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1

C677T and A1298C Mutations in the MTHFR Gene and Survival in Colorectal Cancer  

Microsoft Academic Search

Background and aims: Our preliminary results laboratory have shown some association between C677T and A1298C MTHFR mutations and factors influencing survival in colorectal cancer. We studied the survival of patients with colorectal cancer depending on the initial Dukes- MAC stage of the disease at the time of diagnosis and the MTHFR mutation present. Methods: We randomly selected 69 patients with

Gelu Osian; Lucia Procopciuc; Liviu Vlad; Cornel Iancu; Teodora Mocan; Lucian Mocan

2

The Common Mutations C677T and A1298C in the Human Methylenetetrahydrofolate Reductase Gene Are Associated with Hyperhomocysteinemia and Cardiovascular Disease in Hemodialysis Patients  

Microsoft Academic Search

Background: Plasma total homocysteine (tHcy) level might be an important risk factor for the development of cardiovascular disease (CVD) in dialysis patients. While both renal failure and mutations of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene may result in hyperhomocysteinemia and CVD, the distinct roles of the thermolabile MTHFR mutation at nucleotide C677T and the more recently described mutation at nucleotide A1298C

Y. S. Haviv; V. Shpichinetsky; N. Goldschmidt; I. Abou Atta; A. Ben-Yehuda; G. Friedman

2002-01-01

3

Methyltetrahydrofolate reductase C677T gene mutation and hyperhomocysteinemia as a novel risk factor for diabetic nephropathy.  

PubMed

Hyperhomocysteinemia is a well-defined risk factor for endothelial dysfunction and atherosclerosis. A point mutation (677 C-T) of MTHFR gene results in a significant increase at plasma homocysteine levels. In this study we aimed to evaluate the effects of MTHFR gene mutation and consequent hyperhomocysteinemia on the development of diabetic microvascular complications in comparison with the other defined risk factors. Diabetic patients without a history of macrovascular complication or overt nephropathy enrolled into the study. The presence of MTHFR 677 C-T point mutation was evaluated by Real-Time PCR technique by using a LightCycler. MTHFR heterozygous mutation was present in 24 patients over 52. Patients with diabetes were divided into two groups according to the presence of MTHFR gene mutation. Both groups were well matched regarding age and diabetes duration. Metabolic parameters, plasma homocysteine, microalbuminuria, folic acid, and vitamin B12 levels were also studied. Presence of neuropathy and retinopathy were evaluated by specific tests. Duration of diabetes, BMI, systolic and diastolic blood pressure, plasma CRP, HbA1c, and lipid levels were not different between the two groups. Plasma homocysteine (12.89 +/- 1.74 and 8.98 +/- 1.91 micromol/l; P < 0.0001) and microalbuminuria levels (73.40 +/- 98.15 and 29.53 +/- 5.08 mg/day; P = 0.021) were significantly higher in the group with MTHFR gene mutation while creatinine clearance levels (101.1 +/- 42.6 and 136.21 +/- 51.50 ml/min; P = 0.008) were significantly lower. Sixteen over 22 (73%) of the patients with diabetic nephropathy had MTHFR gene mutation, while this was only 27% (8 over 30) in normoalbuminuric patients (P = 0.017). There was a significant correlation of plasma homocysteine level with microalbuminuria (r = 0.54; P = 0.031) in the patients with diabetic nephropathy who had C677T polymorphism. We did not find any specific association of MTHFR gene mutation and hyperhomocysteinemia with retinopathy or neuropathy. PMID:19598005

Ukinc, Kubilay; Ersoz, Halil Onder; Karahan, Caner; Erem, Cihangir; Eminagaoglu, Selcuk; Hacihasanoglu, Arif Bayram; Yilmaz, Mustafa; Kocak, Mustafa

2009-10-01

4

Metabolic effects of C677T and A1298C mutations at the MTHFR gene in Brazilian children with neural tube defects  

Microsoft Academic Search

Background: Methylenetetrahydrofolate reductase (MTHFR) deficiency leads to impairment in folate metabolism and is implicated as a risk factor for neural tube defects (NTDs). Both C677T and A1298C MTHFR mutations are associated with NTDs, in some populations. Methods: The frequencies of the C677T and A1298C MTHFR mutations were determined in 25 children with NTDs, case mothers and 75 healthy individuals from

Andrea L. A Cunha; Mario H Hirata; Chong A Kim; Elvira M Guerra-Shinohara; Kymio Nonoyama; Rosario D. C Hirata

2002-01-01

5

The C677T mutation of the 5,10-methylenetetrahydrofolate reductase gene is a moderate risk factor for spina bifida in Italy.  

PubMed Central

OBJECTIVE: To estimate the risk for spina bifida associated with the common mutation C677T of the MTHFR gene in a country with a relatively low prevalence of NTDs. DESIGN: Case-control study. SUBJECTS: Cases: 203 living patients affected with spina bifida (173 myelomeningocele and 30 lipomeningocele); controls: 583 subjects (306 young adults and 277 unselected newborns) from northern and central-southern Italy. SETTING: Cases: three spina bifida centres; young adult controls: DNA banks; newborn controls: regional neonatal screening centres. MAIN OUTCOME MEASURES: Prevalence of the C677T genotypes in cases and controls by place of birth; odds ratios for spina bifida and estimated attributable fraction. RESULTS: The prevalence of T/T, T/C, and C/C genotype was 16.6%, 53.7%, and 29.7% in controls and 25.6%, 43.8%, and 30.6% in cases, respectively. We found no differences between type of defect or place of birth. The odds ratio for spina bifida associated with the T/T genotype v C/C plus T/C was 1.73 (95% CI 1.15, 2.59) and the corresponding attributable fraction was 10.8%. No increased risk was found for heterozygous patients (OR=0.79, 95% CI 0.53-1.18). CONCLUSION: This study, as well as the meta-analysis we updated, shows that homozygosity for the MTHFR C677T mutation is a moderate risk factor in Europe, and even in Italy where there is a relatively low prevalence of spina bifida. The estimated attributable fraction associated with this risk factor explains only a small proportion of cases preventable by periconceptional folic acid supplementation. Thus, other genes involved in folate-homocysteine metabolism, their interaction, and the interaction between genetic and environmental factors should be investigated further. PMID:9863598

de Franchis, R; Buoninconti, A; Mandato, C; Pepe, A; Sperandeo, M P; Del Gado, R; Capra, V; Salvaggio, E; Andria, G; Mastroiacovo, P

1998-01-01

6

The Association between Two Common Mutations C677T and A1298C in Human Methylenetetrahydrofolate Reductase Gene and the Risk for Diabetic Nephropathy in Type II Diabetic Patients1  

Microsoft Academic Search

Mutations of the methylenetetrahydrofolate reductase (MTHFR) gene have been shown to be associated with a predisposition to developing diabetic nephropathy (DN) in specific populations. The frequency of two MTHFR mutations, a recently described mutation in the human MTHFR gene A1298C and C677T, whose association with DN is already known, was determined in an Israeli Jewish population with type 2 diabetes

Vlad Shpichinetsky; Itamar Raz; Yechiel Friedlander; Neta Goldschmidt; Isaiah D. Wexler; Arie Ben-Yehuda; Gideon Friedman

7

MTHFR Gene C677T Polymorphism in Autism Spectrum Disorders  

PubMed Central

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.

Oztop, Didem Behice; Ozkul, Yusuf

2014-01-01

8

[Prevalence of methylenetetrahydrofolate reductase (MTHFR) gene polymorphism (C677T) in the Hungarian population].  

PubMed

MTHFR encodes a critical enzyme in folate and homocysteine metabolism and the C677T allele of the MTHFR gene has some association with an increased risk for neural-tube defects and for adult cardiovascular diseases. As part of an international collaborative study the prevalence of C677T homozygous genotype was 11.1% while the frequency of C677T heterozygous condition was 45.2% in the Hungarian neonate sample. These findings underscore the clinical importance of the C677T variant in the Hungarian population and urge population-based prevention of conditions related to such gene. PMID:11433922

Czeizel, E; Tímár, L; Botto, L

2001-06-10

9

C677T MTHFR Mutation and Factor V Leiden Mutation in Patients with TIA\\/Minor Stroke  

Microsoft Academic Search

A common C677T mutation in the gene for the enzyme 5,10-methylenetetrahydrofolate reductase (5,10-MTHFR) has been linked to elevated levels of homocysteine and was therefore suspected to be a candidate genetic risk factor for arterial occlusive disease. Another mutation, factor V Leiden, has been established as a common hereditary risk factor for venous thrombosis, but its role in arterial disease remains

Wolfgang Lalouschek; Susanne Aull; Wolfgang Serles; Peter Schnider; Christine Mannhalter; Ingrid Pabinger-Fasching; Lüder Deecke; Karl Zeiler

1999-01-01

10

Infant C677T mutation in MTHFR, maternal periconceptional vitamin use, and cleft lip.  

PubMed

Studies have reported an association between homozygosity for a variant form of the methylenetetrahydrofolate reductase (MTHFR) gene and risk for neural tube defects. Because of MTHFR's involvement with folate metabolism and evidence that maternal use of a multivitamin with folic acid in early pregnancy reduces risk for cleft lip with or without cleft palate (CLP), we hypothesized that infants homozygous for the C677T genotype would be at increased risk for CLP because of lower MTHFR enzymatic activity. Data were derived from a large population-based, case-control study of fetuses and liveborn infants among a cohort of 1987 to 1989 California births. The analyses involved 310 infants with isolated CLP whose mothers completed a telephone interview and whose DNA was available from newborn screening blood specimens and involved 383 control infants without a congenital anomaly whose mothers completed a telephone interview and whose DNA was available. Cases and controls were genotyped TT if homozygous for the C677T allele, CT if heterozygous for the C677T allele, and CC if homozygous for the C677 (wild-type) allele. Odds ratios for CLP were 0.89 (0.55 to 1.4) and 0.78 (0.56 to 1.1) for infants with TT versus CC and infants with CT versus CC genotypes, respectively. Compared with the CC genotype, the odds ratios for CLP among infants with the TT genotype were 0.74 (0.39 to 1.4) for those infants whose mothers were users and 1.4 (0.54 to 3.6) for those infants whose mothers were not users of multivitamins containing folic acid periconceptionally. The two estimates were not statistically heterogeneous (P = 0.30). Our results did not indicate increased risks for CLP among infants homozygous for the C677T genotype, nor do they indicate an interaction between infant C677T genotype and maternal multivitamin use on the occurrence of CLP. PMID:9843036

Shaw, G M; Rozen, R; Finnell, R H; Todoroff, K; Lammer, E J

1998-11-16

11

Prevalence of MTHFR gene polymorphisms (C677T and A1298C) among Tamilians  

Microsoft Academic Search

We have investigated the incidence of the C677T and A1298C methylene tetrahydrofolate reductase (MTHFR) gene single nucleotide polymorphisms (SNPs) in the South Indian Tamil Nadu population with a total number of 72 individuals. The MTHFR genotyping was performed using the polymerase chain reaction followed by restriction enzyme analysis. Homozygosity for the MTHFR A1298C SNP was detected in 15.3% (11\\/72) of

T. Angeline; Nirmala Jeyaraj; Selena Granito; Gregory J. Tsongalis

2004-01-01

12

Hyperhomocysteinaemia and MTHFR C677T gene polymorphism in renal transplant recipients  

Microsoft Academic Search

AIMTo study the effect of folate treatment on hyperhomocysteinaemia and the effect of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism on total homocysteine and folate concentrations after renal transplantation.METHODSA total of 30 transplanted children and adolescents were investigated for total homocysteine and folate serum concentrations before and after folate treatment, as well as for the presence of the MTHFR C677T polymorphism.RESULTSThe allele

A J Szabó; T Tulassay; B Melegh; T Szabó; Á Vannay; A Fekete; Z Süveges; G S Reusz

2001-01-01

13

Combined heterozygosity for methylenetetrahydrofolate reductase (MTHFR) mutations C677T and A1298C is associated with abruptio placentae but not with intrauterine growth restriction  

Microsoft Academic Search

Objective: This study was undertaken to investigate the involvement of MTHFR gene mutations C677T and A1298C implicated in vascular disease, in patients with abruptio placentae and intrauterine growth restriction (IUGR). Study Design: DNA was extracted from blood samples of 54 patients with placental vasculopathy (18 patients with abruptio placentae and 36 with IUGR) and 114 control patients and amplified by

Gabriël S. Gebhardt; Charlotte L. Scholtz; Renate Hillermann; Hein J. Odendaal

2001-01-01

14

Factor V gene G1691A mutation, prothrombin gene G20210A mutation, and MTHFR gene C677T mutation are not risk factors for pulmonary thromboembolism in Chinese population  

Microsoft Academic Search

A mutation in coagulant factor V gene, a substitution in the 3? untranslated region of prothrombin gene, and a variant in 5,10-methylenetetrahydrofolate reductase (MTHFR) gene have been reported to be related to venous thromboembolism in Caucasians, but this relationship remains in debate in other populations. In this case–control study, we aimed to determine the prevalence of these three mutations in

Yanhui Lu; Yanfen Zhao; Guozhang Liu; Xiaoling Wang; Zhihong Liu; Baiping Chen; Rutai Hui

2002-01-01

15

Hyperhomocysteinaemia and MTHFR C677T gene polymorphism in renal transplant recipients  

PubMed Central

AIM—To study the effect of folate treatment on hyperhomocysteinaemia and the effect of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism on total homocysteine and folate concentrations after renal transplantation.?METHODS—A total of 30 transplanted children and adolescents were investigated for total homocysteine and folate serum concentrations before and after folate treatment, as well as for the presence of the MTHFR C677T polymorphism.?RESULTS—The allele frequency of C677T polymorphism in the MTHFR gene in the study population (0.33) was not different to that in controls (0.38). Before folate treatment the homocysteine concentration was raised in all groups; following folate supplementation it was significantly decreased in the CC and CT groups, but not in the TT group. In patients with CC genotype, serum homocysteine correlated with serum creatinine and cholesterol, and time since transplantation before treatment.?CONCLUSION—Folate supplementation appears to be an effective strategy to normalise total homocysteine concentration in renal transplanted children and adolescents.?? PMID:11420199

Szabo, A; Tulassay, T; Melegh, B; Szabo, T; Szabo, A; Vannay, A; Fekete, A; Suveges, Z; Reusz, G

2001-01-01

16

Recurrent cerebral venous thrombosis associated with heterozygote methylenetetrahydrofolate reductase C677T mutation and sickle cell trait without homocysteinemia: an autopsy case report and review of literature.  

PubMed

Elevated blood homocysteine concentration and certain genetic mutations have been associated with increased risk for developing arterial and venous thrombosis. A common mutation of methylenetetrahydrofolate reductase, MTHFR C677T, has been associated with elevated homocysteine concentration and increased risk for developing thrombosis in homozygote carriers. Heterozygote carriers for this gene mutation, if associated with other major or minor risk factors for thrombophilia, appear to be prone to develop thrombosis. A postmortem genetic testing for common mutations resulting in thrombophilia should be performed in all individuals who die as a result of thrombosis, regardless of predisposing risk factors, to determine the true prevalence of mutations in these individuals, and to assess the true role of a certain mutation, such as heterozygote MTHFR C677T, in the pathogenesis of thrombosis. Postmortem genetic testing for common mutations associated with thrombophilia in selected cases has potentially life-saving importance to surviving family members. We report a case of recurrent cerebral venous thrombosis in a 19 year old male with history of sickle cell trait, obesity, and high normal blood homocysteine, who was heterozygote for MTHFR C677T mutation. PMID:25074331

Ali, Z; Troncoso, J C; Fowler, D R

2014-09-01

17

A1298C methylenetetrahydrofolate reductase mutation and coronary artery disease: relationships with C677T polymorphism and homocysteine\\/folate metabolism  

Microsoft Academic Search

5, 10-Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme in homocysteine\\/methionine metabolism. The most-studied\\u000a C677T polymorphism in the MTHFR gene results in a thermolabile variant with reduced activity, and is associated with increased\\u000a levels of total plasma homocysteine, a risk factor for coronary artery disease. A new mutation in the MTHFR gene (A1298C)\\u000a has also been reported to lower enzyme activity.

S. Friso; D. Girelli; E. Trabetti; C. Stranieri; O. Olivieri; E. Tinazzi; N. Martinelli; G. Faccini; P. F. Pignatti; R. Corrocher

2002-01-01

18

Increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryos  

Microsoft Academic Search

The pathogenesis of spontaneous abortion is complex, presumably involving the interaction of several genetic and environmental factors. The methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms are commonly associated with defects in folate dependent homocysteine metabolism and have been implicated as risk factors for recurrent embryo loss in early pregnancy. In the present study we have determined the prevalence of

Henrik Zetterberg; Björn Regland; Mona Palmér; Anne Ricksten; Lars Palmqvist; Lars Rymo; Demetrios A Arvanitis; Demetrios A Spandidos; Kaj Blennow

2002-01-01

19

Factor V G1691A, Prothrombin G20210A, and Methylenetetrahydrofolate Reductase [MTHFR] C677T Gene Polymorphism in Angiographically Documented Coronary Artery Disease  

Microsoft Academic Search

Background: Single point mutations in the genes coding for factor V [G1691A; Leiden], prothrombin [PRT; G20210A], and methylenetetrahydrofolate reductase [MTHFR, C677T] were shown to be major inherited predisposing factors for venous thromboembolism. However, their contribution in the development of coronary artery disease [CAD] remains controversial. The aim of the study was to examine the association of these mutations in CAD.

Wassim Y. Almawi; Ghada Ameen; Hala Tamim; Ramzi R. Finan; Noha Irani-Hakime

2004-01-01

20

The role of hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR) C677T mutation in patients with retinal artery occlusion  

Microsoft Academic Search

PURPOSE: Hyperhomocysteinemia has been established as an important risk factor for cardiovascular diseases. The aim of the present study was to investigate whether hyperhomocysteinemia and\\/or homozygosity for the methylenetetrahydrofolate reductase (MTHFR) C677T mutation are associated with an increased risk for retinal artery occlusion (RAO).DESIGN: Retrospective case-control study.METHODS: We studied 105 consecutive patients with retinal artery occlusion and 105 age and

Martin Weger; Olaf Stanger; Hannes Deutschmann; Franz Josef Leitner; Wilfried Renner; Otto Schmut; Jürgen Semmelrock; Anton Haas

2002-01-01

21

MTHFR C677T and A1298C gene polymorphisms and hyperhomocysteinemia as risk factors of diabetic nephropathy in type 2 diabetes patients  

Microsoft Academic Search

Point mutations in methylenetetrahydrofolate reductase (MTHFR) and hyperhomocysteinemia were implicated in the pathogenesis of diabetic nephropathy (DN) in many ethnic groups. This study addressed the association of C677T and A1298C single nucleotide polymorphisms (SNPs) of MTHFR gene with DN in Tunisian type 2 diabetes (T2DM) patients. Study subjects comprised 93 DN patients, 267 patients with normoalbuminuria, and 400 control subjects.

Nabil Mtiraoui; Intissar Ezzidi; Molka Chaieb; Hela Marmouche; Zied Aouni; Arbi Chaieb; Touhami Mahjoub; Martine Vaxillaire; Wassim Y. Almawi

2007-01-01

22

Hyperhomocyst(e)inaemia, but not MTHFR C677T mutation, as a risk factor for non-arteritic ischaemic optic neuropathy  

Microsoft Academic Search

BACKGROUND\\/AIMSHyperhomocyst(e)inaemia has been identified as a strong risk factor for stroke, myocardial infarction, and deep vein thrombosis. A point mutation of methylene tetrahydrofolate reductase (MTHFR C677T) has been associated with increased plasma homocyst(e)ine levels. To investigate whether hyperhomocyst(e)inaemia and\\/or MTHFR C677T mutation are associated with non-arteritic ischaemic optic neuropathy (NAION), a case-control study including 59 consecutive patients with NAION and

Martin Weger; Olaf Stanger; Hannes Deutschmann; Michael Simon; Wilfried Renner; Otto Schmut; Jürgen Semmelrock; Anton Haas

2001-01-01

23

Association of MTHFR gene polymorphism C677T with susceptibility to late-onset alzheimer’s disease  

Microsoft Academic Search

Increased total plasma homocysteine (t-Hcy) levels are found to be associated with Alzheimer’s disease (AD). Because the methylenetetrahydrofolate\\u000a reductase (MTHFR) gene encodes a key enzyme that influences the metabolism of homocysteine, it has been considered as a possible genetic risk\\u000a factor for AD. Although the MTHFR gene C677T polymorphism has a significant impact on reducing enzyme activity and increasing t-Hcy

Binbin Wang; Feng Jin; Rui Kan; Shun Ji; Chuanfang Zhang; Zeping Lu; Chenguang Zheng; Ze Yang; Li Wang

2005-01-01

24

Methylenetetrahydrofolate reductase (MTHFR) c677t gene variant modulates the homocysteine folate correlation in a mild folate-deficient population  

Microsoft Academic Search

Background: A large body of evidence links plasma concentrations of homocysteine and cardiovascular disease. Several genetic and environmental variables may modulate such relationship. We investigated the influence of methylenetetrahydrofolate reductase (MTHFR) gene variants C677T, A1298C, and T1317C on homocysteine, folate, and cobalamin concentrations in a sample of individuals from a mild folate deficiency population to better clarify the complex interactions

Alexandre C. Pereira; Isolmar Tadeu Schettert; Antônio Alberto F. Morandini Filho; Elvira Maria Guerra-Shinohara; José E. Krieger

2004-01-01

25

Stromelysin-1 5A/6A and eNOS T-786C polymorphisms, MTHFR C677T and A1298C mutations, and cigarette-cannabis smoking: a pilot, hypothesis-generating study of gene-environment pathophysiological associations with Buerger's disease.  

PubMed

Buerger's disease (BD) etiologies are poorly understood. Beyond smoking cessation, medical-surgical treatments have limited success. We hypothesized that mutations associated with arterial vasospasm (stromelysin-1 5A/6A, eNOS T-786C) and C677T-A1298C methylene tetrahydrofolate reductase (MTHFR) interacted with cigarette-cannabis smoking, reducing vasodilatory nitric oxide (NO), promoting arterial spasm-thrombosis. Of 21 smoking BD patients (14 men [2 siblings], 7 women; 20 white, 1 African-American), compared to 21 age-gender-race matched healthy controls, 5A/6A stromelysin- 1 homozygosity was present in 7 of 21 (33%) BD cases versus 5 of 21 (24%) controls (risk ratio 1.4; 95% confidence interval [CI] 0.5-3.7), and eNOS T-786C homozygosity was present in 3 of 21 (14%) BD cases versus 1 of 21 (5%) controls (risk ratio 3.0; 95% CI 0.3-26.6). C677T MTHFR homozygosity or compound C677T-A1298C heterozygosity was present in 7 of 21 cases (33%) versus 11 of 21 controls (52%) (risk ratio 0.6; 95% CI 0.3-1.3). In 18 patients who stopped and 3 who continued smoking, all stromelysin-1 5A/6A and/or eNOS heterozygotes-homozygotes, superficial phlebitis, lower limb gangrenous ulcers, and intractable ischemic rest pain with arterial occlusion progressed despite conventional medical therapy, threatening amputation. In 15 patients, to increase vasodilatory NO via endothelial NO synthase, l-arginine (15 g/day) was given, along with folic acid (5 mg), vitamin B6 (100 mg), and B12 (2000 mg/day) to optimize homocysteine metabolism and reduce asymmetric dimethylarginine, a NO synthase inhibitor. Unexpectedly quickly and strikingly, within 8 weeks to 8 months receiving l-arginine-folic acid, 11 of 15 treated patients improved with uniform pain reduction, ulcer healing, and in 5, full recovery of previously absent peripheral pulses. In smokers homo/heterozygous for stromelysin-1 5A/6A and eNOS T-786C mutations, we speculate that the development and severity of BD are related to a gene-environment vasospastic interaction with reduced NO-mediated vasodilatation. Increasing NO production by l-arginine while optimizing homocysteine metabolism by folic acid-B6-B12 may have therapeutic benefit. Further blinded, placebo-controlled studies are needed to determine whether our observations can be generalized to larger BD cohorts. PMID:17000887

Glueck, Charles J; Haque, Mofiz; Winarska, Magdalena; Dharashivkar, Swapna; Fontaine, Robert N; Zhu, Binghua; Wang, Ping

2006-10-01

26

Association of a Common Allelic Polymorphism (C677T) in the Methylene Tetrahydrofolate Reductase Gene with a Reduced Risk of Osteoporotic Fractures. A Case Control Study in Danish Postmenopausal Women  

Microsoft Academic Search

Twin studies indicate a substantial genetic component in the development of osteoporosis. One of the latest studied candidate genes is the one coding for methylene tetrahydrofolate reductase (MTHFR) (C677T) in which a point mutation gives rise to a thermolabile variant of MTHFR. The aim of this study was to investigate the influence of this mutation on peripheral measures of bone

H. L. Jřrgensen; J. S. Madsen; B. Madsen; M. M. A. Saleh; B. Abrahamsen; M. Fenger; J. B. Lauritzen

2002-01-01

27

Methylenetetrahydrofolate reductase C677T genotype affects promoter methylation of tumor-specific genes in sporadic colorectal cancer through an interaction with folate\\/vitamin B12 status  

Microsoft Academic Search

AIM: To evaluate joint effects of Methylentetra- hydrofolate reductase (MTHFR ) C677T genotypes, and serum folate\\/vitamin B12 concentrations on promoter methylation of tumor-associated genes among Iranian colorectal cancer patients. METHODS: We examined the associations between MTHFR C677T genotype, and promoter methylation of P16 , hMLH1 , and hMSH2 tumor-related genes among 151 sporadic colorectal cancer patients. The promoter methylation of

Pooneh Mokarram; Fakhraddin Naghibalhossaini

2008-01-01

28

Fetal folate C677T methylenetetrahydrofolate reductase gene polymorphism and low birth weight.  

PubMed

The aim of this study was to determine if fetal C677T methylenetetrahydrofolate reductase (MTHFR) genotype contributes to low birth weight. The study group consisted of 243 term babies with a birth weight<10th centile for gestational age, with subgroup analyses for those <1st centile. The control group consisted of 132 term babies with a birth weight 3.3-3.8 kg. Odds ratio analyses with 95% confidence intervals (CI) were calculated for carriage of the t allele and overall genotype frequencies. There was no significant difference in carriage of the t allele between study and control groups, odds ratio (OR) 0.79 (95% CI, 0.57-1.09). No differences were observed for frequencies of heterozygote and recessive homozygote genotypes for the two populations. In the subgroup analyses, no statistical differences were observed in the t allele frequency, frequency of the heterozygote or homozygote genotype. Trends were seen and the study suggests that fetal C677T MTHFR genotype may be a factor contributing to birth weight. The potential may exist to influence clinical outcome by maternal folate supplementation. PMID:16390701

Glanville, T; Yates, Z; Ovadia, L; Walker, J J; Lucock, M; Simpson, N A B

2006-01-01

29

Methylenetetrahydrofolate reductase C677T gene polymorphism and essential hypertension: A meta-analysis of 10,415 subjects  

PubMed Central

The methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism has been suggested to be associated with the risk of essential hypertension (EH), however, results remain inconclusive. To investigate this association, the present meta-analysis of 27 studies including 5,418 cases and 4,997 controls was performed. The pooled odds ratio (OR) and its corresponding 95% confidence interval were calculated using the random-effects model. A significant association between the MTHFR C677T gene polymorphism and EH was found under the allelic (OR, 1.32; 95% CI, 1.20–1.45; P=0.000), dominant (OR, 1.39; 95% CI, 1.25–1.55; P=0.000), recessive (OR, 1.38; 95% CI, 1.18–1.62; P=0.000), homozygote (OR, 1.59; 95% CI, 1.32–1.92; P=0.000), and heterozygote (OR, 1.32; 95% CI, 1.20–1.45; P=0.000) genetic models. A strong association was also revealed in subgroups, including Asian, Caucasian and Chinese. The Japanese subgroup did not show any significant association under all models. Meta-regression analyses suggested that the study design was a potential source of heterogeneity, whereas the subgroup analysis additionally indicated that the population origin may also be an explanation. Another subgroup analysis revealed that hospital-based studies have a stronger association than population-based studies, however, the former suffered a greater heterogeneity. Funnel plot and Egger’s test manifested no evidence of publication bias. In conclusion, the present study supports the evidence for the association between the MTHFR C677T gene polymorphism and EH in the whole population, as well as in subgroups, such as Asian, Caucasian and Chinese. The carriers of the 677T allele are susceptible to EH. PMID:25054014

YANG, KE-MING; JIA, JIAN; MAO, LI-NA; MEN, CHEN; TANG, KANG-TING; LI, YAN-YAN; DING, HAI-XIA; ZHAN, YI-YANG

2014-01-01

30

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

PubMed Central

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

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

2000-01-01

31

C677T polymorphism of the MTHFR gene and variant hemoglobins: a study in newborns from Salvador, Bahia, Brazil.  

PubMed

The C677T polymorphism in the methylenetetrahydrofolate reductase gene (MTHFR) is associated with an increase in total homocysteine serum levels (tHcy), described as a risk factor for cardiovascular disease. Eight hundred forty-three neonates from two different maternity hospitals, one public and another private, in Salvador, Bahia, Brazil were screened for this polymorphism by PCR and RFLP. The T-allele frequency in the total sample was 0.23, and the prevalence rates of heterozygous and homozygous carriers were 36.2% and 5.3%, respectively. The T-allele frequency differed and the T/T genotype was more prevalent at the private maternity hospital. The hemoglobin (Hb) profile was investigated by HPLC in 763 newborns. The frequency of variant Hb was higher at the public than at the private maternity hospital. The association of the C677T polymorphism and the Hb profile was investigated in 683 newborns, showing a relatively high frequency of variant Hbs and the T allele. These data could provide an important basis for further studies focusing on potential risks of vaso-occlusive events in these individuals. PMID:15073633

Couto, Fábio David; Adorno, Elisângela Vitória; Menezes, Joelma Figueiredo; Moura Neto, José Pereira; Ręgo, Marco Antônio Vasconcelos; Reis, Mitermayer Galvăo dos; Gonçalves, Marilda Souza

2004-01-01

32

Molecular Analysis of Factor V Leiden, Factor V Hong Kong, Factor II G20210A, Methylenetetrahydrofolate Reductase C677T, and A1298C Mutations Related to Turkish Thrombosis Patients  

Microsoft Academic Search

Inherited gene disorders related to the hemostatic system have been documented as risk factors for thrombosis. The roles of factor V Hong Kong (FV Hong Kong), factor V Leiden (FV Leiden), factor II G20210A (FII G20210A), methylenetetrahydrofolate reductase (MTHFR) C677T, and MTHFR A1298C mutations in Turkish patients with thrombosis (270 patients) compared with healthy controls (114 subjects) were evaluated. Polymerase

Bilgen Dölek; Serpil Eraslan; Sevim Ero?lu; Belgin Eroglu Kesim; Turgut Ulutin; Altan Yalç?ner; Yahya R. Laleli; Nermin Gözükirm?z?

2007-01-01

33

Dietary folate intake in combination with MTHFR C677T genotype and promoter methylation of tumor suppressor and DNA repair genes in sporadic colorectal adenomas  

Microsoft Academic Search

Methylation of the promoter region of tumor suppressor genes is increasingly recognized to play a role in cancer development through silencing of gene transcription. We examined the associations between dietary folate intake, MTHFR C677T genotype, and promoter methylation of six tumor suppressor and DNA repair genes. Patients with colorectal adenoma (n = 149) and controls (n = 286) with folate

M. van den Donk; M. van Engeland; E. P. M. Pellis; B. J. M. Witteman; F. J. Kok; J. Keijer; E. Kampman

2007-01-01

34

Stromelysin-1 5A\\/6A and eNOS T-786C Polymorphisms, MTHFR C677T and A1298C Mutations, and Cigarette-Cannabis Smoking: A Pilot, Hypothesis-Generating Study of Gene-Environment Pathophysiological Associations With Buerger’s Disease  

Microsoft Academic Search

Buerger’s disease (BD) etiologies are poorly understood. Beyond smoking cessation, medical-surgical treatments have limited success. We hypothesized that mutations associated with arterial vasospasm (stromelysin-1 5A\\/6A, eNOS T-786C) and C677T-A1298C methylene tetrahydrofolate reductase (MTHFR) interacted with cigarette-cannabis smoking, reducing vasodilatory nitric oxide (NO), promoting arterial spasm-thrombosis. Of 21 smoking BD patients (14 men [2 siblings], 7 women; 20 white, 1 African-American),

Charles J. Glueck; Mofiz Haque; Magdalena Winarska; Swapna Dharashivkar; Robert N. Fontaine; Binghua Zhu; Ping Wang

2006-01-01

35

The methylentetrahydrofolate reductase C677T point mutation is a risk factor for vascular access thrombosis in hemodialysis patients  

Microsoft Academic Search

Background: Many reports indicate that a high homocysteine (Hcy) level is a potential risk factor for such thrombotic diseases as arteriosclerosis, myocardial infarction, and cerebral infarction in healthy individuals or hemodialysis (HD) patients. The methylentetrahydrofolate reductase (MTHFR) C677T polymorphism has been reported to be closely related to plasma Hcy level. Methods: Using a cross-sectional design in this study, the relationship

Mizuya Fukasawa; Kazumichi Matsushita; Manabu Kamiyama; Yuki Mikami; Isao Araki; Zentaro Yamagata; Masayuki Takeda

2003-01-01

36

An association between the methylenetetrahydrofolate reductase (MTHFR) C677T mutation and inflammation markers related to cardiovascular disease  

Microsoft Academic Search

BackgroundProspective studies have identified many markers of systemic inflammation that are powerful predictors of future cardiovascular events. The methylenetetrahydrofolate reductase (MTHFR) C677T genotype, a common polymorphism that induces hyperhomocysteinaemia, has been proposed as a genetic risk factor for cardiovascular disease. In this work, we evaluated the relationship between the levels of inflammation markers and MTHFR genotype among cardiovascular disease free

George V. Z. Dedoussis; Demosthenes B. Panagiotakos; Christos Pitsavos; Christina Chrysohoou; John Skoumas; Despoina Choumerianou; Christodoulos Stefanadis

2005-01-01

37

Association of the C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene with schizophrenia: Association is significant in men but not in women  

Microsoft Academic Search

Schizophrenia is a complex and common psychiatric disorder with a polygenic inheritance. In our previous report, we showed an association between the methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms and schizophrenia in patients from Bakirkoy in Istanbul, Turkey [Sazci, A., Ergul, E., Guzelhan, Y., Kaya, G., Kara, I., 2003. Methylenetetrahydrofolate reductase gene polymorphisms in patients with schizophrenia. Mol. Brain

Ali Sazci; Emel Ergul; Ismail Kucukali; Ihsan Kara; Guner Kaya

2005-01-01

38

Methylenetetrahydrofolate reductase gene polymorphisms are associated with ischemic and hemorrhagic stroke: Dual effect of MTHFR polymorphisms C677T and A1298C  

Microsoft Academic Search

Hyperhomocysteinemia is an independent risk factor for ischemic stroke. The enzyme methylenetetrahydrofolate reductase (MTHFR) plays a critical role in modulating the levels of plasma homocysteine. Two polymorphisms in the MTHFR gene, C677T, A1298C result in reduced enzyme activity. The mechanisms of ischemic and hemorrhagic stroke are not well understood. Although controversial, previous studies have shown evidence of causality of both

Ali Sazci; Emel Ergul; Nese Tuncer; Gurler Akpinar; Ihsan Kara

2006-01-01

39

Polymorphisms C677T and A1298C in the MTHFR gene in Mexican patients with rheumatoid arthritis treated with methotrexate: implication with elevation of transaminases  

Microsoft Academic Search

Rheumatoid arthritis (RA) is the prototype of the rheumatic diseases worldwide. Methotrexate (MTX) is the drug of first choice in the treatment of this disease due to its immunosuppressant effect. However, side events are present in 30% of the patients. The C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene are involved in the metabolism of MTX. Earlier studies

J P Mena; M Salazar-Páramo; L González-López; J I Gámez-Nava; L Sandoval-Ramirez; J D Sánchez; L E Figuera; F J Muńoz-Valle; M Vazquez del Mercado; I P Dávalos

2011-01-01

40

Genotypes of the C677T and A1298C polymorphisms of the MTHFR gene as a cause of human spontaneous embryo loss  

Microsoft Academic Search

BACKGROUND: Polymorphisms C677T and A1298C of the MTHFR gene have been implicated in fetal viability. In this study, we determined the allele and genotype frequencies of these polymorphisms in different populations, includ- ing spontaneous abortion (SA) fetal tissues, with the objective of evaluating their impact on fetal viability. METHODS: 342 samples of fetal tissues, selected from SA occurring during the

G. Callejon; A. Mayor-Olea; A. J. Jimenez; M. J. Gaitan; A. R. Palomares; F. Martinez; M. Ruiz; Armando Reyes-Engel

2007-01-01

41

Methylenetetrahydrofolate reductase gene C677T and A1298C polymorphisms, plasma homocysteine, folate, and vitamin B 12 levels and the extent of coronary artery disease  

Microsoft Academic Search

The question of whether mild hyperhomocysteinemia is a risk factor for coronary artery disease (CAD) has long been debated and is still unclear. We investigated whether there is a link between methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms or plasma homocysteine and CAD. This is a case-control study that included 2,121 consecutive patients (cases) with angiographically proved CAD and

Klaus Kölling; Gjin Ndrepepa; Werner Koch; Siegmund Braun; Julinda Mehilli; Albert Schömig; Adnan Kastrati

2004-01-01

42

Effects of the C677T and A1298C polymorphisms of the MTHFR gene on the genetic predisposition for diabetic nephropathy  

Microsoft Academic Search

Background. Methylenetetrahydrofolate reductase (MTHFR) is a regulatory enzyme of homocysteine metabolism. The C677T polymorphism of the MTHFR gene has been reported to be associated with elevated plasma homocysteine in patients with low folic acid intake. A recently reported second common poly- morphism, A1298C, may increase homocysteine, but only in individuals carryingthe T677 allele. This study aimed to investigate the influence

Dariusz Moczulski; Hanna Fojcik; Ewa Zukowska-Szczechowska; Ilona Szydlowska; Wladyslaw Grzeszczak

2003-01-01

43

Evaluation of the MTHFR C677T allele and the MTHFR gene locus in a German spina bifida population  

Microsoft Academic Search

A number of recent studies have demonstrated that the occurrence and recurrence risk of neural tube defects (NTD) is reduced\\u000a by folic acid supplementation before and during pregnancy. Epidemiological studies have shown low plasma folate and raised\\u000a plasma homocysteine in women with spina bifida aperta (SB) children suggesting an abnormal folate metabolism. The 5,10-methylenetetrahydrofolate\\u000a reductase (MTHFR) variant C677T, resulting in

M. C. Koch; K. Stegmann; A. Ziegler; B. Schröter; A. Ermert

1998-01-01

44

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

PubMed

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

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

2014-08-01

45

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

PubMed Central

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

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

2014-01-01

46

The MTHFR C677T polymorphism modifies age at onset in Parkinson's disease.  

PubMed

Hyperhomocysteinemia is a risk factor for Parkinson's disease (PD) and may result from genetic mutations or/and environmental factors. 5,10-methylenetetrahydrofolate reductase (MTHFR) is a folate-dependent enzyme that catalyzed remethylation of homocysteine (Hcy) and the MTHFR C677T polymorphism makes the MTHFR enzyme thermolabile causing hyperhomocysteinemia. In this study we analyzed whether two functional polymorphisms of MTHFR gene, A1298C and C677T, affect age of onset in PD. We enrolled 120 patients with sporadic PD. Patients were divided into three groups based on MTHFR C677T polymorphisms: (a) homozygotes wild type (CC) (b) heterozygotes (CT) and (c) homozygotes carriers of mutation (TT). MTHFR SNPs were analyzed using High-Resolution Melt analysis and ANOVA was performed to assess whether polymorphisms of MTHFR gene could influence age of onset. The MTHFR A1298C polymorphism had no effect on PD age at onset (p = 1.0) while there was a significant association with MTHFR C677T (p = 0.019 Bonferroni-adjusted post hoc) showing an earlier onset in CC as compared with TT. (p = 0.024). No differences were found for vascular load assessed with magnetic resonance imaging, pharmacological therapy and cognitive state for two MTHFR SNPs. Our results suggest a possible association of MTHFR C677T with age at onset of PD and may have important implications regarding the role of MTHFR. PMID:24052451

Vallelunga, Annamaria; Pegoraro, Valentina; Pilleri, Manuela; Biundo, Roberta; De Iuliis, Angela; Marchetti, Mauro; Facchini, Silvia; Formento Dojot, Patrizia; Antonini, Angelo

2014-01-01

47

Association between C677T and A1298C MTHFR gene polymorphism and nonsyndromic orofacial clefts in the Turkish population: a case-parent study.  

