography (OCT) are two useful tools for differential diagnosis. PMID:26160353

  7. Red blood cell PK deficiency: An update of PK-LR gene mutation database.

    PubMed

    Canu, Giulia; De Bonis, Maria; Minucci, Angelo; Capoluongo, Ettore

    2016-03-01

    Pyruvate kinase (PK) deficiency is known as being the most common cause of chronic nonspherocytic hemolytic anemia (CNSHA). Clinical PK deficiency is transmitted as an autosomal recessive trait, that can segregate neither in homozygous or in a compound heterozygous modality, respectively. Two PK genes are present in mammals: the pyruvate kinase liver and red blood cells (PK-LR) and the pyruvate kinase muscle (PK-M), of which only the first encodes for the isoenzymes normally expressed in the red blood cells (R-type) and in the liver (L-type). Several reports have been published describing a large variety of genetic defects in PK-LR gene associated to CNSHA. Herein, we present a review of about 250 published mutations and six polymorphisms in PK-LR gene with the corresponding clinical and molecular data. We consulted the PubMed website for searching mutations and papers, along with two main databases: the Leiden Open Variation Database (LOVD, https://grenada.lumc.nl/LOVD2/mendelian_genes/home.php?select_db=PKLR) and Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/gene.php?gene=PKLR) for selecting, reviewing and listing the annotated PK-LR gene mutations present in literature. This paper is aimed to provide useful information to clinicians and laboratory professionals regarding overall reported PK-LR gene mutations, also giving the opportunity to harmonize data regarding PK-deficient individuals. PMID:26832193

  8. Quantification of the paternal allele bias for new germline mutations in the retinoblastoma gene

    SciTech Connect

    Morrow, J.F.; Rapaport, J.M.; Dryia, T.P.

    1994-09-01

    New germline mutations in the human retinoblastoma gene preferentially arise on a paternally derived allele. In nonhereditary retinoblastoma, the initial somatic mutation seems to have no such bias. The few previous reports of these phenomena included relatively few cases (less than a dozen new germline or initial somatic mutations), so that the magnitude of the paternal allele bias for new germline mutations is not known. Knowledge of the magnitude of the bias is valuable for genetic counseling, since, for example, patients with new germline mutations who reproduce transmit risk for retinoblastoma according to the risk that the transmitted allele has a germline mutation. We sought to quantitate the paternal allele bias and to determine whether paternal age is a factor possibly accounting for it. We studied 311 families with retinoblastoma (261 simplex, 50 multiplex) that underwent clinical genetic testing and 5 informative families recruited from earlier research. Using RFLPs and polymorphic microsatellites in the retinoblastoma gene, we could determine the parental origin of 45 new germline mutations and 44 probable initial somatic mutations. Thirty-seven of the 45 new germline mutations, or 82%, arose on a paternal allele while only 24 of the 44 initial somatic mutations (55%) did so. Increased paternal age does not appear to account for the excess of new paternal germline mutations, since the average age of fathers of children with new germline mutations (29.4 years, n=26, incomplete records on 11) was not significantly different from the average age of fathers of children with maternal germline mutations or somatic initial mutations (29.8 years, n=35, incomplete records on 17).

  9. Asymptomatic carriers for homozygous novel mutations in the FKRP gene: the other end of the spectrum.

    PubMed

    de Paula, Flavia; Vieira, Natássia; Starling, Alessandra; Yamamoto, Lydia Uraco; Lima, Bruno; de Cássia Pavanello, Rita; Vainzof, Mariz; Nigro, Vincenzo; Zatz, Mayana

    2003-12-01

    Autosomal recessive limb-girdle muscular dystrophy linked to 19q13.3 (LGMD2I) was recently related to mutations in the fukutin-related protein gene (FKRP) gene. Pathogenic changes in the same gene were detected in congenital muscular dystrophy patients (MDC1C), a severe disorder. We have screened 86 LGMD genealogies to assess the frequency and distribution of mutations in the FKRP gene in Brazilian LGMD patients. We found 13 Brazilian genealogies, including 20 individuals with mutations in the FKRP gene, and identified nine novel pathogenic changes. The commonest C826A European mutation was found in 30% (9/26) of the mutated LGMD2I alleles. One affected patient homozygous for the FKRP (C826A) mutation also carries a missense R125H change in one allele of the caveolin-3 gene (responsible for LGMD1C muscular dystrophy). Two of her normal sibs were found to be double heterozygotes. In two unrelated LGMD2I families, homozygous for novel missense mutations, we identified four asymptomatic carriers, all older than 20 years. Genotype-phenotype correlation studies in the present study as well as in patients from different populations suggests that the spectrum of variability associated with mutations in the FKRP gene seems to be wider than in other forms of LGMD. It also reinforces the observations that pathogenic mutations are not always determinant of an abnormal phenotype, suggesting the possibility of other mechanisms modulating the severity of the phenotype that opens new avenues for therapeutic approaches. PMID:14647208

  10. High accuracy mutation detection in leukemia on a selected panel of cancer genes.

    PubMed

    Kalender Atak, Zeynep; De Keersmaecker, Kim; Gianfelici, Valentina; Geerdens, Ellen; Vandepoel, Roel; Pauwels, Daphnie; Porcu, Michal; Lahortiga, Idoya; Brys, Vanessa; Dirks, Willy G; Quentmeier, Hilmar; Cloos, Jacqueline; Cuppens, Harry; Uyttebroeck, Anne; Vandenberghe, Peter; Cools, Jan; Aerts, Stein

    2012-01-01

    With the advent of whole-genome and whole-exome sequencing, high-quality catalogs of recurrently mutated cancer genes are becoming available for many cancer types. Increasing access to sequencing technology, including bench-top sequencers, provide the opportunity to re-sequence a limited set of cancer genes across a patient cohort with limited processing time. Here, we re-sequenced a set of cancer genes in T-cell acute lymphoblastic leukemia (T-ALL) using Nimblegen sequence capture coupled with Roche/454 technology. First, we investigated how a maximal sensitivity and specificity of mutation detection can be achieved through a benchmark study. We tested nine combinations of different mapping and variant-calling methods, varied the variant calling parameters, and compared the predicted mutations with a large independent validation set obtained by capillary re-sequencing. We found that the combination of two mapping algorithms, namely BWA-SW and SSAHA2, coupled with the variant calling algorithm Atlas-SNP2 yields the highest sensitivity (95%) and the highest specificity (93%). Next, we applied this analysis pipeline to identify mutations in a set of 58 cancer genes, in a panel of 18 T-ALL cell lines and 15 T-ALL patient samples. We confirmed mutations in known T-ALL drivers, including PHF6, NF1, FBXW7, NOTCH1, KRAS, NRAS, PIK3CA, and PTEN. Interestingly, we also found mutations in several cancer genes that had not been linked to T-ALL before, including JAK3. Finally, we re-sequenced a small set of 39 candidate genes and identified recurrent mutations in TET1, SPRY3 and SPRY4. In conclusion, we established an optimized analysis pipeline for Roche/454 data that can be applied to accurately detect gene mutations in cancer, which led to the identification of several new candidate T-ALL driver mutations. PMID:22675565

  11. Sequence analysis of tyrosinase gene in ocular and oculocutaneous albinism patients: introducing three novel mutations

    PubMed Central

    Khordadpoor-Deilamani, Faravareh; Karimipoor, Morteza; Javadi, Gholamreza

    2015-01-01

    Purpose Albinism is a heterogeneous genetic disorder of melanin synthesis that results in hypopigmented eyes (in patients with ocular albinism) or hair, skin, and eyes (in individuals with oculocutaneous albinism). It is associated with decreased visual acuity, nystagmus, strabismus, and photophobia. The tyrosinase gene is known to be involved in both oculocutaneous albinism and autosomal recessive ocular albinism. In this study, we aimed to screen the mutations in the TYR gene in the nonsyndromic OCA and autosomal recessive ocular albinism patients from Iran. Methods The tyrosinase gene was examined in 23 unrelated patients with autosomal recessive ocular albinism or nonsyndromic OCA using DNA sequencing and bioinformatics analysis. Results TYR gene mutations were identified in 14 (app. 60%) albinism patients. Conclusions We found 10 mutations, 3 of which were novel. No mutation was found in our ocular albinism patients, but one of them was heterozygous for the p.R402Q polymorphism. PMID:26167114

  12. Germline Mutations of the Paired–Like Homeobox 2B (PHOX2B) Gene in Neuroblastoma

    PubMed Central

    Trochet, Delphine; Bourdeaut, Franck; Janoueix-Lerosey, Isabelle; Deville, Anne; de Pontual, Loïc; Schleiermacher, Gudrun; Coze, Carole; Philip, Nicole; Frébourg, Thierry; Munnich, Arnold; Lyonnet, Stanislas; Delattre, Olivier; Amiel, Jeanne

    2004-01-01

    Neuroblastoma (NB) is a frequent pediatric tumor for which recurrent somatic rearrangements are known. Germline mutations of predisposing gene(s) are suspected on the basis of rare familial cases and the association of NB with other genetically determined congenital malformations of neural crest–derived cells—namely, Hirschsprung disease (HSCR) and/or congenital central hypoventilation syndrome (CCHS). We recently identified the paired–like homeobox 2B (PHOX2B) gene as the major disease-causing gene in isolated and syndromic CCHS, which prompted us to regard it as a candidate gene in NB. Here, we report on germline mutations of PHOX2B in both a familial case of NB and a patient with the HSCR-NB association. PHOX2B, therefore, stands as the first gene for which germline mutations predispose to NB. PMID:15024693