PubMed

Two common MTHFR gene polymorphisms (C677T and A1298C) have been implicated in the etiology of nonsyndromic cleft lip/palate (nsCL/P). To investigate the genotype association among nsCL/P in the Turkish population, 56 case-parent trios were recruited into the study. Genotype frequencies were compared to two groups of controls from the same population. A total of 46 case-parent trios were included in transmission disequilibrium test (TDT) analysis. The mothers of the study group had a higher frequency of 677TT genotype, with a three-fold increased risk of having nsCL/P offspring (odds ratio [OR]: 3.14, p=0.03). The combined 677CT/1298AC genotype was also common among these mothers (28%), but it did not reach statistical significance (OR: 2.27, p=0.07). TDT analysis for (C677T) T allele transmission did not reveal a significant association. In conclusion, mothers carrying 677TT genotype or with 677CT/1298AC combined genotype have increased risk of having nsCL/P offspring; therefore, higher periconceptional folic acid supplementation should be advised for decreasing the recurrence risk. PMID:23692788

Semiç-Jusufagiç, Aida; Bircan, R?fat; Çelebiler, Özhan; Erdim, Melike; Akarsu, Nurten; Elçio?lu, Nursel H

2012-01-01

48

Hyperhomocysteinemia and of Methylenetetrahydrofolate Reductase (C677T) Genetic Polymorphism in Patients with Deep Vein Thrombosis  

PubMed Central

Aim: To determine the concentration of total plasma homocysteine (tHcy) as well as different genotypes of methylenetetrahydrofolate reductase MTHFR (C677T) in healthy subjects and patients with deep vein thrombosis (DVT). Material and methods: The investigation comprised a total of 160 subjects divided in two main groups: 80 healthy subjects (control group) and 80 patients with deep vein thrombosis. Concentration of tHcy was determined by spectrophotometric cyclic enzymatic method and mutation of MTHFR (C677T) gene was examined by polymerase chain reaction according to Schneider. Results: The results obtained for plasma tHcy in the control group were 11.62ą3.43 ?mol/L, while tHcy level was significantly higher in patients with deep vein thrombosis as compared to the control group, 15.19ą3.63 ?mol/L (?<0.001). The analysis of the results has shown that MTHFR (C677T) genetic polymorphism was responsible for mild to moderate hyperhomocysteinemia in the majority of subjects. Conclusion: The level of tHcy in the examined patients was significantly higher in comparison with the control group. Multiple regression analysis has shown that tHcy level in CT and TT genotypes of MTHFR (C677T) was statistically higher in comparison with CC genotype of MTHFR (C677T) in both, the control group and the DVT patients. PMID:24167429

Brezovska-Kavrakova, Julijana; Krstevska, Marija; Bosilkova, Gordana; Alabakovska, Sonja; Panov, Saso; Orovchanec, Nikola

2013-01-01

49

Folate intake, alcohol consumption, and the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism: influence on prostate cancer risk and interactions  

PubMed Central

Purpose: Folate is essential to DNA methylation and synthesis and may have a complex dualistic role in prostate cancer. Alcohol use may increase risk and epigenetic factors may interact with lifestyle exposures. We aimed to characterize the independent and joint effects of folate intake, alcohol consumption, and the MTHFR C677T gene polymorphism on prostate cancer risk, while accounting for intakes of vitamins B2, B6, B12, methionine, total energy, and confounders. Methods: A case-control study was conducted at Kingston General Hospital of 80 incident primary prostate cancer cases and 334 urology clinic controls, all with normal age-specific PSA levels (to exclude latent prostate cancers). Participants completed a questionnaire on folate and alcohol intakes and potential confounders prior to knowledge of diagnosis, eliminating recall bias, and blood was drawn for MTHFR genotyping. Joint effects of exposures were assessed using unconditional logistic regression and significance of multiplicative and additive interactions using general linear models. Results: Folate, vitamins B2, B6, B12, methionine, and the CT and TT genotypes were not associated with prostate cancer risk. The highest tertile of lifetime alcohol consumption was associated with increased risk (OR = 2.08; 95% CI: 1.12–3.86). Consumption of >5 alcoholic drinks per week was associated with increased prostate cancer risk among men with low folate intake (OR = 2.38; 95% CI: 1.01–5.57), and higher risk among those with the CC MTHFR genotype (OR = 4.43; 95% CI: 1.15–17.05). Increased risk was also apparent for average weekly alcohol consumption when accounting for the multiplicative interaction between folate intake and MTHFR C677T genotype (OR = 3.22; 95% CI: 1.36–7.59). Conclusion: Alcohol consumption is associated with increased prostate cancer risk, and this association is stronger among men with low folate intake, with the CC MTHFR genotype, and when accounting for the joint effect of folate intake and MTHFR C677T genotype. PMID:22912935

Kobayashi, Lindsay C.; Limburg, Heather; Miao, Qun; Woolcott, Christy; Bedard, Leanne L.; Massey, Thomas E.; Aronson, Kristan J.

2012-01-01

50

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

PubMed

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

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

51

The association of p53 mutations and p53 codon 72, Her 2 codon 655 and MTHFR C677T polymorphisms with breast cancer in Northern Greece  

Microsoft Academic Search

The aim of this study was to explore a possible association between p53 codon 72, Her 2 codon 655 and MTHFR C677T polymorphisms and breast cancer in Northern Greece. We examined 42 women with breast cancer and 51 controls. A total of 42 women with breast cancer as well as healthy controls were investigated and results showed that p53 codon

Theodora G. Kalemi; Alexandros F. Lambropoulos; Maria Gueorguiev; Sofia Chrisafi; Konstantinos T. Papazisis; Alexandros Kotsis

2005-01-01

52

Polymorphism C776G in the transcobalamin II gene and homocysteine, folate and vitamin B 12 concentrations. Association with MTHFR C677T and A1298C and MTRR A66G polymorphisms in healthy children  

Microsoft Academic Search

One of the etiologies of hyperhomocysteinemia is decreased vitamin B12. Genetic variation in the transcobalamin II gene, the transporter of vitamin B12 to the cells, may produce altered homocysteine levels. We determined transcobalamin II C776G polymorphism, homocysteine, folate and vitamin B12 levels and analyzed the interactive effect with the methylenetetrahydrofolate reductase C677T and A1298C and methionine synthase reductase A66G polymorphisms

Ana C. M. Aléssio; Nelci F. Höehr; Lúcia H. Siqueira; Sérgio P. Bydlowski; Joyce M. Annichino-Bizzacchi

2007-01-01

53

C677T and A1298C Polymorphisms of the Methylenetetrahydrofolate Reductase Gene: Incidence and Effect of Combined Genotypes on Plasma Fasting and Post-Methionine Load Homocysteine in Vascular Disease  

Microsoft Academic Search

Background: Moderately increased plasma concentra- tions of total homocysteine (tHcy) have been shown to be an important risk factor for vascular diseases. Two common polymorphisms of the methylenetetrahydro- folate reductase (MTHFR) gene, the thermolabile C677T and a more recently reported A1298C polymorphism, may contribute to hyperhomocysteinemia. Methods: Using PCR and restriction fragment length polymorphism analysis, we studied the prevalence of

Naomi Q. Hanson; Omer Aras; Feng Yang; Michael Y. Tsai

54

MTHFR gene C677T and A1298C polymorphisms and homocysteine levels in primary open angle and primary closed angle glaucoma  

Microsoft Academic Search

PURPOSE: To investigate the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C genotypes and plasma concentrations of total homocysteine (tHcy) in Pakistani patients with primary open angle glaucoma (POAG) and primary closed angle glaucoma (PCAG). METHODS: This was a prospective case-control study. A total of 295 patients (173 POAG, 122 PCAG) and 143 age- and sex-matched controls were subdivided into two ethnic

Shazia Micheal; Raheel Qamar; Farah Akhtar; Muhammad Imran Khan; Wajid Ali Khan; Asifa Ahmed

2009-01-01

55

Association of the C677T and A1298C polymorphisms in the 5,10 methylenetetrahydrofolate reductase gene in patients with migraine risk  

Microsoft Academic Search

Although controversial, diminished activity of 5,10 methylenetetrahydrofolate reductase (MTHFR), a regulatory enzyme of homocysteine metabolism, may predispose to migraine in Turkish people. In a case-control study, we determined the prevalence of two common MTHFR polymorphisms,C677T and A1298C, in 102 migraine patients (23 migraine with aura, 70 migraine without aura and nine with tension-type headache) and compared it to that of

Ihsan Kara; Ali Sazci; Emel Ergul; Guner Kaya; Gamze Kilic

2003-01-01

56

MTHFR gene C677T and A1298C polymorphisms and homocysteine levels in primary open angle and primary closed angle glaucoma  

PubMed Central

Purpose To investigate the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C genotypes and plasma concentrations of total homocysteine (tHcy) in Pakistani patients with primary open angle glaucoma (POAG) and primary closed angle glaucoma (PCAG). Methods This was a prospective case-control study. A total of 295 patients (173 POAG, 122 PCAG) and 143 age- and sex-matched controls were subdivided into two ethnic groups, Punjabis (Punjab province, central Pakistan) and Pathans (North-West Frontier Province, northern Pakistan). Genotypes of the MTHFR C677T and A1298C polymorphisms were detected by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). An enzyme-linked immunosorbent assay was used to determine the total serum homocysteine (tHcy) levels. Associations were determined by logistic regression analysis. Results Frequency distributions of genotypes and combined genotypes as well as homocysteine levels were obtained. The overall distribution of the C677T genotype was found to be significantly associated with PCAG (CC 69%, CT 21%, TT 10%; p=0.001, ?2=12.6), but not with POAG (CC 71%, CT 28%, TT 1%; p=0.98, ?2=0.02) as compared to the controls (CC 71%, CT 29%, TT 1%). The Pathan cohorts revealed no association with the disease; however, the Punjabis demonstrated a significant association with PCAG (CC 75%, CT 11%, TT 13%; p<0.001, ?2=17.2). PCAG in the Punjabi subjects was also significantly associated with the A1298C polymorphism (AA 43%, AC 54%, CC 3%; p<0.001, ?2=33.9) as compared to the controls. Combined genotype data showed no association with POAG; however, a significant association with all combined genotypes was observed in the overall PCAG subjects (p<0.05, ?2=20.1). This difference was particularly apparent in the TTAA and TTAC combinations that were completely absent in the control groups (p<0.05. ?2=49.6). Mean serum tHcy levels were found to be significantly increased in the POAG (15.2ą1.28 ľmol/l, p<0.001) and PCAG (20.8ą4.8 ľmol/l) groups as compared to the controls (10.0ą0.97 ľmol/l). The tHcy levels in the TT and AC genotype were significantly elevated in the PCAG group (67ą12.39 ľmol/l, p<0.001; 23ą5.94 ľmol/l, p=0.027) as compared to the controls. Conclusion The TT and AC genotypes of MTHFR C677T and A1298C polymorphisms and the combined genotype TTAC were associated with PCAG in Punjabi subjects of Pakistani origin and correlated with the high serum tHcy levels seen in these patients. PMID:19936026

Micheal, Shazia; Qamar, Raheel; Akhtar, Farah; Khan, Muhammad Imran; Khan, Wajid Ali

2009-01-01

57

Methylenetetrahydrofolate Reductase Gene Germ-Line C677T and A1298C SNPs are Associated with Colorectal Cancer Risk in the Turkish Population.  

PubMed

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

Ozen, Filiz; Sen, Metin; Ozdemir, Ozturk

2014-01-01

58

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

PubMed Central

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

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

2014-01-01

59

A Case Control Study on the Contribution of Factor V-Leiden, Prothrombin G20210A, and MTHFR C677T Mutations to the Genetic Susceptibility of Deep Venous Thrombosis  

Microsoft Academic Search

Background: Insofar as the inherited prothrombotic single nucleotide polymorphisms (SNPs) factor V G1691A (FV-Leiden), prothrombin (PRT) G20210A, and methylenetetrahydrofolate reductase (MTHFR), C677T are inherited risk factors of venous thromboembolism (VTE), the aim of this study was to determine the prevalence of single and combined SNPs in 198 patients with documented deep venous thrombosis (DVT), and 697 control subjects, and to

Wassim Y. Almawi; Hala Tamim; Raghid Kreidy; Georgina Timson; Elias Rahal; Malak Nabulsi; Ramzi R. Finan; Noha Irani-Hakime

2005-01-01

60

Exploring the Effects of Methylenetetrahydrofolate Reductase Gene Variants C677T and A1298C on the Risk of Orofacial Clefts in 261 Norwegian Case-Parent Triads  

Microsoft Academic Search

Folic acid and the methylenetetrahydrofolate reductase (MTHFR) gene have both been implicated in the etiology of orofacial clefts. The authors selected 261 case-parent triads (173 cases with cleft lip with or without cleft palate (CL\\/P) and 88 cases with cleft palate only (CPO)) from a Norwegian population-based study of orofacial clefts (May 1996-1998). A case-parent triad design was used to

Astanand Jugessur; Allen J. Wilcox; Rolv T. Lie; Jeffrey C. Murray; Jack A. Taylor

2003-01-01

61

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

Microsoft Academic Search

Elevation in homocysteine and methylenetetrahydrofolate reductase (MTHFR) gene variants, C677T and A1298C, have been linked\\u000a with atherothrombosis. However their exact contribution to coronary artery disease (CAD) remains controversial. Moreover,\\u000a data from Tunisian patients are scarse. We examined the association of MTHFR C677T and A1298C, and changes in plasma homocysteine\\u000a in 352 Tunisian patients with angiographically-demonstrated CAD, and 390 age and

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

2009-01-01

62

Review and pooled analysis of studies on MTHFR C677T polymorphism and esophageal cancer  

Microsoft Academic Search

Esophageal cancer has been associated with tobacco and alcohol consumption, gastric reflux, exposure to nitrosamines from food or other environmental sources, and diets lacking folate. Susceptibility to esophageal cancer may be modified by functional polymorphisms in genes along the folate metabolic pathway, such as methylenetetrahydrofolate reductase (MTHFR). The C677T polymorphism is the most common functional variant, leading to a reduction

S. M. Langevin; D. Lin; K. Matsuo; C. M. Gao; T. Takezaki; R. Z. Stolzenberg-Solomon; M. Vasavi; Q. Hasan; E. Taioli

2009-01-01

63

Evaluation of GenoFlow Thrombophilia Array Test Kit in Its Detection of Mutations in Factor V Leiden (G1691A), Prothrombin G20210A, MTHFR C677T and A1298C in Blood Samples from 113 Turkish Female Patients.  

PubMed

Thrombophilia is a heritable blood disease characterized by an increased tendency to form abnormal blood clots that can block blood vessels. In obstetrics and gynecology, it has been shown by a number of reports that a proportion of recurrent miscarriages involve thrombophilia-related mutations, in particular, Factor V G1691A, prothrombin G20210A, and MTHFR C677T and A1298C. In this study, we examined the frequency of these four mutations in 113 female Turkish patients who had prior complications in pregnancy, using the DiagCor GenoFlow Thrombophilia Array Test kit. Heterozygous MTHFR C677T and A1298C mutations were detected in 46% of the patients, and among these patients, 60% of them carried double heterozygous mutations. In contrast, the heterozygous Factor V G1691A and prothrombin G20210A were detected only in a smaller number of patients, respectively, 13% and 3%. The GenoFlow kit demonstrated 100% concordance with results from Sanger sequencing, which can be translated into sensitivity and specificity both at 100% within this series of patients. PMID:25153695

Aytekin, Ebru; Ergun, Sezen Guntekin; Ergun, Mehmet Ali; Percin, Ferda E

2014-11-01

64

A Common Mutation A1298C in Human Methylenetetrahydrofolate Reductase Gene: Association with Plasma Total Homocysteine and Folate Concentrations1  

Microsoft Academic Search

Methylenetetrahydrofolate reductase (MTHFR) is one of the main regulatory enzymes of homocys- teine metabolism. Previous studies revealed that a common mutation in MTHFR gene C677T is related to hyperhomocysteinemia and occlusive vascular pathology. In the current study, we determined the prevalence of a newly described mutation in the human MTHFR gene A1298C, and the already known C677T mutation, and related

Gideon Friedman; Netta Goldschmidt; Yechiel Friedlander; Arie Ben-Yehuda; Jacob Selhub; Sharona Babaey; Malka Mendel; Miriam Kidron; Hanoch Bar-On

65

Association between factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations and events of the arterial circulatory system: a meta-analysis of published studies  

Microsoft Academic Search

BackgroundThe association between the inherited gene mutations of factor V, prothrombin, and homocysteine metabolism and venous thromboembolic events is accepted widely; however, their influence on the arterial circulatory system remains controversial.

Robert J Kim; Richard C Becker

2003-01-01

66

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

ERIC Educational Resources Information Center

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…

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

2008-01-01

67

The methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and tumor risk: evidence from 134 case-control studies.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism, which is essential for DNA synthesis and methylation. Genetic variations in the MTHFR gene seem to contribute to a decreased activity of MTHFR, ultimately confer increased susceptibility to cancer. As the most extensively studied polymorphism, MTHFR C677T polymorphism was shown to contribute to cancer susceptibility but the results were inconsistent. The authors performed a meta-analysis including 134 studies (46,207 cases and 69,160 controls) to address the issue. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to assess the association. Overall, a significant elevated risk of cancer was associated with the MTHFR C677T polymorphism in T-allele versus C-allele comparison (OR = 1.06, 95% CI 1.02-1.11, P(heterogeneity) < 0.001), homozygote model (OR = 1.08, 95% CI 1.01-1.17, P(heterogeneity) < 0.001) and dominant model (OR = 1.05, 95% CI 1.00-1.10, P(heterogeneity) < 0.001). In the stratified analyses, significantly increased cancer risks were indicated among Asians in all genetic models except for heterozygote model. Further analysis revealed that C677T was significantly associated with an increased risk of esophageal and stomach cancer. This meta-analysis supports an association between the MTHFR C677T polymorphism and increased risk of esophageal and stomach cancer, especially among Asians. Additionally, more high-quality studies and that the covariates responsible for heterogeneity should be controlled to obtain a more conclusive response about the function of MTHFR C677T in cancer. PMID:24744129

Tang, Min; Wang, Shang-Qian; Liu, Bian-Jiang; Cao, Qiang; Li, Bing-Jie; Li, Peng-Chao; Li, Yong-Fei; Qin, Chao; Zhang, Wei

2014-07-01

68

Hyperhomocyst(e)inemia and MTHFR C677T genotypes in patients with central retinal vein occlusion  

Microsoft Academic Search

Background: Elevated plasma homocyst(e)ine is a major risk factor for venous thrombosis and cardiovascular disease. Homozygosity for the MTHFR C677T mutation and low plasma folate levels increase plasma homocyst(e)ine concentrations. The aim of this retrospective case-control study was to investigate a possible association between hyperhomocyst(e)inemia and central retinal vein occlusion. Methods: Our study included 78 consecutive patients with central retinal

Martin Weger; Olaf Stanger; Hannes Deutschmann; Werner Temmel; Wilfried Renner; Otto Schmut; Jürgen Semmelrock; Anton Haas

2002-01-01

69

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with osteoporotic vertebral fractures, but is a weak predictor of BMD  

Microsoft Academic Search

Osteoporosis is a common disease with a strong genetic component. Linkage studies have suggested linkage between BMD and loci on chromosome 1. The MTHFR gene is located on chromosome 1. MTHFR catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methylenetetrahydrofolate, which is used for homocysteine methylation to methionine. The rare genotype (TT) of the C677T polymorphism has previously been demonstrated to be

Morten M. Villadsen; Mathias H. Bünger; Mette Carstens; Liselotte Stenkjćr; Bente L. Langdahl

2005-01-01

70

MTHFR C677T and A1298C polymorphisms are risk factors for Down’s syndrome in Indian mothers  

Microsoft Academic Search

Downs syndrome (DS), a chromosomal disorder due to trisomy 21, results mostly from nondisjunction in maternal meiosis. The present case-control study examined the association of genetic polymorphisms with predisposition to nondisjunction. Two common polymorphisms (SNPs), C677T and A1298C, in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene involved in folate metabolism, are known to lower the activity of this enzyme. Three hundred and

Amit Kumar Rai; Satya Singh; Stuti Mehta; Ashok Kumar; L. K. Pandey; Rajiva Raman

2006-01-01

71

Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism  

Microsoft Academic Search

This study investigated whether a polymor- phism in the 5,10-methylenetetrahydrofo- late reductase (MTHFR) gene (C677T) modi- fies responses to methotrexate (MTX) in patients undergoing bone marrow transplan- tation. About 10% to 12% of the population carry the MTHFR TT genotype (enzyme activ- ity, 30% of wild type (CC)). Patients (n 5 220) with chronic myelogenous leukemia under- went marrow allografts

Cornelia M. Ulrich; Yutaka Yasui; Rainer Storb; Mark M. Schubert; John L. Wagner; Jeannette Bigler; Kiley S. Ariail; Cassie L. Keener; Sue Li; Hao Liu; Federico M. Farin; John D. Potter

2001-01-01

72

Migraine and MTHFR C677T genotype in a population-based sample  

Microsoft Academic Search

OBJECTIVE: Migraine with aura is associated with increased risk of stroke. The MTHFR C677T genotype has been associated with increased risk of migraine in selected clinical samples and with elevated homocysteine, a risk factor for stroke. We assessed the association of the MTHFR C677T variant with migraine and the mediating effect of cardiovascular risk factors and metabolic markers of genotype

Ann I. Scher; Gisela M. Terwindt; W. M. Monique Verschuren; Mark C. Kruit; Henk J. Blom; Hisanori Kowa; Rune R. Frants; Arn M. J. M. van den Maagdenberg; Mark van Buchem; Michel D. Ferrari; Lenore J. Launer

2006-01-01

73

MTHFR polymorphisms C677T and A1298C and associations with IVF outcomes in Brazilian women.  

PubMed

The aim of this study was to investigate the association between MTHFR gene polymorphisms and IVF outcomes in Brazilian women undergoing assisted reproduction treatment. A prospective study was conducted in the Human Reproduction Department at the ABC University School of Medicine and the Ideia Fertility Institute between December 2010 and April 2012. The patient population was 82 women undergoing assisted reproduction cycles. The MTHFR polymorphisms C677T and A1298C were evaluated and compared with laboratory results and pregnancy rates. The C677T variant was associated with proportions of mature (P=0.006) and immature (P=0.003) oocytes whereas the A1298C variant was associated with number of oocytes retrieved (P=0.044). The polymorphisms, whether alone or in combination, were not associated with normal fertilization, good-quality embryo or clinical pregnancy rates. This study suggests that the number and maturity of oocytes retrieved may be related to the MTHFR polymorphisms C677T and A1298C. It is believed that folate has a crucial function in human reproduction and that folate deficiency can compromise the function of the metabolic pathways it is involved in, leading to an accumulation of homocysteine. The gene MTHFR encodes the 5-MTHFR enzyme, which is involved in folate metabolism, and C677T/A1298C polymorphisms of this gene are related to decreased enzyme activity and consequent changes in homocysteine concentration. Folate deficiency and hyperhomocysteinaemia can also compromise fertility and lead to pregnancy complications by affecting the development of oocytes, preparation of endometrial receptivity, implantation of the embryo and pregnancy. In folliculogenesis, hyperhomocysteinaemia can activate apoptosis, leading to follicular atresia and affecting the maturity of oocytes and the quality of embryos cultured in vitro. This study was performed to investigate the association between MTHFR polymorphisms and IVF outcomes in women undergoing assisted reproduction treatment. PMID:24746944

D'Elia, Priscila Queiroz; dos Santos, Aline Amaro; Bianco, Bianca; Barbosa, Caio Parente; Christofolini, Denise Maria; Aoki, Tsutomu

2014-06-01

74

Association of MTHFR C677T polymorphism and risk of cerebrovascular disease in Chinese population: an updated meta-analysis.  

PubMed

A variety of epidemiological studies have evaluated the association between methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism and cerebrovascular disease, but the results were inconsistent. The present meta-analysis was therefore performed to investigate the relationship between C677T polymorphism and cerebrovascular disease in Chinese population. Systematically searching for related studies from PubMed, Embase, Web of Science, CBMdisc and CNKI databases up to 20 September 2013 and manual searching of the reference lists of identified articles was performed. Information was extracted to calculate for the additive, dominant, and recessive models using the pooled odds ratios (ORs) along with 95 % confidence intervals (CIs), using Review Manager 5.0, STATA 11.0 and SPSS 17. Logistic regression, fixed or random effects model, subgroup analysis, sensitivity analysis, meta-regression analysis and publication bias were conducted to improve the comprehensive analysis. A total of 68 case-control studies containing 7,990 cases and 6,941 controls were included in the final meta-analysis. Evidence of significant association between C677T polymorphism and risk of cerebrovascular disease was found in all three genetic models (additive model OR 1.472, 95 % CI 1.368-1.585, P L < 0.001 (CT vs. CC); OR 1.819, 95 % CI 1.666-1.985, P L < 0.001 (TT vs. CC); dominant model OR 1.77, 95 % CI 1.57-1.98, p < 0.00001; and recessive model OR 1.54, 95 % CI 1.39-1.71, p < 0.00001, respectively) based on the overall population. In addition, the results were verified by the subgroup analysis and sensitivity analysis. The present meta-analysis suggests that MTHFR gene C677T polymorphism is significantly associated with increased risk of cerebrovascular disease. TT genotype may act as an independent risk factor for cerebrovascular disease in Chinese population. PMID:24603976

Zhang, Ming-Jie; Li, Jing-Cheng; Yin, Yan-Wei; Li, Bing-Hu; Liu, Yun; Liao, Shao-Qiong; Gao, Chang-Yue; Zhang, Li-Li

2014-05-01

75

MTHFR C677T Polymorphism and Risk of Congenital Heart Defects: Evidence from 29 Case-Control and TDT Studies  

PubMed Central

Background Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme for folate metabolism in humans; it is encoded by the MTHFR gene. Several studies have assessed the association between MTHFR C677T polymorphism and the risk of congenital heart defects (CHDs), while the results were inconsistent. Methods and Findings Multiple electronic databases were searched to identify relevant studies published up to July 22, 2012. Data from case-control and TDT studies were integrated in an allelic model using the Catmap and Metafor software. Twenty-nine publications were included in this meta-analysis. The overall meta-analysis showed significant association between MTHFR C677T polymorphism and CHDs risk in children with heterogeneity (Pheterogeneity?=?0.000) and publication bias (Pegger?=?0.039), but it turned into null after the trim-and-fill method was implemented (OR?=?1.12, 95% CI?=?0.95–1.31). Nevertheless, positive results were obtained after stratified by ethnicity and sample size in all subgroups except the mixed population. For mothers, there was significant association between the variant and CHDs without heterogeneity (Pheterogeneity?=?0.150, OR?=?1.16, 95% CI?=?1.05–1.29) and publication bias (Pegger?=?0.981). However, the results varied across each subgroup in the stratified analysis of ethnicity and sample size. Conclusions Both infant and maternal MTHFR C677T polymorphisms may contribute to the risk of CHDs. PMID:23536781

Gong, Fangqi; Zhu, Weihua; Fu, Songling

2013-01-01

76

Methylenetetrahydrofolate reductase polymorphism (MTHFR C677T) and bone mineral density in Chinese men and women  

Microsoft Academic Search

The relationship between MTHFR (C677T) genotypes of the methylenetetrahydrofolate reductase, bone mineral density (BMD), and vertebral fracture was studied in 657 Chinese men and women. No association between MTHFR (C677T) and BMD was found in postmenopausal women (aged 55–59 years, n = 178), elderly women (aged 70–79 years, n = 247), or elderly men (aged 70–79 years, n = 232)

M. Li; E. M. C. Lau; J. Woo

2004-01-01

77

MTHFR C677T polymorphism and osteoporotic fracture in postmenopausal women: a meta-analysis.  

PubMed

Numerous studies have evaluated the association between MTHFR C677T polymorphism and osteoporotic fracture risk in postmenopausal women. However, the results have been inconsistent. We performed a meta-analysis of the association between MTHFR C677T polymorphism and osteoporotic fracture risk in postmenopausal women. Only seven case-control studies were retrieved, with a total of 4258 patients and 3454 healthy controls. Meta-analysis results showed no significant association between MTHFR C677T polymorphism and osteoporotic fracture risk in postmenopausal women for all genetic models (for TT vs CC: OR=0.99, 95%CI=0.72-1.39; for TT vs TC: OR=1.02, 95%CI=0.87-1.20; for CC+TC vs TT: OR=0.96, 95%CI=0.71-1.28; for TT+TC vs CC: OR=0.93, 95%CI=0.84-1.03). In the subgroup analysis by ethnicity, the results also showed no significant association between MTHFR C677T polymorphism and susceptibility to osteoporotic fracture in postmenopausal women in both Caucasian and Asian populations. In conclusion, this meta-analysis suggests that MTHFR C677T polymorphism may not be associated with susceptibility to osteoporotic fracture in postmenopausal women. PMID:25222234

Guan, J Z; Wu, M; Xiao, Y Z; Zhou, J S; Wang, Z D

2014-01-01

78

MTHFR C677T polymorphism: association with lymphoid neoplasm and effect on methotrexate therapy.  

PubMed

The aim of this study was to detect the possible role of methylene tetrahydrofolate reductase gene polymorphism (MTHFR C677T) in the pathogenesis of lymphoid neoplasms and to investigate the influence of this polymorphism on methotrexate toxicity in adult ALL patients treated with methotrexate maintenance therapy. There was a statistically significant increase in the risk of non-Hodgkin lymphoma in patients with CT genotype (OR, 2.9; 95% CI, 1.3-6.3; P = 0.007) and combined CT + TT genotype (OR, 3.2; 95% CI, 1.5-6.6; P = 0.006). While no significant association was found between this polymorphism and ALL risk. The patients with ALL treated with methotrexate during maintenance therapy were observed for signs of toxicity. MTHFR 677C>T polymorphism (CT + TT) was significantly overrepresented among cases with hepatic toxicity (OR = 15.6; 95% CI, 2.6-81.3; P = 0.001). In addition, they were overrepresented among cases with mucositis, anemia, thrombocytopenia, and leukopenia. However, it did not reach statistical significance level. Further studies on larger number of subjects are necessary. Additional studies on the role of MTHFR gene polymorphism with environment (folate intake) interaction are needed to confirm the role of these genetic polymorphisms. PMID:24592886

Ayad, Mona W; El Naggar, Amel A; El Naggar, Mostafa

2014-07-01

79

Is the prevalence of MTHFR C677T polymorphism associated with ultraviolet radiation in Eurasia?  

PubMed

The methylenetetrahydrofolic acid reductase (MTHFR) C677T polymorphism causes an amino-acid change from alanine to valine and results in the enzyme becoming thermolabile and half decreased activity. Its prevalence varies among global population. We collected data about MTHFR C677T polymorphism prevalence from epidemiology studies, as well as ultraviolet (UV) radiations and some other climatological factors from the internet. The results of the correlation and quadric regression showed that there was inverse U-shape relationship between T allele frequency and UV radiation. The explanatory power of UV radiation was stronger than latitude and all climatological factors. Our results supported the hypothesis that the distribution pattern of MTFHR C677T polymorphism in Eurasia might be the result of interaction of genetic and environmental natural selection, especially the UV radiation. PMID:22992775

Yafei, Wang; Lijun, Pei; Jinfeng, Wang; Xiaoying, Zheng

2012-12-01

80

Effect of multivitamins on plasma homocysteine in patients with the 5,10 methylenetetrahydrofolate reductase C677T homozygous state.  

PubMed

The role of hyperhomocysteinemia (HHcy) as a cardiovascular risk factor remains a matter of debate, while it correlates with folates, it demonstrates inverse correlation with plasma homocysteine (Hcy) levels and vitamin B12 levels and reduces plasma Hcy levels following supplementation with multivitamins. The purpose of this study was to demonstrate that administering multivitamins at specific doses for 90 days restores normal plasma Hcy levels in women who are homozygous for the thermolabile variant of 5,10 methylenetetrahydrofolate reductase (MTHFR C677T). We enrolled 106 healthy females aged between 30 and 42 years, who were non-smokers, non-vegetarian, normotensive and who had no history of food abuse in the previous months. Only females were enrolled in order to rule out any bias due to the variation in Hcy plasma concentrations between males and females. Patient blood sampling was performed in order to determine plasma Hcy, serum folic acid and vitamin B12 levels. Furthermore, molecular characterization of the C677T polymorphism present in the MTHFR gene, was also performed. The results of this study demonstrated that supplementation with specific multivitamins restores normal plasma Hcy levels, regardless of the MTHFR genotype. Furthermore, it is unnecessary to adminster high doses of folate to reduce plasma Hcy levels, and administering high doses of folate may cause pro-inflammatory and pro-proliferative effects. PMID:23818036

Dell'edera, Domenico; Tinelli, Andrea; Milazzo, Giusi Natalia; Malvasi, Antonio; Domenico, Carone; Pacella, Elena; Pierluigi, Compagnoni; Giuseppe, Tarantino; Marcello, Guido; Francesco, Lomurno; Epifania, Annunziata Anna

2013-08-01

81

Methylenetetrahydrofolate reductase polymorphism C677T is not associated to the risk of cervical dysplasia  

Microsoft Academic Search

The aim of the study was to explore a possible association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and cervical neoplasia. A total of 229 women were subjected to cytologic and colposcopic evaluation. Ninety-one of them were found to be normal, and served as the control group, while the other 138 of them had present or past histologically proven cervical pathology

A. F Lambropoulos; T Agorastos; Z. J Foka; S Chrisafi; T. C Constantinidis; J Bontis; A Kotsis

2003-01-01

82

Biological and clinical implications of the MTHFR C677T polymorphism  

Microsoft Academic Search

The enzyme methylenetetrahydrofolate reductase (MTHFR) directs folate species either to DNA synthesis or to homocysteine (Hcy) remethylation. The common MTHFR C677T polymorphism affects the activity of the enzyme and hence folate distribution. Under conditions of impaired folate status, the homozygous TT genotype has been regarded as harmful because it is associated with a high concentration of plasma total Hcy, increased

Per Magne Ueland; Steinar Hustad; Jřrn Schneede; Helga Refsum; Stein Emil Vollset

2001-01-01

83

Effects of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism on executive function in schizophrenia  

Microsoft Academic Search

BackgroundThe methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism has been associated with both overall schizophrenia risk and severity of negative symptoms. This study examined whether schizophrenia patients homozygous for the risk allele (T\\/T) exhibit greater impairment in executive function, and determined the extent to which MTHFR's effects on negative symptoms underlie this relationship.

Joshua L. Roffman; Anthony P. Weiss; Thilo Deckersbach; Oliver Freudenreich; David C. Henderson; Shaun Purcell; Donna H. Wong; Charles H. Halsted; Donald C. Goff

2007-01-01

84

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and gastric cancer susceptibility  

PubMed Central

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

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

85

The common MTHFR C677T and A1298C variants are not associated with the risk of non-syndromic cleft lip\\/palate in northern Venezuela  

Microsoft Academic Search

Non-syndromic cleft lip with or without cleft palate (nsCL\\/P) is among the most common major birth defects, with complex inheritance involving multiple genes and environmental factors. Numerous studies of MTHFR, encoding methylenetetrahydrofolate reductase, which catalyzes the rate-limiting step of folic acid biosynthesis, have shown inconsistent association of two common hypomorphic allelic variants, C677T and A1298C, in nsCL\\/P patients and, in

Mehmet A. Sözen; Marie M. Tolarova; Richard A. Spritz

2009-01-01

86

MTHFR ( C677T and A1298C ) Polymorphisms and Risk of Sporadic Distal Colorectal Adenoma in the UK Flexible Sigmoidoscopy Screening Trial (United Kingdom)  

Microsoft Academic Search

Objective  The purpose of this study was to further evaluate the role of low activity MTHFR variants as well as to explore interactive effects between alcoholic drink consumption and MTHFR variants and risk of distal colorectal adenomatous polyps.\\u000a \\u000a \\u000a \\u000a Methods  We examined the relationship between MTHFR C677T and A1298C gene polymorphisms and risk of distal adenomas in one of the largest case control

Panagiota N. Mitrou; Mark A. Watson; Alexandre S. Loktionov; Christopher Cardwell; Marc J. Gunter; Wendy S. Atkin; Christopher P. Macklin; Tom Cecil; Timothy D. Bishop; John Primrose; Sheila A. Bingham

2006-01-01

87

The 5,10-methylenetetrahydrofolate reductase C677T polymorphism interacts with smoking to increase homocysteine  

Microsoft Academic Search

Elevated homocysteine is a risk marker for several human pathologies. Risk factors for elevated homocysteine include low folate and homozygosity for the T allele of the 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism. Because nitric oxide may inhibit folate catabolism and endothelial nitric oxide synthase activity is reduced in smokers, we postulated that smoking status might modify the impact of the MTHFR

Karen S Brown; Leo A. J Kluijtmans; Ian S Young; Liam Murray; Dorothy McMaster; Jayne V Woodside; John W. G Yarnell; Colin A Boreham; Helene McNulty; J. J. Strain; Joseph McPartlin; John M Scott; Laura E Mitchell; Alexander S Whitehead

2004-01-01

88

The MTHFR C677T polymorphism is associated with depressive episodes in patients from Northern Ireland  

Microsoft Academic Search

Low plasma folate and its derivatives have been linked with depressive disorders in studies dating back over 30 years. A thermolabile variant (677C>T) of the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) is associated with low serum folate. The present study aimed to explore whether the thermolabile variant of MTHFR is associated with a vulnerability to depressive episodes. MTHFR C677T genotype frequencies in

Christopher B. Kelly; Anne P. McDonnell; Timothy G. Johnston; Ciaran Mulholland; Stephen J. Cooper; Dorothy McMaster; Alun Evans; Alexander S. Whitehead

2004-01-01

89

Positive association between MTHFR C677T polymorphism and oral cancer risk: a meta-analysis.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) is a central enzyme involved in regulating the metabolic function of folate, which plays a pivotal role in DNA synthesis, repair, and methylation. The role of MTHFR C677T polymorphism in oral cancer risk has been reported with conflicting evidence. We conducted this study to appropriately estimate the effect size. We searched eligible studies in medicine-specific databases (PubMed, EMBASE, and Web of Knowledge) using (polymorphism) OR (polymorphisms) AND (methylenetetrahydrofolate reductase) OR (MTHFR) AND (oral cancer). A total of seven studies were summarized. This meta-analysis of the combined data showed a marginal association of MTHFR C677T polymorphism with oral cancer risk [odds ratio (OR)?=?0.86, 95% confidence interval (CI)?=?0.73-1.00 for CT vs. CC]. We also found decreased oral cancer risk in Asian population and hospital-based studies. Moreover, heavy drinkers were found to have a significantly higher risk of developing such cancer as compared to the non-heavy drinkers. These results suggest that MTHFR C677T polymorphism may play a role in oral cancer carcinogenesis in Asian population and heavy drinkers. PMID:24488626

Jia, Juan; Ma, Zheng; Wu, Shuangjiang

2014-05-01

90

MTHFR C677T Predisposes to POAG but Not to PACG in a North Indian Population: A Case Control Study  

PubMed Central

Hyperhomocysteinemia induced by the C677T genetic variant in MTHFR (methylenetetrahydrofolate reductase) has been implicated in neuronal cell death of retinal ganglion cells (RGC), which is a characteristic feature of glaucoma. However, association of MTHFR C677T with glaucoma has been controversial because of inconsistent results across association studies. Association between MTHFR C677T and glaucoma has not been reported in Indian population. Therefore, with a focus on neurodegenerative death of RGC in glaucoma, the current study aimed to investigate association of MTHFR C677T with Primary Open Angle Glaucoma (POAG) and Primary Angle Closure Glaucoma (PACG) in a North Indian population. A total of 404 participants (231 patients and 173 controls) were included in this study. Genotyping was performed by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism. A few random samples were also tested by direct sequencing. Genotypic and allelic distributions of the POAG and PACG cohorts were compared to that of controls by chi-square test and odds ratios were reported with 95% confidence intervals. Genotypic and allelic distributions between POAG cases and controls were significantly different (p?=?0.03 and p?=?0.01 respectively). Unlike POAG, we did not find significant difference in the genotypic and allelic distributions of C677T between PACG cases and controls (p>0.05). We also observed a higher proportion of TT associated POAG in females than that in males. However, this is a preliminary indication of gender specific risk of C677T that needs to be replicated in a larger cohort of males and females. The present investigation on MTHFR C677T and glaucoma reveals that the TT genotype and T allele of this polymorphism are significant risk factors for POAG but not for PACG in North Indian population. Ours is the first report demonstrating association of MTHFR C677T with POAG but not PACG in individuals from North India. PMID:25054348

Gupta, Shashank; Bhaskar, Pradeep Kumar; Bhardwaj, Ritu; Chandra, Abhishek; Chaudhry, Vidya Nair; Chaudhry, Prashaant; Ali, Akhtar; Mukherjee, Ashim; Mutsuddi, Mousumi

2014-01-01

91

The methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and cancer risk: The Croatian case–control study  

Microsoft Academic Search

Objectives:Methylation abnormalities appear to be important for the pathogenesis of many cancer types. Since methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the methylation process catalyzing reduction of 5,10-methylenetetrahydrofolate to 5-methyl-tetrahydrofolate, C677T polymorphism, which decreases enzyme activity, may be associated with cancer susceptibility. The aim of this work was to investigate the distribution of MTHFR C677T polymorphism between various types

Ante Reljic; Ana-Maria Simundic; Elizabeta Topic; Nora Nikolac; Danijel Justinic; Mario Stefanovic

2007-01-01

92

Laboratory informatics based evaluation of methylene tetrahydrofolate reductase C677T genetic test overutilization  

PubMed Central

Background: Laboratory data can provide a wide range of information to estimate adherence to guidelines and proper utilization of genetic testing. The methylene tetrahydrofolate reductase (MTHFR) C677T variant has been demonstrated to have negligible utility in patient management. However, the testing of this variant remains pervasive. The purpose of this study was to develop methods to analyze concordance of clinician ordering practices with national guidelines. Methods: We used laboratory data to extract specific data elements including patient demographics, timestamps, physician ordering logs and temporal relationship to chemistry requests to examine 245 consecutive MTHFR tests ordered in 2011 at an academic tertiary center. A comprehensive chart review was used to identify indications for testing. These results were correlated with a retrospective analysis of 4,226 tests drawn at a range of hospitals requesting testing from a national reference laboratory over a 2-year period. MTHFR ordering practices drawn from 17 institutions were examined longitudinally from 2002 to 2011. Results: Indications for testing included cerebrovascular events (40.0%) and venous thrombosis (39.1%). Family history prompted testing in eight cases. Based on acceptable hypercoagulability guidelines recommending MTHFR C677T testing only in the presence of elevated serum homocysteine, 10.6% (22/207) of adult patients met an indicated threshold at an academic tertiary center. Among 77 institutions, 14.5% (613/4226) of MTHFR testing met recommendations. Conclusion: We demonstrate an effective method to examine discreet elements of a molecular diagnostics laboratory information system at a tertiary care institution and to correlate these findings at a national level. Retrospective examination of clinicians’ request of MTHFR C677T genetic testing strongly suggests that clinicians have failed to adjust their ordering practices in light of evolving scientific and professional organization recommendations. PMID:24392247

Cohen, David A.; Shirts, Brian H.; Jackson, Brian R.; Parker, Lisa S.

2013-01-01

93

Interaction between the MTHFR C677T polymorphism and traumatic childhood events predicts depression  

PubMed Central

Childhood trauma is associated with the onset and recurrence of major depressive disorder (MDD). The thermolabile T variant of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) is associated with a limited (oxidative) stress defense. Therefore, C677T MTHFR could be a potential predictor for depressive symptomatology and MDD recurrence in the context of traumatic stress during early life. We investigated the interaction between the C677T MTHFR variant and exposure to traumatic childhood events (TCEs) on MDD recurrence during a 5.5-year follow-up in a discovery sample of 124 patients with recurrent MDD and, in an independent replication sample, on depressive symptomatology in 665 healthy individuals from the general population. In the discovery sample, Cox regression analysis revealed a significant interaction between MTHFR genotype and TCEs on MDD recurrence (P=0.017). Over the 5.5-year follow-up period, median time to recurrence was 191 days for T-allele carrying patients who experienced TCEs (T+ and TCE+); 461 days for T? and TCE+ patients; 773 days for T+ and TCE? patients and 866 days for T? and TCE? patients. In the replication sample, a significant interaction was present between the MTHFR genotype and TCEs on depressive symptomatology (P=0.002). Our results show that the effects of TCEs on the prospectively assessed recurrence of MDD and self-reported depressive symptoms in the general population depend on the MTHFR genotype. In conclusion, T-allele carriers may be at an increased risk for depressive symptoms or MDD recurrence after exposure to childhood trauma. PMID:23900311

Lok, A; Bockting, C L H; Koeter, M W J; Snieder, H; Assies, J; Mocking, R J T; Vinkers, C H; Kahn, R S; Boks, M P; Schene, A H

2013-01-01

94

Association of MTHFR C677T and SHMT 1 C1420T with susceptibility to ESCC and GCA in a high incident region of Northern China  

Microsoft Academic Search

Objective  To assess the association between the C to T transition in the methylenetetrahydro folate reductase gene (MTHFR C677T) and the C to T transition in the serine hydroxymethyltransferase\\u000a \\u000a 1\\u000a gene (SHMT\\u000a \\u000a 1\\u000a C1420T) and the increased risk of carcinogenesis of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma\\u000a (GCA) in a population of high incident region of Northern China.

Yimin Wang; Wei Guo; Yutong He; Zhifeng Chen; Denggui Wen; Xiufeng Zhang; Na Wang; Yan Li; Hui Ge; Jianhui Zhang

2007-01-01

95

5,10-Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms: genotype frequency and association with homocysteine and folate levels in middle-southern Italian adults.  

PubMed

Two genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene (C677T and A1298C) can influence the plasma homocysteine (Hcy) levels, especially in the presence of an inadequate folate status. The aim of this study was to evaluate the frequencies of C677T and of A1298C MTHFR polymorphisms and their correlation with Hcy and serum folate concentrations in a population of blood donors living in a region of middle-southern Italy (the Molise Region). One hundred ninety seven blood donors were studied for total plasma Hcy, serum folate and C677T and A1298C MTHFR genotypes. The frequency of C677T genotypes was 20.8% (CC), 49.8% (CT) and 29.4% (TT); for the A1298C genotypes: 48.7% (AA), 43.7% (AC) and 7.6% (CC). Hcy and serum folate concentrations were significantly different among genotypes of the C677T polymorphism (CC versus CT versus TT: <0.0001 both for Hcy and folate), with Hcy values increasing, and serum folate decreasing, from CC to TT subjects. Regarding to A1298C polymorphism, the difference among genotypes (AA versus AC versus CC; p: 0.026 for Hcy and 0.014 for serum folate), showed an opposite trend for both parameters, with Hcy higher in the wild-type and lower in the homozygotes and serum folate higher in CC than in AA subjects. In conclusion, we found a high frequency of MTHFR allele associated with high level of Hcy and low levels of folate in an Italian southern population. PMID:24277487

Zappacosta, Bruno; Graziano, Mirella; Persichilli, Silvia; Di Castelnuovo, Augusto; Mastroiacovo, Pierpaolo; Iacoviello, Licia

2014-01-01

96

Variable contribution of the MTHFR C677T polymorphism to non-syndromic cleft lip and palate risk in China.  

PubMed

Non-syndromic cleft lip with or without cleft palate (nsCL/P) is one of the most common craniofacial malformations among newborn infants. It has been demonstrated that periconceptional folic acid supplementation may reduce the occurrence of offspring with clefts, particularly in the North China; however, the mechanism remains unknown. Our study of a thermolabile polymorphism (C677T) of methylenetetrahydrofolate reductase (MTHFR) gene in 170 Chinese case-parent triads revealed a moderate association between this MTHFR polymorphism and nsCL/P in a population from North China, but not in a population from South China. Moreover, the study revealed that the heterozygous parents in the North were about twice as likely to transmit the high-risk T allele to affected cases, as that observed in the South (OR = 2.24, 95% CI: 1.08-4.65). Thus, the MTHFR polymorphism is a significant risk factor for nsCL/P in this Northern Chinese population. Our study suggested possible genetic heterogeneity in the development of nsCL/P among Northern and Southern populations in China. PMID:16470725

Zhu, JiangHui; Ren, AiGuo; Hao, Ling; Pei, LiJun; Liu, JianMeng; Zhu, HuiPing; Li, Song; Finnell, Richard H; Li, Zhu

2006-03-15

97

Meta-analyses of the methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and risk of head and neck and lung cancer  

Microsoft Academic Search

Authors report the results of four meta-analyses of studies that examined the association between methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and head and neck cancer (nine studies, 2076 cases and 4834 controls for C677T; four studies, 1439 cases and 3941 controls for A1298C), and lung cancer (ten studies, 5274 cases and 7435 controls for C677T; seven studies, 5098 cases

Stefania Boccia; Paolo Boffetta; Paul Brennan; Gualtiero Ricciardi; Francesco Gianfagna; Keitaro Matsuo; Cornelia M. van Duijn; Rayjean J. Hung

2009-01-01

98

Methylenetetrahydrofolate Reductase C677T Polymorphism and Susceptibility to Cervical Cancer and Cervical Intraepithelial Neoplasia: A Meta-Analysis  

PubMed Central

Background A number of studies have explored the association between methyl enetetrahydrofolate reductase (MTHFR) C677T polymorphism and susceptibility to cervical cancer and cervical intraepithelial neoplasia (CIN). However, results remained controversial. To address this gap, we decided to conduct a meta-analysis of all available published studies. Methods Electronic literature searches of the PubMed, EmBase and Medline databases were performed up to April 30, 2012. Fixed-effects or random-effects model was used to calculate the pooled ORs for different genetic models. Results A total of 12 case-control studies were ultimately identified. No statistical correlation was found between C677T variants and cervical cancer for the overall population. However, subgroup analyses on the White women pointed to a significant protective effect for individuals heterozygous or homozygous for the T-allele (for CT vs. CC: OR?=?0.72, 95% CI 0.59–0.88; for TT vs. CC: OR?=?0.69, 95% CI?=?0.49–0.97; for CT+TT vs. CC: OR?=?0.71, 95% CI 0.59–0.86). C677T variants were associated with neither combined nor stratified CIN among the overall population. Conclusions This meta-analysis suggests that White women with mutant C677T genotypes might have a lower risk of cervical cancer, yet lacking enough statistical robustness. Further investigations are needed to get more insight into the role of this polymorphism in cervical carcinogenesis. PMID:23029458

Zhang, Qiong Hua; Hu, Ting Ting; Luo, Min Hong; Li, Mei Qing; Chen, Qing

2012-01-01

99

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

PubMed Central

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

2010-01-01

100

Effects of Maternal 5,10-Methylenetetrahydrofolate Reductase C677T and A1298C Polymorphisms and Tobacco Smoking on Infant Birth Weight in a Japanese Population  

PubMed Central

Background Intracellular folate hemostasis depends on the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. Because 5,10-MTHFR 677TT homozygosity and tobacco smoking are associated with low folate status, we tested the hypothesis that smoking in mothers with 5,10-MTHFR C677T or A1298C polymorphisms would be independently associated with lower birth weight among their offspring. Methods We assessed 1784 native Japanese mother-child pairs drawn from the ongoing birth cohort of The Hokkaido Study on Environment and Children’s Health. Data (demographic information, hospital birth records, and biological specimens) were extracted from recruitments that took place during the period from February 2003 to March 2006. Maternal serum folate were assayed by chemiluminescent immunoassay, and genotyping of 5,10-MTHFR C677T/A1298C polymorphisms was done using a TaqMan allelic discrimination assay. Results The prevalence of folate deficiency (<6.8 nmol/L) was 0.3%. The 5,10-MTHFR 677CT genotype was independently associated with an increase of 36.40 g (95% CI: 2.60 to 70.30, P = 0.035) in mean infant birth weight and an increase of 90.70 g (95% CI: 6.00 to 175.50, P = 0.036) among male infants of nonsmokers. Female infants of 677TT homozygous passive smokers were 99.00 g (95% CI: ?190.26 to ?7.56, P = 0.034) lighter. The birth weight of the offspring of smokers with 5,10-MTHFR 1298AA homozygosity was lower by 107.00 g (95% CI: ?180.00 to ?33.90, P = 0.004). Conclusions The results suggest that, in this population, maternal 5,10-MTHFR C677T polymorphism, but not the 5,10-MTHFR A1298C variant, is independently associated with improvement in infant birth weight, especially among nonsmokers. However, 5,10-MTHFR 1298AA might be associated with folate impairment and could interact with tobacco smoke to further decrease birth weight. PMID:22277790

Yila, Thamar Ayo; Sasaki, Seiko; Miyashita, Chihiro; Braimoh, Titilola Serifat; Kashino, Ikuko; Kobayashi, Sumitaka; Okada, Emiko; Baba, Toshiaki; Yoshioka, Eiji; Minakami, Hisanori; Endo, Toshiaki; Sengoku, Kazuo; Kishi, Reiko

2012-01-01

101

Methylenetetrahydrofolate reductase (MTHFR) C677T and thymidylate synthase promoter (TSER) polymorphisms in Indonesian children with and without leukemia  

Microsoft Academic Search

Genetic variations in the polymorphic tandem repeat sequence of the enhancer region of the thymidylate synthase promoter (TSER), as well as in methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, influence methotrexate sensitivity. We studied these polymorphisms in children with acute lymphoblastic leukaemia (ALL) and in subjects without malignancy in Indonesia and Holland.The frequencies of TT and CT genotypes were two-fold higher in

Elisa Giovannetti; Dewa G. Ugrasena; Eddy Supriyadi; Laura Vroling; Antonino Azzarello; Desiree de Lange; Godefridus J. Peters; Anjo J. P. Veerman; Jacqueline Cloos

2008-01-01

102

Methylenetetrahydrofolate reductase C677T and A1298C variants do not affect ongoing pregnancy rates following IVF  

Microsoft Academic Search

BACKGROUND: There is concern that IVF could compromise normal imprinting and methylation of DNA. Methyl- enetetrahydrofolate reductase (MTHFR) regulates the flow of folic acid-derived, one-carbon moieties for methylation and is critical to early embryonic development. Therefore, we hypothesized that common polymorphisms in MTHFR could associate with IVF outcome. METHODS: MTHFR C677T and A1298C polymorphism genotyping was per- formed on 374

A. T. Dobson; R. M. Davis; M. P. Rosen; S. Shen; P. F. Rinaudo; J. Chan; M. I. Cedars

2006-01-01

103

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

Microsoft Academic Search

Hyperhomocysteinemia can result from decreased methylenetetrahydrofolate reductase (MTHFR) enzyme activity, owing to genetic\\u000a polymorphisms and\\/or inadequate folate intake. This study was aimed at investigating the prevalence of C677T and A1298C MTHFR\\u000a polymorphisms, and their impact on hyperhomocysteinemia in 95 epileptic patients and 98 controls. Double gradient-denaturing\\u000a gradient gel electrophoresis screening revealed that the frequency of T677 polymorphic allele was similar

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

2004-01-01

104

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

Microsoft Academic Search

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

Elena De Mattia; Giuseppe Toffoli

2009-01-01

105

Methylenetetrahydrofolate reductase C677T and A1298C polymorphism and changes in homocysteine concentrations in women with idiopathic recurrent pregnancy losses  

Microsoft Academic Search

Because they have been described as strong risk factors for idiopathic recurrent pregnancy losses (RPLs), we assessed the association between the methylenetetrahydrofolate reductase (MTHFR) single-nucleotide polymorphisms (SNPs) C677T and A1298C and hyperhomocysteinemia in Tunisian women with idiopathic RPL. Study subjects comprised 200 patients with more than three consecutive RPLs, and 200 age-matched parous control women. C677T and A1298C SNPs were

N Mtiraoui; L Ghazouani; R R Finan; W Y Almawi; T Mahjoub

2006-01-01

106

Maternal Methylenetetrahydrofolate Reductase C677T Polymorphism and Down Syndrome Risk: A Meta-Analysis from 34 Studies  

PubMed Central

Background Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme of folate metabolic pathway which catalyzes the irreversible conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. 5-methyltetrahydrofolate donates methyl group for the methylation of homocysteine to methionine. Several studies have investigated maternal MTHFR C677T polymorphism as a risk factor for DS, but the results were controversial and inconclusive. To come into a conclusive estimate, authors performed a meta-analysis. Aim A meta-analysis of published case control studies was performed to investigate the association between maternal MTHFR C677T polymorphism and Down syndrome. Methods PubMed, Google Scholar, Elsevier, Springer Link databases were searched to select the eligible case control studies using appropriate keywords. The pooled odds ratio (OR) with 95%confidence interval were calculated for risk assessment. Results Thirty four studies with 3,098 DS case mothers and 4,852 control mothers were included in the present meta-analysis. The pooled OR was estimated under five genetic models and significant association was found between maternal MTHFR 677C>T polymorphism and Down syndrome under four genetic models except recessive model (for T vs. C, OR?=?1.26, 95% CI?=?1.09–1.46, p?=?0.001; for TT vs. CC, OR?=?1.49, 95% CI?=?1.13–1.97, p?=?0.008; for CT vs. CC, OR?=?1.29, 95% CI?=?1.10–1.51, p?=?0.001; for TT+CT vs. CC, OR?=?1.35, 95% CI?=?1.13–1.60, p?=?0.0008; for TT vs. CT+CC, OR?=?0.76, 95% CI?=?0.60–0.94, p?=?0.01). Conclusion The results of the present meta-analysis support that maternal MTHFR C677T polymorphism is a risk factor for DS- affected pregnancy. PMID:25265565

Rai, Vandana; Yadav, Upendra; Kumar, Pradeep; Yadav, Sushil Kumar; Mishra, Om Prakesh

2014-01-01

107

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

PubMed

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

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

2014-05-01

108

Changes in lifestyle and total homocysteine in relation to MTHFR(C677T) genotype: the Inter99 study  

Microsoft Academic Search

Background:Reduction in total homocysteine (tHcy) may be clinically relevant in the prevention of cardiovascular disease (CVD) in the general population.Objective:To examine the effects of changes in various lifestyle habits and lifestyle related biological CVD risk markers on changes in tHcy in relation to MTHFR(C677T) genotype.Design:A 1 year follow-up study.Setting:Copenhagen County, Denmark.Subjects:Statistical analyses were based on a population-based sample of 915

L L N Husemoen; T F Thomsen; M Fenger; T Jřrgensen; LLN Husemoen

2006-01-01

109

The effect of MTHFR(C677T) genotype on plasma homocysteine concentrations in healthy children is influenced by gender  

Microsoft Academic Search

Objective:To explore the influence of gender, together with folate status, on the relation between the common methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and plasma total homocysteine (tHcy) concentrations in healthy children.Design:Cross-sectional study by face-to-face interview.Setting and subjects:A total of 186 sixth-grade students participated from twelve randomly selected primary schools in Volos, Greece.Methods:Fasting tHcy, folate, and vitamin B12 were measured in plasma.

C Papoutsakis; N Yiannakouris; Y Manios; E Papaconstantinou; F Magkos; K H Schulpis; A Zampelas; A L Matalas

2006-01-01

110

Association of MTHFR C677T and A1298C polymorphisms with non-Hodgkin lymphoma susceptibility: evidence from a meta-analysis.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism and DNA synthesis. A number of studies have examined the association of MTHFR C677T and A1298C polymorphisms with non-Hodgkin lymphoma (NHL) susceptibility; however, the conclusions were contradictory. We searched available publications assessing the polymorphisms of MTHFR and NHL susceptibility from MEDLINE, EMBASE and CBM. Genotype-based mRNA expression analysis was performed using data from 270 individuals with three different ethnicities. Ultimately, a total of 7448 cases and 11146 controls from 25 studies were included for the C677T polymorphism, 6173 cases and 9725 controls from 19 studies for the A1298C polymorphism. Pooled results indicated that neither C677T nor A1298C polymorphism was associated with NHL susceptibility. However, C677T polymorphism showed a statistically significantly increased risk for Caucasians, but a decreased risk for Asians in the subgroup analysis by ethnicity. The same variants may confer increased susceptibility to develop follicular lymphoma (FL). Moreover, A1298C polymorphism was associated with increased NHL risk for Asians. This meta-analysis indicated that C677T polymorphism was associated with altered NHL susceptibility for Caucasians, Asians and FL. Increased NHL risk was also shown for A1298C among Asians. These findings warrant validation in large and well-designed prospective studies. PMID:25146845

He, Jing; Liao, Xiao-Yu; Zhu, Jin-Hong; Xue, Wen-Qiong; Shen, Guo-Ping; Huang, Shao-Yi; Chen, Wei; Jia, Wei-Hua

2014-01-01

111

The polymorphism of methylenetetrahydrofolate reductase C677T but not A1298C contributes to gastric cancer.  

PubMed

Increasing epidemiological studies have revealed the important role of methylenetetrahydrofolate reductase (MTHFR) in carcinogenesis. The association of MTHFR A1298C and MTHFR C677T polymorphisms with the risk for gastric cancer remains obscure due to inconsistent findings in independent studies among diverse ethnicities. A meta-analysis based on all available publications on this genetic association was performed. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated to estimate the effect of MTHFR variants on gastric carcinogenesis. Totally, 25 eligible case-control studies were included into the meta-analysis according to the inclusion criteria. The MTHFR C677T polymorphism was demonstrated to significantly increase the susceptibility to gastric cancer (OR(T vs. C)?=?1.21, 95% CI 1.10-1.34; OR(TT vs. CC?)=?1.47, 95% CI 1.22-1.76; OR(TC vs. CC?)=?1.20, 95% CI 1.03-1.40; OR(TT + TC vs. CC)?=?1.27, 95% CI 1.10-1.47; OR(TT vs. CC + TC?)=?1.29, 95% CI 1.15-1.46), whereas no significant correlation was observed when assessing the MTHFR A1298C polymorphism (OR(C vs. A?)=?1.00, 95% CI 0.90-1.10; OR(CC vs. AA)?=?0.99, 95% CI 0.75-1.31; OR(CA vs. AA?)=?1.01, 95% CI 0.89-1.14; OR(CC + CA vs. AA)?=?1.00, 95% CI 0.89-1.13; OR(CC vs. AA + CA)?=?0.97, 95% CI 0.74-1.27). Subgroup analyses by ethnicity and source of controls further confirmed the findings in overall analysis. The meta-analysis suggests that the polymorphism of MTHFR C677T but not MTHFR A1298C confers a risk effect on the development of gastric cancer among Asians and Caucasians, which provides a new insight into the gastric cancer pathogenesis. PMID:23897558

Lv, Long; Wang, Ping; Sun, Beicheng; Chen, Gong

2014-01-01

112

MTHFR C677T has differential influence on risk of MSI and MSS colorectal cancer  

Microsoft Academic Search

The majority of colorectal cancer (CRC) exhibiting the micosatellite instability (MSI) phenotype is due to hypermethylation of the hMLH1 gene promoter. We aimed to test the hypothesis that polymorphisms in genes coding for enzymes involved in folate metabolism play a role in altered promoter-specific hypermethy- lation and thus predispose to MSI CRC. Analysis of MSI was performed in 1685 CRCs,

Richard A. Hubner; Steven Lubbe; Ian Chandler; Richard S. Houlston

2007-01-01

113

Methylenetetrahydrofolate reductase C677T polymorphism and predisposition towards esophageal squamous cell carcinoma in a German Caucasian and a northern Chinese population  

Microsoft Academic Search

Purpose Folate deficiency is considered to increase the risk of developing esophageal cancer. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme involved in folate metabolism. A single C ? T substitution at nucleotide 677 of the MTHFR cDNA influences enzyme activity. The purpose of this study is to compare the association of the MTHFR C677T polymorphism with susceptibility to esophageal squamous

Jianhui Zhang; Rainer B. Zotz; Yan Li; Rui Wang; Sybille Kiel; Wolfgang A. Schulz; Denggui Wen; Zhifeng Chen; Liwei Zhang; Shijie Wang; Helmut E. Gabbert; Mario Sarbia

2004-01-01

114

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

Microsoft Academic Search

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,

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

2010-01-01

115

Meta-analyses of blood homocysteine levels for gender and genetic association studies of the MTHFR C677T polymorphism in schizophrenia.  

PubMed

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

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

2014-09-01

116

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

PubMed Central

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

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

117

Gene Polymorphisms of Homocysteine Metabolism-Related Enzymes in Chinese Patients with Occlusive Coronary Artery or Cerebral Vascular Diseases  

Microsoft Academic Search

The mutations in homocysteine (Hcy) metabolism-related enzyme genes including methylenetetrahydrofolate reductase (MTHFR) C677T, cystathionine ?-synthase (CBS) 844ins68, and methionine synthase (MS) A2756G have been identified as genetic risk factors for thromboembolic events. It has been noticed that these gene mutations have heterogeneous distributions among different ethnic groups or geographic areas. The data on the prevalence of the gene mutations in

Guangsen Zhang; Chongwen Dai

2001-01-01

118

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

PubMed Central

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

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

2014-01-01

119

Dietary intake of folate and riboflavin, MTHFR C677T Genotype, and colorectal adenoma risk: a Dutch case-control study  

Microsoft Academic Search

We investigated the associations between dietary intake of folate and vitamin B2, MTHFR C677T genotype, and colorectal adenomas in a Dutch case-control study. Data of cases with at least one histologically confirmed colorectal adenoma (n = 768) and controls with no history of any type of colorectal polyp (n = 709) were included. Dietary intake was assessed using a food-frequency

M. van den Donk; G. M. Buijsse; S. W. van den Berg; M. C. Ocké; J. L. Harryvan; F. M. Nagengast; F. J. Kok; E. Kampman

2005-01-01

120

Assessment of tailor-made prevention of atherosclerosis with folic acid supplementation: randomized, double-blind, placebo-controlled trials in each MTHFR C677T genotype  

Microsoft Academic Search

This study aimed at assessing the effect of folic acid supplementation quantitatively in each MTHFR C677T genotype and considered the efficiency of tailor-made prevention of atherosclerosis. Study design was genotype-stratified, randomized, double-blind, placebo-controlled trials. The setting was a Japanese company in the chemical industry. Subjects were 203 healthy men after exclusion of those who took folic acid or drugs known

Koichi Miyaki; Mitsuru Murata; Haruhito Kikuchi; Izumi Takei; Takeo Nakayama; Kiyoaki Watanabe; Kazuyuki Omae

2005-01-01

121

Association of polymorphisms MTHFR C677T and A1298C with risk of colorectal cancer, genetic and epigenetic characteristic of tumors, and response to chemotherapy  

Microsoft Academic Search

Background and aims  The enzyme MTHFR plays an important role in folate metabolism, and folate is implicated in carcinogenesis due to its role in DNA methylation,\\u000a repair, and synthesis. We analyze the relationship of MTHFR C677T and A1298C polymorphisms with biological, clinicopathological, genetic and epigenetic features of tumors, and the patient\\u000a outcome after treatment with 5-FU-based chemotherapy to determine the contribution

Antonia M. Fernández-Peralta; Lydia Daimiel; Nargisse Nejda; Daniel Iglesias; Vicente Medina Arana; Juan J. González-Aguilera

2010-01-01

122

Meta and pooled analyses of the methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and gastric cancer risk: A Huge-GSEC review  

Microsoft Academic Search

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the metabolism of folate, whose role in gastric carcinogenesis is controversial. The authors performed a meta-analysis and individual data pooled analysis of case-control studies that examined the association between C677T and A1298C polymorphisms (the former being associated with low folate serum levels) and gastric cancer (meta-analyses: 16 studies, 2,727 cases and 4,640

Stefania Boccia; Rayjean Hung; Gualtiero Ricciardi; Francesco Gianfagna; Matthias P. A. Ebert; Jing-Yuan Fang; Chang-Ming Gao; T. Götze; Francesco Graziano; M. Lacasańa-Navarro; Dongxin Lin; L. López-Carrillo; You-Lin Qiao; Hongbing Shen; Rachael Stolzenberg-Solomon; Toshiro Takezaki; Yu-Rong Weng; Fang Fang Zhang; P. Tikka-Kleemola; Paolo Boffetta; Emanuela Taioli

2008-01-01

123

The C677T methylenetetrahydrofolate reductase variant and third trimester obstetrical complications in women with unexplained elevations of maternal serum alpha-fetoprotein  

PubMed Central

Introduction The C677T MTHFR variant has been associated with the same third trimester pregnancy complications as seen in women who have elevations of maternal serum ?-fetoprotein (MSAFP). We hypothesized that these women with third trimester pregnancy complications and MSAFP elevations would have an increased frequency of the variant compared to an abnormal study control group (women with MSAFP elevations without pregnancy complications) as well as to normal population controls. Methods Women who had unexplained elevations of MSAFP in pregnancy were ascertained retrospectively. The frequency of the C677T MTHFR variant among those women with unexplained elevations of MSAFP who had experienced later pregnancy complications was compared to that of women with unexplained elevations of MSAFP without complications as well as to that of the previously established Manitoba frequency. Results Women who had complications of pregnancy and an unexplained MSAFP elevation had a higher allele frequency for the C677T MTHFR variant (q = 0.36,) compared to women with MSAFP elevations and normal pregnancy outcomes (q = 0.25, OR 1.73 95% CI 1.25–2.37, p = 0.03). The frequency was also higher than that of the population controls (q= 0.25, OR 1.70 95% CI 1.11–2.60, p = 0.007). The frequency in women with MSAFP elevations without pregnancy complications was not significantly different from that of the population controls (p = 0.41). Conclusion Women with unexplained elevations of MSAFP and who experience complications in later pregnancy are more likely to have one or two alleles of the C677T MTHFR variant. PMID:15352998

Bjorklund, Natalie K; Evans, Jane A; Greenberg, Cheryl R; Seargeant, Lorne E; Schneider, Carol E; Chodirker, Bernard N

2004-01-01

124

Plasma homocysteine, methylene tetrahydrofolate reductase C677T and factor II G20210A polymorphisms, factor VIII, and VWF in central retinal vein occlusion  

Microsoft Academic Search

AIMSTo determine whether plasma homocysteine, methylene tetrahydrofolate reductase (MTHFR) C677T and factor II G20210A polymorphisms, factor VIII, and vWF are risk factors for central retinal vein occlusion (CRVO).METHODProspective comparison of 63 consecutive patients with central retinal vein occlusion and 63 age matched controls. Plasma homocysteine and vWF were estimated by ELISA, the MTFHR and factor II G20210A polymorphisms determined by

S Boyd; D Owens; T Gin; K Bunce; H Sherafat; D Perry; P G Hykin

2001-01-01

125

Synergistic effects of the MTHFR C677T and A1298C polymorphisms on the increased risk of micro- and macro-albuminuria and progression of diabetic nephropathy among Iranians with type 2 diabetes mellitus  

Microsoft Academic Search

ObjectivesTo find whether polymorphisms of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C are risk factors for diabetic nephropathy (DN) among type 2 diabetes mellitus (T2DM) patients from Western Iran.

Mehrali Rahimi; Ali Hasanvand; Zohreh Rahimi; Asad Vaisi-Raygani; Hadi Mozafari; Mansour Rezaei; Javad Zargooshi; Farid Najafi; Ebrahim Shakiba

2010-01-01

126

Association of the MTHFR C677T and A1298C polymorphisms with methotrexate toxicity in rheumatoid arthritis: a meta-analysis.  

PubMed

The aim of this study was to explore whether the C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase (MTHFR) play a role in methotrexate (MTX) toxicity in rheumatoid arthritis (RA). MEDLINE and EMBASE database searches and subsequent manual searches were utilized to identify articles in which C677T and A1298C MTHFR polymorphisms were evaluated in RA patients taking MTX. A meta-analysis was conducted to identify associations between MTHFR polymorphisms and MTX toxicity. Twelve studies comprising a total of 2,288 RA patients were included in our meta-analysis. Meta-analysis revealed an association between the overall toxicity of MTX and the MTHFR 677TT genotype (odds ratio [OR]?=?1.615, 95 % confidence interval [CI]?=?1.185-2.200, p?=?0.002). Stratification by ethnicity indicated an association between the MTHFR 677TT genotype and the overall toxicity of MTX in East Asians (OR?=?1.583, 95 % CI?=?1.075-2.331, p?=?0.020). The toxicity of MTX also was found to be associated with the TT genotype in patients taking folate (OR?=?1.893, 95 % CI?=?1.283-2.793, p?=?0.001). Stratification by toxicity type indicated an association between the MTHFR 677TT genotype and any adverse effects (OR?=?1.716, 95 % CI?=?1.127-2.612, p?=?0.012). Meta-analysis stratified by toxicity type indicated an association between the MTHFR 1298CC genotype and any adverse effects (OR?=?0.501, 95 % CI?=?0.284-0.886, p?=?0.017). The results of our meta-analysis suggest that the MTHFR C677T and A1298C polymorphisms are associated with MTX toxicity in RA patients. PMID:24794492

Song, Gwan Gyu; Bae, Sang-Cheol; Lee, Young Ho

2014-12-01

127

Effect of lifestyle factors on plasma total homocysteine concentrations in relation to MTHFR(C677T) genotype. Inter99 (7)  

Microsoft Academic Search

Objective: To examine the associations between various lifestyle factors—smoking habits, physical activity, dietary habits, coffee, tea, and alcohol consumption—and homocysteine (tHcy) in relation to MTHFR(C677T) genotype.Design: Cross-sectional population-based study.Setting: Residents of Copenhagen County, Denmark.Subjects: A random sample of 6457 men and women aged 30–60 years drawn from the Civil Registration System and invited to a health examination in 1999–2001. A

L L N Husemoen; T F Thomsen; M Fenger; T Jřrgensen; LLN Husemoen

2004-01-01

128

Different roles of MTHFR C677T and A1298C polymorphisms in colorectal adenoma and colorectal cancer: a meta-analysis  

Microsoft Academic Search

Association studies on the MTHFR polymorphisms (C677T and A1298C) in colorectal cancer (CRC) and colorectal adenoma have shown conflicting results. We performed\\u000a a meta-analysis to better assess the purported associations. Overall, the 677T allele (10,131 patients and 15,362 controls)\\u000a showed a small but significant protective effect against CRC compared to the 677C allele [P=0.0003, odds ratio (OR)=0.93; 95% confidence interval

Yan Huang; Shizhong Han; Yao Li; Yumin Mao; Yi Xie

2007-01-01

129

Association between MTHFR C677T and A1298C Polymorphisms and NSCL/P Risk in Asians: A Meta-Analysis  

PubMed Central

Objective Several studies have reported the association between methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and nonsyndromic cleft lip with or without palate (NSCL/P) in Asian populations. However, findings have been conflicting. In order to investigate the association, a meta-analysis was performed. Methods We searched Pubmed, MedLine and EmBase database to selected eligible studies. The pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were calculated using fixed effects model or random effects model to assess the association between MTHFR polymorphisms and NSCL/P in both Asian children and mothers. Results Finally, nine case-control studies were included. Overall, the MTHFR C677T polymorphism and NSCL/P showed pooled ORs (95%CI) of 1.41(1.23–1.61) in Asian children, and 1.70(1.19–2.42) in Asian mothers. Subgroup analyses by geographical locations further identified the association in Eastern Asian children, Western/Central Asian children and mothers, but not in Eastern Asian mothers. However, no significant relationship between MTHFR A1298C polymorphism and NSCL/P was found in this meta-analysis. Conclusions The MTHFR 677T allele was associated with an increased risk of NSCL/P in Asian populations. PMID:24658649

Zhao, Mengmeng; Ren, Yangwu; Shen, Li; Zhang, Yue; Zhou, Baosen

2014-01-01

130

Association of Corticosteroids and Factor V, Prothrombin, and MTHFR Gene Mutations With Avascular Osteonecrosis in Renal Allograft Recipients  

Microsoft Academic Search

The mechanism of posttransplantation avascular osteonecrosis (AVN) is controversial. Besides an increased bone marrow pressure due to reduced blood supply, enhanced coagulation has been considered. We investigated the associations of factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations as well as cumulative corticosteroid doses with AVN in renal allograft recipients. The records of 39 volunteer patients and 11 patients

A. Celik; D. Tekis; F. Saglam; S. Tunali; N. Kabakci; D. Ozaksoy; M. Manisali; M. A. Ozcan; M. Meral; H. Gülay; T. Camsari

2006-01-01

131

Are effects of MTHFR (C677T) genotype on BMD confined to women with low folate and riboflavin intake? Analysis of food records from the Danish osteoporosis prevention study  

Microsoft Academic Search

We have previously found BMD and fracture risk to be significantly associated with the MTHFR (C677T) polymorphism in healthy postmenopausal women in the first years after menopause. Since then, other cohort studies have suggested that sufficient intake of riboflavin and\\/or folate may have the potential to prevent development of low BMD in women with the TT genotype. This could to

Bo Abrahamsen; Jonna Skov Madsen; Charlotte Landbo Tofteng; Lis Stilgren; Else Marie Bladbjerg; Sřren Risom Kristensen; Kim Brixen; Leif Mosekilde

2005-01-01

132

Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia  

E-print Network

(MTHFR) gene at positions C677T and A1298C were associated with lower risk of adult acute lymphocytic an association between polymorphic variants at positions C677T and A1298C in the folate-metabolizing gene 5,10- methylenetetrahydrofolate reductase (MTHFR), and a decreased risk of adult acute lymphocytic leukemia (ALL).1 Similar

California at Berkeley, University of

133

The Frequent 5,10-Methylenetetrahydrofolate Reductase C677T Polymorphism Is Associated with a Common Haplotype in Whites, Japanese, and Africans  

PubMed Central

The common 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism causes decreased activity of this enzyme and can be associated with mild-to-moderate hyperhomocysteinemia in homozygotes, particularly when there is folic acid deficiency, as well as with vascular dementia, arterial thrombosis, venous thrombosis, neural-tube defects, and fetal loss. When folic acid intake is sufficient, homozygotes for MTHFR 677T appear to be protected against colon cancer and acute lymphatic leukemia, and fetuses bearing this genotype have an augmented survival. The distribution of MTHFR 677T is worldwide, but its frequency in different populations varies extensively. In the present study, we addressed the question of whether the MTHFR 677T alteration has an ancestral origin or has occurred repeatedly. We analyzed the frequency distribution of the previously described polymorphism A1298C in exon 7 and of three intronic dimorphisms, in white Israelis (Jews and Arabs), Japanese, and Ghanaian Africans. The 677T allele was, remarkably, associated with one haplotype, G-T-A-C, in white and Japanese homozygotes. Among the Africans, analysis of maximum likelihood also disclosed an association with the G-T-A-C haplotype, although none of the 174 subjects examined was homozygous for MTHFR 677T. These results suggest that the MTHFR 677T alteration occurred on a founder haplotype that may have had a selective advantage. PMID:11781870

Rosenberg, Nurit; Murata, Mitsuru; Ikeda, Yasuo; Opare-Sem, Ohene; Zivelin, Ariella; Geffen, Eli; Seligsohn, Uri

2002-01-01

134

Age-Related Changes in the Global DNA Methylation Profile of Leukocytes Are Linked to Nutrition but Are Not Associated with the MTHFR C677T Genotype or to Functional Capacities  

PubMed Central

Global DNA methylation of peripheral blood leukocytes has been recently proposed as a potential biomarker for disease risk. However, the amplitude of the changes in DNA methylation associated with normal aging and the impacts of environmental changes on this variation are still unclear. In this context, we evaluated the association of global DNA methylation with nutritional habits, tobacco smoking, body mass index (BMI), clinical laboratory parameters, polymorphism C677T MTHFR, functional cognition and the daily practice of physical activity in a cancer-free older population. Leukocyte global DNA methylation from 126 older individuals was quantified using a high-throughput ELISA-based method. Global DNA hypomethylation was observed in older individuals when compared to a younger population (p?=?0.0469), confirming changes in DNA methylation in the aging process. Furthermore, the methylation profile of elders was correlated with the daily ingestion of carbohydrates (p?=?0.0494), lipids (p?=?0.0494), vitamin B6 (p?=?0.0421), magnesium (p?=?0.0302), and also to the serum levels of total protein (p?=?0.0004), alpha 2 globulin (p?=?0.0013) and albumin (p?=?0.0015). No statistically significant difference was observed when global DNA methylation were stratified according to C677T MTHFR genotypes (p?=?0.7200), BMI (p?=?0.1170), smoking habit (p?=?0.4382), physical activity in daily life (p?=?0.8492), scored cognitive function (p?=?0.7229) or depression state (p?=?0.8301). Our data indicate that age-related variations in the global DNA methylation profile of leukocytes might be modulated by the daily intake of carbohydrates, lipids, vitamin B6, and magnesium and be associated with serum protein levels, however it is independent of C677T MTHFR genotype and not correlated with BMI, smoking habit, cognitive function or the routine physical activities. PMID:23285094

Gomes, Marcus V. M.; Toffoli, Leandro V.; Arruda, Douglas W.; Soldera, Larissa M.; Pelosi, Gislaine G.; Neves-Souza, Rejane D.; Freitas, Eliane R.; Castro, Denilson T.; Marquez, Audrey S.