  13. The Association of Pre-S/S Gene Mutations and Hepatitis B Virus Vertical Transmission

    PubMed Central

    Yin, Yuzhu; Zhang, Peizhen; Tan, Zhangmin; Zhou, Jin; Wu, Lingling; Hou, Hongying

    2016-01-01

    Background HBV Pre-S/S gene mutations can occur before or after implementation of combined vaccination program. HBV Prs-S/S gene mutation is a risk factor of vaccination failure and frequently causes HBV vertical transfection. Objectives To assess the association of hepatitis B virus (HBV) S gene mutations with vertical transmission. Patients and Methods In this prospective nested case-control study, a total of 60 pregnant women with positive serum HBsAg and HBV DNA ≥ 107 IU/mL were divided into a case group (15 cases with vaccination failure) and a control group (45 cases with vaccination success) according to whether their infants tested positive for HBV infection. Mothers and their children in the case group were further sub-divided into groups including mothers, newborns and infant (the same newborns at age of seven months). The pre-S/S gene mutations were detected by PCR and sequenced and its association with vertical transmission of HBV was analyzed. Results HBV genotype B was the dominant genotype in the both groups’ mothers. Each mother-child pair in case group had the same HBV genotype. There were no significant differences in mutation frequencies of HBV Pre-S/S gene between case and control groups’ mothers (Fragment 1 (M): 2 vs. 4, P > 0.05; Fragment 2 (M): 10 vs. 10, P > 0.05), or among the mothers, newborns and infants in the case group (Fragment 1 (M): 2, 2, and 3, respectively, P > 0.05; Fragment 2 (M): 10, 10 and 10 respectively, P > 0.05). Mutation site analysis of the both groups’ mothers demonstrated 108 different mutation sites in the HBV pre-S/S gene, with 105 silent mutations and 5 missense mutations including ntA826G, ntC531T, ntT667C, ntC512T and ntC546A. Among 15 mother-newborn-infant pairs with successful PCR and sequence in case group, 7 (41.17%) mother-newborn pairs, 9 (60.00%) mother-infant pairs and 3 (20.00%) infant-newborn pairs had different mutation sites. Conclusions HBV in children due to vaccination failure was resulted from vertical transmission. HBV Pre-S/S gene mutations were prevalent and could occur before or after vaccination. Therefore, simply analyzing mutation frequency of HBV gene was not of value. To advance blocking HBV vertical transmission, future studies should focus on specific mutation sites, potentially associated with vaccination failure. PMID:27226799

  14. Mutation and expression of the p53 gene during chemical hepatocarcinogenesis in F344 rats.

    PubMed

    Fu, Yan; Deng, Weiguo; Kawarada, Yoshihiko; Kawagoe, Masami; Ma, Ying Zhe; Li, Xinghua; Guo, Naxin; Kameda, Takashi; Terada, Kunihiko; Sugiyama, Toshihiro

    2003-07-01

    Inactivation of the p53 gene is one of the most frequent genetic alterations in carcinogenesis. We studied gene mutations, the mRNA expression of p53, and the accumulation of p53 protein in chemical hepatocarcinogenesis in rats. Samples consisting of 44 precancerous foci and 18 cancerous foci were collected by laser capture microdissection (LCM), and analyzed for mutations in rat p53 gene exons 5-8 by PCR-single-strand conformational polymorphism (PCR-SSCP). We found that 25 PCR-SSCP bands of exons 6/7 and 8 were altered in 22/62 (35.4%) LCM samples. Direct p53 gene sequencing showed that 20/62 (9 precancer, 11 cancer) (32.3%) LCM samples exhibited 34 point mutations. Ten LCM samples exhibited double or triple mutations in exons 6/7 and 8 simultaneously. A quantitative analysis of p53 mRNA showed that p53 mRNA peaked at an early stage (week 6) in the precancerous lesion, 20 times that of adjacent normal tissue, and returned to normal by week 23. Similar to precancer, p53 mRNA in cancer was five times as high as that of adjacent normal tissue at week 12, and was closer to normal at week 23. When p53 mRNA declined from a high to low, positive immunostaining for the p53 protein began to be seen in precancerous and cancerous foci, suggesting that the p53 protein had accumulated in these foci. Results show that p53 gene mutation is present in initial chemical hepatocarcinogenesis and p53 mRNA concentration is clearly elevated before gene mutation. Once the p53 gene has mutated, mRNA concentration progressively declines, suggesting that mutation leads to inactivation of the p53 gene. PMID:12850271

  15. A novel mutation in SACS gene in a family from southern Italy.

    PubMed

    Criscuolo, C; Banfi, S; Orio, M; Gasparini, P; Monticelli, A; Scarano, V; Santorelli, F M; Perretti, A; Santoro, L; De Michele, G; Filla, A

    2004-01-13

    A form of autosomal recessive spastic ataxia (ARSACS) has been described in the Charlevoix and Saguenay regions of Quebec. So far a frameshift and a nonsense mutation have been identified in the SACS gene. The authors report a new mutation (1859insC), leading to a frameshift with a premature termination of the gene product sacsin, in two sisters from consanguineous parents. The phenotype is similar to previously described patients with ARSACS. PMID:14718706

  16. Identification of 45 novel mutations in the nebulin gene associated with autosomal recessive nemaline myopathy.

    PubMed

    Lehtokari, Vilma-Lotta; Pelin, Katarina; Sandbacka, Maria; Ranta, Salla; Donner, Kati; Muntoni, Francesco; Sewry, Caroline; Angelini, Corrado; Bushby, Kate; Van den Bergh, Peter; Iannaccone, Susan; Laing, Nigel G; Wallgren-Pettersson, Carina

    2006-09-01

    Nemaline myopathy (NM) is a clinically and genetically heterogeneous disorder of skeletal muscle caused by mutations in at least five different genes encoding thin filament proteins of the striated muscle sarcomere. We have previously described 18 different mutations in the last 42 exons of the nebulin gene (NEB) in 18 families with NM. Here we report 45 novel NEB mutations detected by denaturing high-performance liquid chromatography (dHPLC) and sequence analysis of all 183 NEB exons in NM patients from 44 families. Altogether we have identified, including the deletion of exon 55 identified in the Ashkenazi Jewish population, 64 different mutations in NEB segregating with autosomal recessive NM in 55 families. The majority (55%) of the mutations in NEB are frameshift or nonsense mutations predicted to cause premature truncation of nebulin. Point mutations (25%) or deletions (3%) affecting conserved splice signals are predicted in the majority of cases to cause in-frame exon skipping, possibly leading to impaired nebulin-tropomyosin interaction along the thin filament. Patients in 18 families had one of nine missense mutations (14%) affecting conserved amino acids at or in the vicinity of actin or tropomyosin binding sites. In addition, we found the exon 55 deletion in four families. The majority of the patients (in 49/55 families) were shown to be compound heterozygous for two different mutations. The mutations were found in both constitutively and alternatively expressed exons throughout the NEB gene, and there were no obvious mutational hotspots. Patients with more severe clinical pictures tended to have mutations predicted to be more disruptive than patients with milder forms. PMID:16917880

  17. A Leri-Weill dyschondrosteosis patient confirmed by mutation analysis of SHOX gene.

    PubMed

    Choi, Won Bok; Seo, Seung Hyeon; Yoo, Woo Hyun; Kim, Su Young; Kwak, Min Jung

    2015-09-01

    Leri-Weill dyschondrosteosis is characterized by SHOX deficiency, Madelung deformity, and mesomelic short stature. In addition, SHOX deficiency is associated with idiopathic short stature, Turner syndrome, and Langer mesomelic dysplasia. We report the first case of a Leri-Weill dyschondrosteosis patient confirmed by SHOX gene mutation analysis in Korea. The patient, who was a 7-year-old female, showed short stature. Her height and weight were 108.9 cm (<3rd percentile) and 19.7 kg (5th-10th percentile), respectively. Her arm span, height of trunk, leg length, and sitting length were 100.5 cm, 58 cm, 50.9 cm, and 62.5 cm, respectively. Her body proportion was 1.13:1. Extremities to trunk ratio was 2.61. Her hand radiograph showed Madelung deformity. And the growth hormone stimulation test showed a normal response. Furthermore, because of Madelung deformity with idiopathic short stature, she was suspected of SHOX deficiency. We performed SHOX gene mutation analysis and found a c.491G>A (p.W164X) mutation of the SHOX gene. Accordingly, this patient was diagnosed with Leri-Weill dyschondrosteosis. Recently, many mutations have been reported in the SHOX gene. However, to date, mutation analysis of the SHOX gene for Leri-Weill dyschondrosteosis has not been reported in Korea as yet. We report the first case of a Leri-Weill dyschondrosteosis patient confirmed by mutation analysis of the SHOX gene. PMID:26512353

  18. A Leri-Weill dyschondrosteosis patient confirmed by mutation analysis of SHOX gene

    PubMed Central

    Choi, Won Bok; Seo, Seung Hyeon; Yoo, Woo Hyun; Kim, Su Young

    2015-01-01

    Leri-Weill dyschondrosteosis is characterized by SHOX deficiency, Madelung deformity, and mesomelic short stature. In addition, SHOX deficiency is associated with idiopathic short stature, Turner syndrome, and Langer mesomelic dysplasia. We report the first case of a Leri-Weill dyschondrosteosis patient confirmed by SHOX gene mutation analysis in Korea. The patient, who was a 7-year-old female, showed short stature. Her height and weight were 108.9 cm (<3rd percentile) and 19.7 kg (5th-10th percentile), respectively. Her arm span, height of trunk, leg length, and sitting length were 100.5 cm, 58 cm, 50.9 cm, and 62.5 cm, respectively. Her body proportion was 1.13:1. Extremities to trunk ratio was 2.61. Her hand radiograph showed Madelung deformity. And the growth hormone stimulation test showed a normal response. Furthermore, because of Madelung deformity with idiopathic short stature, she was suspected of SHOX deficiency. We performed SHOX gene mutation analysis and found a c.491G>A (p.W164X) mutation of the SHOX gene. Accordingly, this patient was diagnosed with Leri-Weill dyschondrosteosis. Recently, many mutations have been reported in the SHOX gene. However, to date, mutation analysis of the SHOX gene for Leri-Weill dyschondrosteosis has not been reported in Korea as yet. We report the first case of a Leri-Weill dyschondrosteosis patient confirmed by mutation analysis of the SHOX gene. PMID:26512353

  19. Novel mutations in SKIV2L and TTC37 genes in Malaysian children with trichohepatoenteric syndrome.

    PubMed

    Lee, Way Seah; Teo, Kai Ming; Ng, Ruey Terng; Chong, Sze Yee; Kee, Boon Pin; Chua, Kek Heng

    2016-07-15

    Trichohepatoenteric syndrome (THES) is a rare autosomal recessive disorder that is classically associated with intractable diarrhea with an onset within the first few months of life. Herein, we investigated and reported novel mutations in two causal genes in 3 Malaysian cases. Genomic DNA was extracted from peripheral blood obtained from patients in two Malaysian Chinese families. The exons of SKIV2L and TTC37 genes were amplified and sequenced by bi-directional sequencing to identify the point mutations within the coding sequence. Three Chinese boys from two families with characteristic features and clinical course were diagnosed with THES. In family-1, two point mutations were identified in the SKIV2L gene (c.1891G>A and c.3187C>T). In family-2, a single-nucleotide duplication (c.3426dupA) was found in the TTC37 gene. These mutations cause the production of abnormal non-functional gene product leading to the clinical manifestations in the patients. We reported three point mutations, which have not been previously described in other patients with THES in SKIV2L and TTC37 genes, including one nonsense, one frameshift, and one missense mutations. PMID:27050310

  20. A nonsense mutation in the HOXD13 gene underlies synpolydactyly with incomplete penetrance.

    PubMed

    Kurban, Mazen; Wajid, Muhammad; Petukhova, Lynn; Shimomura, Yutaka; Christiano, Angela M

    2011-10-01

    Synpolydactyly 1 (SPD1; OMIM 186000), also known as type II syndactyly, is a dominantly inherited limb malformation that is characterized by an increased number of digits. SPD1 is most commonly caused by polyalanine repeat expansions in the coding region of the HOXD13 gene, which are believed to show a dominant-negative effect. In addition, missense and out-of-frame deletion mutations in the HOXD13 gene are also known to cause SPD, and the mechanism responsible for the phenotype appears to be haploinsufficiency. Here, we analyzed a large consanguineous family from Pakistan with SPD showing a wide variation in phenotype among affected individuals. We performed genetic linkage analysis, which identified a region on chromosome 2 containing the HOXD13 gene. Haplotype analysis with microsatellite markers suggested segregation of the phenotype with HOXD13 gene with incomplete penetrance. Direct sequencing analysis of HOXD13 gene revealed a nonsense mutation, designated as Q248X. All affected individuals with the severe SPD phenotype are homozygous for the mutation, whereas those with the mild SPD phenotype are heterozygous for the mutation. Furthermore, some unaffected individuals also carry the mutation in the heterozygous state, showing incomplete penetrance. Our results show the first nonsense mutation in the HOXD13 gene underlying a severe form of SPD in the homozygous state, and a milder form of SPD with ∼50% penetrance in the heterozygous state, most likely because of the production of 50% of protein compared with normal individuals. PMID:21814222

  1. A nonsense mutation in the HOXD13 gene underlies synpolydactyly with incomplete penetrance

    PubMed Central

    Kurban, Mazen; Wajid, Muhammad; Petukhova, Lynn; Shimomura, Yutaka; Christiano, Angela M

    2012-01-01

    Synpolydactyly 1 (SPD1; OMIM 186000), also known as type II syndactyly, is a dominantly inherited limb malformation that is characterized by an increased number of digits. SPD1 is most commonly caused by polyalanine repeat expansions in the coding region of the HOXD13 gene, which are believed to show a dominant-negative effect. In addition, missense and out-of-frame deletion mutations in the HOXD13 gene are also known to cause SPD, and the mechanism responsible for the phenotype appears to be haploinsufficiency. Here, we analyzed a large consanguineous family from Pakistan with SPD showing a wide variation in phenotype among affected individuals. We performed genetic linkage analysis, which identified a region on chromosome 2 containing the HOXD13 gene. Haplotype analysis with microsatellite markers suggested segregation of the phenotype with HOXD13 gene with incomplete penetrance. Direct sequencing analysis of HOXD13 gene revealed a nonsense mutation, designated Q248X. All affected individuals with the severe SPD phenotype are homozygous for the mutation, while those with the mild SPD phenotype are heterozygous for the mutation. Furthermore, some unaffected individuals also carry the mutation in the heterozygous state, showing incomplete penetrance. Our results demonstrate the first nonsense mutation in the HOXD13 gene underlying a severe form of SPD in the homozygous state, and a milder form of SPD with approximately 50% penetrance in the heterozygous state, most likely due to the production of 50% of protein compared to normal individuals.. PMID:21814222

  2. Multigene panel analysis identified germline mutations of DNA repair genes in breast and ovarian cancer.

    PubMed

    Hirotsu, Yosuke; Nakagomi, Hiroshi; Sakamoto, Ikuko; Amemiya, Kenji; Oyama, Toshio; Mochizuki, Hitoshi; Omata, Masao

    2015-09-01

    Approximately 5-10% of all breast and/or ovarian cancer cases are considered as inherited. BRCA1 and BRCA2 tumor suppressor genes account for a high penetrance of hereditary cases, but familial cases without mutations in these genes can also occur. Despite their low penetrance, other hereditary cancer-related genes are known to be associated with breast and ovarian cancer risk. However, the extent to which these genes prevail in breast and ovarian cancer remains to be elucidated. To estimate the frequency of mutations in these predisposition genes, we analyzed the germline mutations of 25 hereditary cancer-related genes in 155 patients using targeted next-generation sequencing. These subjects included 11 BRCA1/2 mutation-positive cases and 144 negative cases. Of these, three patients (1.9%) had pathogenic mutations in ATM, MRE11A, or MSH6, all of which have a central role in DNA repair and the mismatch repair pathway. The MSH6 splice-site mutation (IVS6+1G>T) was predicted to be pathogenic, as demonstrated by invitro and immunohistochemical analyses. These results suggested deficiencies in cellular DNA repair functions result in the development of breast and ovarian cancer. PMID:26436112

  3. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma | Office of Cancer Genomics

    Cancer.gov

    In a recent Nature article, Morin et al. uncovered a novel role for chromatin modification in driving the progression of two non-Hodgkin lymphomas (NHLs), follicular lymphoma and diffuse large B-cell lymphoma. Through DNA and RNA sequencing of 117 tumor samples and 10 assorted cell lines, the authors identified and validated 109 genes with multiple mutations in these B-cell NHLs. Of the 109 genes, several genes not previously linked to lymphoma demonstrated positive selection for mutation including two genes involved in histone modification, MLL2 and MEF2B.

  4. Human gene mutation database-a biomedical information and research resource.

    PubMed

    Krawczak, M; Ball, E V; Fenton, I; Stenson, P D; Abeysinghe, S; Thomas, N; Cooper, D N

    2000-01-01

    Although 20 years have elapsed since the first single basepair substitution underlying an inherited disease in humans was characterised at the DNA level, the initiative has only recently been taken to establish central database resources for pathological genetic variants. Disease-associated gene lesions are currently collected and publicised by the Human Gene Mutation Database (HGMD) in Cardiff, locus-specific mutation databases, and to some extent also by the Genome Database (GDB) and Online Mendelian Inheritance in Man (OMIM). To date, HGMD represents the only comprehensive and publicly available database of gene lesions underlying human inherited disease. By July 1999, HGMD contained over 18,000 different mutations from some 900 human genes, the majority being single basepair substitutions. In addition to its potential as an information resource for clinicians and genetic counsellors, HGMD has allowed molecular geneticists to address a variety of biological questions through meta-analysis of the collated data. HGMD also promises to assist research workers in optimising mutation search strategies for a given gene. A questionnaire sent out to, and answered by, the editors of 20 key journals revealed that human genetics journals are increasingly reluctant to publish mutation reports. Electronic data submission and publication facilities are therefore urgently required. The World Wide Web (WWW) provides an excellent medium within which to combine the centralised management of basic mutation data, including rigorous quality control, with the possibility of publishing additional mutation-related information. In response to these needs, HGMD has both instituted a collaboration with Springer-Verlag GmbH, Heidelberg, to potentiate free online submission and electronic publication of human gene mutation data and developed links with the curators of locus-specific mutation databases. PMID:10612821