2012-01-01

135

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

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

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

2014-06-01

136

Methylenetetrahydrofolate reductase gene polymorphism as a risk factor for diabetic nephropathy: a meta-analysis  

Microsoft Academic Search

Investigations into the association between diabetic nephropathy (DN) and MTHFR C677T gene polymorphism in several case–control\\u000a studies has yielded contradictory results. To shed light on these inconclusive findings, a meta-analysis of all available\\u000a studies relating the C677T polymorphism to the risk of developing DN was conducted. The PubMed database was searched, and\\u000a case–control studies investigating the association between MTHFR C677T

Elias Zintzaras; Katrin Uhlig; George N. Koukoulis; Afroditi A. Papathanasiou; Ioannis Stefanidis

2007-01-01

137

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

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

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

2014-01-01

138

Estudo do polimorfismo C677T do gene da metilenotetrahidrofolato redutase (MTHFR) em pacientes com mucosite de trato gastrointestinal após transplante alogęnico de medula óssea.  

E-print Network

??Oral mucositis remains an important side-effect and life-threatening complication of hematopoietic stem cell transplantation. It can occurs in 100% of patients underwenting allogeneic stem cell… (more)

Fabio Luiz Coracin

2009-01-01

139

Effect of Riboflavin Status on the Homocysteine-lowering Effect of Folate in Relation to the MTHFR (C677T) Genotype  

Microsoft Academic Search

Background: Riboflavin (vitamin B2) is the precursor for FAD, the cofactor for methylenetetrahydrofolate reductase (MTHFR). MTHFR catalyzes the formation of 5-methyltetrahydrofolate, which acts as a methyl donor for homocysteine remethylation. Individuals with the MTHFR 677C3 T mutation have increased plasma total homocysteine (tHcy) concentrations, particularly in as- sociation with low folate status. It has been proposed that riboflavin may act

Stuart J. Moat; Pauline A. L. Ashfield-Watt; Hilary J. Powers; Robert G. Newcombe; Ian F. W. McDowell

2003-01-01

140

Detection of Thrombophilic Mutations Related to Spontaneous Abortions by a Multiplex SNaPshot Method  

PubMed Central

Spontaneous abortion is a significant clinical problem of different etiologies. Certain thrombophilia gene mutations have been associated with an increased risk of spontaneous abortion. Also, mutations in folate-related genes can lead to abnormal chromosomal segregation during meiosis which is the most common cause of spontaneous abortion. We have developed a multiplex single-base extension reaction assay that allows simultaneous analysis of 10 different mutations in thrombophilia- and folate-related genes (Factor V Leiden G1691A, Factor V H1299R, Factor II G20210A, Factor XIII V34L, PAI-I -675 4G/5G, FGB -455G/A, MTHFR C677T, MTHFR A1298C, MTR A2756G, and MTRR A66G). Using this method we have studied 232 women who had a spontaneous abortion and 209 of their male partners. Prevalence of Factor II G20210A and Factor V H1299R mutations was significantly higher in the women than in their male partners (2.4% and 0.7%, respectively [p=0.0499] for the Factor II mutation and 9.3% and 5.7%, respectively [p=0.0485] for the Factor V mutation). The prevalence of MTHFR C677T, MTHFR A1298C, MTR A2756G, and MTRR A66G mutations did not differ between the studied groups. In conclusion, we have developed a rapid, simple, reliable, and inexpensive multiplex SNaPshot method for determination of 10 thrombophilic mutations that may result in spontaneous abortions. PMID:22023244

Madjunkova, Svetlana; Volk, Marija; Peterlin, Borut

2012-01-01

141

Prevalence of factor V Leiden, FII G20210A, FXIII Val34Leu and MTHFR C677T polymorphisms in cancer patients with and without venous thrombosis  

Microsoft Academic Search

Venous thromboembolism (VTE) is a common complication in patients with malignant disease. In addition to well-established acquired risk factors for VTE, several genetic risk factors, mainly related to the haemostatic system, are known to influence thrombotic risk. However, the contribution of gene abnormalities to thrombotic tendency in cancer patients remains poorly explored. We performed a prospective study to evaluate the

Eduardo Ramacciotti; Nelson Wolosker; Pedro Puech-Leao; Eduardo Antônio Zeratti; Paula Regina Gusson; Auro del Giglio; Rendrik F. Franco

2003-01-01

142

The allele frequency of mutations in four genes that confer enhanced susceptibility to venous thromboembolism in an unselected group of New York State newborns.  

PubMed

The frequencies of Factor V G1691A (FVL), prothrombin (PT) G20210A, 5'10'methylenetetrahydrofolate reductase (MTHFR) C677T, and methionine synthase (MS) A2756G (four mutations associated with an increased risk of venous thromboembolism [VTE]) were determined in a sample of approximately 1500 New York State residents. Dried blood spots from approximately equal numbers of Caucasians, African-Americans and Hispanics were anonymously obtained from the New York State Department of Health Newborn Screening Program. Following PCR amplification of dried blood spot DNA, allele-specific oligonucleotide hybridization was used to detect mutant alleles. The total number of individuals at increased genetic risk for VTE was 271 (17.5%) of the 1553 persons tested. Increased genetic risk was defined as the heterozygous state for FVL or PT and the homozygous state for the MTHFR or MS polymorphisms. Sixteen individuals had more than one genetic risk factor. The MS gene variant allele frequencies for African-Americans and Hispanics are the first to be reported. This report also provides an estimate of the variant PT allele in the largest group of Hispanics studied to date. PMID:10963782

Conroy, J M; Trivedi, G; Sovd, T; Caggana, M

2000-08-15

143

Capillary electrophoresis of gene mutation.  

PubMed

This chapter illustrates the usefulness of capillary electrophoresis (CE) for the detection of gene mutation, i.e., point mutation, methylation, and microsatellite analysis. In order to provide a general description of the main results and challenges in the field, some relevant applications and reviews on CE of gene mutation are tabulated. Furthermore, some detailed experimental procedures are shown. Several CE methods of gene mutation detection were developed including the following: (1) single-strand conformation polymorphism with capillary electrophoresis; (2) SNaPshot analysis; (3) constant denaturant capillary electrophoresis; (4) microsatellite analysis; and (5) methylation analysis. PMID:18392579

Xu, Guowang; Shi, Xianzhe; Zhao, Chunxia; Yuan, Kailong; Weng, Qianfeng; Gao, Peng; Tian, Jing

2008-01-01

144

Thrombophilic gene polymorphism studies in G6PD deficient individuals from Saudi population  

PubMed Central

We performed a study to evaluate the role of three single nucleotide polymorphisms (SNPs), factor V Leiden G1691A (FVL), prothrombin gene mutation G20210A (PRT or FII-G20210A) and methylenotetrahydrofolate reductase variant C677T (MTHFRC677T), as risk factors for G6PD in Saudi populations. Our results did not show any association with the three Thrombophilic genes with FVL gene, no statistical analysis have shown any association with either allele or genotype frequencies OR=0.566, p=.0.667, (95% CI=0.014-22.48) and OR=0.569, p=0.251¸ (95% CI=0.014-22.96).In PRT gene G20210A for G Vs A, p=0.774; OR=0.566 (95%CI; 0.011-29.6); AA+GA Vs GG; p=0.502; OR=0.569 (95%CI=0.010-2969). G and A allele frequencies were similar between cases and controls with no statistical significance. In the MTHFR gene none of the genotypes or allele frequency cannot show any association OR=1.281, p=.0.667, (95% CI=0.414-3.958) and OR=1.1.172, p=0.800¸ (95% CI=0.343-4.008). Similarly, the difference of T allele frequencies between patients and controls was not found any association. In conclusion, our finding indicates that the prevalence of G1691A, G20210A and C677T mutations in G6PD deficient individuals is not statistically different compared to normal subjects and G6PD is not associated with these thrombophilic mutations in Saudi population. PMID:23275730

Alharbi, Khalid K; Khan, Imran Ali; Syed, Rabbani

2012-01-01

145

Mutations in cardiovascular connexin genes.  

PubMed

Connexins (Cxs) form a family of transmembrane proteins comprising 21 members in humans. Cxs differ in their expression patterns, biophysical properties and ability to combine into homomeric or heteromeric gap junction channels between neighbouring cells. The permeation of ions and small metabolites through gap junction channels or hemichannels confers a crucial role to these proteins in intercellular communication and in maintaining tissue homeostasis. Among others, Cx37, Cx40, Cx43, Cx45 and Cx47 are found in heart, blood and lymphatic vessels. Mutations or polymorphisms in the genes coding for these Cxs have not only been implicated in cardiovascular pathologies but also in a variety of other disorders. While mutations in Cx43 are mostly linked to oculodentodigital dysplasia, Cx47 mutations are associated with Pelizaeus-Merzbacher-like disease and lymphoedema. Cx40 mutations are principally linked to atrial fibrillation. Mutations in Cx37 have not yet been described, but polymorphisms in the Cx37 gene have been implicated in the development of arterial disease. This review addresses current knowledge on gene mutations in cardiovascular Cxs systematically and links them to alterations in channel properties and disease. PMID:24966059

Molica, Filippo; Meens, Merlijn J P; Morel, Sandrine; Kwak, Brenda R

2014-09-01

146

MTHFR homozygous mutation and additional risk factors for cerebral infarction in a large Italian family.  

PubMed

Several cases with cerebral infarctions associated with the C677T mutation in the methylenetetrahydrofolate reductase gene (MTHFR) have been reported. Given the large number of asymptomatic individuals with the MTHFR mutation, additional risk factors for cerebral infarction should be considered. This study describes a large family with the MTHFR mutation and a combination of heterozygous factor V Leiden mutations and different additional exogenous and endogenous thrombogenic risk factors. Psychomotor retardation and a left fronto-insular infarct associated with the MTHFR mutation together with diminished factor VII and low level of protein C was documented in the first patient. In the second patient, generalized epilepsy and a malacic area in the right nucleus lenticularis was associated with the MTHFR mutation and a low level of protein C. In the third patient, right hemiparesis and a left fronto-temporal porencephalic cyst were documented, together with the MTHFR mutation and hyperhomocysteinemia. An extensive search of additional circumstantial and genetic thrombogenic risk factors should be useful for prophylaxis and prognosis of infants with cerebral infarctions associated with the MTHFR mutation and of their related family members. PMID:19068258

Del Balzo, Francesca; Spalice, Alberto; Perla, Massimo; Properzi, Enrico; Iannetti, Paola

2009-01-01

147

Ocular vascular thrombotic events: a diagnostic window to familial thrombophilia (compound factor V Leiden and prothrombin gene heterozygosity) and thrombosis.  

PubMed

In a 12-member, 3-generation kindred with conjoint inheritance of G1691A factor V Leiden (FVL) and G20210A prothrombin gene (PTG) mutations, identified through a proband with amaurosis fugax and his father with nonarteritic ischemic optic neuropathy (NAION), the authors' hypothesis was that ocular thrombosis was a diagnostic window to familial thrombophilia-thrombosis. The authors used polymerase chain reaction (PCR) measures for thrombophilia (FVL, PTG, C677T-A1298C methylenetetrahydrofolate reductase [MTHFR], platelet glycoprotein PLA1A2) and hypofibrinolysis (plasminogen activator inhibitor-1 4G4G). The 39-year-old white male proband, with amaurosis fugax and transient ischemic attacks (TIA), was found to be a compound heterozygote for FVL and PTG mutations. His symptoms resolved only after coumadin. His 44-year-old brother (deep venous thrombosis [DVT]) and 46-year-old sister (DVT, pulmonary embolus [PE]) were compound FVL-PTG gene heterozygotes. Of 4 asymptomatic children born to these 3 siblings, 2 were FVL heterozygotes and 2 PTG heterozygotes. The proband's 69-year-old father, with NAION and ischemic stroke, had PTG heterozygosity, familial high factor VIII, and compound MTHFR C677T-A1298C mutation with homocysteinemia. The proband's 61-year-old aunt had PTG heterozygosity, recurrent DVT, and mesenteric artery thrombosis. The proband's 67-year-old mother, free of thrombotic events, was a FVL heterozygote, had high factor VIII, and PAI-1 4G4G homozygosity. In this extended kindred, ocular thrombotic events (amaurosis fugax, NAION) were associated with variegated thrombotic events, including TIA, ischemic stroke, DVT, PE, and mesenteric artery thrombosis, and opened a diagnostic window to family screening and treatment for complex thrombophilias, which had previously been undiagnosed. PMID:18796459

Glueck, Charles J; Wang, Ping

2009-02-01

148

The effect of the C677T and A1298C polymorphisms in the methylenetetrahydrofolate reductase gene on homocysteine levels in elderly men and women from the British regional heart study  

Microsoft Academic Search

Total blood levels of homocysteine (tHcy) have been shown to depend on both environmental and genetic factors, and to be associated with the risk of developing atherosclerosis with its complications of coronary heart disease (CHD) and stroke. In this study, 408 men and 346 women from two towns, Dewsbury and Maidstone were examined for tHcy levels and genotyped for the

V. Dekou; P. Whincup; O. Papacosta; S. Ebrahim; L. Lennon; P. M. Ueland; H. Refsum; S. E. Humphries; V. Gudnason

2001-01-01

149

The Human Gene Mutation Database: 2008 update  

Microsoft Academic Search

The Human Gene Mutation Database (HGMDŽ) is a comprehensive core collection of germline mutations in nuclear genes that underlie or are associated with human inherited\\u000a disease. Here, we summarize the history of the database and its current resources. By December 2008, the database contained\\u000a over 85,000 different lesions detected in 3,253 different genes, with new entries currently accumulating at a

Peter D Stenson; Matthew Mort; Edward V Ball; Katy Howells; Andrew D Phillips; Nick ST Thomas; David N Cooper

2009-01-01

150

Genes and mutations causing retinitis pigmentosa  

PubMed Central

Retinitis pigmentosa (RP) is a heterogeneous set of inherited retinopathies with many disease-causing genes, many known mutations, and highly varied clinical consequences. Progress in finding treatments is dependent on determining the genes and mutations causing these diseases, which includes both gene discovery and mutation screening in affected individuals and families. Despite the complexity, substantial progress has been made in finding RP genes and mutations. Depending on the type of RP, and the technology used, it is possible to detect mutations in 30–80% of cases. One of the most powerful approaches to genetic testing is high-throughput ‘deep sequencing’, that is, next-generation sequencing (NGS). NGS has identified several novel RP genes but a substantial fraction of previously unsolved cases have mutations in genes that are known causes of retinal disease but not necessarily RP. Apparent discrepancy between the molecular defect and clinical findings may warrant reevaluation of patients and families. In this review, we summarize the current approaches to gene discovery and mutation detection for RP, and indicate pitfalls and unsolved problems. Similar considerations apply to other forms of inherited retinal disease. PMID:23701314

Daiger, SP; Sullivan, LS; Bowne, SJ

2013-01-01

151

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

PubMed

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

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

2014-01-01

152

Researchers Find Gene Mutation That May Protect Against Heart Disease  

MedlinePLUS

... Researchers Find Gene Mutation That May Protect Against Heart Disease Rare genetic variation appears to cut the risk ... 2014 Related MedlinePlus Pages Genes and Gene Therapy Heart Diseases WEDNESDAY, Nov. 12, 2014 (HealthDay News) -- Mutations that ...

153

Mutation pattern of human immunodeficiency virus genes  

Microsoft Academic Search

Summary Human immunodeficiency viruses (HIVs) show extensive genetic variation. This feature is the fundamental cause of pathogenicity of HIVs and thwarts efforts to develop effective vaccines. To understand the mutation mechanism of these viruses, we analyzed nucleotide sequences ofenv andgag genes of the viruses by use of molecular evolutionary methods and estimated the direction and frequency of nucleotide substitutions. Results

Etsuko N. Moriyama; Yasuo Ina; Kazuho Ikeo; Nobuaki Shimizu; Takashi Gojobori

1991-01-01

154

Mutational robustness of ribosomal protein genes.  

PubMed

The distribution of fitness effects (DFE) of mutations is of fundamental importance for understanding evolutionary dynamics and complex diseases and for conserving threatened species. DFEs estimated from DNA sequences have rarely been subject to direct experimental tests. We used a bacterial system in which the fitness effects of a large number of defined single mutations in two ribosomal proteins were measured with high sensitivity. The obtained DFE appears to be unimodal, where most mutations (120 out of 126) are weakly deleterious and the remaining ones are potentially neutral. The DFEs for synonymous and nonsynonymous substitutions are similar, suggesting that in some genes, strong fitness constraints are present at the level of the messenger RNA. PMID:21051637

Lind, Peter A; Berg, Otto G; Andersson, Dan I

2010-11-01

155

Towards linked open gene mutations data  

PubMed Central

Background With the advent of high-throughput technologies, a great wealth of variation data is being produced. Such information may constitute the basis for correlation analyses between genotypes and phenotypes and, in the future, for personalized medicine. Several databases on gene variation exist, but this kind of information is still scarce in the Semantic Web framework. In this paper, we discuss issues related to the integration of mutation data in the Linked Open Data infrastructure, part of the Semantic Web framework. We present the development of a mapping from the IARC TP53 Mutation database to RDF and the implementation of servers publishing this data. Methods A version of the IARC TP53 Mutation database implemented in a relational database was used as first test set. Automatic mappings to RDF were first created by using D2RQ and later manually refined by introducing concepts and properties from domain vocabularies and ontologies, as well as links to Linked Open Data implementations of various systems of biomedical interest. Since D2RQ query performances are lower than those that can be achieved by using an RDF archive, generated data was also loaded into a dedicated system based on tools from the Jena software suite. Results We have implemented a D2RQ Server for TP53 mutation data, providing data on a subset of the IARC database, including gene variations, somatic mutations, and bibliographic references. The server allows to browse the RDF graph by using links both between classes and to external systems. An alternative interface offers improved performances for SPARQL queries. The resulting data can be explored by using any Semantic Web browser or application. Conclusions This has been the first case of a mutation database exposed as Linked Data. A revised version of our prototype, including further concepts and IARC TP53 Mutation database data sets, is under development. The publication of variation information as Linked Data opens new perspectives: the exploitation of SPARQL searches on mutation data and other biological databases may support data retrieval which is presently not possible. Moreover, reasoning on integrated variation data may support discoveries towards personalized medicine. PMID:22536974

2012-01-01

156

A child with Diamond-Blackfan anemia, methylenetetrahydrofolate reductase mutation, and perinatal stroke.  

PubMed

Diamond-Blackfan anemia is a congenital hypoproliferative anemia known to be associated with diverse physical anomalies affecting the thumb, craniofacial bones, urogenital system, and heart; prematurity; and fetal demise. We report the case of a 16-month-old boy with Diamond-Blackfan anemia noted to have decreased use of his right side since birth. Magnetic resonance imaging demonstrated a large area of encephalomalacia in the left middle cerebral artery territory. Magnetic resonance angiography showed marked attenuation of the left middle cerebral artery, suggesting a remote thromboembolic event. The laboratory results were remarkable for a decreased hemogolobin of 9.5 g/dL and increased platelets of 591,000/microL. He was heterozygous for the methylenetetrahydrofolate reductase gene C677T mutation. An echocardiogram demonstrated a patent foramen ovale versus an atrial septal defect with left to right shunting. Perinatal stroke may be a rare complication of Diamond-Blackfan anemia in the setting of other risk factors. PMID:14696910

Butrum, Matthew W; Williams, Linda S; Golomb, Meredith R

2003-11-01

157

A Recurring FBN1 Gene Mutation in Neonatal Marfan Syndrome  

Microsoft Academic Search

Background: Marfan syndrome is an autosomal domi- nant disorder of connective tissue caused by mutations in the fibrillin 1 gene (FBN1). FBN1 mutations have been associated with a broad spectrum of phenotypes. Neo- natal Marfan syndrome has unique clinical manifesta- tions and mutations. Objective: To determine if there is a discernible geno- typic-phenotypic correlation associated with the unique mutation in

Amanda M. Jacobs; Ivanka Toudjarska; Andrew Racine; Petros Tsipouras; Michael W. Kilpatrick; Alan Shanske

2002-01-01

158

Childhood Peanut Allergy May Be Linked to Skin Gene Mutation  

MedlinePLUS

... on this page, please enable JavaScript. Childhood Peanut Allergy May Be Linked to Skin Gene Mutation Study ... Friday, October 24, 2014 Related MedlinePlus Pages Food Allergy Genes and Gene Therapy Skin Conditions FRIDAY, Oct. ...

159

Mutation analysis of the gene involved in adrenoleukodystrophy  

SciTech Connect

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.

Oost, B.A. van; Ligtenberg, M.J.L. [Univ. Hospital Nijmegen (Netherlands); Kemp, S.; Bolhuis, P.A. [Academic Medical Center, Amsterdam (Netherlands)

1994-09-01

160

Overview of skin diseases linked to connexin gene mutations.  

PubMed

Mutations in skin-expressed connexin genes, such as connexins 26, 30, 30.3, 31, and 43, have been linked to several human hereditary diseases with multiple organ involvement. Mutations in connexin 26 are linked to diseases including Vohwinkel syndrome, keratitis-ichthyosis deafness, and hystrix-like ichthyosis deafness syndromes, palmoplantar keratoderma with deafness, deafness with Clouston-like phenotype, and Bart-Pumphrey syndrome. Mutations in connexin 30 are correlated with Clouston syndrome. Connexin 30.3 and 31 mutations lead to erythrokeratoderma variabilis, and mutations in connexin 43 are correlated with oculodentodigital dysplasia. Provided is a review of these mutations and related skin disorders. PMID:23675785

Avshalumova, Lyubov; Fabrikant, Jordan; Koriakos, Angie

2014-02-01

161

Comparison of somatic mutation frequency among immunoglobulin genes  

PubMed Central

We analyzed the frequency of somatic mutation in immunoglobulin genes from hybridomas that secrete anti-(4-hydroxy-3-nitrophenyl)acetyl (NP) monoclonal antibodies. A high frequency of mutation (3.3-4.4%) was observed in both the rearranged VH186.2 and V lambda 1 genes, indicating that somatic mutation occurs with similar frequency in these genes in spite of the absence of an intron enhancer in lambda 1 chain genes. In contrast to the high frequency in J-C introns, only two nucleotide substitutions occurred at positions -462 and -555 in the 5' noncoding region in one of the lambda 1-chain genes and in none of the other three so far studied. Since a similar low frequency of somatic mutation was observed in the 5' noncoding region of inactive lambda 2- chain genes rendered inactive because of incorrect rearrangement, this region may not be a target or alternatively, may be protected from the mutator system. We observed a low frequency of nucleotide substitution in unrearranged V lambda 1 genes (approximately 1/15 that of rearranged genes). Together with previous results (Azuma T., N. Motoyama, L. Fields, and D. Loh, 1993. Int. Immunol. 5:121), these findings suggest that the 5' noncoding region, which contains the promoter element, provides a signal for the somatic mutator system and that rearrangement, which brings the promoter into close proximity to the enhancer element, should increase mutation efficiency. PMID:8294856

1994-01-01

162

Mutations in Putative Mutator Genes of Mycobacterium tuberculosis Strains of the W-Beijing Family  

Microsoft Academic Search

Alterations in genes involved in the repair of DNA mutations (mut genes) result in an increased mutation fre- quency and better adaptability of the bacterium to stressful conditions. W-Beijing genotype strains displayed unique missense alterations in three putative mut genes, including two of the mutT type (Rv3908 and mutT2) and ogt. These polymorphisms were found to be characteristic and unique

Mina Ebrahimi Rad; Pablo Bifani; Carlos Martin; Kristin Kremer; Sofia Samper; Jean Rauzier; Barry Kreiswirth; Jesus Blazquez; Marc Jouan; Dick van Soolingen; Brigitte Gicquel

2003-01-01

163

Mutations of the BRAF gene in human cancer  

Microsoft Academic Search

Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS-RAF-MEK-ERK-MAP kinase pathway mediates cellular responses to growth

Helen Davies; Graham R. Bignell; Charles Cox; Philip Stephens; Sarah Edkins; Sheila Clegg; Jon Teague; Hayley Woffendin; Mathew J. Garnett; William Bottomley; Neil Davis; Ed Dicks; Rebecca Ewing; Yvonne Floyd; Kristian Gray; Sarah Hall; Rachel Hawes; Jaime Hughes; Vivian Kosmidou; Andrew Menzies; Catherine Mould; Adrian Parker; Claire Stevens; Stephen Watt; Steven Hooper; Rebecca Wilson; Hiran Jayatilake; Barry A. Gusterson; Colin Cooper; Janet Shipley; Darren Hargrave; Katherine Pritchard-Jones; Norman Maitland; Georgia Chenevix-Trench; Gregory J. Riggins; Darell D. Bigner; Giuseppe Palmieri; Antonio Cossu; Adrienne Flanagan; Andrew Nicholson; Judy W. C. Ho; Suet Y. Leung; Siu T. Yuen; Barbara L. Weber; Hilliard F. Seigler; Timothy L. Darrow; Hugh Paterson; Richard Marais; Christopher J. Marshall; Richard Wooster; Michael R. Stratton; P. Andrew Futreal

2002-01-01

164

Modeling Autism by SHANK Gene Mutations in Mice  

PubMed Central

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

Jiang, Yong-hui; Ehlers, Michael D.

2013-01-01

165

Novel KRAS Gene Mutations in Sporadic Colorectal Cancer  

PubMed Central

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

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

166

Germline mutations of TP53 gene in breast cancer.  

PubMed

Germline alterations of the TP53 gene encoding the p53 protein have been observed in the majority of families with the Li-Fraumeni syndrome, a rare dominantly inherited disorder with breast cancer. Genomic DNA samples of 182 breast cancer cases and 186 controls were sequenced for TP53 mutations in the exon 5-9 and intervening introns 5, 7-9. Direct sequencing was done using Applied Biosystem 3730 DNA analyzer. In the present study, we observed nine mutations in the sequenced region, of which five were novel. Hardy-Weinberg equilibrium (HWE) was done for all the mutations; C14181T, T14201G, and G13203A have shown deviation from HWE. High linkage disequilibrium (LD) was observed between C14181T (rs129547788) and T14201G (rs12951053) (r (2)?=?0.98.3; D'?=?1.00), whereas other observed mutations do not show strong LD with any of the other mutations. None of the intronic mutations has shown significant association with the breast cancer, two exonic mutations G13203A (rs28934578) and A14572G are significantly (P?=?0.04, P?=?0.007) associated with breast cancer. Germline mutations observed in DNA-binding domain of the gene showed significant association with breast cancer. This study reports five novel germline mutations in the TP53 gene out of which one mutation may confer significant risk to the breast cancer. Mutations in DNA-binding domain of TP53 gene may play role in the early onset and prognosis of breast cancer. The population-based studies of germline mutations in DNA-binding domain of TP53 gene helps in identification of individuals and families who are at risk of developing cancers. PMID:24929325

Damineni, Surekha; Rao, Vadlamudi Raghavendra; Kumar, Satish; Ravuri, Rajasekar Reddy; Kagitha, Sailaja; Dunna, Nageswara Rao; Digumarthi, Raghunadharao; Satti, Vishnupriya

2014-09-01

167

CFTR gene mutations in isolated chronic obstructive pulmonary disease  

SciTech Connect

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.

Pignatti, P.F.; Bombien, C.; Marigo, C. [and others

1994-09-01

168

Hereditary gene mutations in Korean patients with isolated erythrocytosis.  

PubMed

Most cases of erythrocytosis occur secondary to chronic tissue hypoxia or as a clonal disease such as polycythemia vera with somatic mutations in the Janus kinase 2 (JAK2) gene. Rarely, erythrocytosis is caused by hereditary gene mutations. This study investigated hereditary gene mutations in 38 unrelated Korean patients with isolated erythrocytosis without (1) JAK2 mutation and (2) secondary causes of erythrocytosis other than smoking history. Direct sequencing analyses were performed on six genes associated with hereditary erythrocytosis [HBB, exon 2 and exon 3 of HBA2, VHL, EGLN1 (previously PHD2), exon 12 of EPAS1 (previously HIF2A), and exons 5-8 of EPOR]. As a result, mutations were detected in five patients (three never smokers and two current smokers) out of 38 patients (13.2 %). The mutations detected in those five patients were EPOR:p.W439*, EPOR:p.G212C, HBB:p.H98Q (or conventionally H97Q, Hb Malmö [? 97(FG4) His > Gln]), HBB:p.V138M (V137M), and EGLN1:p.L279Tfs43*, all in heterozygous state. No patient had mutations in HBA2, VHL, or in EPAS1. This study indicates that workup for hereditary gene mutations is needed for isolated erythrocytosis with or without smoking history. PMID:24482100

Jang, Ja-Hyun; Seo, Ja Young; Jang, Junho; Jung, Chul Won; Lee, Ki-O; Kim, Sun-Hee; Kim, Hee-Jin

2014-06-01

169

Amelogenesis Imperfecta and Screening of Mutation in Amelogenin Gene  

PubMed Central

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

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

2014-01-01

170

Three novel aniridia mutations in the human PAX6 gene.  

PubMed

Aniridia (iris hypoplasia) is an autosomal dominant congenital disorder of the eye. Mutations in the human aniridia (PAX6) gene have now been identified in many patients from various ethnic groups. In the study reported here we describe PAX6 mutations in one sporadic and five familial cases with aniridia. Of the four different mutations identified, one was identical to a previously reported mutation (C-->T transition at codon 240), and three were novel: two in the glycine-rich region and one in the proline/serine/threonine-rich (PST) region. One PAX6 mutation found in the PST region was associated with cataracts in an aniridia family. Another splice mutation in the PST domain occurred in an aniridia patient with anosmia (inability to smell). The six new aniridia cases reported here have mutations predicted to generate incomplete PAX6 proteins. These results support the theory that human aniridia is caused by haploinsufficiency of PAX6. PMID:7550230

Martha, A; Strong, L C; Ferrell, R E; Saunders, G F

1995-01-01

171

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

PubMed Central

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

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

172

Fukutin Gene Mutations Cause Dilated Cardiomyopathy with Minimal  

E-print Network

Fukutin Gene Mutations Cause Dilated Cardiomyopathy with Minimal Muscle Weakness Terumi Murakami cardiomyopathy with no or minimal limb girdle muscle involvement and normal intelligence, associated with a compound heterozygous FKTN mutation. One patient died by rapid progressive dilated cardiomyopathy at 12

Campbell, Kevin P.

173

Phenotypic Involvement in Females with the FMR1 Gene Mutation.  

ERIC Educational Resources Information Center

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)

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

1998-01-01

174

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, ...

175

New approaches to understanding p53 gene tumor mutation spectra  

Microsoft Academic Search

The first p53 gene mutation arising in a human tumor was described a decade ago by Baker et al. [S.J. Baker, E.R. Fearon, J.M. Nigro, S.R. Hamilton, A.C. Preisinger, J.M. Jessup, P. van Tuinen, D.H. Ledbetter, D.F. Barker, Y. Nakamura, R. White, B. Vogelstein, Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas, Science 244 (1989) 217–221]. There are

Monica Hollstein; Manfred Hergenhahn; Qin Yang; Helmut Bartsch; Zhao-Qi Wang; Pierre Hainaut

1999-01-01

176

Independent mutational events are rare in the ATM gene: haplotype prescreening enhances mutation detection rate.  

PubMed

Mutations in the ATM gene are responsible for the autosomal recessive disorder ataxia-telangiectasia (A-T). Many different mutations have been identified using various techniques, with detection efficiencies ranging from 57 to 85%. In this study, we employed short tandem repeat (STR) haplotypes to enhance mutation identification in 55 unrelated A-T families of Iberian origin (20 Spanish, 17 Brazilian, and 18 Hispanic-American); we were able to identify 95% of the expected mutations. Allelic sizes were standardized based on a reference sample (CEPH 1347-2). Subsequent mutation screening was performed by PTT, SSCP, and DHPLC, and abnormal regions were sequenced. Many STR haplotypes were found within each population and six haplotypes were observed across several of these populations. Single nucleotide polymorphism (SNP) haplotypes further suggested that most of these common mutations are ancestrally related, and not hot spots. However, two mutations (8977C>T and 8264_8268delATAAG) may indeed be recurring mutational events. Common haplotypes were present in 13 of 20 Spanish A-T families (65%), in 11 of 17 Brazilian A-T families (65%), and, in contrast, in only eight of 18 Hispanic-American families (44%). Three mutations were identified that would be missed by conventional screening strategies. In all, 62 different mutations (28 not previously reported) were identified and their associated haplotypes defined, thereby establishing a new database for Iberian A-T families, and extending the spectrum of worldwide ATM mutations. PMID:12815592

Mitui, Midori; Campbell, Catarina; Coutinho, Gabriela; Sun, Xia; Lai, Chih-Hung; Thorstenson, Yvonne; Castellvi-Bel, Sergi; Fernandez, Luis; Monros, Eugenia; Carvalho, Beatriz Tavares Costa; Porras, Oscar; Fontan, Gumersindo; Gatti, Richard A

2003-07-01

177

DNA Methylation and Mutator Genes in Escherichia coli K-12  

PubMed Central

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

Marinus, Martin G.

2010-01-01

178

DNA methylation and mutator genes in Escherichia coli K-12.  

PubMed

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

Marinus, Martin G

2010-10-01

179

Spectrum of Perforin Gene Mutations in Familial Hemophagocytic Lymphohistiocytosis  

PubMed Central

Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive disease of early childhood characterized by nonmalignant accumulation and multivisceral infiltration of activated T lymphocytes and histiocytes (macrophages). Cytotoxic T and natural killer (NK) cell activity is markedly reduced or absent in these patients, and mutations in a lytic granule constituent, perforin, were recently identified in a number of FHL individuals. Here, we report a comprehensive survey of 34 additional patients with FHL for mutations in the coding region of the perforin gene and the relative frequency of perforin mutations in FHL. Perforin mutations were identified in 7 of the 34 families investigated. Six children were homozygous for the mutations, and one patient was a compound heterozygote. Four novel mutations were detected: one nonsense, two missense, and one deletion of one amino acid. In four families, a previously reported mutation at codon 374, causing a premature stop codon, was identified, and, therefore, this is the most common perforin mutation identified so far in FHL patients. We found perforin mutations in 20% of all FHL patients investigated (7/34), with a somewhat higher prevalence, ?30% (6/20), in children whose parents originated from Turkey. No other correlation between the type of mutation and the phenotype of the patients was evident from the present study. Our combined results from mutational analysis of 34 families and linkage analysis of a subset of consanguineous families indicate that perforin mutations account for 20%–40% of the FHL cases and the FHL 1 locus on chromosome 9 for ?10%, whereas the major part of the FHL cases are caused by mutations in not-yet-identified genes. PMID:11179007

Göransdotter Ericson, Kim; Fadeel, Bengt; Nilsson-Ardnor, Sofie; Söderhäll, Cilla; Samuelsson, AnnaCarin; Janka, Gritta; Schneider, Marion; Gürgey, Aytemiz; Yalman, Nevin; Révész, Tom; Egeler, R. Maarten; Jahnukainen, Kirsi; Storm-Mathiesen, Ingebjörg; Haraldsson, Ásgeir; Poole, Janet; de Saint Basile, Genevičve; Nordenskjöld, Magnus; Henter, Jan-Inge

2001-01-01

180

Mutations in putative mutator genes of Mycobacterium tuberculosis strains of the W-Beijing family.  

PubMed

Alterations in genes involved in the repair of DNA mutations (mut genes) result in an increased mutation frequency and better adaptability of the bacterium to stressful conditions. W-Beijing genotype strains displayed unique missense alterations in three putative mut genes, including two of the mutT type (Rv3908 and mutT2) and ogt. These polymorphisms were found to be characteristic and unique to W-Beijing phylogenetic lineage. Analysis of the mut genes in 55 representative W-Beijing isolates suggests a sequential acquisition of the mutations, elucidating a plausible pathway of the molecular evolution of this clonal family. The acquisition of mut genes may explain in part the ability of the isolates of W-Beijing type to rapidly adapt to their environment. PMID:12890325

Ebrahimi-Rad, Mina; Bifani, Pablo; Martin, Carlos; Kremer, Kristin; Samper, Sofia; Rauzier, Jean; Kreiswirth, Barry; Blazquez, Jesus; Jouan, Marc; van Soolingen, Dick; Gicquel, Brigitte

2003-07-01

181

Mutational and Phylogenetic Analyses of the Mycobacterial mbt Gene Cluster ?§  

PubMed Central

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 significant organizational differences originating from an intricate evolutionary path that might have included horizontal gene transfers. Altogether, the findings reported herein advance our understanding of the genetic requirements for the biosynthesis of an important mycobacterial secondary metabolite with relevance to virulence. PMID:21873494

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

182

Mutational and phylogenetic analyses of the mycobacterial mbt gene cluster.  

PubMed

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 significant organizational differences originating from an intricate evolutionary path that might have included horizontal gene transfers. Altogether, the findings reported herein advance our understanding of the genetic requirements for the biosynthesis of an important mycobacterial secondary metabolite with relevance to virulence. PMID:21873494

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

2011-11-01

183

Spectrum of ABCR gene mutations in autosomal recessive macular dystrophies  

Microsoft Academic Search

Stargardt disease (STGD) and late-onset fundus flavimaculatus (FFM) are autosomal recessive conditions leading to macular degenerations in childhood and adulthood, respectively. Recently, mutations of the photoreceptor cell-specific ATP binding transporter gene (ABCR) have been reported in Stargardt disease. Here, we report on the screening of the whole coding sequence of the ABCR gene in 40 unrelated STGD and 15 FFM

Jean-Michel Rozet; Sylvie Gerber; Eric Souied; Isabelle Perrault; Sophie Châtelin; Imad Ghazi; Corinne Leowski; Jean-Louis Dufier; Arnold Munnich; Josseline Kaplan; J-M Rozet

1998-01-01

184

Pyridoxine responsiveness in novel mutations of the PNPO gene  

PubMed Central

Objective: To determine whether patients with pyridoxine-responsive seizures but normal biomarkers for antiquitin deficiency and normal sequencing of the ALDH7A1 gene may have PNPO mutations. Methods: We sequenced the PNPO gene in 31 patients who fulfilled the above-mentioned criteria. Results: We were able to identify 11 patients carrying 3 novel mutations of the PNPO gene. In 6 families, a homozygous missense mutation p.Arg225His in exon 7 was identified, while 1 family was compound heterozygous for a novel missense mutation p.Arg141Cys in exon 5 and a deletion c.279_290del in exon 3. Pathogenicity of the respective mutations was proven by absence in 100 control alleles and expression studies in CHO-K1 cell lines. The response to pyridoxine was prompt in 4, delayed in 2, on EEG only in 2, and initially absent in another 2 patients. Two unrelated patients homozygous for the p.Arg225His mutation experienced status epilepticus when switched to pyridoxal 5?-phosphate (PLP). Conclusions: This study challenges the paradigm of exclusive PLP responsiveness in patients with pyridoxal 5?-phosphate oxidase deficiency and underlines the importance of consecutive testing of pyridoxine and PLP in neonates with antiepileptic drug–resistant seizures. Patients with pyridoxine response but normal biomarkers for antiquitin deficiency should undergo PNPO mutation analysis. PMID:24658933

Paul, Karl; Mills, Philippa; Clayton, Peter; Paschke, Eduard; Maier, Oliver; Hasselmann, Oswald; Schmiedel, Gudrun; Kanz, Simone; Connolly, Mary; Wolf, Nicole; Struys, Eduard; Stockler, Sylvia; Abela, Lucia; Hofer, Doris

2014-01-01

185

Mutations in TGFBR2 gene cause spontaneous cervical artery dissection.  