  5. Three novel PHEX gene mutations in four Chinese families with X-linked dominant hypophosphatemic rickets

    SciTech Connect

    Kang, Qing-lin; Xu, Jia; Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233; Medical College of Soochow University, Suzhou, Jiangsu province 215000 ; Zhang, Zeng; Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 ; He, Jin-wei; Lu, Lian-song; Medical College of Soochow University, Suzhou, Jiangsu province 215000 ; Fu, Wen-zhen; Zhang, Zhen-lin

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer In our study, all of the patients were of Han Chinese ethnicity, which were rarely reported. Black-Right-Pointing-Pointer We identified three novel PHEX gene mutations in four unrelated families with XLH. Black-Right-Pointing-Pointer We found that the relationship between the phenotype and genotype of the PHEX gene was not invariant. Black-Right-Pointing-Pointer We found that two PHEX gene sites, p.534 and p.731, were conserved. -- Abstract: Background: X-linked hypophosphatemia (XLH), the most common form of inherited rickets, is a dominant disorder that is characterized by renal phosphate wasting with hypophosphatemia, abnormal bone mineralization, short stature, and rachitic manifestations. The related gene with inactivating mutations associated with XLH has been identified as PHEX, which is a phosphate-regulating gene with homologies to endopeptidases on the X chromosome. In this study, a variety of PHEX mutations were identified in four Chinese families with XLH. Methods: We investigated four unrelated Chinese families who exhibited typical features of XLH by using PCR to analyze mutations that were then sequenced. The laboratory and radiological investigations were conducted simultaneously. Results: Three novel mutations were found in these four families: one frameshift mutation, c.2033dupT in exon 20, resulting in p.T679H; one nonsense mutation, c.1294A > T in exon 11, resulting in p.K432X; and one missense mutation, c.2192T > C in exon 22, resulting in p.F731S. Conclusions: We found that the PHEX gene mutations were responsible for XLH in these Chinese families. Our findings are useful for understanding the genetic basis of Chinese patients with XLH.

  6. Point Mutations Effects on Charge Transport Properties of the Tumor-Suppressor Gene p53

    NASA Astrophysics Data System (ADS)

    Roemer, Rudolf A.; Shih, Chi-Tin; Roche, Stephan

    2008-03-01

    We report on a theoretical study of point mutations effects on charge transfer properties in the DNA sequence of the tumor-suppressor p53 gene. On the basis of effective tight-binding models which simulate hole propagation along the DNA, a statistical analysis of mutation-induced charge transfer modifications is performed. In contrast to non-cancerous mutations, mutation hotspots tend to result in significantly weaker changes of transmission properties. This suggests that charge transport could play a significant role for DNA-repairing deficiency yielding carcinogenesis.

  7. An evaluation of common breast cancer gene mutations in a population of Ashkenazi Jews.

    PubMed Central

    Lalloo, F; Cochrane, S; Bulman, B; Varley, J; Elles, R; Howell, A; Evans, D G

    1998-01-01

    OBJECTIVES: In view of the recent reports of recurrent mutations in BRCA1 and BRCA2 in the Ashkenazi Jewish population, we have undertaken to assess the frequency of these mutations in this population attending for genetic counselling and risk assessment of familial breast cancer. DESIGN: Mutation screening for the 185delAG and the 5382insC mutations in BRCA1 and the 6174delT mutation in BRCA2 was performed on DNA samples from either subjects affected by breast or ovarian cancer or obligate gene carriers. The likelihood of the cancers being hereditary in each family was calculated. SUBJECTS: Blood samples were obtained from 26 affected subjects or obligate gene carriers from 23 Ashkenazi Jewish families, all with a history of either early onset breast or ovarian cancers, or multiple cases of breast or ovarian cancer. RESULTS: Twelve mutations have been identified in the 23 families (52%) of which eight (67%) were the 185delAG mutation, three (25%) were the 6174delT mutation, and one (8%) was the 5382insC mutation. While the majority of these mutations were identified in families with a greater than 50% probability of being hereditary under the CASH segregation model, three mutations were identified in families with a 35% or less probability. CONCLUSIONS: Genetic screening of the recurrent mutations in Ashkenazi Jewish families will lead to the availability of predictive testing in a reasonably large proportion, even if the family history of breast/ovarian cancer is not particularly strong. In our view it is possible to reassure high risk unaffected members of these families, if the screening is negative for these mutations, even if a sample from an affected member of the family is unavailable for previous screening. PMID:9475087

  8. Identification of 28 novel mutations in the Bardet-Biedl syndrome genes: the burden of private mutations in an extensively heterogeneous disease.

    PubMed

    Muller, Jean; Stoetzel, C; Vincent, M C; Leitch, C C; Laurier, V; Danse, J M; Hellé, S; Marion, V; Bennouna-Greene, V; Vicaire, S; Megarbane, A; Kaplan, J; Drouin-Garraud, V; Hamdani, M; Sigaudy, S; Francannet, C; Roume, J; Bitoun, P; Goldenberg, A; Philip, N; Odent, S; Green, J; Cossée, M; Davis, E E; Katsanis, N; Bonneau, D; Verloes, A; Poch, O; Mandel, J L; Dollfus, H

    2010-03-01

    Bardet-Biedl syndrome (BBS), an emblematic disease in the rapidly evolving field of ciliopathies, is characterized by pleiotropic clinical features and extensive genetic heterogeneity. To date, 14 BBS genes have been identified, 3 of which have been found mutated only in a single BBS family each (BBS11/TRIM32, BBS13/MKS1 and BBS14/MKS4/NPHP6). Previous reports of systematic mutation detection in large cohorts of BBS families (n > 90) have dealt only with a single gene, or at most small subsets of the known BBS genes. Here we report extensive analysis of a cohort of 174 BBS families for 12/14 genes, leading to the identification of 28 novel mutations. Two pathogenic mutations in a single gene have been found in 117 families, and a single heterozygous mutation in 17 families (of which 8 involve the BBS1 recurrent mutation, M390R). We confirm that BBS1 and BBS10 are the most frequently mutated genes, followed by BBS12. No mutations have been found in BBS11/TRIM32, the identification of which as a BBS gene only relies on a single missense mutation in a single consanguineous family. While a third variant allele has been observed in a few families, they are in most cases missenses of uncertain pathogenicity, contrasting with the type of mutations observed as two alleles in a single gene. We discuss the various strategies for diagnostic mutation detection, including homozygosity mapping and targeted arrays for the detection of previously reported mutations. PMID:20177705

  9. First Case Report of EX3del4765 Mutation in PAH Gene in Asian Population

    PubMed Central

    Soltani, Ziba; Karami, Fatemeh; Yassaee, Vahidreza; Hashemi Gorji, Feyzollah; Talebzadeh, Mahdieh; Miryounesi, Mohammad

    2016-01-01

    Introduction: Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism, which is caused by mutation in phenylalanine hydroxylase (PAH) gene. Most of the PAH mutations are missense mutations (67%), which are followed by small or large deletions (13%). Case Presentation: We reported a patient with classic PKU and his parents harboring a large deletion in exon 3 (EX3del4765) of PAH gene. This is the first case report of EX3del4765 in Asian patients with PKU. Conclusions: This finding may help improve early detection, differential diagnosis, genetic counseling, and even treatment of patients with PKU.

  10. Fatal familial insomnia: a second kindred with mutation of prion protein gene at codon 178.

    PubMed

    Medori, R; Montagna, P; Tritschler, H J; LeBlanc, A; Cortelli, P; Tinuper, P; Lugaresi, E; Gambetti, P

    1992-03-01

    Fatal familial insomnia (FFI), a condition characterized by inability to sleep, dysautonomia, motor disturbances, and selective thalamic atrophy is a prion disease linked to a GAC----AAC mutation at codon 178 of the prion gene. These data were obtained from one kindred. We now report a second kindred affected by FFI and carrying the same mutation. The finding of the same disease phenotype and genotype in a second family further validates FFI as a distinct disease entity and a phenotype of the GAC----AAC mutation at codon 178 of the prion gene. PMID:1347910

  11. Genomic organization of SLC3A1, a transporter gene mutated in cystinuria

    SciTech Connect

    Pras, E.; Sood, R.; Raben, N.

    1996-08-15

    The SLC3A1 gene encodes a transport protein for cystine and the dibasic amino acids. Recently mutations in this gene have been shown to cause cystinuria. We report the genomic structure and organization of SLC3A1, which is composed of 10 exons and spans nearly 45 kb. Until now screening for mutations in SLC3A1 has been based on RT-PCR amplification of illegitimate mRNA transcripts from white blood cells. In this report we provide primers for amplification of exons from genomic DNA, thus simplifying the process of screening for SLC3A1 mutations in cystinuria. 20 refs., 3 figs., 2 tabs.

  12. Detection of mutations in the glycine decarboxylase gene in patients with nonketotic hyperglycinaemia.

    PubMed

    Sellner, Loryn; Edkins, Edward; Greed, Lawrence; Lewis, Barry

    2005-02-01

    Nonketotic hyperglycinaemia (NKH) is an autosomal recessive disorder of glycine metabolism caused by a deficiency in the mitochondrial glycine cleavage enzyme. The majority of cases are caused by mutations in the P-protein, one of the four components of the glycine cleavage enzyme, also known as glycine decarboxylase (GLDC). Previous studies searching for causative mutations in NKH patients have only looked for a limited number of specific mutations or only screened part of the gene, and in many cases either no mutation or only one mutation was found, which is of limited use for prenatal diagnosis. In this study, we describe the screening of the entire GLDC gene in 3 NKH families by D-HPLC analysis of all 25 exons, identifying two point mutations and two large deletions (exon 8 and exons 2-15) using a combination of D-HPLC analysis, long range PCR, Southern blot and sequencing. For complete prenatal testing both mutations need to be identified, and we suggest that screening of the entire gene as well as deletional analysis should be considered in those subjects where only one mutation has been identified. PMID:15670722

  13. A cancer-predisposing "hot spot" mutation of the fumarase gene creates a dominant negative protein.

    PubMed

    Lorenzato, Annalisa; Olivero, Martina; Perro, Mario; Brière, Jean Jacques; Rustin, Pierre; Di Renzo, Maria Flavia

    2008-02-15

    The Fumarase (Fumarate Hydratase, FH) is a tumor suppressor gene whose germline heterozygous mutations predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC). The FH gene encodes an enzyme of the Krebs cycle, functioning as a homotetramer and catalyzing the hydration of fumarate to malate. Among the numerous FH mutations reported so far, the R190H missense mutation is the most frequent in HLRCC patients. Here we show the functional analyses of the R190H, in comparison to the better characterized E319Q mutation. We first expressed wild-type and mutated proteins in FH deficient human skin fibroblasts, using lentiviral vectors. The wild-type transgene was able to restore the FH enzymatic activity in cells, while the R190H- and E319Q-FH were not. More interestingly, when the same transgenes were expressed in normal, FH-proficient cells, only the R190H-FH reduced the endogenous FH enzymatic activity. By enforcing the expression of equal amount of wild-type and R190H-FH in the same cell, we showed that the mutated FH protein directly inhibited enzymatic activity by nearly abrogating the FH homotetramer formation. These data demonstrate the dominant negative effect of the R190H missense mutation in the FH gene and suggest that the FH tumor-suppressing activity might be impaired in cells carrying a heterozygous mutation. PMID:17960613

  14. Novel point mutations in the ERG11 gene in clinical isolates of azole resistant Candida species

    PubMed Central

    Silva, Danielly Beraldo dos Santos; Rodrigues, Luana Mireli Carbonera; de Almeida, Adriana Araújo; de Oliveira, Kelly Mari Pires; Grisolia/, Alexéia Barufatti

    2016-01-01

    The azoles are the class of medications most commonly used to fight infections caused by Candida sp. Typically, resistance can be attributed to mutations in ERG11 gene (CYP51) which encodes the cytochrome P450 14α-demethylase, the primary target for the activity of azoles. The objective of this study was to identify mutations in the coding region of theERG11 gene in clinical isolates of Candidaspecies known to be resistant to azoles. We identified three new synonymous mutations in the ERG11 gene in the isolates of Candida glabrata (C108G, C423T and A1581G) and two new nonsynonymous mutations in the isolates of Candida krusei - A497C (Y166S) and G1570A (G524R). The functional consequence of these nonsynonymous mutations was predicted using evolutionary conservation scores. The G524R mutation did not have effect on 14α-demethylase functionality, while the Y166S mutation was found to affect the enzyme. This observation suggests a possible link between the mutation and dose-dependent sensitivity to voriconazole in the clinical isolate of C. krusei. Although the presence of the Y166S in phenotype of reduced azole sensitivity observed in isolate C. kruseidemands investigation, it might contribute to the search of new therapeutic agents against resistant Candida isolates. PMID:26982177

  15. Mutational landscape of gingivo-buccal oral squamous cell carcinoma reveals new recurrently-mutated genes and molecular subgroups.

    PubMed

    2013-01-01

    Gingivo-buccal oral squamous cell carcinoma (OSCC-GB), an anatomical and clinical subtype of head and neck squamous cell carcinoma (HNSCC), is prevalent in regions where tobacco-chewing is common. Exome sequencing (n=50) and recurrence testing (n=60) reveals that some significantly and frequently altered genes are specific to OSCC-GB (USP9X, MLL4, ARID2, UNC13C and TRPM3), while some others are shared with HNSCC (for example, TP53, FAT1, CASP8, HRAS and NOTCH1). We also find new genes with recurrent amplifications (for example, DROSHA, YAP1) or homozygous deletions (for example, DDX3X) in OSCC-GB. We find a high proportion of C>G transversions among tobacco users with high numbers of mutations. Many pathways that are enriched for genomic alterations are specific to OSCC-GB. Our work reveals molecular subtypes with distinctive mutational profiles such as patients predominantly harbouring mutations in CASP8 with or without mutations in FAT1. Mean duration of disease-free survival is significantly elevated in some molecular subgroups. These findings open new avenues for biological characterization and exploration of therapies. PMID:24292195

  16. RAS gene mutations in acute and chronic myelocytic leukemias, chronic myeloproliferative disorders, and myelodysplastic syndromes

    SciTech Connect

    Janssen, J.W.G.; Steenvoorden, A.C.M.; Lyons, J.; Anger, B.; Boehlke, J.U.; Bos, J.L.; Seliger, H.; Bartram, C.R.

    1987-12-01

    The authors report on investigations aimed at detecting mutated RAS genes in a variety of preleukemic disorders and leukemias of myeloid origin. DNA transfection analyses (tumorigenicity assay) and hybridization to mutation-specific oligonucleotide probes established NRAS mutations in codon 12 or 61 of 4/9 acute myelocytic leukemias (AML) and three AML lines. Leukemic cells of another AML patient showed HRAS gene activation. By using a rapid and sensitive dot-blot screening procedure based on the combination of in vitro amplification of RAS-specific sequences and oligonucleotide hybridization they additionally screened 15 myelodysplastic syndromes, 26 Philadelphia chromosome-positive chronic myelocytic leukemias in chronic or acute phase, and 19 other chronic myeloproliferative disorders. A mutation within NRAS codon 12 could thus be demonstrated in a patient with idiopathic myelofibrosis and in another with chronic myelomonocytic leukemia. Moreover, mutated NRAS sequences were detected in lymphocytes, in granulocytes, as well as in monocytes/macrophages of the latter case.

  17. RAS gene mutations in acute and chronic myelocytic leukemias, chronic myeloproliferative disorders, and myelodysplastic syndromes.

    PubMed Central

    Janssen, J W; Steenvoorden, A C; Lyons, J; Anger, B; Bhlke, J U; Bos, J L; Seliger, H; Bartram, C R

    1987-01-01

    We report on investigations aimed at detecting mutated RAS genes in a variety of preleukemic disorders and leukemias of myeloid origin. DNA transfection analyses (tumorigenicity assay) and hybridization to mutation-specific oligonucleotide probes established NRAS mutations in codon 12 or 61 of 4/9 acute myelocytic leukemias (AML) and three AML lines. Leukemic cells of another AML patient showed HRAS gene activation. By using a rapid and sensitive dot-blot screening procedure based on the combination of in vitro amplification of RAS-specific sequences and oligonucleotide hybridization we additionally screened 15 myelodysplastic syndromes, 26 Philadelphia chromosome-positive chronic myelocytic leukemias in chronic or acute phase, and 19 other chronic myeloproliferative disorders. A mutation within NRAS codon 12 could thus be demonstrated in a patient with idiopathic myelofibrosis and in another with chronic myelomonocytic leukemia. Moreover, mutated NRAS sequences were detected in lymphocytes, in granulocytes, as well as in monocytes/macrophages of the latter case. Images PMID:3122217

  18. Tyrosinase gene mutations in the Chinese Han population with OCA1.

    PubMed

    Liu, Ning; Kong, Xiang Dong; Shi, Hui Rong; Wu, Qing Hua; Jiang, Miao

    2014-01-01

    Oculocutaneous albinism (OCA) is a heterogeneous autosomal recessive genetic disorder that affects melanin synthesis. OCA results in reduced or absent pigmentation in the hair, skin and eyes. Type 1 OCA (OCA1) is the result of tyrosinase (TYR) gene mutations and is a severe disease type. This study investigated TYR mutations in a Chinese cohort with OCA1. This study included two parts: patient genetic study and prenatal genetic diagnosis. A total of 30 OCA1 patients were subjected to TYR gene mutation analysis. Ten pedigrees were included for prenatal genetic diagnosis. A total of 100 unrelated healthy Chinese individuals were genotyped for controls. The coding sequence and the intron/exon junctions of TYR were analysed by bidirectional DNA sequencing. In this study, 20 mutations were identified, four of which were novel. Of these 30 OCA1 patients, 25 patients were TYR compound heterozygous; two patients carried homozygous TYR mutations; and three were heterozygous. Among the ten prenatally genotyped fetuses, three fetuses carried compound heterozygous mutations and seven carried no mutation or only one mutant allele of TYR and appeared normal at birth. In conclusion, we identified four novel TYR mutations and showed that molecular-based prenatal screening to detect TYR mutations in a fetus at risk for OCA1 provided essential information for genetic counselling of couples at risk. PMID:25577957