PubMed

Mutations in the genes encoding transforming growth factor ? receptors 1 and 2 (TGFBR1 and TGFBR2) have recently been associated with hereditary connective tissue disorders with widespread vascular involvement, including arterial dissection. To determine whether mutations in these genes cause spontaneous cervical artery dissection (sCAD), all coding exons of TGFBR1 and TGFBR2 were sequenced in 56 consecutive patients with sCAD. Novel TGFBR2 disease causing mutations were found in two patients. The two mutations were the pK327R substitution affecting the kinase domain of TGFBR2 and the pC138R substitution falling in the extracellular domain of the protein, involved in TGF? binding and signalling. No TGFBR1 mutation was found. The findings indicate that TGFBR2 gene mutations are responsible for sCAD in 3.6% (95% CI 0.0 to 8.4) of cases, have implications in understanding the role of TGF? signalling in the pathogenesis of sCAD and emphasise the importance of considering molecular characterisation of the TGFBR2 gene in these patients, regardless of the presence of clinical features suggestive of hereditary connective tissue disorders. PMID:21270064

Pezzini, Alessandro; Drera, Bruno; Del Zotto, Elisabetta; Ritelli, Marco; Carletti, Monica; Tomelleri, Gianpaolo; Bovi, Paolo; Giossi, Alessia; Volonghi, Irene; Costa, Paolo; Magoni, Mauro; Padovani, Alessandro; Barlati, Sergio; Colombi, Marina

2011-12-01

186

Mutations in the filaggrin gene and food allergy  

PubMed Central

The results of long-term epidemiological studies show that the number of people suffering from allergic diseases, especially from food allergies and atopic dermatitis (AD), is still increasing. Although the research thus far has been conducted mainly in Europe, North America, and Asia, there are also data appearing from the first studies in that field among the African population. This may indicate the importance of the problem of allergic diseases. The discovery that loss-of-function mutations in the gene coding filaggrin (FLG) are the cause of ichthyosis vulgaris marked a significant breakthrough in understanding the pathogenesis of allergic diseases. The presence of mutations in the filaggrin gene is also an important factor that predisposes to such allergic diseases as: allergic rhinitis, atopic dermatitis, atopic asthma, and food allergy. So far, over 40 loss-of-function mutations and numerous silent mutations in filaggrin have been discovered. PMID:25276250

Markiewicz, Lidia; Wroblewska, Barbara

2014-01-01

187

Translational readthrough at nonsense mutations in the HSF1 gene of Saccharomyces cerevisme  

Microsoft Academic Search

The HSF1 gene of Saccharomyces cerevisiae directs the synthesis of the heat shock transcription factor, HSF. The gene is essential; disruption mutations are lethal. Using a plasmid shuffle screen, we isolated mutations in the HSF1 gene after in vitro mutagenesis of plasmid DNA with hydroxylamine. From a collection of both conditional (temperature-sensitive) and unconditional lethal mutations, we recovered mutations that

Jennifer B. Kopczynski; Amanda C. Raff; J. José Bonner

1992-01-01

188

Frequent mutations in chromatin-remodeling genes in pulmonary carcinoids  

PubMed Central

Pulmonary carcinoids are rare neuroendocrine tumors of the lung. The molecular alterations underlying the pathogenesis of these tumors 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-remodeling 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 tumors, TP53 and RB1 mutations are rare events, suggesting that pulmonary carcinoids are not early progenitor lesions of the highly aggressive lung neuroendocrine tumors but arise through independent cellular mechanisms. These data also suggest that inactivation of chromatin remodeling genes is sufficient to drive transformation in pulmonary carcinoids. PMID:24670920

Lu, Xin; Sun, Ruping; Ozretic, Luka; Seidal, Danila; Zander, Thomas; Leenders, Frauke; George, Julie; Muller, Christian; Dahmen, Ilona; Pinther, Berit; Bosco, Graziella; Konrad, Kathryn; Altmuller, Janine; Nurnberg, Peter; Achter, Viktor; Lang, Ulrich; Schneider, Peter M; Bogus, Magdalena; Soltermann, Alex; Brustugun, Odd Terje; Helland, Aslaug; Solberg, Steinar; Lund-Iversen, Marius; Ansen, Sascha; Stoelben, Erich; Wright, Gavin M.; Russell, Prudence; Wainer, Zoe; Solomon, Benjamin; Field, John K; Hyde, Russell; Davies, Michael PA.; Heukamp, Lukas C; Petersen, Iver; Perner, Sven; Lovly, Christine; Cappuzzo, Federico; Travis, William D; Wolf, Jurgen; Vingron, Martin; Brambilla, Elisabeth; Haas, Stefan A.; Buettner, Reinhard; Thomas, Roman K

2014-01-01

189

Gene-Specific Function Prediction for Non-Synonymous Mutations in Monogenic Diabetes Genes  

PubMed Central

The rapid progress of genomic technologies has been providing new opportunities to address the need of maturity-onset diabetes of the young (MODY) molecular diagnosis. However, whether a new mutation causes MODY can be questionable. A number of in silico methods have been developed to predict functional effects of rare human mutations. The purpose of this study is to compare the performance of different bioinformatics methods in the functional prediction of nonsynonymous mutations in each MODY gene, and provides reference matrices to assist the molecular diagnosis of MODY. Our study showed that the prediction scores by different methods of the diabetes mutations were highly correlated, but were more complimentary than replacement to each other. The available in silico methods for the prediction of diabetes mutations had varied performances across different genes. Applying gene-specific thresholds defined by this study may be able to increase the performance of in silico prediction of disease-causing mutations. PMID:25136813

Li, Quan; Liu, Xiaoming; Gibbs, Richard A.; Boerwinkle, Eric; Polychronakos, Constantin; Qu, Hui-Qi

2014-01-01

190

Mutations in many genes affect aggressive behavior in Drosophila melanogaster  

PubMed Central

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

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

2009-01-01

191

Novel Somatic and Germline Mutations in Cancer Candidate Genes in Glioblastoma, Melanoma, and Pancreatic Carcinoma  

Microsoft Academic Search

A recent systematic sequence analysis of well-annotated human protein coding genes or consensus coding sequences led to the identification of 189 genes displaying somatic mutations in breast and colorectal cancers. Based on their mutation prevalence, a subset of these genes was identified as cancer candidate (CAN)genes as they could be potentially involved in cancer. We evaluated the mutational profiles of

Asha Balakrishnan; Fonnet E. Bleeker; Simona Lamba; Monica Rodolfo; Maria Daniotti; Aldo Scarpa; Sieger Leenstra; Carlo Zanon; Alberto Bardelli

2007-01-01

192

Mutator gene and hereditary non-polyposis colorectal cancer  

DOEpatents

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.

de la Chapelle, Albert (Helsingfors, FI); Vogelstein, Bert (Baltimore, MD); Kinzler, Kenneth W. (Baltimore, MD)

2008-02-05

193

DCEG Scientists Identify New Gene Mutation Related to Familial Melanoma  

Cancer.gov

Scientists have identified a rare inherited mutation in a gene that can increase the risk of familial melanoma, according to a study that appeared online in Nature Genetics on March 30, 2014. Although the finding does not offer immediate benefit to patients, variation in the Protection of Telomeres-1 (POT1) gene provides additional clues as to the origins of melanoma and may open new avenues in prevention and treatment research. Read the full NCI Benchmarks blog post about this study.

194

Dominant negative mutator mutations in the mutS gene of Escherichia coli.  

PubMed Central

The MutS protein of Escherichia coli is part of the dam-directed MutHLS mismatch repair pathway which rectifies replication errors and which prevents recombination between related sequences. In order to more fully understand the role of MutS in these processes, dominant negative mutS mutations on a multicopy plasmid were isolated by screening transformed wild-type cells for a mutator phenotype, using a Lac+ papillation assay. Thirty-eight hydroxylamine- and 22 N-methyl-N'-nitro-N-nitrosoguanidine-induced dominant mutations were isolated. Nine of these mutations altered the P-loop motif of the ATP-binding site, resulting in four amino acid substitutions. With one exception, the remaining sequenced mutations all caused substitution of amino acids conserved during evolution. The dominant mutations in the P-loop consensus caused severely reduced repair of heteroduplex DNA in vivo in a mutS mutant host strain. In a wild-type strain, the level of repair was decreased by the dominant mutations to between 12 to 90% of the control value, which is consistent with interference of wild-type MutS function by the mutant proteins. Increasing the wild-type mutS gene dosage resulted in a reversal of the mutator phenotype in about 60% of the mutant strains, indicating that the mutant and wild-type proteins compete. In addition, 20 mutant isolates showed phenotypic reversal by increasing the gene copies of either mutL or mutH. There was a direct correlation between the levels of recombination and mutagenesis in the mutant strains, suggesting that these phenotypes are due to the same function of MutS. PMID:8071216

Wu, T H; Marinus, M G

1994-01-01

195

Mutations in the p53 Tumor Suppressor Gene  

PubMed Central

Inactivation of the p53 tumor suppressor is a frequent event in tumorigenesis. In most cases, the p53 gene is mutated, giving rise to a stable mutant protein whose accumulation is regarded as a hallmark of cancer cells. Mutant p53 proteins not only lose their tumor suppressive activities but often gain additional oncogenic functions that endow cells with growth and survival advantages. Interestingly, mutations in the p53 gene were shown to occur at different phases of the multistep process of malignant transformation, thus contributing differentially to tumor initiation, promotion, aggressiveness, and metastasis. Here, the authors review the different studies on the involvement of p53 inactivation at various stages of tumorigenesis and highlight the specific contribution of p53 mutations at each phase of cancer progression. PMID:21779514

Rivlin, Noa; Brosh, Ran; Oren, Moshe; Rotter, Varda

2011-01-01

196

MODY2 caused by a novel mutation of GCK gene.  

PubMed

Maturity-onset diabetes of the young type 2 (MODY2) is an autosomal dominant inherited disease caused by heterozygous inactivating mutations in the glucokinase (GCK) gene and is characterized by mild noninsulin-dependent fasting hyperglycemia. It is treated with diet only, and complications are extremely rare. We present a report of a family with MODY2 caused by a novel NM_000162.3:c.878T>C mutation in exon 8 of the GCK gene. Testing for MODY2 and reporting all novel mutations are important to avoid difficulties in the interpretation of genetic test results and to provide fast and definitive diagnosis for all patients with this disease. PMID:23155715

Pulst, Kerti; Arbo, Triin; Kahre, Tiina; Peet, Aleksandr; Tillmann, Vallo

2012-01-01

197

International team identifies critical genes mutated in stomach cancer  

Cancer.gov

An international team of scientists, led by researchers from the Duke-NUS Graduate Medical School in Singapore and National Cancer Centre of Singapore, has identified hundreds of novel genes that are mutated in stomach cancer, the second-most lethal cancer worldwide.

198

Growth and Skeletal Development in Families with NOGGIN Gene Mutations  

Microsoft Academic Search

Introduction: There is a scarcity of data on height as well as bone densitometry in humans with NOGGIN mutations. Methods: In 2 families with symphalangism, anthropometry, bone densitometry and genetic analysis of the NOGGIN gene were performed. Results: In family A, the height standard deviation scores of the affected father and son were –0.4 and 3.5, respectively. In family B,

C. D. Oxley; R. Rashid; D. R. Goudie; G. Stranks; D. U. Baty; W. Lam; C. J. Kelnar; S. F. Ahmed

2008-01-01

199

Genome truncation vs mutational opportunity: can new genes arise via gene duplication?—Part 1  

Microsoft Academic Search

Gene duplication and lateral gene transfer are observed biological phenomena. Their purpose is still a matter of deliberation among creationist and Intelligent Design researchers, but both may serve functions in a process leading to rapid acquisition of adaptive phenotypes in novel environments. Evolutionists claim that copies of duplicate genes are free to mutate and that natural selection subsequently favours useful

Royal Truman; Peter Borger

200

Detecting negative selection on recurrent mutations using gene genealogy  

PubMed Central

Background Whether or not a mutant allele in a population is under selection is an important issue in population genetics, and various neutrality tests have been invented so far to detect selection. However, detection of negative selection has been notoriously difficult, partly because negatively selected alleles are usually rare in the population and have little impact on either population dynamics or the shape of the gene genealogy. Recently, through studies of genetic disorders and genome-wide analyses, many structural variations were shown to occur recurrently in the population. Such “recurrent mutations” might be revealed as deleterious by exploiting the signal of negative selection in the gene genealogy enhanced by their recurrence. Results Motivated by the above idea, we devised two new test statistics. One is the total number of mutants at a recurrently mutating locus among sampled sequences, which is tested conditionally on the number of forward mutations mapped on the sequence genealogy. The other is the size of the most common class of identical-by-descent mutants in the sample, again tested conditionally on the number of forward mutations mapped on the sequence genealogy. To examine the performance of these two tests, we simulated recurrently mutated loci each flanked by sites with neutral single nucleotide polymorphisms (SNPs), with no recombination. Using neutral recurrent mutations as null models, we attempted to detect deleterious recurrent mutations. Our analyses demonstrated high powers of our new tests under constant population size, as well as their moderate power to detect selection in expanding populations. We also devised a new maximum parsimony algorithm that, given the states of the sampled sequences at a recurrently mutating locus and an incompletely resolved genealogy, enumerates mutation histories with a minimum number of mutations while partially resolving genealogical relationships when necessary. Conclusions With their considerably high powers to detect negative selection, our new neutrality tests may open new venues for dealing with the population genetics of recurrent mutations as well as help identifying some types of genetic disorders that may have escaped identification by currently existing methods. PMID:23651527

2013-01-01

201

Genetic Association Analyses of Nitric Oxide Synthase Genes and Neural Tube Defects Vary by Phenotype  

PubMed Central

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

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.

2014-01-01

202

40 CFR 798.5300 - Detection of gene mutations in somatic cells in culture.  

Code of Federal Regulations, 2010 CFR

...true Detection of gene mutations in somatic cells in culture. 798.5300 Section 798.5300...5300 Detection of gene mutations in somatic cells in culture. (a) Purpose. Mammalian cell culture systems may be used to detect...

2010-07-01

203

Localization of temperature-sensitive transformation mutations and back mutations in the Rous sarcoma virus src gene.  

PubMed Central

Cloning and sequencing of two temperature-sensitive transforming mutations of Rous sarcoma virus reveal that their lesions are due to distinct but close single amino acid changes near the carboxy terminus of the v-src gene product. Back mutations to wild type result from second mutations at either nearby or distant sites. Images PMID:3009882

Fincham, V J; Wyke, J A

1986-01-01

204

Gene Mutations Gene a finite segment of DNA specified  

E-print Network

for humans ranges from 50 to 250 rads (0.5 -2.5 Gy). ¡ Drosophila fruit flies have a doubling dose 15 times of needed amino acids or by addition of drugs. ¡ Looked for growth of mutated cells. ¡ Rate for a specific established. #12;Damage to Nucleic Acids #12;Examples for human repair ¡ Xeroderma pigmantosum ­ inability

Massey, Thomas N.

205

AID-initiated purposeful mutations in immunoglobulin genes.  

PubMed

Exposure brings risk to all living organisms. Using a remarkably effective strategy, higher vertebrates mitigate risk by mounting a complex and sophisticated immune response to counter the potentially toxic invasion by a virtually limitless army of chemical and biological antagonists. Mutations are almost always deleterious, but in the case of antibody diversification there are mutations occurring at hugely elevated rates within the variable (V) and switch regions (SR) of the immunoglobulin (Ig) genes that are responsible for binding to and neutralizing foreign antigens throughout the body. These mutations are truly purposeful. This chapter is centered on activation-induced cytidine deaminase (AID). AID is required for initiating somatic hypermutation (SHM) in the V regions and class switch recombination (CSR) in the SR portions of Ig genes. By converting C --> U, while transcription takes place, AID instigates a cascade of mutational events involving error-prone DNA polymerases, base excision and mismatch repair enzymes, and recombination pathways. Together, these processes culminate in highly mutated antibody genes and the B cells expressing antibodies that have achieved optimal antigenic binding undergo positive selection in germinal centers. We will discuss the biological role of AID in this complex process, primarily in terms of its biochemical properties in relation to SHM in vivo. The chapter also discusses recent advances in experimental methods to characterize antibody dynamics as a function of SHM to help elucidate the role that the AID-induced mutations play in tailoring molecular recognition. The emerging experimental techniques help to address long-standing conundrums concerning evolution-imposed constraints on antibody structure and function. PMID:17560274

Goodman, Myron F; Scharff, Matthew D; Romesberg, Floyd E

2007-01-01

206

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

SciTech Connect

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.

Koike, R.; Onodera, O.; Tabe, H. [Miigate Univ. (Japan)] [and others

1994-09-01

207

PDCD10 Gene Mutations in Multiple Cerebral Cavernous Malformations  

PubMed Central

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

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

208

Mutation analysis of the HFE gene in Brazilian populations.  

PubMed

We analyzed the frequency of the C282Y and H63D mutations in the HFE gene in 227 individuals from Brazil comprising 71 Caucasians, 91 racially mixed Caucasian African-derived Amerindians (both populations from Southeast Brazil), 85 African-derived subjects (from Northeast Brazil) and 75 Parakană Indians. Allelic frequency of the mutation C. 845G(A (C282Y) was 1.4% in the Caucasian population, 1.1% in the African-derived population, 1.1% in the racially mixed normal controls and 0% in the Parakană Indians. In the African-derived population, the C282Y mutation was present on chromosomes bearing the haplotype 6/1h according to Beutler and West (1997). Allelic frequency of the mutation C. 187C(G (H63D) was 16.3% in the Caucasian population, 7.5% in the African-derived population, 9.8% in the racially mixed controls and 0% in the Amerindians. The presence of these mutations in the African-derived population reflects the fact that these subjects may have undergone a non-identified racial admixture in their past history. The absence of both defects in the Amerindians suggests that these mutations have emerged after the migration of Polynesians to America, or that they may not have reached the Polynesian population until after the migration to America had occurred. PMID:10660479

Agostinho, M F; Arruda, V R; Basseres, D S; Bordin, S; Soares, M C; Menezes, R C; Costa, F F; Saad, S T

1999-01-01

209

TGFBI gene mutations in a Korean population with corneal dystrophy  

PubMed Central

Purpose To investigate the clinical and genetic features of Korean patients with corneal dystrophies associated with mutations in the human transforming growth factor-?-induced (TGFBI) gene. Methods In this study, 387 subjects (71 families and 89 individuals - 268 patients having TGFBI corneal dystrophies and 119 normal relatives) were assessed. All subjects underwent a complete ophthalmologic evaluation, including biomicroscopic inspection and dilated fundus examination. As a control, 100 individuals without corneal disease were selected from the general population. The polymerase chain reaction (PCR) and direct sequencing were used to screen for mutations in TGFBI. Results All subjects recruited exhibited a range of corneal dystrophies, including Thiel-Behnke corneal dystrophy (TBCD, R555Q; 6 families and 4 individuals), granular corneal dystrophy type 2 (GCD2, R124H; 61 families and 80 individuals), lattice corneal dystrophy (LCD; 4 families and 5 individuals; 7 with type 1 [R124C], and 2 with a variant [L527R, P542R]). The disease showed an autosomal dominant inheritance pattern in all families. Conclusions R124H in GCD2 was the most common mutation. GCD1 and Reis-Bucklers corneal dystrophy were not found. In the GCD2 patients there were a large number of laser refractive surgery-induced corneal opacities. A spontaneous R124H mutation was confirmed in an already mutated allele that resulted in a change from a heterozygous into a homozygous form. Also, a novel mutation, P527R, was identified in LCD. PMID:22876129

Cho, Kyong Jin; Mok, Jee Won; Na, Kyung Sun; Rho, Chang Rae; Byun, Yong Soo; Hwang, Ho Sik; Hwang, Kyu Yeon

2012-01-01

210

Novel truncating thyroglobulin gene mutations associated with congenital hypothyroidism.  

PubMed

Mutations in the thyroglobulin (TG) gene have been reported to cause congenital hypothyroidism (CH) and we have been investigating the genetic architecture of CH in a large cohort of consanguineous/multi-case families. Our aim in this study was to determine the genetic basis of CH in four affected individuals coming from two separate consanguineous families. Since CH is usually inherited in autosomal recessive manner in consanguineous/multi-case families, we adopted a two-stage strategy of genetic linkage studies and targeted sequencing of the TG gene. First we investigated the potential genetic linkage of families to any known CH locus using microsatellite markers and then determined the pathogenic mutations in linked-genes by Sanger sequencing. Both families showed potential linkage to TG locus and we detected two previously unreported nonsense TG mutations (p.Q630X and p.W637X) that segregated with the disease status in both families. This study highlights the importance of molecular genetic studies in the definitive diagnosis and classification of CH, and also adds up to the limited number of nonsense TG mutations in the literature. It also suggests a new clinical testing strategy using next-generation sequencing in all primary CH cases. PMID:23949896

Cangul, Hakan; Boelaert, Kristien; Dogan, Murat; Saglam, Yaman; Kendall, Michaela; Barrett, Timothy G; Maher, Eamonn R

2014-03-01

211

Rapid detection of common mutations in the arylsulfatase A gene  

SciTech Connect

Metachromatic leukodystrophy (MLD), an autosomal recessive lysosomal storage disease results from a deficiency of arylsulfatase A activity. This disease is usually fatal within a few years of onset in the pediatric age group. A pseuodeficiency occurs in up to 15% of alleles in the general population which significantly decreases enzyme activity. Although there is no clinical phenotype associated with the pseudodeficiency, the decreased enzyme activity can complicate interpretation of biochemical assay results particularly in the case of potential heterozygous carriers of MLD. Two mutations have been found to be simultaneously associated with the pseudodeficiency: one at a glycosylatin site in exon 6 and one in the polyA addition signal. Another mutation, the `I` allele has been reported in up to 50% of alleles in the severe infantile onset form of MLD. The deleterious mutation in this case is in the +1 position of intron 2. In order to screen for these commonly occurring mutations in the arylsulfatase A gene, a simple combination of PCR amplification from genomic DNA and restriction enzyme digestions was developed for each situation. In the case of the pseuodeficiency mutations, oligonucleotide primers were designed which incorporated a single base mismatch 3 bases upstream from the 3{prime} end of the primer so that the presence of the mutation created new MaeIII restriction site in the case of the glycosylation site or an RsaI site in the case of the polyA site. The `I` allele mutation creates a new MvaI site without the use of mismatches. These tests have successfully detected the mutations in individuals suspected of having the pseudodeficiency on the basis of biochemical assay. The `I` allele was detected in 1 of 16 MLD alleles analyzed.

Coulter-Mackie, M.B. [Univ. of Western Ontario (Canada)]|[CPRI, London, Ontario (Canada)

1994-09-01

212

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

Code of Federal Regulations, 2010 CFR

...2010-07-01 true TSCA in vitro mammalian cell gene mutation test. 799.9530 Section... § 799.9530 TSCA in vitro mammalian cell gene mutation test. (a) Scope. ...section 4 of TSCA. The in vitro mammalian cell gene mutation test can be used to...

2010-07-01

213

Screening for mutations in the PKD1 gene  

SciTech Connect

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.

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

1994-09-01

214

Effects of destrin pathway mutations on the gene expression profile.  

PubMed

This study aimed to explore the interaction and crosstalk between pathways in response to destrin mutations. All the pathways from the MINT database were downloaded, a protein-protein interaction network was then constructed, and the crosstalk between pathways was investigated, in particular, the overlap of 2 significant pathway analysis results. As expected, the results showed that regulation of the actin cytoskeleton was the significant pathway of destrin mutations in mice. Further analysis indicated that 28 significant pathways cross-talked with the pathway regulating the actin cytoskeleton. Importantly, 3 pathways, including regulation of actin cytoskeleton pathway, pathways in cancer, and the B cell receptor signaling pathway were linked by inositol phosphate metabolism based on crosstalk analysis of Gene Ontology relationships among pathways. All of these pathways have been demonstrated to participate in cytoskeleton dynamics. These findings might provide valuable insights into cytoskeleton dynamic abnormalities in destrin mutations of corneal diseases. PMID:24782051

Xu, J N; Liu, X; Wang, H; Hu, C M; Luo, Q H; Zhou, Q Q

2014-01-01

215

De Novo Mutations in Ataxin-2 Gene and ALS Risk  

PubMed Central

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

Laffita-Mesa, Jose Miguel; Rodriguez Pupo, Jorge Michel; Moreno Sera, Raciel; Vazquez Mojena, Yaimee; Kouri, Vivian; Laguna-Salvia, Leonides; Martinez-Godales, Michael; Valdevila Figueira, Jose A.; Bauer, Peter O.; Rodriguez-Labrada, Roberto; Zaldivar, Yanetza Gonzalez; Paucar, Martin; Svenningsson, Per; Perez, Luis Velazquez

2013-01-01

216

Endemic polycythemia in Russia: mutation in the VHL gene.  

PubMed

Chuvash polycythemia (CP) is an autosomal recessive condition that is endemic in the Russian mid-Volga River region of Chuvashia. We previously found that CP patients may have increased serum erythropoietin (EPO) levels, ruled out linkage to both the EPO and EPO receptor (EPOR) gene loci, and hypothesized that the defect may lie in the oxygen homeostasis pathway. We now report a study of five multiplex Chuvash families which confirms that CP is associated with significant elevations of serum EPO levels and rules out a location for the CP gene on chromosome 11 as had been reported by other investigators or a mutation of the HIF-1 alpha gene. Using a genome-wide screen, we localized a region on chromosome 3 with a LOD score >2. After sequencing three candidate genes, we identified a C to T transition at nucleotide 598 (an R200W mutation) in the von Hippel-Lindau (VHL) gene. The VHL protein (pVHL) downregulates the alpha subunit of hypoxia-inducible factor 1 (HIF-1 alpha), the main regulator of hypoxia adaptation, by targeting the protein for degradation. In the simplest scenario, disruption of pVHL function causes a failure to degrade HIF-1 alpha resulting in accumulation of HIF-1 alpha, upregulation of downstream target genes such as EPO, and the clinical manifestation of polycythemia. These findings strongly suggest that CP is a congenital disorder of oxygen homeostasis. PMID:11987242

Ang, Sonny O; Chen, Hua; Gordeuk, Victor R; Sergueeva, Adelina I; Polyakova, Lydia A; Miasnikova, Galina Y; Kralovics, Robert; Stockton, David W; Prchal, Josef T

2002-01-01

217

Mutational Analysis of Angiogenin Gene in Parkinson's Disease  

PubMed Central

Mutations in the angiogenic factor, angiogenin (ANG), have been identified in patients with both familial and sporadic amyotrophic lateral sclerosis (ALS) and are thought to have a neuroprotective function. Parkinsonism has been noted in kindreds with ANG mutations and variants in the ANG gene have been found to associate with PD in two Caucasian populations. We therefore hypothesized that mutations in ANG may also contribute to idiopathic Parkinson's disease (PD). We sequenced ANG gene in a total of 1498 participants comprising 750 PD patients and 748 age/gender matched controls from Taiwan. We identified one novel synonymous substitution, c.C100T (p.L10L), in a single heterozygous state in one PD patient, which was not observed in controls. The clinical phenotypes and [99mTc]-TORDAT-SPECT images of the p.L10L carrier were similar to that seen in idiopathic PD. In addition, we also identified one common variant, c.T330G (p.G110G, rs11701), which was previously reported to associate with PD risk in Caucasians. However, the frequency of TG/GG genotype was comparable between PD cases and controls (odds ratio: 0.85, 95% confidence interval: 0.29–2.55, P?=?0.78). Our results did not support that ANG rs11701 variant is a genetic risk factor for PD in our population. We conclude that mutations in ANG are not a common cause for idiopathic PD. PMID:25386690

Chen, Meng-Ling; Wu, Ruey-Meei; Tai, Chun-Hwei; Lin, Chin-Hsien

2014-01-01

218

Mutation profile of BBS genes in Iranian patients with Bardet-Biedl syndrome: genetic characterization and report of nine novel mutations in five BBS genes.  

PubMed

Bardet-Biedl syndrome (BBS) is a rare ciliopathy disorder that is clinically and genetically heterogeneous with 18 known genes. This study was performed to characterize responsible genes and mutation spectrum in a cohort of 14 Iranian families with BBS. Sanger sequencing of the most commonly mutated genes (BBS1, BBS2 and BBS10) accounting for ?50% of BBS patients determined mutations only in BBS2, including three novel mutations. Next, three of the remaining patients were subjected to whole exome sequencing with 96% at 20 × depth of coverage that revealed novel BBS4 mutation. Observation of no mutation in the other patients represents the possible presence of novel genes. Screening of the remaining patients for six other genes (BBS3, BBS4, BBS6, BBS7, BBS9 and BBS12) revealed five novel mutations. This result represents another indication for the genetic heterogeneity of BBS and extends the mutational spectrum of the disease by introducing nine novel mutations in five BBS genes. In conclusion, although BBS1 and BBS10 are among the most commonly mutated genes in other populations like Caucasian, these two seem not to have an important role in Iranian patients. This suggests that a different strategy in molecular genetics diagnostic approaches in Middle Eastern countries such as Iran should be considered. PMID:24849935

Fattahi, Zohreh; Rostami, Parvin; Najmabadi, Amin; Mohseni, Marzieh; Kahrizi, Kimia; Akbari, Mohammad Reza; Kariminejad, Ariana; Najmabadi, Hossein

2014-07-01

219

Autosomal Recessive Retinitis Pigmentosa and E150K Mutation in the Opsin Gene*S  

E-print Network

Autosomal Recessive Retinitis Pigmentosa and E150K Mutation in the Opsin Gene*S Received with an autosomal dominant (adRP), autosomal recessive (arRP), or X-linked pattern of inheritance. Although to be associated with autosomal recessive retinitis pigmentosa (arRP). The first reported case of arRP associated

Palczewski, Krzysztof

220

Human lysozyme gene mutations cause hereditary systemic amyloidosis  

Microsoft Academic Search

HEREDITARY non-neuropathic systemic amyloidosis (Ostertag-type)1 is a rare autosomal dominant disease in which amyloid deposition in the viscera is usually fatal by the fifth decade. In some families it is caused by mutations in the apolipoprotein AI gene2,3 but in two unrelated English families under our care the amyloid deposits did not contain apoAI, despite a report that this may

M. B. Pepys; P. N. Hawkins; D. R. Booth; D. M. Vigushin; G. A. Tennent; A. K. Soutar; N. Totty; O. Nguyen; C. C. F. Blake; C. J. Terry; T. G. Feest; A. M. Zalin; J. J. Hsuan

1993-01-01

221

Optimization of gene sequences under constant mutational pressure and selection  

NASA Astrophysics Data System (ADS)

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.

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

1999-12-01

222

Inherited Mutations in Breast Cancer Genes—Risk and Response  

Microsoft Academic Search

Germ-line mutations in BRCA1 and BRCA2 confer a high risk of developing breast cancer. They account, however, for only 40% of strongly familial breast cancer cases.\\u000a Intensive genome-wide searches for other highly-penetrant BRCA genes that, individually account for a sizeable fraction of the remaining heritability has not identified any plausible candidates.\\u000a The “missing heritability” is thought to be due to

Andrew Y. Shuen; William D. Foulkes

2011-01-01

223

Mutations in Known Genes Account for 58% of Autosomal Dominant Retinitis Pigmentosa (adRP)  

Microsoft Academic Search

Inherited retinal diseases such as autosomal dominant retinitis pigmentosa (adRP) are strikingly complex, with mutations in\\u000a many different genes causing the same disease, with many different mutations in each gene, and with different clinical consequences\\u000a resulting from the same mutation, even within the same family. for example, mutations in sixteen genes are known to cause\\u000a adRP and an additional two

Stephen P. Daiger; Lori S. Sullivan; Anisa I. Gire; David G. Birch; John R. Heckenlively; Sara J. Bowne

224

The FBN2 gene: new mutations, locus-specific database (Universal Mutation Database FBN2), and genotype-phenotype correlations.  

PubMed

Congenital contractural arachnodactyly (CCA) is an extremely rare disease, due to mutations in the FBN2 gene encoding fibrillin-2. Another member of the fibrillin family, the FBN1 gene, is involved in a broad phenotypic continuum of connective-tissue disorders including Marfan syndrome. Identifying not only what is in common but also what differentiates these two proteins should enable us to better comprehend their respective functions and better understand the multitude of diseases in which these two genes are involved. In 1995 we created a locus-specific database (LSDB) for FBN1 mutations with the Universal Mutation Database (UMD) tool. To facilitate comparison of identified mutations in these two genes and search for specific functional areas, we created an LSDB for the FBN2 gene: the UMD-FBN2 database. This database lists 26 published and six newly identified mutations that mainly comprise missense and splice-site mutations. Although the number of described FBN2 mutations was low, the frequency of joint dislocation was significantly higher with missense mutations when compared to splice site mutations. PMID:18767143

Frédéric, Melissa Yana; Monino, Christine; Marschall, Christoph; Hamroun, Dalil; Faivre, Laurence; Jondeau, Guillaume; Klein, Hanns-Georg; Neumann, Luitgard; Gautier, Elodie; Binquet, Christine; Maslen, Cheryl; Godfrey, Maurice; Gupta, Prateek; Milewicz, Dianna; Boileau, Catherine; Claustres, Mireille; Béroud, Christophe; Collod-Béroud, Gwenaëlle

2009-02-01

225

Methylenetetrahydrofolate reductase gene variants and antipsychotic-induced weight gain and metabolic disturbances.  

PubMed

Weight gain and metabolic disturbances represent serious side-effects in antipsychotic (AP) treatment, particularly with clozapine and olanzapine. The methylenetetrahydrofolate reductase (MTHFR) gene is a key determinant in the folate metabolism and previous studies reported a significant effect on AP-induced weight gain and related metabolic abnormalities. Thus, we investigated MTHFR gene variants and changes in several important metabolic parameters in AP-treated patients. In this study, two functional MTHFR polymorphisms, rs1801133 (C677T) and rs1801131 (A1298C), were investigated for changes in weight and metabolic parameters. Genotypic associations were evaluated in a large population (n = 347 including 66 first episode psychosis, FEP patients) treated mostly with clozapine and olanzapine. We did not detect any genotypic association with weight changes (p > 0.05) in our total sample and in the sample refined for ancestry and medication. In our allelic analyses, we observed a trend for the 677-C allele to be associated with weight gain in the total sample (p = 0.03). This effect appeared to be driven by the FEP patients where those carrying the C-allele gained, on average, twice as much weight. Exploratory analyses revealed a significant association between the C677T and the A1298C polymorphism with HDL cholesterol serum levels in patients (p = 0.031). Overall we did not detect a major effect of two functional MTHFR gene variants and AP-induced weight gain. However, our findings suggest an effect of the C677T polymorphism in FEP patients and changes in weight and cholesterol levels. Further investigations in a larger sample are required. PMID:24725652

Kao, A C C; Rojnic Kuzman, M; Tiwari, A K; Zivkovic, M V; Chowdhury, N I; Medved, V; Kekin, I; Zai, C C; Lieberman, J A; Meltzer, H Y; Bozina, T; Bozina, N; Kennedy, J L; Sertic, J; Müller, D J

2014-07-01

226

Analysis of gene mutations among South Indian patients with maple syrup urine disease: identification of four novel mutations.  

PubMed

Maple syrup urine disease (MSUD) is predominantly caused by mutations in the BCKDHA, BCKDHB and DBT genes, which encode for the E1alpha, E1beta and E2 subunits of the branched-chain alpha-keto acid dehydrogenase complex, respectively. Because disease causing mutations play a major role in the development of the disease, prenatal diagnosis at gestational level may have significance in making decisions by parents. Thus, this study was aimed to screen South Indian MSUD patients for mutations and assess the genotype-phenotype correlation. Thirteen patients diagnosed with MSUD by conventional biochemical screening such as urine analysis by DNPH test, thin layer chromatography for amino acids and blood amino acid quantification by HPLC were selected for mutation analysis. The entire coding regions of the BCKDHA, BCKDHB and DBT genes were analyzed for mutations by PCR-based direct DNA sequencing. BCKDHA and BCKDHB mutations were seen in 43% of the total ten patients, while disease-causing DBT gene mutation was observed only in 14%. Three patients displayed no mutations. Novel mutations were c.130C>T in BCKDHA gene, c. 599C>T and c.121_122delAC in BCKDHB gene and c.190G>A in DBT gene. Notably, patients harbouring these mutations were non-responsive to thiamine supplementation and other treatment regimens and might have a worse prognosis as compared to the patients not having such mutations. Thus, identification of these mutations may have a crucial role in the treatment as well as understanding the molecular mechanisms in MSUD. PMID:24772966

Narayanan, M P; Menon, Krishnakumar N; Vasudevan, D M

2013-10-01

227

[Analysis of mutations in the phenylalanine hydroxylase gene in Ukrainian families at high risk for phenylketonuria].  

PubMed

The data on analysis of phenylalanine hydroxilase (PAH) gene mutations in 39 phenylketonuria (PKU) families from Ukraine are presented. Obtained results indicate that the most common mutation observed in the Ukrainian population is R408W mutation (66.6%). Besides two minor mutations R158Q (2.6%) and Y414C (1.25%) were revealed. PMID:11391893

Nechiporenko, M V; Lalivshits, L A

2000-01-01

228

Atrichia Caused by Mutations in the Vitamin D Receptor Gene is a Phenocopy of Generalized Atrichia Caused by Mutations in the Hairless Gene  

Microsoft Academic Search

Generalized atrichia with papules is a rare disorder characterized by loss of hair shortly after birth and development of cutaneous cysts. Mutations in the hairless gene (HR) cause this phenotype in both mouse and human. Here we present a case of atrichia with papules in a patient with a normal HAIRLESS gene but with mutations in both alleles of the

Jeffrey Miller; Karima Djabali; Tai Chen; Yaping Liu; Michael Ioffreda; Stephen Lyle; Angela M. Christiano; Michael Holick; George Cotsarelis

2001-01-01

229

Mutations and a polymorphism in the tuberin gene  

SciTech Connect

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.

Northup, H.; Rodriguez, J.A.; Au, K.S.; Rodriguez, E. [Univ. of Texas Medical School, Houston, TX (United States)

1994-09-01

230

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

PubMed

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. PMID:24856830

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

2014-06-01

231

Cohesin gene mutations in tumorigenesis: from discovery to clinical significance  

PubMed Central

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

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

2014-01-01

232

Methylenetetrahydrofolate reductase (MTHFR) 677C>T gene polymorphism as a possible factor for reducing clinical severity of psoriasis  

PubMed Central

Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme in homocysteine/methionine metabolism. It catalysis the formation of 5-methyltetrahydrofolate (5-methyl-THF), which is the methyl donor for synthesis of methionine from homocysteine (Hcy). Decreases in folate consumption due to MTHFR polymorphism may affect production rate of keratinocytes of which had faster reproduction rates with a continuous DNA turnover and this may affect the clinical picture of psoriasis. This study aimed to investigate correlation of C677T polymorphisms in the MTHFR gene with severity of psoriasis and to evaluate the status of plasma Hcy, folate and vitamin B12 levels in patient with chronic plaque psoriasis. The study included 60 patients with chronic plaque psoriasis. The C677T polymorphisms were genotyped using PCR (Qiagen). Psoriasis Area and Severity Index (PASI) score below 7 was defined as mild, between 7 and 12 as moderate, and above 12 as severe disease. There was a significant difference between the severity of disease classification (p<0.05) with respect to the C677T polymorphism in the MTHFR gene. Severe involvement (PASI score >12) was observed in 38.46% of wild type (CC), but only 12.50% of homozygote (TT) and 7.69% of heterozygote (CT) patients. Significant differences between gene polymorphism and Hcy levels were noted in TT and CT genotypes respectively (p=0.025 and p=0.040). Plasma Hcy, folate and vitamin B12 levels were not correlated with the PASI score. Our data indicate a possible correlation of MTHFR polymorphism with severity of psoriasis. PMID:24753765

Karabacak, Ercan; Aydin, Ersin; Ozcan, Omer; Dogan, Bilal; Gultepe, Mustafa; Cosar, Alpaslan; Muftuoglu, Tuba

2014-01-01

233

40 CFR 798.5300 - Detection of gene mutations in somatic cells in culture.  

Code of Federal Regulations, 2011 CFR

...CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798.5300 Detection of gene mutations in somatic...kinase locus in L5178Y mouse lymphoma cells. I. Application to genetic toxicology testing,” Mutation Research,...

2011-07-01

234

U Penn researchers classify gene mutations in a children's cancer that may point to improved treatments  

Cancer.gov

Oncology researchers studying gene mutations in the childhood cancer neuroblastoma are refining their diagnostic tools to predict which patients are more likely to respond to drugs called ALK inhibitors that target such mutations.

235

BCS1L gene mutation causing GRACILE syndrome: case report.  

PubMed

GRACILE syndrome is a rare autosomal recessive disease characterized by fetal growth retardation, Fanconi type aminoaciduria, cholestasis, iron overload, profound lactic acidosis, and early death. It is caused by homozygosity for a missense mutation in the BCS1L gene. The BCS1L gene encodes a chaperone responsible for assembly of respiratory chain complex III. Here we report that a homozygous mutation c.296C > T (p.P99L), in the first exon of BCS1L gene found in an affected 2-month-old boy of asymptomatic consanguineous parents results in GRACILE syndrome. This genotype is associated with a severe clinical presentation. So far no available treatments have changed the fatal course of the disease, and the metabolic disturbance responsible is still not clearly identified. Therefore, providing prenatal diagnosis in families with previous affected infants is of major importance. Mitochondrial disorders are an extremely heterogeneous group of diseases sharing, in common, the fact that they all ultimately impair the function of the mitochondrial respiratory chain. A clinical picture with fetal growth restriction, postnatal lactacidosis, aminoaciduria, hypoglycemia, coagulopathy, elevated liver enzymes, and cholestasis should direct investigations on mitochondrial disorder. PMID:24655110

Kasapkara, Çi?dem Seher; Tümer, Leyla; Ezgü, Fatih Suheyl; Küçükçongar, Aynur; Hasano?lu, Alev

2014-07-01

236

High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands.  