  19. De Novo Truncating FUS Gene Mutation as a Cause of Sporadic Amyotrophic Lateral Sclerosis

    PubMed Central

    DeJesus-Hernandez, Mariely; Kocerha, Jannet; Finch, NiCole; Crook, Richard; Baker, Matt; Desaro, Pamela; Johnston, Amelia; Rutherford, Nicola; Wojtas, Aleksandra; Kennelly, Kathleen; Wszolek, Zbigniew K.; Graff-Radford, Neill; Boylan, Kevin; Rademakers, Rosa

    2010-01-01

    Mutations in the gene encoding fused in sarcoma (FUS) were recently identified as a novel cause of amyotrophic lateral sclerosis (ALS), emphasizing the genetic heterogeneity of ALS. We sequenced the genes encoding superoxide dismutase (SOD1), TAR DNA-binding protein 43 (TARDBP) and FUS in 99 sporadic and 17 familial ALS patients ascertained at Mayo Clinic. We identified two novel mutations in FUS in two out of 99 (2.0%) sporadic ALS patients and established the de novo occurrence of one FUS mutation. In familial patients, we identified three (17.6%) SOD1 mutations, while FUS and TARDBP mutations were excluded. The de novo FUS mutation (g.10747A>G; IVS13-2A>G) affects the splice-acceptor site of FUS intron 13 and was shown to induce skipping of FUS exon 14 leading to the C-terminal truncation of FUS (p.G466VfsX14). Subcellular localization studies showed a dramatic increase in the cytoplasmic localization of FUS and a reduction of normal nuclear expression in cells transfected with truncated compared to wild-type FUS. We further identified a novel in-frame insertion/deletion mutation in FUS exon 12 (p.S402 P411delinsGGGG) which is predicted to expand a conserved poly-glycine motif. Our findings extend the mutation spectrum in FUS leading to ALS and describe the first de novo mutation in FUS. PMID:20232451

  20. De novo mutations in histone modifying genes in congenital heart disease

    PubMed Central

    Zaidi, Samir; Choi, Murim; Wakimoto, Hiroko; Ma, Lijiang; Jiang, Jianming; Overton, John D.; Romano-Adesman, Angela; Bjornson, Robert D.; Breitbart, Roger E.; Brown, Kerry K.; Carriero, Nicholas J.; Cheung, Yee Him; Deanfield, John; DePalma, Steve; Fakhro, Khalid A.; Glessner, Joseph; Hakonarson, Hakon; Italia, Michael; Kaltman, Jonathan R.; Kaski, Juan; Kim, Richard; Kline, Jennie K.; Lee, Teresa; Leipzig, Jeremy; Lopez, Alexander; Mane, Shrikant M.; Mitchell, Laura E.; Newburger, Jane W.; Parfenov, Michael; Pe'er, Itsik; Porter, George; Roberts, Amy; Sachidanandam, Ravi; Sanders, Stephan J.; Seiden, Howard S.; State, Mathew W.; Subramanian, Sailakshmi; Tikhonova, Irina R.; Wang, Wei; Warburton, Dorothy; White, Peter S.; Williams, Ismee A.; Zhao, Hongyu; Seidman, Jonathan G.; Brueckner, Martina; Chung, Wendy K.; Gelb, Bruce D.; Goldmuntz, Elizabeth; Seidman, Christine E.; Lifton, Richard P.

    2013-01-01

    Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births1. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. By analysis of exome sequencing of parent-offspring trios, we compared the incidence of de novo mutations in 362 severe CHD cases and 264 controls. CHD cases showed a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging mutations. Similar odds ratios were seen across major classes of severe CHD. We found a marked excess of de novo mutations in genes involved in production, removal or reading of H3K4 methylation (H3K4me), or ubiquitination of H2BK120, which is required for H3K4 methylation2–4. There were also two de novo mutations in SMAD2; SMAD2 signaling in the embryonic left-right organizer induces demethylation of H3K27me5. H3K4me and H3K27me mark `poised' promoters and enhancers that regulate expression of key developmental genes6. These findings implicate de novo point mutations in several hundred genes that collectively contribute to ~10% of severe CHD. PMID:23665959

  1. Spectrum of HLXB9 gene mutations in Currarino syndrome and genotype-phenotype correlation.

    PubMed

    Crétolle, C; Pelet, A; Sanlaville, D; Zérah, M; Amiel, J; Jaubert, F; Révillon, Y; Baala, L; Munnich, A; Nihoul-Fékété, C; Lyonnet, S

    2008-07-01

    Currarino syndrome (CS) is a rare congenital malformation described in 1981 as the association of three main features: typical sacral malformation (sickle-shaped sacrum or total sacral agenesis below S2), hindgut anomaly, and presacral tumor. In addition to the triad, tethered cord and/or lipoma of the conus are also frequent and must be sought, as they may lead to severe complications if not treated. The HLXB9 gene, located at 7q36, is disease-causing. It encodes the HB9 transcription factor and interacts with DNA through a highly evolutionarily conserved homeodomain early in embryological development. Thus far, 43 different heterozygous mutations have been reported in patients fulfilling CS criteria. Mutation detection rate is about 50%, and reaches 90% in familial cases. Here, we report 23 novel mutations in 26 patients among a series of 50 index cases with CS, and review mutational reports published since the identification of the causative gene. Three cytogenetic anomalies encompassing the HLXB9 gene are described for the first time. Truncating mutations (frameshifts or nonsense mutations) represent 57% of those identified, suggesting that haploinsufficiency is the basis of CS. No obvious genotype-phenotype correlation can be drawn thus far. Genetic heterogeneity is suspected, since at least 19 of the 24 patients without HLXB9 gene mutation harbor subtle phenotypic variations. PMID:18449898

  2. Mutational analysis of the PEX gene in patients with X-linked hypophosphatemic rickets.

    PubMed Central

    Holm, I A; Huang, X; Kunkel, L M

    1997-01-01

    X-linked hypophosphatemic rickets (HYP) is a dominant disorder characterized by renal phosphate wasting and abnormal vitamin D metabolism. PEX, the gene that is defective in HYP and is located on Xp22.1, is homologous to members of the neutral endopeptidase family. However, the complete coding sequence of the PEX cDNA, the structure of the PEX gene, and the role that PEX plays in phosphate transport remain unknown. We determined the genomic structure of the published PEX gene, which was found to be composed of 18 short exons, and demonstrated that the genomic organization of PEX shares homology to members of the family of neutral endopeptidases. Primer sets were designed from the intron sequence, to amplify each PEX exon from genomic DNA of HYP patients. Mutations in PEX were identified in 9/22 unrelated HYP patients, confirming that defects in PEX are responsible for HYP. The mutations detected included three nonsense mutations, a 1-bp deletion leading to a frameshift, a donor splice-site mutation, and missense mutations in four patients. Although the entire PEX gene has not been identified and some mutations may have been missed, the lack of detection of mutations in the remaining 13 patients, especially in 1 patient who has an apparently balanced, de novo 9;13 translocation, implies that there may be other loci involved in the generation of the HYP phenotype. Images Figure 3 Figure 4 PMID:9106524

  3. Distribution of Gene Mutations Associated with Familial Normosmic Idiopathic Hypogonadotropic Hypogonadism

    PubMed Central

    Gürbüz, Fatih; Kotan, L. Damla; Mengen, Eda; Şıklar, Zeynep; Berberoğlu, Merih; Dökmetaş, Sebila; Kılıçlı, Mehmet Fatih; Güven, Ayla; Kirel, Birgül; Saka, Nurçin; Poyrazoğlu, Şükran; Cesur, Yaşar; Doğan, Murat; Özen, Samim; Özbek, Mehmet Nuri; Demirbilek, Hüseyin; Kekil, M. Burcu; Temiz, Fatih; Önenli Mungan, Neslihan; Yüksel, Bilgin; Topaloğlu, Ali Kemal

    2012-01-01

    Objective: Normosmic idiopathic hypogonadotropic hypogonadism (nIHH) is characterized by failure of initiation or maintenance of puberty due to insufficient gonadotropin release, which is not associated with anosmia/hyposmia. The objective of this study was to determine the distribution of causative mutations in a hereditary form of nIHH. Methods: In this prospective collaborative study, 22 families with more than one affected individual (i.e. multiplex families) with nIHH were recruited and screened for genes known or suspected to be strong candidates for nIHH. Results: Mutations were identified in five genes (GNRHR, TACR3, TAC3, KISS1R, and KISS1) in 77% of families with autosomal recessively inherited nIHH. GNRHR and TACR3 mutations were the most common two causative mutations occurring with about equal frequency. Conclusions: Mutations in these five genes account for about three quarters of the causative mutations in nIHH families with more than one affected individual. This frequency is significantly greater than the previously reported rates in all inclusive (familial plus sporadic) cohorts. GNRHR and TACR3 should be the first two genes to be screened for diagnostic purposes. Identification of causative mutations in the remaining families will shed light on the regulation of puberty. Conflict of interest:None declared. PMID:22766261

  4. Gene Mutation Patterns in Patients with Minimally Differentiated Acute Myeloid Leukemia☆

    PubMed Central

    Kao, Hsiao-Wen; Liang, Der-Cherng; Wu, Jin-Hou; Kuo, Ming-Chung; Wang, Po-Nan; Yang, Chao-Ping; Shih, Yu-Shu; Lin, Tung-Huei; Huang, Yu-Hui; Shih, Lee-Yung

    2014-01-01

    Minimally differentiated acute myeloid leukemia (AML-M0) is a rare subtype of AML with poor prognosis. Although genetic alterations are increasingly reported in AML, the gene mutations have not been comprehensively studied in AML-M0. We aimed to examine a wide spectrum of gene mutations in patients with AML-M0 to determine their clinical relevance. Twenty gene mutations including class I, class II, class III of epigenetic regulators (IDH1, IDH2, TET2, DNMT3A, MLL-PTD, ASXL1, and EZH2), and class IV (tumor suppressor genes) were analyzed in 67 patients with AML-M0. Mutational analysis was performed with polymerase chain reaction–based assays followed by direct sequencing. The most frequent gene mutations from our data were FLT3-ITD/FLT3-TKD (28.4%), followed by mutations in IDH1/IDH2 (28.8%), RUNX1 (23.9%), N-RAS/K-RAS (12.3%), TET2 (8.2%), DNMT3A (8.1%), MLL-PTD (7.8%), and ASXL1 (6.3%). Seventy-nine percent (53/67) of patients had at least one gene mutation. Class I genes (49.3%) were the most common mutated genes, which were mutually exclusive. Class III genes of epigenetic regulators were also frequent (43.9%). In multivariate analysis, old age [hazard ratio (HR) 1.029, 95% confidence interval (CI) 1.013-1.044, P = .001) was the independent adverse factor for overall survival, and RUNX1 mutation (HR 2.326, 95% CI 0.978-5.533, P = .056) had a trend toward inferior survival. In conclusion, our study showed a high frequency of FLT3, RUNX1, and IDH mutations in AML-M0, suggesting that these mutations played a role in the pathogenesis and served as potential therapeutic targets in this rare and unfavorable subtype of AML. PMID:25022553

  5. Association of methylenetetrahydrofolate reductase C677T and A1298C polymorphisms with colorectal cancer risk: A meta-analysis.

    PubMed

    Zhao, Mengmeng; Li, Xuelian; Xing, Chengzhong; Zhou, Baosen

    2013-09-01

    Colorectal cancer (CRC) is one of the most common types of cancer worldwide and a leading cause of cancer-related mortality. This meta-analysis was conducted to determine the effect of methylenetetrahydrofolate reductase (MTHFR) mutants on the risk of CRC. A literature search was conducted on PubMed, Medline and the China National Knowledge Infrastructure (CNKI) databases. Eligible studies were collected based on rigorous criteria of inclusion. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by the fixed- or random-effects model. After all the studies were pooled, the OR of CRC for individuals carrying the MTHFR 677TT genotype, compared to the CC genotype, was 0.89 (95% CI: 0.82-0.97). When analyzed by ethnicity, Asians with the MTHFR 1298CC genotype exhibited a decreased risk of CRC (OR=0.69; 95% CI: 0.54-0.89). In a mixed population, a significantly reduced risk of CRC was observed among carriers of the 677TT (OR=0.86; 95% CI: 0.76-0.96) and the 1298CC (OR=0.82; 95% CI: 0.69-0.98) genotypes, compared to the wild-type homozygous genotype. In the subgroup of colon cancer, the OR of 677TT vs. CC+CT was 0.83 (95% CI: 0.72-0.96) and the OR of 1298CC vs. AA+AC was 0.81 (95% CI: 0.69-0.96). In the rectal cancer subgroup, the OR of 677TT vs. CC+CT was 0.86 (95% CI: 0.77-0.97). Therefore, this meta-analysis suggested that the MTHFR 677T and 1298C alleles were associated with a low risk of CRC. PMID:24649029

  6. Identification and in silico analysis of 14 novel GJB1, MPZ and PMP22 gene mutations

    PubMed Central

    Miltenberger-Miltenyi, Gabriel; Schwarzbraun, Thomas; Löscher, Wolfgang N; Wanschitz, Julia; Windpassinger, Christian; Duba, Hans-Christoph; Seidl, Rainer; Albrecht, Gerhard; Weirich-Schwaiger, Helga; Zoller, Heinz; Utermann, Gerd; Auer-Grumbach, Michaela; Janecke, Andreas R

    2009-01-01

    Duplication within the chromosome 17p11.2 (CMT1Adup), peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) and gap junction β1-protein (GJB1) gene mutations are frequent causes of the Charcot-Marie-Tooth disease (CMT). A large number of mutations in these genes are listed in databases. Sequence variants identified in patients are frequently reported as mutations without further evaluation. We analyzed 250 consecutively recruited unrelated Austrian CMT patients for CMT1Adup by microsatellite marker typing, real-time PCR or MLPA, and found 79 duplications (31.6%). The coding regions of the PMP22, MPZ and GJB1 genes were analyzed by direct sequencing in the remaining patients; 28 patients showed mutations, 14 of which were novel. We scored the pathogenicity of novel missense mutations by segregation studies and by their exclusion in control samples. Our comprehensive literature study found that up to 60% of the reported mutations in these genes had not been evaluated regarding their pathogenicity, and the PANTHER bioinformatics tool was used to score novel and published missense variants. The PANTHER program scored known polymorphisms as such, but scored ∼82–88% only of the published and novel mutations as most likely deleterious. Mutations associated with axonal CMT were less likely to be classified as deleterious, and the PMP22 S72L mutation repeatedly associated with severe CMT was classified as a polymorphism using default parameters. Our data suggest that this in silico analysis tool could be useful for assessing the functional impact of DNA variations only as a complementary approach. The CMT1Adup, GJB1, MPZ and PMP22 mutation frequencies were in the range of those described in other CMT patient collectives with different ethnical backgrounds. PMID:19259128

  7. Investigation of mutations in Erg11 gene of fluconazole resistant Candida albicans isolates from Turkish hospitals.

    PubMed

    Manastır, Lerzan; Ergon, M Cem; Yücesoy, Mine

    2011-03-01

    Widespread use of fluconazole has resulted in resistance in strains of Candida. The aim of our study was to investigate Y132H and other mutations in the ERG11 gene in conferring fluconazole resistance to C. albicans isolates. Seven fluconazole-resistant (R)/susceptible dose-dependent (SDD)/trailing and 10 fluconazole-susceptible (S) isolates were included. Restriction enzyme analysis was performed on all isolates for Y132H mutation and sequence analysis was performed for other mutations in the ERG11 gene. None of our strains had Y132H mutation. One single mutation (D153E, E266D, D116E, V437I) was detected in isolates 348, 533, 644, 1453, 2157, while the others had more than one nucleotide change. D116E and E266D, which were two mutations found in fluconazole R/SDD/trailing isolates with the highest frequency, were also detected in azole S strains. K143R, G464S, G465S and V488I mutations were determined in three of the R/SDD isolates. S412T and R469K mutations were detected only in this group of strains by sequence analysis. Mutations such as K143R, G464S, G465S, V488I, S412T and R469K in the ERG11 gene were determined to be effective mechanisms in our fluconazole R/SDD C. albicans isolates. Other mechanisms of resistance, such as overexpression of ERG11 and efflux pumps and mutations in the ERG3 gene should also be investigated. PMID:19732347

  8. Mutations in the CLCN1 gene leading to myotonia congenita Thomsen and generalized myotonia Becker

    SciTech Connect

    Koch, M.C.; Meyer-Kline, C.; Otto, M.

    1994-09-01

    Autosomal dominant inherited myotonia congenita Thomsen (MC) and autosomal recessive generalized myotonia Becker (GM) are non-dystropic muscle disorders in which the symptom myotonia is based on an increased excitability of the muscle fiber membrane due to a reduced sarcolemmal chloride conductance. Affected individuals exhibit myotonic muscle stiffness in all skeletal muscles and a transient muscle weakness is particularly pronounced in the arms and hands of probands with the disorder GM. Recently we have shown linkage of the disorders MC and GM to the gene CLCN1 coding for the skeletal muscle chloride channel on chromosome 7 in German families. In addition we presented data supporting the hypothesis that GM is a genetically homogeneous disorder. Data are presented about an extended screen for mutations in the CLCN1 gene for our MC and GM population. We identified mainly missense mutations leading to altered amino acid codons. The previously described F413C mutation is by far the most common mutation for GM and is found in one family only (P480L, G482R, R496S). In addition we found 5{prime} donor and 3{prime} acceptor splice site mutations at various intron-exon boundaries, as well as a deletion mutation of 14 bp in exon 13. This deletion mutation is the second most common mutation in the GM population with a frequency of 8%. So far we have not determined sites of predominance of mutations in the CLCN1 gene, which could give us more insight into the regions critical for the function of the channel and the fact that the mutations in the gene may lead to dominant and recessive inheritance.