PubMed

Mutations in four genes encoding subunits or cofactors of succinate dehydrogenase (SDH) cause hereditary paraganglioma and pheochromocytoma syndromes. Mutations in SDHB and SDHD are generally the most common, whereas mutations in SDHC and SDHAF2 are far less frequently observed. A total of 1045 DNA samples from Dutch paraganglioma and pheochromocytoma patients and their relatives were analyzed for mutations of SDHB, SDHC, SDHD or SDHAF2. Mutations in these genes were identified in 690 cases, 239 of which were index cases. The vast majority of mutation carriers had a mutation in SDHD (87.1%). The second most commonly affected gene was SDHAF2 (6.7%). Mutations in SDHB were found in only 5.9% of samples, whereas SDHC mutations were found in 0.3% of samples. Remarkably, 69.1% of all carriers of a mutation in an SDH gene in the Netherlands can be attributed to a single founder mutation in SDHD, c.274G>T and p.Asp92Tyr. Moreover, 88.8% of all SDH mutation carriers carry one of just six Dutch founder mutations in SDHB, SDHD and SDHAF2. The dominance of SDHD mutations is unique to the Netherlands, contrasting with the higher prevalence of SDHB mutations found elsewhere. In addition, we found that most SDH mutation-related paragangliomas-pheochromocytomas in the Netherlands can be explained by only six founder mutations in SDHAF2, SDHB and SDHD. The findings underline the regional differences in the SDH mutation spectrum, differences that should be taken into account in the development of effective screening protocols. The results show the crucial role that demographic factors play in the frequency of gene mutations. PMID:21348866

Hensen, E F; van Duinen, N; Jansen, J C; Corssmit, E P M; Tops, C M J; Romijn, J A; Vriends, A H J T; van der Mey, A G L; Cornelisse, C J; Devilee, P; Bayley, J P

2012-03-01

237

Mutation in a reporter gene depends on proximity to and transcription of immunoglobulin variable transgenes.  

PubMed Central

Somatic mutation in immunoglobulin genes is localized to a 2-kilobase region of DNA surrounding and including rearranged variable (V), diversity, and joining (J) gene segments encoding heavy and light chains. To examine the structural basis for targeted mutation, we developed an assay to score mutation on plasmid substrates by using a reporter gene: a bacterial gene encoding an amber-suppressor tRNA molecule was placed 3' of a rearranged kappa VJ gene within the boundaries of mutation. The reporter gene is exquisitely suited for mutational analysis because it is only 200 base pairs (bp), which should not greatly disrupt structure of the immunoglobulin locus, and gene function depends on secondary structure, which means mutation can be scored in many different nucleotide positions. The plasmid was used to make transgenic mice, which were then immunized. The shuttle vector was retrieved by plasmid rescue into an indicator strain of Escherichia coli that contained an amber mutation in its beta-galactosidase gene. Integrity of the tRNA molecule was monitored by colony color, which permitted many transformants to be screened visually. Mutations were not seen in DNA from a transfected B-cell line grown in vitro or in DNA from nonlymphoid tissue of transgenic mice, indicating that the reporter gene was stable during cell division and DNA manipulations. However, when the transgenic mice were immunized, DNA from splenic B cells contained point mutations in the reporter gene at a frequency of 10(-3) per transformant. Sequence analysis of 17 mutated transgenes revealed that the mutations were 1- and 2-bp deletions in the tRNA gene, and one plasmid had an additional 2-bp deletion in the V gene. In contrast, previous studies have shown that mutations in endogenous VJ genes are predominantly nucleotide substitutions and have only 6% deletions. Two other plasmid constructs were analyzed in transgenic lines: no mutations were found when the tRNA gene was placed distal to the VJ gene, and no mutations were seen when the immunoglobulin promoter was deleted. Although we lack direct evidence that the deletions in the tRNA gene are caused by the same mechanism that acts on VJ genes, we have shown that mutations in this assay occur in a manner consistent with immunoglobulin-specific mutation in that they are found in splenic B cells and not in tail tissue, depend on position next to the VJ gene, and require transcription of the VJ gene. Images PMID:1905016

Umar, A; Schweitzer, P A; Levy, N S; Gearhart, J D; Gearhart, P J

1991-01-01

238

Using protein complexes to predict phenotypic effects of gene mutation  

Microsoft Academic Search

Background  Predicting the phenotypic effects of mutations is a central goal of genetics research; it has important applications in elucidating\\u000a how genotype determines phenotype and in identifying human disease genes.\\u000a \\u000a \\u000a \\u000a \\u000a Results  Using a wide range of functional genomic data from the yeast Saccharomyces cerevisiae, we show that the best predictor of a protein's knockout phenotype is the knockout phenotype of other proteins

Hunter B Fraser; Joshua B Plotkin

2007-01-01

239

No Gene-Specific Optimization of Mutation Rate in Escherichia coli  

E-print Network

selection, E. coli. Because mutation is the ultimate source of genetic variation and evolution, accurately to approximately 0.3 among E. coli genes (Martincorena and Luscombe 2013). Assuming that Áf between genes of multiple genes with similar fractions of deleterious mutations. Analyzing published genome sequences of E

Zhang, Jianzhi

240

Identifying photoreceptors in blind eyes caused by RPE65 mutations: Prerequisite for human gene therapy success  

Microsoft Academic Search

Mutations in RPE65, a gene essential to normal operation of the visual (retinoid) cycle, cause the childhood blindness known as Leber congenital amaurosis (LCA). Retinal gene therapy restores vision to blind canine and murine models of LCA. Gene therapy in blind humans with LCA from RPE65 mutations may also have potential for success but only if the retinal photoreceptor layer

Samuel G. Jacobson; Tomas S. Aleman; Artur V. Cideciyan; Alexander Sumaroka; Sharon B. Schwartz; Elizabeth A. M. Windsor; Elias I. Traboulsi; Elise Heon; Steven J. Pittler; Ann H. Milam; Albert M. Maguire; Krzysztof Palczewski; Edwin M. Stone; Jean Bennett

2005-01-01

241

NPHS1 gene mutations in children with Nephrotic Syndrome in northwest Iran.  

PubMed

Idiopathic Nephrotic Syndrome (NS) is the prevalent glomerular disease in childhood. It is treated with steroid and according to its response is defined as steroid sensitive NS (SSNS) and steroid resistance NS (SRNS). Mutation in NPHS 1 gene is reported in children with SRNS and few cases of SSNS. The aim of current study is to evaluate NPHS1 gene mutations in idiopathic NS (SSNS and SSRS) in Northwest Iran. In this cross-sectional analytic study 20 children from Azeri population in Iran with idiopathic NS including 10 cases with SRNS (5 male and 5 female) and 10 cases with SSNS (7 male and 3 female) were evaluated for NPHS1 gene mutations. DNA was extracted from peripheral blood and NPHSI gene analysis was performed by PCR and direct sequencing method with the use of standard primers. Mutations in NPHS1 gene occurred in 6 cases of SSNS including 3 heterozygous and 3 homozygous mutations and in 8 cases of SRNS including 5 homozygous, one compound heterozygous and 2 heterozygous mutations. Overall 6 different mutations were detected in NPHS1 gene: one deletion, one insertion, 3 missense and one nonsense mutations. Mutations in exon 4 and 27 were only seen in SRNS patients. Mutations in NPHS1 gene could occur in both SRNS and SSNS patients; however, considering higher incidence of heterozygous mutations in SSNS, the existence of milder phenotype in these cases would be the reason for steroid response. PMID:24498843

Behbahan, A G; Poorshiri, B; Mortazavi, F; Khaniani, M S; Derakhshan, S M

2013-09-01

242

Novel and convenient methods for Candida tropicalis gene disruption using a mutated hygromycin B resistance gene  

Microsoft Academic Search

We established a novel and convenient method to construct a ura3 strain (ura3\\/ura3) of the asporogenous and diploid yeast, Candida tropicalis, that produces dicarboxylic acid. One copy of the URA3 gene was disrupted using a mutated hygromycin B resistance gene (HYG#). The obtained hygromycin-resistant strain was further transformed with a URA3 disruption cassette and selected on a plate containing 5-fluoroorotic

Akihiro Hara; Mami Arie; Tamotsu Kanai; Toru Matsui; Hitoshi Matsuda; Keizo Furuhashi; Mitsuyoshi Ueda; Atsuo Tanaka

2001-01-01

243

[Acquisition of the drug resistance and Helicobacter pylori gene mutation].  

PubMed

The currently recommended regimen in Japan is a proton pump inhibitor-based triple therapy with two of the antibiotics between clarithromycin, amoxicillin and metronidazole. However, recent years have witnessed a decrease in the rate of eradication due to antimicrobial resistance. Resistance mechanisms of H. pylori are explained by the occurrence of mutations in genomic genes, which may correspond to the 23S rRNA gene in clarithromycin, the pbp1A in amoxicillin, and the rdxA in metronidazole, gyrA in levofloxacin. The resistance of H. pylori strains to clarithromycin is currently estimated at about 30% in Japan, while the resistant rates to metoronidazole and amoxicillin are quite low. The resistant rates of each antibiotics may increase in future, so we need to observe those changes. PMID:19999127

Okimoto, Tadayoshi; Murakami, Kazunari

2009-12-01

244

Mutations of the p53 Gene in Nasal NK\\/T-Cell Lymphoma  

Microsoft Academic Search

Mutations of the p53 tumor suppressor gene are reported in various kinds of malignancies including lymphomas. However, p53 gene mutations in nasal NK\\/T-cell lymphoma have not been reported because most parts of tumors are necrotic and a small amount of living tumor tissues is available for the molecular study. Expression and mutations of the p53 gene were examined in the

Ting Li; Tadashi Hongyo; Mukh Syaifudin; Taisei Nomura; Zhiming Dong; Norihisa Shingu; Shizuo Kojya; Shin-ichi Nakatsuka; Katsuyuki Aozasa

2000-01-01

245

Disease-Causing Mutations in Genes of the Complement System  

PubMed Central

Recent studies have revealed profound developmental consequences of mutations in genes encoding proteins of the lectin pathway of complement activation, a central component of the innate immune system. Apart from impairment of immunity against microorganisms, it is known that hereditary deficiencies of this system predispose one to autoimmune conditions. Polymorphisms in complement genes are linked to, for example, atypical hemolytic uremia and age-dependent macular degeneration. The complement system comprises three convergent pathways of activation: the classical, the alternative, and the lectin pathway. The recently discovered lectin pathway is less studied, but polymorphisms in the plasma pattern-recognition molecule mannan-binding lectin (MBL) are known to impact its level, and polymorphisms in the MBL-associated serine protease-2 (MASP-2) result in defects of complement activation. Recent studies have described roles outside complement and immunity of another MBL-associated serine protease, MASP-3, in the etiology of 3MC syndrome, an autosomal-recessive disorder involving a spectrum of developmental features, including characteristic facial dysmorphism. Syndrome-causing mutations were identified in MASP1, encoding MASP-3 and two additional proteins, MASP-1 and MAp44. Furthermore, an association was discovered between 3MC syndrome and mutations in COLEC11, encoding CL-K1, another molecule of the lectin pathway. The findings were confirmed in zebrafish, indicating that MASP-3 and CL-K1 underlie an evolutionarily conserved pathway of embryonic development. Along with the discovery of a role of C1q in pruning synapses in mice, these recent advances point toward a broader role of complement in development. Here, we compare the functional immunologic consequences of “conventional” complement deficiencies with these newly described developmental roles. PMID:21664996

Degn, S?ren E.; Jensenius, Jens C.; Thiel, Steffen

2011-01-01

246

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

PubMed

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

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

1990-05-01

247

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

PubMed Central

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

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

1990-01-01

248

The Berkeley Drosophila Genome Project Gene Disruption Project: Single P-Element Insertions Mutating 25% of Vital Drosophila Genes  

Microsoft Academic Search

A fundamental goal of genetics and functional genomics is to identify and mutate every gene in model organisms such as Drosophila melanogaster. The Berkeley Drosophila Genome Project (BDGP) gene disruption project generates single P-element insertion strains that each mutate unique genomic open reading frames. Such strains strongly facilitate further genetic and molecular studies of the disrupted loci, but it has

Allan C. Spradling; Dianne Stern; Amy Beaton; E. Jay Rhem; Todd Laverty; Nicole Mozden; Sima Misra; Gerald M. Rubin

249

A meta-analysis of genotypes and haplotypes of methylenetetrahydrofolate reductase gene polymorphisms in breast cancer.  

PubMed

The association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and breast cancer risk has been extensively explored, but their results are conflicting rather than conclusive. To derive a more precise estimation, we carried out not only an updated meta-analysis but also a combined analysis based on all the available studies estimating the association between MTHFR C677T and/or A1298C and breast cancer risk. With respect to C677T polymorphism, the results suggested that 677T allele was associated with significantly elevated breast cancer risk in overall analysis (T vs. C: OR 1.073, 95 % CI 1.028-1.120; TT vs. CC: OR 1.177, 95 % CI 1.072-1.293; TT vs. CC + CT: OR 1.175, 95 % CI 1.073-1.288); Stratifying by ethnicity, significantly increased risk was only found in East Asians (T vs. C: OR 1.150, 95 % CI 1.039-1.273; TT vs. CC: OR 1.441, 95 % CI 1.145-1.814; TT vs. CC + CT: OR 1.413, 95 % CI 1.148-1.739); When stratified by menopausal status, statistically significant association was found for postmenopausal women (CT + TT vs. CC: OR 1.092, 95 % CI 1.011-1.179). In regard to A1298C polymorphism, no significant associations were found between the polymorphism and breast cancer risk. With respect to MTHFR haplotypes, significantly elevated breast cancer risk was associated with 677T-1298C for overall result (OR 1.498, 95 % CI 1.143-1.962) and for Caucasians (OR 2.088, 95 % CI 1.277-3.416) when compared with 677C-1298A; Haplotype 677C-1298C might provide higher protection than 677C-1298A in East Asians (OR 0.840, 95 % CI 0.742-0.949). The combined genotypes for C677T and A1298C produced a significant OR for the 677TT/1298AC relative to 677CC/1298AA in overall population (OR 2.047, 95 % CI 1.275-3.288); When stratified by ethnicity, significant ORs were only found for East Asians (677CC/1298CC vs. 677CC/1298AA: OR 0.686, 95 % CI 0.478-0.985; 677TT/1298AC vs. 677CC/1298AA: OR 2.181, 95 % CI 1.179-4.035). The findings suggest that the MTHFR C677T polymorphism but not A1298C, and some variants on their combined genotypes or haplotypes may be involved with the development of breast cancer. PMID:24973876

Zhong, Shanliang; Chen, Zhiyuan; Yu, Xinnian; Li, Wenjing; Tang, Jinhai; Zhao, Jianhua

2014-09-01

250

Spinal Muscular Atrophy with Pontocerebellar Hypoplasia Is Caused by a Mutation in the VRK1 Gene  

E-print Network

REPORT Spinal Muscular Atrophy with Pontocerebellar Hypoplasia Is Caused by a Mutation in the VRK1 and identified a nonsense mutation in the vaccinia-related kinase 1 gene (VRK1) as a cause of SMA-PCH. VRK1, one]) accounts for 80%­90% of all SMA cases and is primarily caused by recessive mutations in SMN1 (MIM 600354

Friedman, Nir

251

Mutation Hotspots Due to Sunlight in the p53 Gene of Nonmelanoma Skin Cancers  

Microsoft Academic Search

To identify the sites in the p53 tumor suppressor gene most susceptible to carcinogenic mutation by sunlight, the entire coding region of 27 basal cell carcinomas (BCCs) of the skin was sequenced. Fifty-six percent of tumors contained mutations, and these were UV-like: primarily CC --> TT or C --> T changes at dipyrimidine sites. Such mutations can alter more than

Annemarie Ziegler; David J. Leffell; Subrahmanyam Kunala; Harsh W. Sharma; Mae Gailani; Jeffrey A. Simon; Alan J. Halperin; Howard P. Baden; Philip E. Shapiro; Allen E. Bale; Douglas E. Brash

1993-01-01

252

Rifampicin resistance and mutation of the rpoB gene in Mycobacterium tuberculosis  

Microsoft Academic Search

Using 39 clinical isolates of Mycobacterium tuberculosis strains with a broad range of susceptibility to rifampicin, we examined the relationship between the degree of resistance to rifampicin and mutational sites of the rpoB gene. All rifampicin-resistant strains had missense mutations. Twenty strains (95%) had a mutation in the cluster I region, which has also been reported in Escherichia coli [Jin

Hatsumi Taniguchi; Hironori Aramaki; Yoshihiko Nikaido; yasuo Mizuguchi; Masahiro Nakamura; Toshihiko Koga; Shin-ichi Yoshida

1996-01-01

253

Diaminodiphenylsulfone resistance of Mycobacterium leprae due to mutations in the dihydropteroate synthase gene  

Microsoft Academic Search

The nucleotide sequence analysis of the dihydropteroate synthase (DHPS) gene of six diaminodiphenylsulfone-resistant Mycobacterium leprae strains revealed that the mutation was limited at highly conserved amino acid residues 53 or 55. Though the mutation at amino acid residue 55 or its homologous site has been reported in other bacteria, the mutation at residue 53 is the first case in bacteria.

Masanori Kai; Masanori Matsuoka; Noboru Nakata; Shinji Maeda; Masaichi Gidoh; Yumi Maeda; Ken Hashimoto; Kazuo Kobayashi; Yoshiko Kashiwabara

1999-01-01

254

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

PubMed

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

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

255

A report of a national mutation testing service for the MEN1 gene: clinical presentations and implications for mutation testing  

PubMed Central

Introduction: Mutation testing for the MEN1 gene is a useful method to diagnose and predict individuals who either have or will develop multiple endocrine neoplasia type 1 (MEN 1). Clinical selection criteria to identify patients who should be tested are needed, as mutation analysis is costly and time consuming. This study is a report of an Australian national mutation testing service for the MEN1 gene from referred patients with classical MEN 1 and various MEN 1-like conditions. Results: All 55 MEN1 mutation positive patients had a family history of hyperparathyroidism, had hyperparathyroidism with one other MEN1 related tumour, or had hyperparathyroidism with multiglandular hyperplasia at a young age. We found 42 separate mutations and six recurring mutations from unrelated families, and evidence for a founder effect in five families with the same mutation. Discussion: Our results indicate that mutations in genes other than MEN1 may cause familial isolated hyperparathyroidism and familial isolated pituitary tumours. Conclusions: We therefore suggest that routine germline MEN1 mutation testing of all cases of "classical" MEN1, familial hyperparathyroidism, and sporadic hyperparathyroidism with one other MEN1 related condition is justified by national testing services. We do not recommend routine sequencing of the promoter region between nucleotides 1234 and 1758 (Genbank accession no. U93237) as we could not detect any sequence variations within this region in any familial or sporadic cases of MEN1 related conditions lacking a MEN1 mutation. We also suggest that testing be considered for patients <30 years old with sporadic hyperparathyroidism and multigland hyperplasia. PMID:15635078

Cardinal, J; Bergman, L; Hayward, N; Sweet, A; Warner, J; Marks, L; Learoyd, D; Dwight, T; Robinson, B; Epstein, M; Smith, M; Teh, B; Cameron, D; Prins, J

2005-01-01

256

Mutation screening of the DYT6/THAP1 gene in Serbian patients with primary dystonia.  

PubMed

Primary dystonia (PrD) is characterized by sustained muscle contractions, causing twisting and repetitive movements and abnormal postures. Besides DYT1/TOR1A gene, DYT6/THAP1 gene is the second gene known to cause primary pure dystonia. We screened 281 Serbian primary dystonia patients and 106 neurologically healthy control individuals for the GAG deletion in TOR1A gene and for mutations in THAP1 gene by direct sequencing. Nine subjects were found to have the GAG deletion in TOR1A gene. Four coding mutations, including two novel mutations, were identified in the THAP1 gene in five unrelated patients. Two mutations were missense, one was nonsense, and one was 24 bp duplication. None of the coding mutations were seen in 106 control individuals. In addition, one novel nucleotide change in the 5'UTR region of THAP1 gene was detected in two unrelated patients. The mutation frequency of THAP1 gene in Serbian patients with primary dystonia was 1.8 %, similar to the mutation frequency in other populations. Most of the patients reported here with THAP1 mutations had the clinical features of predominantly laryngeal or oromandibular dystonia. Our data expand the genotypic spectrum of THAP1 and strengthen the association with upper body involvement, including the cranial and cervical regions that are usually spared in DYT1-PrD. PMID:23180184

Dobri?i?, Valerija S; Kresojevi?, Nikola D; Svetel, Marina V; Jankovi?, Milena Z; Petrovi?, Igor N; Tomi?, Aleksandra D; Novakovi?, Ivana V; Kosti?, Vladimir S

2013-04-01

257

Free-Radical-Induced Mutation vs Redox Regulation: Costs and Benefits of Genes in Organelles  

E-print Network

Focus Free-Radical-Induced Mutation vs Redox Regulation: Costs and Benefits of Genes in Organelles -- Cytoplasmic genomes -- Gene transfer -- Redox regulation -- Free radical mutagenesis -- Nitrogen fixation, and the precursor polypep- tides are

Allen, John F.

258

Fabry disease: six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene.  

PubMed Central

Fabry disease, an X-linked recessive disorder of glycosphingolipid catabolism, results from the deficient activity of the lysosomal hydrolase, alpha-galactosidase. Southern hybridization analysis of the alpha-galactosidase gene in affected hemizygous males from 130 unrelated families with Fabry disease revealed six with different gene rearrangements and one with an exonic point mutation resulting in the obliteration of an Msp I restriction site. Five partial gene deletions were detected ranging in size from 0.4 to greater than 5.5 kb. Four of these deletions had breakpoints in intron 2, a region in the gene containing multiple Alu repeat sequences. A sixth genomic rearrangement was identified in which a region of about 8 kb, containing exons 2 through 6, was duplicated by a homologous, but unequal crossover event. The Msp I site obliteration, which mapped to exon 7, was detected in an affected hemizygote who had residual enzyme activity. Genomic amplification by the polymerase chain reaction and sequencing revealed that the obliteration resulted from a C to T transition at nucleotide 1066 in the coding sequence. This point mutation, the first identified in Fabry disease, resulted in an arginine356 to tryptophan356 substitution which altered the enzyme's kinetic and stability properties. The detection of these abnormalities provided for the precise identification of Fabry heterozygotes, thereby permitting molecular pedigree analysis in these families which revealed paternity exclusions and the first documented new mutations in this disease. Images PMID:2539398

Bernstein, H S; Bishop, D F; Astrin, K H; Kornreich, R; Eng, C M; Sakuraba, H; Desnick, R J

1989-01-01

259

A polymorphism but no mutations in the GADD45 gene in breast cancers  

Microsoft Academic Search

The p53 gene product is part of a pathway regulating growth arrest at the G1 checkpoint of the cell cycle. Mutation of other components of this pathway, including the products of the ataxia telangiectasia (AT), GADD45, mdm2, and p21WAF1\\/CIP1 genes may have effects comparable to mutations in the p53 gene. The GADD45 gene is induced by ionizing radiation and several

H. Blaszyk; A. Hartmann; S. S. Sommer; J. S. Kovach

1996-01-01

260

Effects of MTHFR gene polymorphism on the clinical and electrophysiological characteristics of migraine  

PubMed Central

Background It was previously shown that the MTHFR gene polymorphism correlated with an increased risk of migraine, particularly migraine with aura. The substitution of cytosine for thymine at the position 677 of the MTHFR gene leads to formation of the thermolabile form of the protein and development of hyperhomocysteinemia, which increases the probability of migraine. The purpose of this study was to determine whether the replacement of C677T in the gene MTHFR influenced any particular symptoms of the disease. Methods We have analyzed clinical and electrophysiological characteristics of 83 patients with migraine (migraine with aura (MA), 19 patients, and migraine without aura (MO), 64 patients, according to the ICHD-II (2003)) taking into account their genotypes of C677T variant of MTHFR. Results We have shown that MA was significantly more prevalent among the T-allele carriers (37.2%), as compared to the ?? genotype patients (0%), ? < 0.0001. Patients with TT genotype were not only more likely to have accompanying symptoms (significant differences were found only for photophobia), but also more sensitive to migraine attack triggers. In RP-VEP test results we observed a trend that the T-allele carriers were presented with the decreased N75/P100 amplitudes and a positive habituation index, as compared to the ?? genotype patients. Conclusions Thus, according to our data, the MTHFR genotypes are associated with several clinical and electrophysiological characteristics of migraine. PMID:23915182

2013-01-01

261

Mutation update for GNE gene variants associated with GNE myopathy.  

PubMed

The GNE gene encodes the rate-limiting, bifunctional enzyme of sialic acid biosynthesis, uridine diphosphate-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). Biallelic GNE mutations underlie GNE myopathy, an adult-onset progressive myopathy. GNE myopathy-associated GNE mutations are predominantly missense, resulting in reduced, but not absent, GNE enzyme activities. The exact pathomechanism of GNE myopathy remains unknown, but likely involves aberrant (muscle) sialylation. Here, we summarize 154 reported and novel GNE variants associated with GNE myopathy, including 122 missense, 11 nonsense, 14 insertion/deletions, and seven intronic variants. All variants were deposited in the online GNE variation database (http://www.dmd.nl/nmdb2/home.php?select_db=GNE). We report the predicted effects on protein function of all variants well as the predicted effects on epimerase and/or kinase enzymatic activities of selected variants. By analyzing exome sequence databases, we identified three frequently occurring, unreported GNE missense variants/polymorphisms, important for future sequence interpretations. Based on allele frequencies, we estimate the world-wide prevalence of GNE myopathy to be ?4-21/1,000,000. This previously unrecognized high prevalence confirms suspicions that many patients may escape diagnosis. Awareness among physicians for GNE myopathy is essential for the identification of new patients, which is required for better understanding of the disorder's pathomechanism and for the success of ongoing treatment trials. PMID:24796702

Celeste, Frank V; Vilboux, Thierry; Ciccone, Carla; de Dios, John Karl; Malicdan, May Christine V; Leoyklang, Petcharat; McKew, John C; Gahl, William A; Carrillo-Carrasco, Nuria; Huizing, Marjan

2014-08-01

262

Five novel mutations in the L1CAM gene in families with X linked hydrocephalus  

Microsoft Academic Search

Five novel mutations have been identified in the gene encoding L1CAM, a neural cell adhesion protein, in families with X linked hydrocephalus (XHC). Interestingly, all five mutations are in the evolutionarily highly conserved Ig-like domains of the protein. The two frameshift mutations (52insC and 955delG) and the nonsense mutation (Trp276Ter) most probably result in functional null alleles and complete absence

S M Gu; U Orth; A Veske; H Enders; K Klunder; M Schlosser; W Engel; E Schwinger; A Gal

1996-01-01

263

Identification of p53 Gene Mutations in Bladder Cancers and Urine Samples  

Microsoft Academic Search

Although bladder cancers are very common, little is known about their molecular pathogenesis. In this study, invasive bladder cancers were evaluated for the presence of gene mutations in the p53 suppressor gene. Of 18 tumors evaluated, 11 (61 percent) were found to have genetic alterations of p53. The alterations included ten point mutations resulting in single amino acid substitutions, and

David Sidransky; Andrew von Eschenbach; Yvonne C. Tsai; Peter Jones; Ian Summerhayes; Fray Marshall; Meera Paul; Pearl Green; Philip Frost; Bert Vogelstein

1991-01-01

264

[The MDR3 gene mutation: a rare cause of progressive familial intrahepatic cholestasis (PFIC)].  

PubMed

A 47-year old man complained about persistant pain and cholestasis 12-years after a cholescystectomy. In his family, all his brothers and sisters had cholecystectomy. Genetic explorations revealed a MDR3 gene mutation. All symptoms disappeared with a treatment by ursodesoxycholic acid. MDR3 gene mutation is to be researched in all cases of familial cholestasis. PMID:16199000

Maisonnette, F; Abita, T; Barriere, E; Pichon, N; Vincensini, J F; Descottes, B

2005-10-01

265

Functional characterization of novel mutations in the human cytochrome b gene  

Microsoft Academic Search

The great variability of the human mitochondrial DNA (mtDNA) sequence induces many difficulties in the search for its deleterious mutations. We illustrate these pitfalls by the analysis of the cytochrome b gene of 21 patients affected with a mitochondrial disease. Eighteen different sequence variations were found, five of which were new mutations. Extensive analysis of the cytochrome b gene of

Frédéric Legros; Evi Chatzoglou; Paule Frachon; Hélčne Ogier de Baulny; Pascal Laforęt; Claude Jardel; Catherine Godinot; Anne Lombčs

2001-01-01

266

Frequent Somatic Mutations of the APC Gene in Human Pancreatic Cancer 1  

Microsoft Academic Search

The APC (adenomatous polyposis coli) gene is responsible for famil- ial adenomatous polyposis and is also associated with the development of sporadic tumors of the colon and stomach. To investigate whether or not mutations of APC play any role in tumors arising in other organs, we examined somatic mutations of this gene in sporadic (nonfamilial) renal cell carcinomas, hepatocellular carcinomas,

Akira Horii; Shuichi Nakatsuru; Yasuo Miyoshi; Hiroki Nagase; Hiroshi Ando; Akio Yanagisawa; Eiju Tsuchiya; Yo Kato; Yusuke Nakamura

267

Mutation analysis of the NSD1 gene in patients with autism spectrum disorders and macrocephaly  

E-print Network

Mutation analysis of the NSD1 gene in patients with autism spectrum disorders and macrocephaly is an overgrowth syndrome characterized by macrocephaly, advanced bone age, characteristic facial features, and learning disabilities, caused by mutations or deletions of the NSD1 gene, located at 5q35. Sotos syndrome

268

A Fixed Point Analysis of a Gene Pool GA with Mutation Alden H. Wright  

E-print Network

A Fixed Point Analysis of a Gene Pool GA with Mutation Alden H. Wright Computer Science University This paper analyzes a recombina- tion/mutation/selection genetic algorithm that uses gene pool recombination grant GR/R47394. repeated applications of crossover is a population in link- age equilibrium (also known

Wright, Alden H.

269

A Fixed Point Analysis of a Gene Pool GA with Mutation Alden H. Wright #  

E-print Network

A Fixed Point Analysis of a Gene Pool GA with Mutation Alden H. Wright # Computer Science This paper analyzes a recombina­ tion/mutation/selection genetic algorithm that uses gene pool recombination by EPSRC grant GR/R47394. repeated applications of crossover is a population in link­ age equilibrium (also

Wright, Alden H.

270

Gene replacement without selection: regulated suppression of amber mutations in Escherichia coli  

Microsoft Academic Search

We have developed a method called ‘gene gorging’ to make precise mutations in the Escherichia coli genome at frequencies high enough (1–15%) to allow direct identification of mutants by PCR or other screen rather than by selection. Gene gorging begins by establishing a donor plasmid carrying the desired mutation in the target cell. This plasmid is linearized by in vivo

Christopher D. Herring; Jeremy D. Glasner; Frederick R. Blattner

2003-01-01

271

Leber congenital amaurosis due to RPE65 mutations and its treatment with gene therapy  

Microsoft Academic Search

Leber congenital amaurosis (LCA) is a rare hereditary retinal degeneration caused by mutations in more than a dozen genes. RPE65, one of these mutated genes, is highly expressed in the retinal pigment epithelium where it encodes the retinoid isomerase enzyme essential for the production of chromophore which forms the visual pigment in rod and cone photoreceptors of the retina. Congenital

Artur V. Cideciyan

2010-01-01

272

Novel mutations in TLR genes cause hyporesponsiveness to Mycobacterium avium subsp. paratuberculosis infection  

Microsoft Academic Search

BACKGROUND: Toll like receptors (TLR) play the central role in the recognition of pathogen associated molecular patterns (PAMPs). Mutations in the TLR1, TLR2 and TLR4 genes may change the ability to recognize PAMPs and cause altered responsiveness to the bacterial pathogens. RESULTS: The study presents association between TLR gene mutations and increased susceptibility to Mycobacterium avium subsp. paratuberculosis (MAP) infection.

Mangesh R Bhide; Rastislav Mucha; Ivan Mikula Jr; Lucia Kisova; Rostislav Skrabana; Michal Novak

2009-01-01

273

Identification of mutation sites on Delta12 desaturase genes from Mortierella alpina 1S-4 mutants.  

PubMed

The mutation sites on the Delta12 desaturase gene in Mortierella alpina Delta12 desaturase-defective mutants SR88, TM912, and Mut48 accumulating Mead acid were identified. Each mutation resulted in an amino acid replacement (H116Y and P166L) in the Delta12 desaturase gene from SR88 and Mut48, respectively. PMID:19217543

Sakuradani, Eiji; Abe, Takahiro; Matsumura, Kenji; Tomi, Akiko; Shimizu, Sakayu

2009-02-01

274

Identification of mutation sites on ?12 desaturase genes from Mortierella alpina 1S-4 mutants  

Microsoft Academic Search

The mutation sites on the ?12 desaturase gene in Mortierella alpina ?12 desaturase-defective mutants SR88, TM912, and Mut48 accumulating Mead acid were identified. Each mutation resulted in an amino acid replacement (H116Y and P166L) in the ?12 desaturase gene from SR88 and Mut48, respectively.

Eiji Sakuradani; Takahiro Abe; Kenji Matsumura; Akiko Tomi; Sakayu Shimizu

2009-01-01

275

Germline Mutations in Genes Within the MAPK Pathway Cause Cardio-facio-cutaneous Syndrome  

Microsoft Academic Search

Cardio-facio-cutaneous (CFC) syndrome is a sporadic developmental disorder involving characteristic craniofacial features, cardiac defects, ectodermal abnormalities, and developmental delay. We demonstrate that heterogeneous de novo missense mutations in three genes within the mitogen-activated protein kinase (MAPK) pathway cause CFC syndrome. The majority of cases (18 out of 23) are caused by mutations in BRAF, a gene frequently mutated in cancer.

Pablo Rodriguez-Viciana; Osamu Tetsu; William E. Tidyman; Anne L. Estep; Brenda A. Conger; Molly Santa Cruz; Frank McCormick; Katherine A. Rauen

2006-01-01

276

Unusual deep intronic mutations in the COL4A5 gene cause X linked Alport syndrome  

Microsoft Academic Search

The X-linked form of Alport syndrome is caused by mutations in the COL4A5 gene in Xq22. This large multiexonic gene has, in the past, been difficult to screen, with several studies detecting only about 50% of mutations. We report three novel intronic mutations that may, in part, explain this poor success rate and demonstrate that single base changes deep within

Kathy King; Frances A. Flinter; Vandana Nihalani; Peter M. Green

2002-01-01

277

Identification of mutation sites on delta5 desaturase genes from Mortierella alpina 1S-4 mutants.  

PubMed

The mutation sites on delta5 desaturase genes in delta5 desaturase-defective mutants derived from arachidonic acid-producing Mortierella alpina 1S-4 were identified. The mutations resulted in an amino acid replacement (G189E or W301Stop) and uncorrected transcription caused by recognition of an AG-terminal newly created on C207A gene mutation, resulting in low or no delta5 desaturase activity in these mutants. PMID:16233793

Abe, Takahiro; Sakuradani, Eiji; Ueda, Takuji; Shimizu, Sakayu

2005-03-01

278

Recurrent and founder mutations in the PMS2 gene  

PubMed Central

Germline mutations in PMS2 are associated with Lynch syndrome (LS), the most common known cause of hereditary colorectal cancer. Mutation detection in PMS2 has been difficult due to the presence of several pseudogenes, but a custom-designed long-range PCR strategy now allows adequate mutation detection. Many mutations are unique. However some mutations are observed repeatedly, across individuals not known to be related, due to the mutation being either recurrent, arising multiple times de novo at hot spots for mutations, or of founder origin, having occurred once in an ancestor. Previously, we observed 36 distinct mutations in a sample of 61 independently ascertained Caucasian probands of mixed European background with PMS2 mutations. Eleven of these mutations were detected in more than one individual not known to be related and of these, six were detected more than twice. These six mutations accounted for 31 (51%) ostensibly unrelated probands. Here we performed genotyping and haplotype analysis in four mutations observed in multiple probands and found two (c.137G>T and exon 10 deletion) to be founder mutations, one (c.903G>T) a probable founder, and one (c.1A>G) where founder mutation status could not be evaluated. We discuss possible explanations for the frequent occurrence of founder mutations in PMS2. PMID:22577899

Tomsic, Jerneja; Senter, Leigha; Liyanarachchi, Sandya; Clendenning, Mark; Vaughn, Cecily P.; Jenkins, Mark A.; Hopper, John L.; Young, Joanne; Samowitz, Wade; de la Chapelle, Albert

2012-01-01

279

Recurrent and founder mutations in the PMS2 gene.  

PubMed

Germline mutations in PMS2 are associated with Lynch syndrome (LS), the most common known cause of hereditary colorectal cancer. Mutation detection in PMS2 has been difficult due to the presence of several pseudogenes, but a custom-designed long-range PCR strategy now allows adequate mutation detection. Many mutations are unique. However, some mutations are observed repeatedly across individuals not known to be related due to the mutation being either recurrent, arising multiple times de novo at hot spots for mutations, or of founder origin, having occurred once in an ancestor. Previously, we observed 36 distinct mutations in a sample of 61 independently ascertained Caucasian probands of mixed European background with PMS2 mutations. Eleven of these mutations were detected in more than one individual not known to be related and of these, six were detected more than twice. These six mutations accounted for 31 (51%) ostensibly unrelated probands. Here, we performed genotyping and haplotype analysis in four mutations observed in multiple probands and found two (c.137G>T and exon 10 deletion) to be founder mutations and one (c.903G>T) a probable founder. One (c.1A>G) could not be evaluated for founder mutation status. We discuss possible explanations for the frequent occurrence of founder mutations in PMS2. PMID:22577899

Tomsic, J; Senter, L; Liyanarachchi, S; Clendenning, M; Vaughn, C P; Jenkins, M A; Hopper, J L; Young, J; Samowitz, W; de la Chapelle, A

2013-03-01

280

Gene mutation patterns in patients with minimally differentiated acute myeloid leukemia.  

PubMed

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

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

2014-06-01

281

Gene Mutation Patterns in Patients with Minimally Differentiated Acute Myeloid Leukemia?  

PubMed Central

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

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

282

Novel germline APC gene mutation in a large familial adenomatous polyposis kindred displaying variable phenotypes.  

PubMed Central

The APC gene is mutated in the germline of people from families where there is a predisposition to develop polyposis coli. Many mutations have been described but the relation between their site and the phenotypic expression of the disease remains unclear. The most commonly seen mutation occurs at codon 1309. Many other mutations have been described towards the 5' end of exon 15 of the APC gene but comparatively few have been seen towards the 3' end. Recent reports have indicated the possibility of a functional boundary with respect to severity and age of onset of disease, which lies towards the 5' end of the gene. This report describes a large family whose affected members present with a very variable phenotype ranging from an early onset and severe form to a comparatively mild later onset one. The mutation that predisposes to disease in this family is at a previously undescribed site that lies towards the 3' end of exon 15 of the APC gene, which results in a stop codon. Interestingly, the stop codon is 63 codons downstream of the mutation and therefore may affect the expression of the disease. The addition of this mutation to the growing list of mutations described in the APC gene may provide some insight into the genotype/phenotype relation of the disease thus contributing to the understanding and significance of mutations at specific sites in the APC gene. Images Figure 2 PMID:7797123

Scott, R J; van der Luijt, R; Spycher, M; Mary, J L; Müller, A; Hoppeler, T; Haner, M; Müller, H; Martinoli, S; Brazzola, P L

1995-01-01

283

Mutational screening of the USH2A gene in Spanish USH patients reveals 23 novel pathogenic mutations  

PubMed Central

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

2011-01-01

284

A P-element insertion screen identified mutations in 455 novel essential genes in Drosophila.  

PubMed Central

With the completion of the nucleotide sequences of several complex eukaryotic genomes, tens of thousands of genes have been predicted. However, this information has to be correlated with the functions of those genes to enhance our understanding of biology and to improve human health care. The Drosophila transposon P-element-induced mutations are very useful for directly connecting gene products to their biological function. We designed an efficient transposon P-element-mediated gene disruption procedure and performed genetic screening for single P-element insertion mutations, enabling us to recover 2500 lethal mutations. Among these, 2355 are second chromosome mutations. Sequences flanking >2300 insertions that identify 850 different genes or ESTs (783 genes on the second chromosome and 67 genes on the third chromosome) have been determined. Among these, 455 correspond to genes for which no lethal mutation has yet been reported. The Drosophila genome is thought to contain approximately 3600 vital genes; 1400 are localized on the second chromosome. Our mutation collection represents approximately 56% of the second chromosome vital genes and approximately 24% of the total vital Drosophila genes. PMID:12586707

Oh, Su-Wan; Kingsley, Tracy; Shin, Hyun-hee; Zheng, Zhiyu; Chen, Hua-Wei; Chen, Xiu; Wang, Hong; Ruan, Peizheng; Moody, Michelle; Hou, Steven X

2003-01-01

285

Molecular Analysis of Bardet-Biedl Syndrome Families: Report of 21 Novel Mutations in 10 Genes  

PubMed Central

Purpose. Bardet-Biedl syndrome (BBS) is genetically heterogeneous with 15 BBS genes currently identified, accounting for approximately 70% of cases. The aim of our study was to define further the spectrum of BBS mutations in a cohort of 44 European-derived American, 8 Tunisian, 1 Arabic, and 2 Pakistani families (55 families in total) with BBS. Methods. A total of 142 exons of the first 12 BBS-causing genes were screened by dideoxy sequencing. Cases in which no mutations were found were then screened for BBS13, BBS14, BBS15, RPGRIP1L, CC2D2A, NPHP3, TMEM67, and INPP5E. Results. Forty-three mutations, including 8 frameshift mutations, 10 nonsense mutations, 4 splice site mutations, 1 deletion, and 20 potentially or probably pathogenic missense variations, were identified in 46 of the 55 families studied (84%). Of these, 21 (2 frameshift mutations, 4 nonsense mutations, 4 splice site mutations, 1 deletion, and 10 missense variations) were novel. The molecular genetic findings raised the possibility of triallelic inheritance in 7 Caucasian families, 1 Arabian family, and 1 Tunisian patient. No mutations were detected for BBS4, BBS11, BBS13, BBS14, BBS15, RPGRIP1L, CC2D2A, NPHP3, TMEM67, or INPP5E. Conclusions. This mutational analysis extends the spectrum of known BBS mutations. Identification of 21 novel mutations highlights the genetic heterogeneity of this disorder. Differences in European and Tunisian patients, including the high frequency of the M390R mutation in Europeans, emphasize the population specificity of BBS mutations with potential diagnostic implications. The existence of some BBS cases without mutations in any currently identified BBS genes suggests further genetic heterogeneity. PMID:21642631

Chen, Jianjun; Smaoui, Nizar; Hammer, Monia Ben Hamed; Jiao, Xiaodong; Riazuddin, S. Amer; Harper, Shyana; Katsanis, Nicholas; Riazuddin, Sheikh; Chaabouni, Habiba; Berson, Eliot L.

2011-01-01

286

Relation of Gene Expression Phenotype to Immunoglobulin Mutation Genotype in B Cell Chronic Lymphocytic Leukemia  

PubMed Central

The most common human leukemia is B cell chronic lymphocytic leukemia (CLL), a malignancy of mature B cells with a characteristic clinical presentation but a variable clinical course. The rearranged immunoglobulin (Ig) genes of CLL cells may be either germ-line in sequence or somatically mutated. Lack of Ig mutations defined a distinctly worse prognostic group of CLL patients raising the possibility that CLL comprises two distinct diseases. Using genomic-scale gene expression profiling, we show that CLL is characterized by a common gene expression “signature,” irrespective of Ig mutational status, suggesting that CLL cases share a common mechanism of transformation and/or cell of origin. Nonetheless, the expression of hundreds of other genes correlated with the Ig mutational status, including many genes that are modulated in expression during mitogenic B cell receptor signaling. These genes were used to build a CLL subtype predictor that may help in the clinical classification of patients with this disease. PMID:11733578

Rosenwald, Andreas; Alizadeh, Ash A.; Widhopf, George; Simon, Richard; Davis, R. Eric; Yu, Xin; Yang, Liming; Pickeral, Oxana K.; Rassenti, Laura Z.; Powell, John; Botstein, David; Byrd, John C.; Grever, Michael R.; Cheson, Bruce D.; Chiorazzi, Nicholas; Wilson, Wyndham H.; Kipps, Thomas J.; Brown, Patrick O.; Staudt, Louis M.

2001-01-01

287

An Ashkenazi founder mutation in the MSH6 gene leading to HNPCC.  

PubMed

Mutations in DNA mismatch repair genes underlie lynch syndrome (HNPCC). Lynch syndrome resulting from mutations in MSH6 is considered to be attenuated in comparison to that caused by mutations in MLH1 and MSH2, thus more likely to be under diagnosed. In this study we report of a common mutation in the MSH6 gene in Ashkenazi Jews. Genetic counseling and diagnostic work-up for HNPCC was conducted in families who attended the high risk clinic for inherited cancer. We identified the mutation c.3984_3987dup in the MSH6 gene in 19 members of four unrelated Ashkenazi families. This mutation results in truncation of the transcript and in loss of expression of the MSH6 protein in tumors. Tumor spectrum among carriers included colon, endometrial, gastric, ovarian, urinary, and breast cancer. All but one family qualified for the Bethesda guidelines and none fulfilled the Amsterdam Criteria. Members of one family also co-inherited the c.6174delT mutation in the BRCA2 gene. The c.3984_3987dup in the MSH6 gene is a mutation leading to HNPCC among Ashkenazi Jews. This is most probably a founder mutation. In contrast to the c.1906G>C founder mutation in the MSH2 gene, tumors tend to occur later in life, and none of the families qualified for the Amsterdam criteria. c.3984_3987dup is responsible for 1/6 of the mutations identified among Ashkenazi HNPCC families in our cohort. Both mutations: c.3984_3987dup and c.1906G>C account for 61% of HNPCC Ashkenazi families in this cohort. These findings are of great importance for counseling, diagnosis, management and surveillance for Ashkenazi families with Lynch syndrome. PMID:19851887

Goldberg, Yael; Porat, Rinnat M; Kedar, Inbal; Shochat, Chen; Galinsky, Daliah; Hamburger, Tamar; Hubert, Ayala; Strul, Hana; Kariiv, Revital; Ben-Avi, Liat; Savion, Moran; Pikarsky, Eli; Abeliovich, Dvorah; Bercovich, Dani; Lerer, Israela; Peretz, Tamar

2010-06-01

288

DHPLC-based mutation analysis of ENG and ALK-1 genes in HHT Italian population.  

PubMed

Hereditary haemorrhagic telangiectasia (HHT or Rendu-Osler-Weber syndrome) is an autosomal dominant disorder characterized by localized angiodysplasia due to mutations in endoglin, ALK-1 gene, and a still unidentified locus. The lack of highly recurrent mutations, locus heterogeneity, and the presence of mutations in almost all coding exons of the two genes makes the screening for mutations time-consuming and costly. In the present study, we developed a DHPLC-based protocol for mutation detection in ALK1 and ENG genes through retrospective analysis of known sequence variants, 20 causative mutations and 11 polymorphisms, and a prospective analysis on 47 probands with unknown mutation. Overall DHPLC analysis identified the causative mutation in 61 out 66 DNA samples (92.4%). We found 31 different mutations in the ALK1 gene, of which 15 are novel, and 20, of which 12 are novel, in the ENG gene, thus providing for the first time the mutational spectrum in a cohort of Italian HHT patients. In addition, we characterized the splicing pattern of ALK1 gene in lymphoblastoid cells, both in normal controls and in two individuals carrying a mutation in the non-invariant -3 position of the acceptor splice site upstream exon 6 (c.626-3C>G). Functional essay demonstrated the existence, also in normal individuals, of a small proportion of ALK1 alternative splicing, due to exon 5 skipping, and the presence of further aberrant splicing isoforms in the individuals carrying the c.626-3C>G mutation. PMID:16429404

Lenato, Gennaro M; Lastella, Patrizia; Di Giacomo, Marilena C; Resta, Nicoletta; Suppressa, Patrizia; Pasculli, Giovanna; Sabbŕ, Carlo; Guanti, Ginevra

2006-02-01

289

Mutations in the CACNA1F and NYX genes in British CSNBX families.  

PubMed

X-linked congenital stationary night blindness (CSNBX) is a genetically and phenotypically heterogeneous non-progressive disorder, characterised by impaired night vision but grossly normal retinal appearance. Other more variable features include reduction in visual acuity, myopia, nystagmus and strabismus. Genetic mapping studies by other groups, and our own studies of British patients, identified key recombination events indicating the presence of at least 2 disease genes on Xp11. Two causative genes (CACNA1F and NYX) for CSNBX have now been identified through positional cloning strategies. In this report, we present the results of comprehensive mutation screening in 14 CSNBX families, three with mutations in the CACNA1F gene and 10 with mutations in the NYX gene. In one family we failed to identify the mutation after testing RP2, RPGR, NYX and CACNA1F. NYX gene mutations are a more frequent cause of CSNBX, although there is evidence for founder mutations. Our report of patient population mutation screening for both CSNBX genes, and our exclusion of RP2 and RGPR, indicates that mutations in CACNA1F and NYX are likely to account for all CSNBX. PMID:12552565

Zito, Ilaria; Allen, Louise E; Patel, Reshma J; Meindl, Alfons; Bradshaw, Keith; Yates, John R; Bird, Alan C; Erskine, Lynda; Cheetham, Michael E; Webster, Andrew R; Poopalasundaram, Subathra; Moore, Anthony T; Trump, Dorothy; Hardcastle, Alison J

2003-02-01

290

Two Arabidopsis methylation-deficiency mutations confer only partial effects on a methylated endogenous gene family  

Microsoft Academic Search

In Arabidopsis a SWI2\\/SNF2 chromatin remodeling factor-related protein DDM1 and a cytosine methyl- transferase MET1 are required for maintenance of genomic cytosine methylation. Mutations in either gene cause global demethylation. In this work we have assessed the effects of these mutations on the PAI tryptophan biosynthetic gene family, which consists of four densely methylated genes arranged as a tail-to-tail inverted

Lisa Bartee; Judith Bender

2001-01-01

291

A novel ANT1 gene mutation with probable germline mosaicism in autosomal dominant progressive external ophthalmoplegia.  

PubMed

Only four different mutations in the adenine nucleotide translocator 1 (ANT1) gene have been found in families with progressive external ophthalmoplegia (PEO). We report a novel heterozygous C to A transversion at nucleotide 269 in the ANT1 gene in a German family with PEO, predicted to convert a highly conserved alanine at codon 90 to aspartic acid. The mutation was identified in three siblings with PEO, one of them additionally suffered from schizoaffective disorder. Microsatellite analysis showed that the mutation was dominant and inherited from the mother who did not carry the mutation in blood, indicating germ-line mosaicism. PMID:15792871

Deschauer, Marcus; Hudson, Gavin; Müller, Tobias; Taylor, Robert W; Chinnery, Patrick F; Zierz, Stephan

2005-04-01

292

Different mutations in the COL4A5 collagen gene in two patients with different features of Alport syndrome  

Microsoft Academic Search

Different mutations in the COL4A5 collagen gene in two patients with different features of Alport syndrome. Alport syndrome is a hereditary renal disease in which progressive renal failure is often accompanied by sensorineural deafness and ocular abnormalities. Recently, mutations were detected in the type IV collagen ?5 chain gene in Alport syndrome patients. We searched for mutations in this gene

Hubert JM Smeets; Jos J Melenhorst; Henny H Lemmink; Cock H Schröder; Marcel R Nelen; Jing Zhou; Sirkka L Hostikka; Karl Tryggvason; Hans-Hilger Ropers; Maaike CE Jansweijer; Leo AH Monnens; Han G Brunner; Bernard A van Oost

1992-01-01

293

[Analysis of mutations and VNTR-polymorphism in the phenylalanine hydroxylase gene].  

PubMed

The data on 5 PAH gene mutations analysis are presented. The most common mutation observed in Ukrainian population was determined to be R408W (66.6%). As well two minor mutations R158Q (2.5%) and Y414C (1.25%) were identified. The allelic variation of the VNTR-polymorphism in 470 healthy volunteers and 39 PKU-patients were analysed. 7 allelic variants and 15 haplotypes were found. The linkage disequilibrium was displayed between mutation R408W and VNTR-haplotypes 03. An advantages of molecular genetic analysis of mutations and VNTR-polymorphism for diagnosis of PKU in Ukraine are discussed. PMID:11642047

Hechyporenko, M V; Kravchenko, S A; Livshyts, L A

2001-01-01

294

Phenylalanine hydroxylase gene mutations in the United States: report from the Maternal PKU Collaborative Study.  

PubMed

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. PMID:8659548

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

1996-07-01

295

Phenylalanine hydroxylase gene mutations in the United States: report from the Maternal PKU Collaborative Study.  

PubMed Central

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

Guldberg, P.; Levy, H. L.; Hanley, W. B.; Koch, R.; Matalon, R.; Rouse, B. M.; Trefz, F.; de la Cruz, F.; Henriksen, K. F.; Guttler, F.

1996-01-01

296

Severe and mild mutations in cis for the methylenetetrahydrofolate reductase (MTHFR) gene, and description of five novel mutations in MTHFR.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, a methyl donor in the conversion of homocysteine to methionine. Patients with severe MTHFR deficiency have hyperhomocysteinemia, hypomethioninemia, and a range of neurological and vascular findings with a variable age at onset. We have previously described nine mutations in patients with severe MTHFR deficiency. A mild form of MTHFR deficiency, associated with a thermolabile enzyme, has been proposed as a genetic risk factor for cardiovascular disease and for neural tube defects. We have shown that a common missense mutation (an alanine-to-valine substitution) encodes this thermolabile variant. We now report an additional five mutations causing severe MTHFR deficiency and an analysis of genotype (alanine/valine status) and enzyme thermolability in 22 patients with this inborn error of metabolism. Six of these patients have four mutations in the MTHFR gene-two rare mutations causing severe deficiency and two mutations for the common alanine-to-valine mutation that results in thermolability. Even in severe MTHFR deficiency, the thermolabile variant is frequently observed, and there is a strong relationship between the presence of this variant and increased enzyme thermolability. PMID:8940272

Goyette, P; Christensen, B; Rosenblatt, D S; Rozen, R

1996-12-01

297

Severe and mild mutations in cis for the methylenetetrahydrofolate reductase (MTHFR) gene, and description of five novel mutations in MTHFR.  

PubMed Central

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, a methyl donor in the conversion of homocysteine to methionine. Patients with severe MTHFR deficiency have hyperhomocysteinemia, hypomethioninemia, and a range of neurological and vascular findings with a variable age at onset. We have previously described nine mutations in patients with severe MTHFR deficiency. A mild form of MTHFR deficiency, associated with a thermolabile enzyme, has been proposed as a genetic risk factor for cardiovascular disease and for neural tube defects. We have shown that a common missense mutation (an alanine-to-valine substitution) encodes this thermolabile variant. We now report an additional five mutations causing severe MTHFR deficiency and an analysis of genotype (alanine/valine status) and enzyme thermolability in 22 patients with this inborn error of metabolism. Six of these patients have four mutations in the MTHFR gene-two rare mutations causing severe deficiency and two mutations for the common alanine-to-valine mutation that results in thermolability. Even in severe MTHFR deficiency, the thermolabile variant is frequently observed, and there is a strong relationship between the presence of this variant and increased enzyme thermolability. Images Figure 1 Figure 2 PMID:8940272

Goyette, P.; Christensen, B.; Rosenblatt, D. S.; Rozen, R.

1996-01-01

298

Rare mutations in the PIK3CA gene contribute to aggressive endometrial cancer.  

PubMed

The molecular basis of endometrial cancer (EC), a common gynecologic malignancy, often includes mutational activation of the PIK3CA and KRAS genes. We aimed to determine the distribution of mutations in the two genes depending on patient clinocopathological characteristics. We sequenced exon 1 of the KRAS gene and exons 9 and 20 of the PIK3CA gene in 108 consecutive EC tumor samples. PIK3CA mutations were present in 24 of the 108 (22.2%) cases and KRAS mutations in 18 of the 108 (16.7%) cases. PIK3CA mutations occurred more frequently in KRAS-mutated samples (7/18, 38.9%; p = 0.06) than in KRAS wild type (17/90, 18.9%) and showed a very high frequency in metastatic tumors (4/9, 44.4%; p = 0.1) and in samples displaying serous differentiation-serous and mixed endometrioid/serous tumors (6/12, 50.0%; p = 0.021)-where KRAS mutations were rare (11.1% and 16.7%, respectively) and did not exist independently of a PIK3CA mutation. Non-hotspot (i.e., non-E542K, -E545K, and -H1047R) mutations in the PIK3CA gene showed higher frequency in metastatic cases (3/9, 33.3%; p = 0.05). Tumors displaying serous differentiation showed a particular pattern-they harbored exclusively mutations in PIK3CA exon 20 (5/12, 41.7%; p = 0.005) and most of these were non-hotspot (4/12, 33.3%; p = 0.02). In all other comparisons exons 9 and 20 mutation distribution did not differ. These results suggest the need for further exploration of the significance of PIK3CA mutations in respect to aggressive EC. PMID:19839777

Konstantinova, Darina; Kaneva, Radka; Dimitrov, Roumen; Savov, Alexey; Ivanov, Stephan; Dyankova, Tzvetanka; Kremensky, Ivo; Mitev, Vanio

2010-02-01

299

Congenital nephrogenic diabetes insipidus with a novel mutation in the aquaporin 2 gene  

PubMed Central

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

PARK, YOUN JONG; BAIK, HAING WOON; CHEONG, HAE IL; KANG, JU HYUNG

2014-01-01

300

Expression of Von Hippel – Lindau (VHL) gene mutation in diagnosed cases of renal cell carcinoma  

PubMed Central

Objective: To evaluate the expression of Von Hippel Lindau (VHL) gene in diagnosed cases of renal cell carcinoma. Methods: This cross sectional study was conducted in department of Pathology, Basic Medical Sciences Institute, JPMC, Karachi, from January 2007 to December 2012. Paraffin embedded blocks of 30 cases of radical nephrectomy specimens diagnosed as renal cell carcinoma including CCRCC 21 (70%) CCPRCC, 3 (10%), PRCC 2 (6.79%), hybrid tumor 4 (13.3%), chromophobe tumor (0%) processed for VHL gene expression on Polymerase Chain Reaction. Results: All the 30 cases previously diagnosed as renal cell carcinoma were processed on PCR, VHL gene mutations were seen in 20 (95.23%) of CCRCC while a single case was negative for VHL mutations. All CCPRCC were negative for VHL mutation. Among the hybrid tumor 03 cases with foci of clear cells show VHL mutation while a single case showing combination of clear cells and chromophobe cells was negative for mutation. Both the cases of PRCC were positive for mutation. Exon 3 mutation at base pair 194 seen in 8 (32%) cases and Exon 2 mutation at base pair 150-159 seen in 17 (68%) cases. None of the cases showed Exon 1 mutation. Conclusion: The present study shows that majority of CCRCC showed VHL mutation including the hybrid tumor with clear cell component in our population. PMID:25097537

Shahzad, Humera; Kehar, Shahnaz Imdad; Ali, Shahzad; Tariq, Naila

2014-01-01

301

TET2 gene mutation is unfavorable prognostic factor in cytogenetically normal acute myeloid leukemia patients with NPM1+ and FLT3-ITD - mutations.  

PubMed

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

Tian, Xiaopeng; Xu, Yang; Yin, Jia; Tian, Hong; Chen, Suning; Wu, Depei; Sun, Aining

2014-07-01

302

Determining the frequency of de novo germline mutations in DNA mismatch repair genes  

PubMed Central

Background Carriers of a germline mutation in a DNA mismatch repair (MMR) gene—that is, persons with Lynch syndrome—have substantially high risks of colorectal (CRC), endometrial, and several other cancers. The proportion of carriers who have de novo mutations (not inherited from either parent) is not known. This study reports a case series of de novo mutations in MMR genes and estimates the frequency of de novo mutation in MMR genes using the Colon Cancer Family Registry. Methods Screening for germline MLH1, MSH2, MSH6, and PMS2 mutations was performed for all incident CRC cases recruited from cancer registries (population based probands) displaying microsatellite instability (MSI) or loss of expression of MMR genes by immunohistochemistry (IHC) and probands with CRC in multi-case families recruited from clinics (clinic based probands), regardless of MSI or IHC status. All relatives of probands with a pathogenic mutation who donated a blood sample underwent testing for the mutation identified in the proband. Results Of 261 probands (202 clinic based, 59 population based) with MMR gene mutations for whom it was possible to determine the origin of the mutation, six (2.3%, 95% CI 0.9% to 5.0%) were confirmed as de novo, and the remaining 255 (97.7%, 95% CI 95.0% to 99.1%) were inherited. Of the de novo mutation carriers, three were clinic based probands (1.5%, 95% CI 0.3% to 4.5%) and three were population based probands (5.1%, 95% CI 1.2% to 14.5%). Two were in MLH1, three in MSH2, and one in MSH6. Conclusion De novo MMR gene mutations are uncommon causes of Lynch syndrome. PMID:21636617

Win, Aung Ko; Jenkins, Mark A; Buchanan, Daniel D; Clendenning, Mark; Young, Joanne P; Giles, Graham G; Goldblatt, Jack; Leggett, Barbara A; Hopper, John L; Thibodeau, Stephen N; Lindor, Noralane M

2012-01-01

303

Mutation analysis of the cathepsin C gene in Indian families with Papillon-Lef?vre syndrome  

PubMed Central

Background PLS is a rare autosomal recessive disorder characterized by early onset periodontopathia and palmar plantar keratosis. PLS is caused by mutations in the cathepsin C (CTSC) gene. Dipeptidyl-peptidase I encoded by the CTSC gene removes dipeptides from the amino-terminus of protein substrates and mainly plays an immune and inflammatory role. Several mutations have been reported in this gene in patients from several ethnic groups. We report here mutation analysis of the CTSC gene in three Indian families with PLS. Methods Peripheral blood samples were obtained from individuals belonging to three Indian families with PLS for genomic DNA isolation. Exon-specific intronic primers were used to amplify DNA samples from individuals. PCR products were subsequently sequenced to detect mutations. PCR-SCCP and ASOH analyses were used to determine if mutations were present in normal control individuals. Results All patients from three families had a classic PLS phenotype, which included palmoplantar keratosis and early-onset severe periodontitis. Sequence analysis of the CTSC gene showed three novel nonsense mutations (viz., p.Q49X, p.Q69X and p.Y304X) in homozygous state in affected individuals from these Indian families. Conclusions This study reported three novel nonsense mutations in three Indian families. These novel nonsense mutations are predicted to produce truncated dipeptidyl-peptidase I causing PLS phenotype in these families. A review of the literature along with three novel mutations reported here showed that the total number of mutations in the CTSC gene described to date is 41 with 17 mutations being located in exon 7. PMID:12857359

Selvaraju, Veeriah; Markandaya, Manjunath; Prasad, Pullabatla Venkata Siva; Sathyan, Parthasarathy; Sethuraman, Gomathy; Srivastava, Satish Chandra; Thakker, Nalin; Kumar, Arun

2003-01-01

304

Effect of KCNJ5 Mutations on Gene Expression in Aldosterone-Producing Adenomas and Adrenocortical Cells  

PubMed Central

Context: Primary aldosteronism is a heterogeneous disease that includes both sporadic and familial forms. A point mutation in the KCNJ5 gene is responsible for familial hyperaldosteronism type III. Somatic mutations in KCNJ5 also occur in sporadic aldosterone producing adenomas (APA). Objective: The objective of the study was to define the effect of the KCNJ5 mutations on gene expression and aldosterone production using APA tissue and human adrenocortical cells. Methods: A microarray analysis was used to compare the transcriptome profiles of female-derived APA samples with and without KCNJ5 mutations and HAC15 adrenal cells overexpressing either mutated or wild-type KCNJ5. Real-time PCR validated a set of differentially expressed genes. Immunohistochemical staining localized the KCNJ5 expression in normal adrenals and APA. Results: We report a 38% (18 of 47) prevalence of KCNJ5 mutations in APA. KCNJ5 immunostaining was highest in the zona glomerulosa of NA and heterogeneous in APA tissue, and KCNJ5 mRNA was 4-fold higher in APA compared with normal adrenals (P < 0.05). APA with and without KCNJ5 mutations displayed slightly different gene expression patterns, notably the aldosterone synthase gene (CYP11B2) was more highly expressed in APA with KCNJ5 mutations. Overexpression of KCNJ5 mutations in HAC15 increased aldosterone production and altered expression of 36 genes by greater than 2.5-fold (P < 0.05). Real-time PCR confirmed increases in CYP11B2 and its transcriptional regulator, NR4A2. Conclusions: KCNJ5 mutations are prevalent in APA, and our data suggest that these mutations increase expression of CYP11B2 and NR4A2, thus increasing aldosterone production. PMID:22628608

Monticone, Silvia; Hattangady, Namita G.; Nishimoto, Koshiro; Mantero, Franco; Rubin, Beatrice; Cicala, Maria Verena; Pezzani, Raffaele; Auchus, Richard J.; Ghayee, Hans K.; Shibata, Hirotaka; Kurihara, Isao; Williams, Tracy A.; Giri, Judith G.; Bollag, Roni J.; Edwards, Michael A.; Isales, Carlos M.

2012-01-01

305

Profile of TP53 gene mutations in sinonasal cancer.  

PubMed

Genetic alterations underlying the development of the cancer of the nose and paranasal sinuses (sinonasal cancer, SNC), a rare cancer that can be included in the group of head and neck cancers, are still largely unknown. We recently reported that TP53 mutations are a common feature of SNC, with an overall frequency of 77%, and they show association to adenocarcinoma and wood-dust exposure [15]. In this study, we report in detail the sequence change for 159 TP53 mutations identified by direct sequencing. More than half of the mutations (60%, 95/159) were missense mutations; there were also 28 (18%) frameshift or nonsense mutations, and 36 (23%) intronic or silent mutations. In coding region, the most common base change detected was C-->T transition (43/125; 34% of base changes in the coding region). G-->T transversions occurred at a frequency of 10% (12/125), which is less than reported in mutation databases for head and neck squamous cell carcinoma (24%). Characteristically, in our SNC series, the mutations were scattered over a large number of codons, codon 248 being the most frequent target of base substitution. Codon 135 was the second most frequently mutated codon; this nucleotide position has not been reported before as frequently mutated in head and neck cancer or human cancer in general. About half of all tumours with TP53 mutations carried more than one mutation. Interestingly, 86% (19/22) of the silent mutations detected had occurred in tumours with multiple mutations. PMID:20025891

Holmila, Reetta; Bornholdt, Jette; Suitiala, Tuula; Cyr, Diane; Dictor, Michael; Steiniche, Torben; Wolff, Henrik; Wallin, Hĺkan; Luce, Daničle; Husgafvel-Pursiainen, Kirsti

2010-04-01

306

Exclusion of growth factor gene mutations as a common cause of Sotos syndrome.  

PubMed

Sotos syndrome is characterized by somatic overgrowth, i.e., macrocephaly and tall stature. Because the cause and pathogenesis of Sotos syndrome remain unknown, we selected nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3) as possible genes mutated in Sotos syndrome. In seven patients with the classic phenotype, we excluded mutations in these growth factor genes. It is possible that these three genes are not involved in the cause of Sotos syndrome, or alternatively, mutations could not be identified in the small number of patients studied. PMID:11426446

Lin, A E; Liu, Q; Mannheim, G B; Darras, B T

2001-01-01

307

Prevalence of Mutations in eyeGENE Probands With a Diagnosis of Autosomal Dominant Retinitis Pigmentosa  

PubMed Central

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

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

308

Phenylalanine hydroxylase gene mutations in the United States: Report from the maternal PKU collaborative study  

SciTech Connect

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.

Guldberg, P.; Henriksen, K.F.; Guettler, F. [John F. Kennedy Inst., Glostrup (Denmark)] [and others

1996-07-01

309

DNA repair genes are selectively mutated in diffuse large B cell lymphomas  

PubMed Central

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

de Miranda, Noel FCC; Peng, Roujun; Georgiou, Konstantinos; Wu, Chenglin; Sorqvist, Elin Falk; Berglund, Mattias; Chen, Longyun; Gao, Zhibo; Lagerstedt, Kristina; Lisboa, Susana; Roos, Fredrik; van Wezel, Tom; Teixeira, Manuel R.; Rosenquist, Richard; Sundstrom, Christer; Enblad, Gunilla; Nilsson, Mats; Zeng, Yixin; Kipling, David

2013-01-01

310

Novel ABCC8 (SUR1) gene mutations in Asian Indian children with congenital hyperinsulinemic hypoglycemia.  

PubMed

Congenital hyperinsulinemic hypoglycemia (HI) is a heterogeneous genetic disorder of insulin secretion characterized by persistent hypoglycemia, most commonly associated with inactivating mutations of the ?-cell ATP-sensitive K(+) channel (K(ATP) channel) genes ABCC8 (encoding SUR1) and KCNJ11(encoding Kir6.2). This study aimed to screen the mutations in the genes associated with congenital HI in Asian Indian children. Recessive mutations of these genes cause hyperinsulinism that is unresponsive to treatment with channel agonists like diazoxide. Dominant K(ATP) mutations have been associated with diazoxide-responsive disease. The KCNJ11, ABCC8, GCK, HNF4A, and GLUD1 genes were analyzed by sequence analysis in 22 children with congenital HI. We found 10 novel mutations (c.1delA, c.61delG, c.267delT, c.619-629delCCCGAGGACCT, Gln444*, Leu724Pro, Ala847Thr, Trp898*, IVS30-2A>C, and Leu1454Arg) and two known mutations (Gly111Arg and Arg598*) in the ABCC8 gene. This study describes novel and known ABCC8 gene mutations in children with congenital HI. This is the first large genetic screening study on HI in India and our results will help clinicians in providing optimal treatment for patients with hyperinsulinemia and in assisting affected families with genetic counseling. PMID:25117148

Jahnavi, Suresh; Poovazhagi, Varadarajan; Kanthimathi, Sekar; Balamurugan, Kandasamy; Bodhini, Dhanasekaran; Yadav, Jaivinder; Jain, Vandana; Khadgawat, Rajesh; Sikdar, Mahuya; Bhavatharini, Ayurchelvan; Das, Ashok Kumar; Kaur, Tanvir; Mohan, Viswanathan; Radha, Venkatesan

2014-09-01

311

Hybrid curation of gene-mutation relations combining automated extraction and crowdsourcing  

PubMed Central

Background: This article describes capture of biological information using a hybrid approach that combines natural language processing to extract biological entities and crowdsourcing with annotators recruited via Amazon Mechanical Turk to judge correctness of candidate biological relations. These techniques were applied to extract gene– mutation relations from biomedical abstracts with the goal of supporting production scale capture of gene–mutation–disease findings as an open source resource for personalized medicine. Results: The hybrid system could be configured to provide good performance for gene–mutation extraction (precision ?82%; recall ?70% against an expert-generated gold standard) at a cost of $0.76 per abstract. This demonstrates that crowd labor platforms such as Amazon Mechanical Turk can be used to recruit quality annotators, even in an application requiring subject matter expertise; aggregated Turker judgments for gene–mutation relations exceeded 90% accuracy. Over half of the precision errors were due to mismatches against the gold standard hidden from annotator view (e.g. incorrect EntrezGene identifier or incorrect mutation position extracted), or incomplete task instructions (e.g. the need to exclude nonhuman mutations). Conclusions: The hybrid curation model provides a readily scalable cost-effective approach to curation, particularly if coupled with expert human review to filter precision errors. We plan to generalize the framework and make it available as open source software. Database URL: http://www.mitre.org/publications/technical-papers/hybrid-curation-of-gene-mutation-relations-combining-automated PMID:25246425

Burger, John D.; Doughty, Emily; Khare, Ritu; Wei, Chih-Hsuan; Mishra, Rajashree; Aberdeen, John; Tresner-Kirsch, David; Wellner, Ben; Kann, Maricel G.; Lu, Zhiyong; Hirschman, Lynette

2014-01-01

312

p53 and K-ras gene mutations in carcinoma of the rectum among Finnish women  

PubMed Central

Aims/Background—The aim of this study was to identify p53 and K-ras gene mutations in carcinoma of the rectum among Finnish women. Mutation patterns might give clues to aetiological factors when comparisons are made with other human tumours. Methods—Of 134 women with carcinoma of the rectum, paraffin wax embedded specimens of the tumour tissue were obtained from 118 patients. Genomic DNA was extracted, and exons 4–8 of the p53 gene and codons 12/13 and 61 of the K-ras gene were amplified, and analysed for mutations by single strand conformation polymorphism and direct sequencing. The production of p53 and K-ras proteins was studied by immunohistochemistry. Results—The overall crude frequency for mutations in the p53 gene was 35% but the true frequency appears to be higher (up to 56%). In the K-ras gene, the mutation frequency (15%) was significantly lower than that reported for colon cancer. In the p53 gene, the mutation frequency increased significantly with patient age. In a high proportion of patients (14%) the rectal tumours contained small subclones of tumour cells that displayed extremely rare mutations at codons 110 and 232 of the p53 gene. Hot spot codon 175 mutations were significantly less common in rectal cancer than in cancer of the colon. Conclusions—Rectal cancer among Finnish women has characteristics in the mutations of the p53 and K-ras genes that are uncommon in other human tumours, including cancer of the colon. A biological explanation of these findings is not clear at present, but might be associated with an unidentified genetic factor in Finland. PMID:10884918

Servomaa, K; Kiuru, A; Kosma, V-M; Hirvikoski, P; Rytomaa, T

2000-01-01

313

Interacting genes that affect microtubule function in Drosophila melanogaster: Two classes of mutation revert the failure to complement between hay sup nc2 and mutations in tubulin genes  

SciTech Connect

The recessive male sterile mutation hay{sup nc2} of Drosophila melanogaster fails to complement certain {beta}{sub 2}-tubulin and {alpha}-tubulin mutations, suggesting that the haywire product plays a role in microtubule function, perhaps as a structural component of microtubules. The genetic interaction appears to require the presence of the aberrant product encoded by hay{sup nc2}, which may act as a structural poison. Based on this observation, the authors have isolated ten new mutations with EMS that revert the failure to complement between hay{sup nc2} and B2t{sup n}. The revertants tested behaved as intragenic mutations of hay in recombination tests, and feel into two phenotypic classes, suggesting two functional domains of the hay gene product. Some revertants were hemizygous viable and less severe than hay{sup nc2} in their recessive phenotype. These mutations might revert the poison by restoring the aberrant product encoded by the hay{sup nc2} allele to more wild-type function. Most of the revertants were recessive lethal mutations, indicating that the hay gene product is essential for viability. These more extreme mutations could revert the poison by destroying the ability of the aberrant haywire{sup nc2} product to interact structurally with microtubules. Flies heterozygous for the original hay{sup nc2} allele and an extreme revertant show defects in both the structure and the function of the male meiotic spindle.

Regan, C.L.; Fuller, M.T. (Univ. of Colorado, Boulder (USA))

1990-05-01

314

Mutations of the CYP1B1 gene in congenital anterior staphylomas  

PubMed Central

Purpose Here, we present two patients with congenital anterior staphyloma, with mutations in the CYP1B1 gene. Methods We reviewed the medical records, including the genetic analysis. Results Two unrelated patients presented with congenital anterior staphylomas. Both patients showed mutations in the CYP1B1 gene. The first patient, the product of a consanguineous marriage, showed a homozygous misssense mutation g.3987G>A (p.G61E). The second patient had compound heterozygous misssense mutations [g.4160 G>T (p.A119S) and g.8131 C>G (p.L432V)]. Conclusion CYP1B1 gene mutation may be associated with congenital anterior staphylomas. PMID:24591815

Al Judaibi, Ramzi; Abu-Amero, Khaled K; Morales, Jose; Al Shahwan, Sami; Edward, Deepak P

2014-01-01

315

Mutations in the SLC3A1 transporter gene in cystinuria  

SciTech Connect

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.

Pras, E.; Raben, N.; Aksentijevich, I. [National Heart, Lung, and Blood Institute, Bethesda, MD (United States)] [and others

1995-06-01

316

Homozygous tyrosinase gene mutation in an American black with tyrosinase-negative (type IA) oculocutaneous albinism.  

PubMed Central

We have identified a tyrosinase gene mutation in an American black with classic, tyrosinase-negative oculocutaneous albinism. This mutation results in an amino acid substitution (Cys----Arg) at codon 89 of the tyrosinase polypeptide. The proband is homozygous for the substitution, suggesting that this mutation may be frequently associated with tyrosinase-negative oculocutaneous albinism in blacks. Images Figure 1 Figure 2 Figure 3 PMID:1899321

Spritz, R A; Strunk, K M; Hsieh, C L; Sekhon, G S; Francke, U

1991-01-01

317

Somatic Mutations of the Protein Kinase Gene Family in Human Lung Cancer  

Microsoft Academic Search

Protein kinases are frequently mutated in human cancer and inhibitors of mutant protein kinases have proven to be effective anticancer drugs. We screened the coding sequences of 518 protein kinases (f1.3 Mb of DNA per sample) for somatic mutations in 26 primary lung neoplasms and seven lung cancer cell lines. One hundred eighty-eight somatic mutations were detected in 141 genes.

Helen Davies; Chris Hunter; Raffaella Smith; Philip Stephens; Chris Greenman; Graham Bignell; Jon Teague; Adam Butler; Sarah Edkins; Claire Stevens; Adrian Parker; Sarah O'Meara; Syd Barthorpe; Lisa Brackenbury; Jody Clements; Jennifer Cole; Ed Dicks; Ken Edwards; Simon Forbes; Matthew Gorton; Kristian Gray; Kelly Halliday; Rachel Harrison; Katy Hills; Jonathon Hinton; David Jones; Vivienne Kosmidou; Ross Laman; Richard Lugg; Andrew Menzies; Janet Perry; Robert Petty; Keiran Raine; Rebecca Shepherd; Alexandra Small; Helen Solomon; Yvonne Stephens; Calli Tofts; Jennifer Varian; Anthony Webb; Sofie West; Sara Widaa; Andrew Yates; Francis Brasseur; Colin S. Cooper; Adrienne M. Flanagan; Anthony Green; Maggie Knowles; Suet Y. Leung; Leendert H. J. Looijenga; Bruce Malkowicz; Marco A. Pierotti; Siu T. Yuen; Sunil R. Lakhani; Douglas F. Easton; Barbara L. Weber; Peter Goldstraw; Andrew G. Nicholson; Richard Wooster; Michael R. Stratton; P. Andrew Futreal

2005-01-01

318

Absence of BRAF gene mutations in uveal melanomas in contrast to cutaneous melanomas  

Microsoft Academic Search

The recent discovery of activating mutations in the BRAF gene in many cutaneous melanomas led us to screen the genomic sequence of BRAF exons 11 and 15 in a series of 48 intraocular (uveal) melanomas, together with control samples from three cutaneous melanomas and the SK-Mel-28 cell line, which has a BRAF mutation. The same mutation was detected in two-thirds

S. C. Edmunds; I. A. Cree; F. Di Nicolantonio; J. L. Hungerford; J. S. Hurren; D. P. Kelsell

2003-01-01

319

Mutation analysis of the G4.5 gene in patients with isolated left ventricular noncompaction  

Microsoft Academic Search

Mutations in the gene G4.5, originally associated with Barth syndrome, have been reported to result in a wide spectrum of severe infantile X-linked cardiomyopathies. The purpose of this study was to investigate patients with isolated left ventricular noncompaction (LVNC) for disease-causing mutations in G4.5. In 27 patients including 10 families with isolated LVNC, mutation analysis of G4.5 was performed using

Rui Chen; Tohru Tsuji; Fukiko Ichida; Karla R Bowles; Xianyi Yu; Sayaka Watanabe; Keiichi Hirono; Shinichi Tsubata; Yuji Hamamichi; Jun Ohta; Yasuharu Imai; Neil E Bowles; Toshio Miyawaki; Jeffrey A Towbin

2002-01-01

320

A new de novo mutation in the GCK gene causing MODY2.  

PubMed

Analysis of glucokinase (GCK) gene in a 15-year-old male identified a new frameshift mutation in exon 4 caused by a heterozygous guanine deletion at position 382 (c.382delG, p.E128Xfs). No mutation was detected in the parents. Polymorphic markers' study excluded false paternity indicating that c.382delG is a novel de novo mutation. PMID:21514682

Cappelli, Alessia; Silvestri, Serena; Tumini, Stefano; Carinci, Silvia; Cipriano, Paola; Massi, Luciano; Staffolani, Paolo; Pianese, Luigi

2011-07-01

321

Low Frequency of PIK3CA Gene Mutations in Hepatocellular Carcinoma in Chinese Population  

Microsoft Academic Search

PI3K\\/AKT constitutes an important pathway regulating the signaling of multiple biological processes and plays a critical role\\u000a in carcinogenesis. PIK3CA gene missense mutations have been reported in many human cancer types. The mutation of it in hepatocellular carcinoma cases\\u000a varies with different races and regions. In this study, we investigated PIK3CA mutation in Chinese hepatocellular carcinoma patients. A total 90

Xun Li; Quanbao Zhang; Wenting He; Wenbo Meng; Jun Yan; Lei Zhang; Xiaoliang Zhu; Tao Liu; Yumin Li; Zhongtian Bai

322

Consequences of Marfan mutations to expression of fibrillin gene and to the structure of microfibrils  

SciTech Connect

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.

Peltonen, L.; Karttunen, L.; Rantamaeki, T. [NPHI, Helsinki (Finland)] [and others

1994-09-01

323

Revisiting MSUD in Portuguese Gypsies: evidence for a founder mutation and for a mutational hotspot within the BCKDHA gene.  