  9. Mutations in STK11 gene in Czech Peutz-Jeghers patients

    PubMed Central

    Vasovčák, Peter; Puchmajerová, Alena; Roubalík, Jan; Křepelová, Anna

    2009-01-01

    Background Peutz-Jeghers syndrome (PJS) is an autosomal dominant hereditary disease characterized by mucocutaneous pigmentation and gastrointestinal hamartomatous polyposis. The germline mutations in the serine/threonine kinase 11 (STK11) gene have been shown to be associated with the disease. Individuals with PJS are at increased risk for development of various neoplasms. The aim of the present study was to characterize the genotype and phenotype of Czech patients with PJS. Methods We examined genomic DNA of 8 individuals from five Czech families by sequencing analysis of STK11 gene, covering its promotor region, the entire coding region and the splice-site boundaries, and by multiplex ligation-dependent probe amplification (MLPA) assay designed for the identification of large exonic deletions or duplications of STK11 gene. Results We found pathogenic mutations in STK11 gene in two families fulfilling the diagnostic criteria of PJS and in one of three sporadic cases not complying with the criteria. The patient with the frameshift mutation in STK11 gene developed aggressive gastric cancer. No other studied proband has developed a carcinoma so far. Conclusion Our results showed that a germline mutation of STK11 gene can be found not only in probands fulfilling the PJS diagnostic criteria, but also in some sporadic cases not complying with the criteria. Moreover, we observed a new case of aggressive gastric cancer in a young patient with a frameshift mutation of STK11 gene. PMID:19615099

  10. De novo mutations from sporadic schizophrenia cases highlight important signaling genes in an independent sample.

    PubMed

    Kranz, Thorsten M; Harroch, Sheila; Manor, Orly; Lichtenberg, Pesach; Friedlander, Yechiel; Seandel, Marco; Harkavy-Friedman, Jill; Walsh-Messinger, Julie; Dolgalev, Igor; Heguy, Adriana; Chao, Moses V; Malaspina, Dolores

    2015-08-01

    Schizophrenia is a debilitating syndrome with high heritability. Genomic studies reveal more than a hundred genetic variants, largely nonspecific and of small effect size, and not accounting for its high heritability. De novo mutations are one mechanism whereby disease related alleles may be introduced into the population, although these have not been leveraged to explore the disease in general samples. This paper describes a framework to find high impact genes for schizophrenia. This study consists of two different datasets. First, whole exome sequencing was conducted to identify disruptive de novo mutations in 14 complete parent-offspring trios with sporadic schizophrenia from Jerusalem, which identified 5 sporadic cases with de novo gene mutations in 5 different genes (PTPRG, TGM5, SLC39A13, BTK, CDKN3). Next, targeted exome capture of these genes was conducted in 48 well-characterized, unrelated, ethnically diverse schizophrenia cases, recruited and characterized by the same research team in New York (NY sample), which demonstrated extremely rare and potentially damaging variants in three of the five genes (MAF<0.01) in 12/48 cases (25%); including PTPRG (5 cases), SCL39A13 (4 cases) and TGM5 (4 cases), a higher number than usually identified by whole exome sequencing. Cases differed in cognition and illness features based on which mutation-enriched gene they carried. Functional de novo mutations in protein-interaction domains in sporadic schizophrenia can illuminate risk genes that increase the propensity to develop schizophrenia across ethnicities. PMID:26091878

  11. Heteroduplex analysis of the dystrophin gene: Application to point mutation and carrier detection

    SciTech Connect

    Prior, T.W.; Papp, A.C.; Snyder, P.J.; Sedra, M.S.; Western, L.M.; Bartolo, C.; Mendell, J.R.; Moxley, R.T.

    1994-03-01

    Approximately one-third of Duchenne muscular dystrophy patients have undefined mutations in the dystrophin gene. For carrier and prenatal studies in families without detectable mutations, the indirect restriction fragment length polymorphism linkage approach is used. Using a multiplex amplification and heteroduplex analysis of dystrophin exons, the authors identified nonsense mutations in two DMD patients. Although the nonsense mutations are predicted to severely truncate the dystrophin protein, both patients presented with mild clinical courses of the disease. As a result of identifying the mutation in the affected boys, direct carrier studies by heteroduplex analysis were extended to other relatives. The authors conclude that the technique is not only ideal for mutation detection but is also useful for diagnostic testing. 29 refs., 4 figs.

  12. Significance of 5,10-methylenetetrahydrofolate reductase gene variants in acute lymphoblastic leukemia in Indian population: an experimental, computational and meta-analysis.

    PubMed

    Bellampalli, Ravishankara; Phani, Nagaraja M; Bhat, Kamalakshi G; Prasad, Krishna; Bhaskaranand, Nalini; Guruprasad, Kanive P; Rai, Padmalatha S; Satyamoorthy, Kapaettu

    2015-05-01

    Acute lymphoblastic leukemia (ALL) arises due to several genetic alterations in progenitor cells, and methotrexate is frequently used as part of the treatment regimen. Although there is evidence for an effect of 5,10-methylenetetrahydrofolate reductase gene (MTHFR) C677T and A1298C variations on drug response in ALL, its risk association for ALL is still unresolved. In a case-control study of 203 patients with ALL and 246 controls and meta-analysis in the Indian population, we showed an insignificant association of MTHFR C677T and A1298C genotypes with childhood and adult ALL. Comprehensive in silico characterization of non-synonymous single nucleotide polymorphisms (nsSNPs) and SNPs of the 3' untranslated region (UTR) revealed nine nsSNPs as deleterious, and three SNPs in the 3'UTR could possibly alter the binding of miRNAs. The study revealed that several overlooked SNPs may contribute to the risk of ALL susceptibility and further studies of these SNPs with functional characterization in a large sample size are required to understand the significant role of MTHFR in ALL development. PMID:25115513

  13. Correlation between the 677C>T polymorphism in the methylene tetrahydrofolate reductase gene and serum homocysteine levels in coronary heart disease.

    PubMed

    Chen, Y Y; Wang, B N; Yu, X P

    2016-01-01

    The aim of the current study was to explore the correlation between serum homocysteine (HCY) levels and the methylene tetrahydrofolate reductase (MTHFR) gene 677C/T polymorphism and coronary heart disease (CHD). We consecutively enrolled 208 patients with CHD confirmed by CTA or coronary angiography from our hospital. An additional 200 healthy volunteers were enrolled as the control group. Serum HCY levels, MTHFR C677T genotype, and other related indicators were evaluated for the two groups. Compared to those in the control group, the serum HCY levels in the CHD patients were significantly higher (P < 0.05). The proportion of individuals with the heterozygous MTHFR CT genotype and homozygous mutant TT genotype among CHD patients was significantly higher than that in the control group (P < 0.05). In the acute coronary syndrome (ACS) subgroup, the proportion of those with the CT and TT genotypes was significantly higher than that of the stable CHD subgroup (P < 0.05). In summary, serum HCY levels were elevated in CHD patients, and the frequency of the CT and TT genotypes were also significantly increased, especially among the ACS subgroup. Taken together, this suggests that serum HCY levels and MTHFR C677T genotypes are correlated with CHD. PMID:27051002

  14. Mutations in the consensus helicase domains of the Werner syndrome gene

    SciTech Connect

    Yu, Chang-En; Oshima, Junko; Wijsman, E.M.

    1997-02-01

    Werner syndrome (WS) is an autosomal recessive disease with a complex phenotype that is suggestive of accelerated aging. WS is caused by mutations in a gene, WRN, that encodes a predicted 1,432-amino-acid protein with homology to DNA and RNA helicases. Previous work identified four WS mutations in the 3{prime} end of the gene, which resulted in predicted truncated protein products of 1,060-1,247 amino acids but did not disrupt the helicase domain region (amino acids 569-859). Here, additional WS subjects were screened for mutations, and the intron-exon structure of the gene was determined. A total of 35 exons were defined, with the coding sequences beginning in the second exon. Five new WS mutations were identified: two nonsense mutations at codons 369 and 889; a mutation at a splice-junction site, resulting in a predicted truncated protein of 760 amino acids; a 1-bp deletion causing a frameshift; and a predicted truncated protein of 391 amino acids. Another deletion is >15 kb of genomic DNA, including exons 19-23; the predicted protein is 1,186 amino acids long. Four of these new mutations either partially disrupt the helicase domain region or result in predicted protein products completely missing the helicase region. These results confirm that mutations in the WRN gene are responsible for WS. Also, the location of the mutations indicates that the presence or absence of the helicase domain does not influence the WS phenotype and suggests that WS is the result of complete loss of function of the WRN gene product. 63 refs., 1 fig., 5 tabs.

  15. Mutational and Phylogenetic Analyses of the Mycobacterial mbt Gene Cluster ▿§

    PubMed Central

    Chavadi, Sivagami Sundaram; Stirrett, Karen L.; Edupuganti, Uthamaphani R.; Vergnolle, Olivia; Sadhanandan, Gigani; Marchiano, Emily; Martin, Che; Qiu, Wei-Gang; Soll, Clifford E.; Quadri, Luis E. N.

    2011-01-01

    The mycobactin siderophore system is present in many Mycobacterium species, including M. tuberculosis and other clinically relevant mycobacteria. This siderophore system is believed to be utilized by both pathogenic and nonpathogenic mycobacteria for iron acquisition in both in vivo and ex vivo iron-limiting environments, respectively. Several M. tuberculosis genes located in a so-called mbt gene cluster have been predicted to be required for the biosynthesis of the core scaffold of mycobactin based on sequence analysis. A systematic and controlled mutational analysis probing the hypothesized essential nature of each of these genes for mycobactin production has been lacking. The degree of conservation of mbt gene cluster orthologs remains to be investigated as well. In this study, we sought to conclusively establish whether each of nine mbt genes was required for mycobactin production and to examine the conservation of gene clusters orthologous to the M. tuberculosis mbt gene cluster in other bacteria. We report a systematic mutational analysis of the mbt gene cluster ortholog found in Mycobacterium smegmatis. This mutational analysis demonstrates that eight of the nine mbt genes investigated are essential for mycobactin production. Our genome mining and phylogenetic analyses reveal the presence of orthologous mbt gene clusters in several bacterial species. These gene clusters display signific