PubMed

Maple syrup urine disease (MSUD) is a rare autosomal recessive disorder of branched-chain amino acid metabolism. In the context of the wide mutational spectrum known for this disease, a few common mutations have been described in populations where founder effects played a major role in modeling diversities. In Portugal, for instance, a high proportion of patients are of Gypsy origin and all share the same mutation (c.117delC-alpha; p.R40GfsX23), causing the neonatal severe form of MSUD. In this study, we used four microsatellite markers closely flanking the BCKDHA gene (E1alpha protein) to demonstrate that c.117delC-alpha is a founder mutation responsible for the high incidence of the disorder among Portuguese Gypsies. These results are of medical relevance since carrier tests and prenatal diagnosis can be offered to families at risk, particularly because the carrier frequency of c.117delC-alpha was estimated at 1.4% among the healthy Portuguese Gypsies from the South of the country. Finally we present evidence that the genomic region of the BCKDHA gene where c.117delC-alpha is located is likely a mutational hotspot, since recurrence of c.117delC-alpha was observed in two distinct population groups. PMID:19456321

Quental, Sofia; Gusmăo, Alfredo; Rodríguez-Pombo, Pilar; Ugarte, Magdalena; Vilarinho, Laura; Amorim, António; Prata, Maria J

2009-05-01

324

Polymorphisms in Drug Metabolism Genes, Smoking, and p53 Mutations in Breast Cancer  

PubMed Central

Polymorphisms in phase I and phase II enzymes may enhance the occurrence of mutations at critical tumor suppressor genes, such as p53, and increase breast cancer risk by either increasing the activation or detoxification of carcinogens and/or endogenous estrogens. We analyzed polymorphisms in CYP1B1, GSTM1, GSTT1, and GSTP1 and p53 mutations in 323 breast tumor samples. Approximately 11% of patients exhibited mutations in p53. Women with mutations had a significantly younger age of diagnosis (P = 0.01) and a greater incidence of tumors classified as stage II or higher (P = 0.002). More women with mutations had a history of smoking (55%) compared to women without mutations (39%). Although none of the genotypes alone were associated with p53 mutations, positive smoking history was associated with p53 mutations in women with the GSTM1 null allele [OR = 3.54; 95% CI = 0.97–12.90 P = 0.06] compared to women with the wild-type genotype and smoking history [OR = 0.62, 95% CI = 0.19–2.07], although this association did not reach statistical significance. To test for gene–gene interactions, our exploratory analysis in the Caucasian cases suggested that individuals with the combined GSTP1 105 VV, CYP1B1 432 LV/VV, and GSTM1 positive genotype were more likely to harbor mutations in p53 [OR = 4.94; 95% CI = 1.11–22.06]. Our results suggest that gene–smoking and gene–gene interactions may impact the prevalence of p53 mutations in breast tumors. Elucidating the etiology of breast cancer as a consequence of common genetic polymorphisms and the genotoxic effects of smoking will enable us to improve the design of prevention strategies, such as lifestyle modifications, in genetically susceptible subpopulations. PMID:17683074

Van Emburgh, Beth O.; Hu, Jennifer J.; Levine, Edward A.; Mosley, Libyadda J.; Case, L. Douglas; Lin, Hui-Yi; Knight, Sommer N.; Perrier, Nancy D.; Rubin, Peter; Sherrill, Gary B.; Shaw, Cindy S.; Carey, Lisa A.; Sawyer, Lynda R.; Allen, Glenn O.; Milikowski, Clara; Willingham, Mark C.; Miller, Mark Steven

2013-01-01

325

UV and Skin Cancer: Specific p53 Gene Mutation in Normal Skin as a Biologically Relevant Exposure Measurement  

Microsoft Academic Search

Many human skin tumors contain mutated p53 genes that probably result from UV exposure. To investigate the link between UV exposure and p53 gene mutation, we developed two methods to detect presumptive UV-specific p53 gene mutations in UV-exposed normal skin. The methods are based on mutant allele-specific PCRs and ligase chain reactions and designed to detect CC to TT mutations

Hisayoshi Nakazawa; Dallas English; Peter L. Randell; Keiko Nakazawa; Nicole Martel; Bruce K. Armstrong; Hiroshi Yamasaki

1994-01-01

326

Two missense mutations of the IRF6 gene in two Japanese families with popliteal pterygium syndrome.  

PubMed

Mutations in the interferon regulatory factor 6 gene (IRF6) cause either popliteal pterygium syndrome (PPS) or Van der Woude syndrome (VWS), allelic autosomal dominant orofacial clefting conditions. To further investigate the IRF6 mutation profile in PPS, we performed mutation analysis of patients from two unrelated Japanese families with PPS and identified mutations in IRF6: c.251G>T (R84L) and c.1271C>T (S424L). We also found R84L, which together with previous reports on R84 mutations, provided another line of evidence that both syndromes could result from the same mutation probably under an influence of a modifier gene(s). This supports the idea that the R84 residue in the DNA binding domain of IRF6 is a mutational hot spot for PPS. A luciferase assay of the S424L protein in the other family demonstrated that the mutation decreased the IRF6 transcriptional activity significantly to 6% of that of the wild-type. This finding suggests that the C-terminus region of IRF6 could have an important function in phosphorylation or protein interaction. To our knowledge, this is the first report of mutations observed in Japanese PPS patients. PMID:20803643

Matsuzawa, Noriko; Kondo, Shinji; Shimozato, Kazuo; Nagao, Toru; Nakano, Motoi; Tsuda, Masayoshi; Hirano, Akiyoshi; Niikawa, Norio; Yoshiura, Koh-Ichiro

2010-09-01

327

Dominance Effects of Deleterious and Beneficial Mutations in a Single Gene of the RNA Virus ?6  

PubMed Central

Most of our knowledge of dominance stems from studies of deleterious mutations. From these studies we know that most deleterious mutations are recessive, and that this recessivity arises from a hyperbolic relationship between protein function (i.e., protein concentration or activity) and fitness. Here we investigate whether this knowledge can be used to make predictions about the dominance of beneficial and deleterious mutations in a single gene. We employed a model system – the bacteriophage ?6 – that allowed us to generate a collection of mutations in haploid conditions so that it was not biased toward either dominant beneficial or recessive deleterious mutations. Screening for the ability to infect a bacterial host that does not permit infection by the wildtype ?6, we generated a collection of mutations in P3, a gene involved in attachment to the host and in phage particle assembly. The resulting collection contained mutations with both deleterious and beneficial effects on fitness. The deleterious mutations in our collection had additive effects on fitness and the beneficial mutations were recessive. Neither of these observations were predicted from previous studies of dominance. This pattern is not consistent with the hyperbolic (diminishing returns) relationship between protein function and fitness that is characteristic of enzymatic genes, but could have resulted from a curve of increasing returns. PMID:24945910

Joseph, Sarah B.; Peck, Kayla M.; Burch, Christina L.

2014-01-01

328

Mutational status of VHL gene and its clinical importance in renal clear cell carcinoma.  

PubMed

The most common subtype of renal cell carcinoma is the clear cell type (ccRCC), accounting for 75 % of cases. Inactivation of VHL gene is thought to be an early event in ccRCC carcinogenesis. Our intention was to assess whether VHL mutational status might provide useful predictive or prognostic information in patients with ccRCC. VHL messenger RNA (mRNA) expression was analyzed by in situ hybridization and its protein by immunohistochemistry on a tissue microarray containing samples from 148 cases. This was validated by qRT-PCR on 62 cases, for which RNA was available. The mutation status was assessed in 91 cases by Sanger sequencing. VHL was found mutated in 57 % of cases, with missense mutations in 26 %, nonsense in 5 %, splice site in 13 %, deletions in 39 %, indels in 8 %, duplications in 8 %, and insertions in 2 % of the cases. The prevalence of mutations by exon was the following: exon 1, 47 %; exon 2, 27 %; and exon 3, 13 %. VHL protein was expressed in a high number of cases (80 %), but significant correlations were not found between protein expression, clinical data, and survival. Importantly, of the 91 samples evaluated by sequencing, 45 were mutated, and 87 % of those were strongly positive. We found 32 novel mutations in the VHL gene in ccRCC. The presence of mutations was not concordant with mRNA or protein expression. Nonsense mutations of the VHL gene appear to be related with poorer prognosis and survival. PMID:25027579

Alves, Mariana Rezende; Carneiro, Felipe Cavalcanti; Lavorato-Rocha, André Mourăo; da Costa, Walter Henriques; da Cunha, Isabela Werneck; de Cássio Zequi, Stęnio; Guimaraes, Gustavo Cardoso; Soares, Fernando Augusto; Carraro, Dirce Maria; Rocha, Rafael Malagoli

2014-09-01

329

Isolation and Characterization of Point Mutations in Mismatch Repair Genes That Destabilize Microsatellites in Yeast  

Microsoft Academic Search

The stability of simple repetitive DNA sequences (microsatellites) is a sensitive indicator of the ability of a cell to repair DNA mismatches. In a genetic screen for yeast mutants with elevated microsatellite instability, we identified strains containing point mutations in the yeast mismatch repair genes, MSH2, MSH3, MLH1, and PMS1. Some of these mutations conferred phenotypes significantly different from those

ELAINE AYRES SIA; MARGARET DOMINSKA; LELA STEFANOVIC; THOMAS D. PETES

2001-01-01

330

Clinical and Biological Features Associated With Epidermal Growth Factor Receptor Gene Mutations in Lung Cancers  

Microsoft Academic Search

Background: Mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene in lung cancers are associated with increased sensitivity of these can- cers to drugs that inhibit EGFR kinase activity. However, the role of such mutations in the pathogenesis of lung cancers is unclear. Methods: We sequenced exons 18 - 21 of the EGFR TK

Hisayuki Shigematsu; Li Lin; Takao Takahashi; Masaharu Nomura; Makoto Suzuki; Ignacio I. Wistuba; Kwun M. Fong; Huei Lee; Shinichi Toyooka; Nobuyoshi Shimizu; Takehiko Fujisawa; Ziding Feng; Jack A. Roth; Joachim Herz; John D. Minna; Adi F. Gazdar

331

Detection of point mutation in the p53 gene using a peptide nucleic acid biosensor  

Microsoft Academic Search

A 17-mer peptide nucleic acid (PNA) is used as the recognition layer of an electrochemical biosensor for detecting a specific mutation in the p53 gene. The performance of the PNA-derived biosensor is compared with that of its DNA counterpart. The significantly higher specificity of the PNA probe greatly improves the detection of a single point mutation, found in many types

Joseph Wang; Gustavo Rivas; Xiaohua Cai; Manuel Chicharro; Concepcion Parrado; Narasaiah Dontha; Asher Begleiter; Michael Mowat; Emil Palecek; Peter E. Nielsen

1997-01-01

332

Low prevalence of glucokinase gene mutations in gestational diabetic patients with good glycemic control.  

PubMed

Glucokinase (GCK) plays a key role in glucose homeostasis. Gestational diabetes mellitus increases the risk of gestational complications in pregnant women and fetuses. We screened for mutations in coding and flanking regions of the GCK gene in pregnant women with or without gestational diabetes in a Brazilian population. A sample of 200 pregnant women classified as healthy (control, N = 100) or with gestational diabetes (N = 100) was analyzed for mutations in the GCK gene. All gestational diabetes mellitus patients had good glycemic control maintained by diet alone and no complications during pregnancy. Mutations were detected by single-strand conformation polymorphism and DNA sequencing. Thirteen of the 200 subjects had GCK gene mutations. The mutations detected were in intron 3 (c.43331A>G, new), intron 6 (c.47702T>C, rs2268574), intron 9 (c.48935C>T, rs2908274), and exon 10 (c.49620G>A, rs13306388). None of these GCK mutations were found to be significantly associated with gestational diabetes mellitus. In summary, we report a low frequency of GCK mutations in a pregnant Brazilian population and describe a new intronic variation (c.43331A>G, intron 3). We conclude that mutations in GCK introns and in non-translatable regions of the GCK gene do not affect glycemic control and are not correlated with gestational diabetes mellitus. PMID:22653590

Frigeri, H R; Santos, I C R; Réa, R R; Almeida, A C R; Fadel-Picheth, C M T; Pedrosa, F O; Souza, E M; Rego, F G M; Picheth, G

2012-01-01

333

A Cluster of Mutations within a Short Triplet Repeat in the C1 Inhibitor Gene  

Microsoft Academic Search

Mutations in the C1 inhibitor gene that result in low functional levels of C1 inhibitor protein cause hereditary angioneurotic edema. This disease is characterized by episodic edema leading to considerable morbidity and death. Among 60 unreported kindred with the disease, four patients were discovered to have mutations clustered within a 12-bp segment of exon 5 from nucleotide 8449 to nucleotide

John J. Bissler; Marco Cicardi; Virginia H. Donaldson; Paul A. Gatenby; Fred S. Rosen; Albert L. Sheffer; Alvin E. Davis III

1994-01-01

334

Mutations and a polymorphism in the factor VIII gene discovered by denaturing gradient gel electrophoresis  

SciTech Connect

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.

Kogan, S.; Gitschier, J. (Univ. of California, San Francisco (USA))

1990-03-01

335

Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis  

Microsoft Academic Search

BACKGROUND & AIMS: We recently identified a single R117H mutation in the cationic trypsinogen gene in several kindreds with an inherited form of acute and chronic pancreatitis (HP1), providing strong evidence that trypsin plays a central role in premature zymogen activation and pancreatitis. However, not all families studied have this mutation. The aim of this study was to determine the

M. C. Gorry; D. Gabbaizedeh; W. Furey; L. K. Gates; RA Preston; C. E. Aston; Y Zhang; C Ulrich; GD Ehrlich; DC Whitcomb

1997-01-01

336

Missense mutation in the Chlamydomonas chloroplast gene that encodes the Rubisco large subunit  

SciTech Connect

The 69-12Q mutant of Chlamydomonas reinhardtii lacks ribulose-1,5-bisphosphate carboxylase activity, but retains holoenzyme protein. It results from a mutation in the chloroplast large-subunit gene that causes an isoleucine-for-threonine substitution at amino-acid residue 173. Considering that lysine-175 is involved in catalysis, it appears that mutations cluster at the active site.

Spreitzer, R.J.; Brown, T.; Chen, Zhixiang; Zhang, Donghong; Al-Abed, S.R. (Univ. of Nebraska, Lincoln (USA))

1988-04-01

337

Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis  

Microsoft Academic Search

expression identical to the 1q-linked form, is due to inactivation of hepcidin, the key regulator of iron homeostasis. Here we report the spectrum of mutations of the hemojuvelin gene (HJV) in 34 patients who did not show hepcidin mutations. This represents the largest cohort of pa- tients with JH collected worldwide. We identified 17 different (16 novel) muta- tions of

Carmela Lanzara; Antonella Roetto; Filomena Daraio; Silvain Rivard; Romina Ficarella; Hervey Simard; Timothy M. Cox; Mario Cazzola; Alberto Piperno; Anne-Paule Gimenez-Roqueplo; Paola Grammatico; Stefano Volinia; Paolo Gasparini; Clara Camaschella

2004-01-01

338

Identification of mutation sites on omega3 desaturase genes from Mortierella alpina 1S-4 mutants.  

PubMed

The mutation sites on omega3 desaturase genes in two omega3 desaturase-defective mutants derived from arachidonic acid-producing Mortierella alpina 1S-4 were identified. The mutations each resulted in an amino acid replacement (W232Stop or W386Stop) which caused a lack of omega3 desaturase activity in these mutants. PMID:19147101

Sakuradani, Eiji; Abe, Takahiro; Shimizu, Sakayu

2009-01-01

339

Mutational hot spot in the p53 gene in human hepatocellular carcinomas  

Microsoft Academic Search

HUMAN hepatocellular carcinomas (HCC) from patients in Qidong, an area of high incidence in China, in which both hepatitis B virus and aflatoxin B1 are risk factors1, were analysed for mutations in p53, a putative tumour-suppressor gene. Eight of the 16 HCC had a point mutation at the third base position of codon 249. The G --> T transversion in

I. C. Hsu; R. A. Metcalf; T. Sun; J. A. Welsh; N. J. Wang; C. C. Harris

1991-01-01

340

Preliminary mutation analysis in the phenylanaline hydroxylase gene in Greek PKU and HPA patients  

Microsoft Academic Search

The presence of nine mutations in the phenylalanine hydroxlase (PAH) gene, previously described in phenylketonuria (PKU) patients of other Mediterranean and European populations, was assessed in 47 Greek PKU and 3 hyperphenylalaninaemia (HPA) patients. Of the nine mutations investigated, only five were detected, characterizing 31 % of the PKU alleles in our patients.

J. Traeger-Synodinos; E. Kanavakis; M. Kalogerakou; K. Soulpi; S. Missiou-Tsangaraki; C. Kattamis

1994-01-01

341

High accuracy mutation detection in leukemia on a selected panel of cancer genes.  

PubMed

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

Kalender Atak, Zeynep; De Keersmaecker, Kim; Gianfelici, Valentina; Geerdens, Ellen; Vandepoel, Roel; Pauwels, Daphnie; Porcu, Michaël; Lahortiga, Idoya; Brys, Vanessa; Dirks, Willy G; Quentmeier, Hilmar; Cloos, Jacqueline; Cuppens, Harry; Uyttebroeck, Anne; Vandenberghe, Peter; Cools, Jan; Aerts, Stein

2012-01-01

342

Quantification of the paternal allele bias for new germline mutations in the retinoblastoma gene  

SciTech Connect

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).

Morrow, J.F.; Rapaport, J.M.; Dryia, T.P. [Massachusetts Eye & Ear Infirmary, Boston, MA (United States)

1994-09-01

343

Aberrant transmembrane signal transduction in Dictyostelium cells expressing a mutated ras gene.  

PubMed Central

Dictyostelium discoideum cells contain a single ras gene (Dd-ras) that is highly homologous to mammalian ras genes. Cell transformation with a vector carrying a ras gene with a (glycine----threonine) missense mutation at position 12 causes an altered morphogenesis. Extracellular cAMP signals regulate morphogenesis and induce chemotaxis and the activation and subsequent desensitization of adenylate and guanylate cyclase. cAMP signal transduction was investigated in Dd-ras-transformed cells. Transformants that overexpress the mutated Dd-ras-Thr12 gene show normal activation and desensitization of adenylate cyclase and normal activation of guanylate cyclase. However, cAMP induces a stronger desensitization of guanylate cyclase stimulation in the Dd-ras-Thr12 transformant than in transformants overexpressing the Dd-ras-Gly12 wild-type gene or in untransformed cells. This effect was correlated with a reduced chemotactic sensitivity of the transformant expressing the mutated Dd-ras-Thr12 gene. PMID:2885843

Van Haastert, P J; Kesbeke, F; Reymond, C D; Firtel, R A; Luderus, E; Van Driel, R

1987-01-01

344

UCSD scientists find gene mutation for aggressive form of pancreatic cancer  

Cancer.gov

Researchers at the University of California, San Diego School of Medicine have identified a mutated gene common to adenosquamous carcinoma tumors – the first known unique molecular signature for this rare, but particularly virulent, form of pancreatic cancer.

345

Methods for the identification of mutations in the human phenylalanine hydroxylase gene using DNA probes  

SciTech Connect

This patent describes a method of detecting a mutation in a phenylalanine hydroxylase gene of human genomic DNA. Also described is an automated method of detecting PKU affected, PKU helerozgotes and normals in fetal to adult human samples.

Woo, S.L.C.; Dilella, A.G.

1990-10-23

346

Mutation profile of the MYO7A gene in Spanish patients with Usher syndrome type I.  

PubMed

Usher syndrome type I is the most severe form of Usher syndrome. It is an autosomal recessive disorder characterized by profound congenital sensorineural deafness, retinitis pigmentosa, and vestibular abnormalities. Mutations in the myosin VIIA gene (MYO7A) are responsible for Usher syndrome type 1B (USH1B). This gene is thought to bear greatest responsibility for USH1 and, depending on the study, has been reported to account for between 24% and 59% of USH1 cases. In this report a mutation screening of the MYO7A gene was carried out in a series of 48 unrelated USH1 families using single strand conformation polymorphism analysis (SSCP) and direct sequencing of those fragments showed an abnormal electrophoretic pattern. Twenty-five mutations were identified in 23 out of the 48 families studied (47.9%). Twelve of these mutations were novel, including five missense mutations, three premature stop codons, three frameshift, and one putative splice-site mutation. Based on our results we can conclude there is an absence of hot spot mutations in the MYO7A gene and that this gene plays a major role in Usher syndrome. PMID:16470552

Jaijo, T; Aller, E; Oltra, S; Beneyto, M; Nájera, C; Ayuso, C; Baiget, M; Carballo, M; Antińolo, G; Valverde, D; Moreno, F; Vilela, C; Perez-Garrigues, H; Navea, A; Millán, J M

2006-03-01

347

1/9/09 2:14 PMResearchers Pinpoint Spontaneous Gene Mutations Responsible for 10 Percent of Non-Familial Cases of Schizophrenia Page 1 of 3http://cumc.columbia.edu/news/press_releases/gene-mutation-schizophrenia.html  

E-print Network

-Familial Cases of Schizophrenia Page 1 of 3http://cumc.columbia.edu/news/press_releases/gene-mutation-schizophrenia Gene Mutations Responsible for 10 Percent of Non-Familial Cases of Schizophrenia NEW YORK (May 30, 2008) ­ Scans of the genome of patients with schizophrenia have revealed rare spontaneous copy number mutations

348

A Network of Cancer Genes with Co-Occurring and Anti-Co-Occurring Mutations  

Microsoft Academic Search

Certain cancer genes contribute to tumorigenesis in a manner of either co-occurring or mutually exclusive (anti-co-occurring) mutations; however, the global picture of when, where and how these functional interactions occur remains unclear. This study presents a systems biology approach for this purpose. After applying this method to cancer gene mutation data generated from large-scale and whole genome sequencing of cancer

Qinghua Cui

2010-01-01

349

Familiar ochronotic arthropathy–caused by a gene mutation traced three hundred years  

Microsoft Academic Search

Authors trace an ochronotic Hungarian family, which moved from Slovakia to Hungary 300 years ago. As the family members lived in a relatively close village community the gene mutation had been survived silently for ages before the clinical symptoms developed. Family tree analysis could detect with the use of allele specific PCR amplification–the p.G161R mutation of the homogentisic acid 1,2-dioxygenase (HGD) gene,

Kálmán Tóth; Zsuzsanna Kiss-Láaszló; Endre Lénárt; Katalin Juhász; Katalin Takács; Tamas Bender; Janos Szabó

2010-01-01

350

A splicing mutation in the ?5(IV) collagen gene of a family with Alport's syndrome  

Microsoft Academic Search

A splicing mutation in the ?5(IV) collagen gene of a family with Alport's syndrome. DNA sequence analysis of the ?5(IV) collagen chain gene (COL4A5) was carried out between exon 47 and 51, which encode the noncollagenous (NC) domain, in eight Japanese families with Alport's syndrome. In one family with X-linked inheritance of the disease, a point mutation (G to C)

Shinsuke Nomura; Gengo Osawa; Tetsujun Sai; Teruo Harano; Keiko Harano

1993-01-01

351

Novel Gene Mutations in Patients With Left Ventricular Noncompaction or Barth Syndrome  

Microsoft Academic Search

Background—Mutations in the gene G4.5 result in a wide spectrum of severe infantile cardiomyopathic phenotypes, including isolated left ventricular noncompaction (LVNC), as well as Barth syndrome (BTHS) with dilated cardiomyopathy (DCM). The purpose of this study was to investigate patients with LVNC or BTHS for mutations in G4.5 or other novel genes. Methods and Results—DNA was isolated from 2 families

Fukiko Ichida; Shinichi Tsubata; Karla R. Bowles; Noriyuki Haneda; Keiichiro Uese; Toshio Miyawaki; W. Jeffrey Dreyer; John Messina; Hua Li; Neil E. Bowles; Jeffrey A. Towbin

2010-01-01

352

Mutation Analysis of 3 Genes in Patients With Leber Congenital Amaurosis  

Microsoft Academic Search

Methods: Samples were screened with single-strand con- formation polymorphism analysis followed by DNA se- quencing of 3 genes (CRX, GUCY2D, and RPE65) known to be associated with LCA. Results: Of the 176 probands, 28 (15.9%) harbored pos- sible disease-causing mutations. The relative contribu- tion of each gene to the total number of mutations was as follows: CRX, 2.8%; GUCY2D, 6.3%;

Andrew J. Lotery; P. Namperumalsamy; Samuel G. Jacobson; Richard G. Weleber; Gerald A. Fishman; Maria A. Musarella; Creig S. Hoyt; Elise Heon; Alex Levin; James Jan; Byron Lam; Ronald E. Carr; Alan Franklin; S. Radha; Jeaneen L. Andorf; Val C. Sheffield; Edwin M. Stone

2000-01-01

353

RPE65 gene: Multiplex PCR and mutation screening in patients from India with retinal degenerative diseases  

Microsoft Academic Search

We used multiplex PCR followed by sequencing to screen for mutations in the 14 exons of theRPE65 gene in early-hildhood-onset autosomal recessive retinitis pigmentosa (arRP) and Leber’s congenital amaurosis (LCA) patients.\\u000a The RPE65 protein is believed to play an important role in the metabolism of vitamin A in the visual cycle and mutations identified\\u000a in the gene could have implications

Biju Joseph; Anuradha Srinivasan; Nagasamy Soumittra; Authiappan Vidhya; Nitin Shridhara Shetty; Satagopan Uthra; Govindasamy Kumaramanickavel

2002-01-01

354

Genotype\\/Phenotype Correlation of Multiple Endocrine Neoplasia Type 1 Gene Mutations in Sporadic Gastrinomas  

Microsoft Academic Search

Multiple endocrine neoplasia type 1 (MEN1) gene mutations are reported in some gastrinomas occurring in patients without MEN1 as well as in some other pancreatic endocrine tumors (PETs). In some inherited syndromes phenotype-genotype correlations exist for dis- ease severity, location, or other manifestations. The purpose of the present study was to correlate mutations of the MEN1 gene in a large

STEPHAN U. GOEBEL; CHRISTINA HEPPNER; A. LEE BURNS; STEPHEN J. MARX; ALLEN M. SPIEGEL; ZHENGPING ZHUANG; IRINA A. LUBENSKY; FATHIA GIBRIL; ROBERT T. JENSEN

2010-01-01

355

Mutational analysis of the RPGRIP1L gene in patients with Joubert syndrome and nephronophthisis  

Microsoft Academic Search

Joubert syndrome (JS) is an autosomal recessive disorder, consisting of mental retardation, cerebellar vermis aplasia, an irregular breathing pattern, and retinal degeneration. Nephronophthisis (NPHP) is found in 17–27% of these patients, which was designated JS type B. Mutations in four separate genes (AHI1, NPHP1, CEP290\\/NPHP6, and MKS3) are linked to JS. However, missense mutations in a new ciliary gene (RPGRIP1L)

M T F Wolf; S Saunier; J F O'Toole; N Wanner; T Groshong; M Attanasio; R Salomon; T Stallmach; J A Sayer; R Waldherr; M Griebel; J Oh; T J Neuhaus; U Josefiak; C Antignac; E A Otto; F Hildebrandt

2007-01-01

356

Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome  

Microsoft Academic Search

We identified a deletion of a gene encoding a subunit of RNA polymerases I and III, POLR1D, in an individual with Treacher Collins syndrome (TCS). Subsequently, we detected 20 additional heterozygous mutations of POLR1D in 252 individuals with TCS. Furthermore, we discovered mutations in both alleles of POLR1C in three individuals with TCS. These findings identify two additional genes involved

J. G. Dauwerse; J. Dixon; S. Seland; C. A. Ruivenkamp; A. van Haeringen; L. H. Hoefsloot; D. J. Peters; A. C. Boers; C. Daumer-Haas; R. Maiwald; C. Zweier; B. Kerr; A. M. Cobo; J. F. Toral; A. J. M. Hoogeboom; D. R. Lohmann; U. Hehr; M. J. Dixon; M. H. Breuning; D. Wieczorek

2011-01-01

357

Whole exome sequencing reveals concomitant mutations of multiple FA genes in individual Fanconi anemia patients  

PubMed Central

Background Fanconi anemia (FA) is a rare inherited genetic syndrome with highly variable clinical manifestations. Fifteen genetic subtypes of FA have been identified. Traditional complementation tests for grouping studies have been used generally in FA patients and in stepwise methods to identify the FA type, which can result in incomplete genetic information from FA patients. Methods We diagnosed five pediatric patients with FA based on clinical manifestations, and we performed exome sequencing of peripheral blood specimens from these patients and their family members. The related sequencing data were then analyzed by bioinformatics, and the FANC gene mutations identified by exome sequencing were confirmed by PCR re-sequencing. Results Homozygous and compound heterozygous mutations of FANC genes were identified in all of the patients. The FA subtypes of the patients included FANCA, FANCM and FANCD2. Interestingly, four FA patients harbored multiple mutations in at least two FA genes, and some of these mutations have not been previously reported. These patients’ clinical manifestations were vastly different from each other, as were their treatment responses to androstanazol and prednisone. This finding suggests that heterozygous mutation(s) in FA genes could also have diverse biological and/or pathophysiological effects on FA patients or FA gene carriers. Interestingly, we were not able to identify de novo mutations in the genes implicated in DNA repair pathways when the sequencing data of patients were compared with those of their parents. Conclusions Our results indicate that Chinese FA patients and carriers might have higher and more complex mutation rates in FANC genes than have been conventionally recognized. Testing of the fifteen FANC genes in FA patients and their family members should be a regular clinical practice to determine the optimal care for the individual patient, to counsel the family and to obtain a better understanding of FA pathophysiology. PMID:24885126

2014-01-01

358

Mutational Analysis of Thirty-two Double-Strand DNA Break Repair Genes in Breast and Pancreatic Cancers  

Microsoft Academic Search

Inactivating mutations in several genes that encode compo- nents of the DNA repair machinery have been associated with an increased risk of breast cancer. To assess whether alterations in other DNA repair genes contribute to breast cancer and to further determine the relevance of these genes to pancreatic cancer, we performed mutational analysis of 32 DNA double-strand break repair genes

Xianshu Wang; Csilla Szabo; Chiping Qian; Peter G. Amadio; Stephen N. Thibodeau; James R. Cerhan; Gloria M. Petersen; Wanguo Liu

2008-01-01

359

Distribution of ?-Globin Gene Mutations in Thalassemia Minor Population of Kerman Province, Iran  

PubMed Central

Background: Mutations in ?-globin gene may result in ?-thalassemia major, which is one of the most common genetic disorders in Iran and some other countries. Knowing the beta-globin mutation spectrum improves the efficiency of prenatal diagnosis in the affected fetuses (major ?-thalassemia) of heterozygote couples. Methods: Couples with high hemoglobin A2 and low mean corpuscular volume were studied as suspicious of ?-thalassemia carriers in Genetic Laboratory of Afzalipour Hospital, Kerman, Iran. We used amplification refractory mutation system, reverse hybridization, and DNA sequencing to determine the spectrum of ?-globin gene mutation in the people who involved with ?-thalassemia minor in this province. Results: Among the 266 subjects, 17 different types of mutation in ?-globin gene were identified. Three of the mutations account for 77.1% of the studied cases. IVSI-5(G> C) was the most frequent mutation (66.2%) followed by IVSII-I (G> A) (6%) and Fr 8–9 (+G) (4.9%). The less frequent mutations include: IVSI-6(T> C), codon 15 (G>A), codon 44 (-C), codon 39 (C>T), codon 8 (-AA), codon30 (G> C), IVSI-110 (G > A), codon 36–37 (-T), 619bp deletion, codon 5 (-CT), IVSI-25bp del, codon 41–42(-TTCT), IVSI-I (G> A), and ?nt30 (T>A) were accounted for 19.5%. Unknown alleles comprised 3.4% of the mutations. Conclusion: However, the frequencies of different mutations reported here are significantly different from those found in other part of the world and even other Iranian provinces. Reporting a number of these mutations in the neighboring countries such as Pakistan can be explained by gene flow phenomenon. PMID:23113009

Saleh-Gohari, N; Bazrafshani, MR

2010-01-01

360

Detection of Heterozygous Truncating Mutations in the BRCA1 and APC Genes by Using a Rapid Screening Assay in Yeast  

Microsoft Academic Search

The detection of inactivating mutations in tumor suppressor genes is critical to their characterization, as well as to the development of diagnostic testing. Most approaches for mutational screening of germ-line specimens are complicated by the fact that mutations are heterozygous and that missense mutations are difficult to interpret in the absence of information about protein function. We describe a novel

Chikashi Ishioka; Takao Suzuki; Michael Fitzgerald; Michael Krainer; Hideki Shimodaira; Akira Shimada; Tadashi Nomizu; Kurt J. Isselbacher; Daniel Haber; Ryunosuke Kanamaru

1997-01-01

361

Three novel PHEX gene mutations in four Chinese families with X-linked dominant hypophosphatemic rickets  

SciTech Connect

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.

Kang, Qing-lin [Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China)] [Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China); Xu, Jia [Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China) [Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China); Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China); Medical College of Soochow University, Suzhou, Jiangsu province 215000 (China); Zhang, Zeng [Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China) [Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China); Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China); He, Jin-wei [Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China)] [Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China); Lu, Lian-song [Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China) [Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China); Medical College of Soochow University, Suzhou, Jiangsu province 215000 (China); Fu, Wen-zhen [Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China)] [Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China); Zhang, Zhen-lin, E-mail: zzl2002@medmail.com.cn [Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China)] [Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233 (China)

2012-07-13

362

Overexpression of genes involved in miRNA biogenesis in medullary thyroid carcinomas with RET mutation.  

PubMed

Abnormal expression of non-coding micro RNA (miRNA) has been described in medullary thyroid carcinoma (MTC). Expression of genes encoding factors involved in miRNA biogenesis results often deregulated in human cancer and correlates with aggressive clinical behavior. In this study, expression of four genes involved in miRNA biogenesis (DICER, DROSHA, DCGR8, and XPO5) was investigated in 54 specimens of MTC. Among them, 33 and 13 harbored RET and RAS mutations, respectively. DICER, DGCR8, and XPO5 mRNA levels were significantly overexpressed in MTC harboring RET mutations, in particular, in the presence of RET634 mutation. When MTCs with RET and RAS mutations were compared, only DGCR8 displayed a significant difference, while MTCs with RAS mutations did not show significant differences with respect to non-mutated tumors. We then attempted to correlate expression of miRNA biogenesis genes with tumor aggressiveness. According to the TNM status, MTCs were divided in two groups and compared (N0 M0 vs. N1 and/or M1): for all four genes no significant difference was detected. Cell line experiments, in which expression of a RET mutation is silenced by siRNA, suggest the existence of a causal relationship between RET mutation and overexpression of DICER, DGCR8, and XPO5 genes. These findings demonstrate that RET- but not RAS-driven tumorigenic alterations include abnormalities in the expression of some important genes involved in miRNA biogenesis that could represent new potential markers for targeted therapies in the treatment of RET-mutated MTCs aimed to restore the normal miRNA expression profile. PMID:24569963

Puppin, Cinzia; Durante, Cosimo; Sponziello, Marialuisa; Verrienti, Antonella; Pecce, Valeria; Lavarone, Elisa; Baldan, Federica; Campese, Antonio Francesco; Boichard, Amelie; Lacroix, Ludovic; Russo, Diego; Filetti, Sebastiano; Damante, Giuseppe

2014-11-01

363

Characterization of in vivo somatic mutations at the hypoxanthine phosphoribosyltransferase gene of a human control population  

SciTech Connect

The ability to recognize a change in mutation spectrum after an exposure to a toxic substance and then relate that exposure to health risk depends on the knowledge of mutations that occur in the absence of exposure. The authors have been studying both the frequency and molecular nature of mutations of the hypoxanthine phosphoribosyltransferase (hprt) gene in peripheral blood lymphocytes as surrogate reporters of genetic damage. The authors have analyzed mutants, one per donor to ensure independence, from a control population in which the quantitative effect of smoking and age on mutant frequency have been well defined. Analyses of cDNA and genomic DNA by polymerase chain reaction and sequencing have identified the mutations in 63 mutants, 45 from males and 18 from females, of which 34 were smokers and 29 were nonsmokers. Slightly less than half of the mutations were base substitutions (28); they were predominantly at GC base pairs (19). Different mutations at the same site indicated that there are features of the hprt polypeptide that affect the mutation spectrum. Two pairs of identical mutations indicated that there may be hot spots. Mutations not previously reported have been detected, indicating that the mutation spectrum is only partly defined. The remainder of the mutations were deletions (32) or insertions/duplications (3); deletions ranged from one base pair to complete loss of the locus. Despite a small average increase in mutant frequency for smokers, an increased proportion of base substitutions at AT base pairs in smokers (p = 0.2) hinted at a smoking-associated shift in the mutation spectrum. Expanding the study to include individuals with larger, smoking-associated increases of mutant frequency will determine the significance of this observation. This background mutation study provides insight into factors that determine the mutation spectra of the hprt locus and provides data for comparison with mutation spectra of other populations. 44 refs., 7 tabs.

Burkhart-Schultz, K.; Thomas, C.B.; Brinson, E.; Jones, I.M. (Lawrence Livermore National Lab., CA (United States)); Thompson, C.L.; Strout, C.L. (National Inst. of Environmental Health Sciences, Research Triangle Park, NC (United States))

1993-04-22

364

Two novel mutations in the myophosphorylase gene in a patient with McArdle disease.  

PubMed

We identified two novel mutations in exon 2 of the myophosphorylase gene in a 33-year-old German women with McArdle disease. The patient was compound heterozygous for a novel nonsense mutation at codon 84 changing tyrosine to stop codon (Y84X) and for a novel missense mutation at codon 93 changing arginine to tryptophan (R93W). These mutations are the first to be described in exon 2 and expand the genetic heterogeneity in patients with McArdle disease. PMID:12508303

Deschauer, Marcus; Hertel, Kathrin; Zierz, Stephan

2003-01-01

365

"20209C-T" a variant mutation of prothrombin gene mutation in a patient with recurrent pregnancy loss.  

PubMed

Recurrent pregnancy loss is considered when a female undergoes at least two consecutive, spontaneous abortions or more than two alternatively. This condition affects approximately 5% of women in reproductive age. Several causes of recurrent abortion have been established, but nevertheless, approximately half of all cases remain unexplained. Thrombophilic disorders have been suggested as a possible cause of recurrent miscarriage. A single 20210 G-A mutation of the 3'-untranslated region of (F2) has been reported as a cause of inherited thrombophilia. The F2 G-A mutation affects 1% to 4% of the US population, and its prevalence is higher among Caucasian women of Southern European descendants. Studies of G20210A polymorphism have also shown conflicting associations with recurrent abortions. In addition to G20210A polymorphism, other mutations affecting the F2 gene have been associated with thrombosis and/or pregnancy complications. PMID:25117109

Prat, Maria; Morales-Indiano, Cristian; Jimenez, Carme; Mas, Virgina; Besses, Carles; Checa, Miguel A; Carreras, Ramon

2014-01-01

366

Genetic characterization of Swedish patients with familial hypercholesterolemia: a heterogeneous pattern of mutations in the LDL receptor gene  

Microsoft Academic Search

Familial hypercholesterolemia (FH) is an autosomal codominant disease, caused by mutations in the LDL receptor gene. To characterize the distribution of genetic aberrations in Swedish FH-patients fulfilling the clinical criteria of FH, we have investigated 150 unrelated Swedish patients for mutations in the LDL receptor gene and for the most common mutation causing familial ligand defective apo B-100 (FDB). Of

S. Lind; E. Rystedt; M. Eriksson; O. Wiklund; B. Angelin; G. Eggertsen

2002-01-01

367

Cellular and molecular aspects of familial hypertrophic cardiomyopathy caused by mutations in the cardiac troponin I gene  

Microsoft Academic Search

Mutations in the cardiac troponin I (CTnI) gene occur in ~5% of families with familial hypertrophic cardiomyopathy (FHC) and 20 mutations in this gene that cause FHC have now been described. The clinical manifestations of CTnI mutations that cause FHC are diverse, ranging from asymptomatic with high life expectancy to severe heart failure and sudden cardiac death. Most of these

Aldrin V. Gomes; James D. Potter

2004-01-01

368

Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly.  

PubMed

Mutations in the PTEN gene are associated with a broad spectrum of disorders, including Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Lhermitte-Duclos disease. In addition, PTEN mutations have been described in a few patients with autism spectrum disorders (ASDs) and macrocephaly. In this study, we screened the PTEN gene for mutations and deletions in 88 patients with ASDs and macrocephaly (defined as >or=2 SD above the mean). Mutation analysis was performed by direct sequencing of all exons and flanking regions, as well as the promoter region. Dosage analysis of PTEN was carried out using multiplex ligation-dependent probe amplification (MLPA). No partial or whole gene deletions were observed. We identified a de novo missense mutation (D326N) in a highly conserved amino acid in a 5-year-old boy with autism, mental retardation, language delay, extreme macrocephaly (+9.6 SD) and polydactyly of both feet. Polydactyly has previously been described in two patients with Lhermitte-Duclos disease and CS and is thus likely to be a rare sign of PTEN mutations. Our findings suggest that PTEN mutations are a relatively infrequent cause of ASDs with macrocephaly. Screening of PTEN mutations is warranted in patients with autism and pronounced macrocephaly, even in the absence of other features of PTEN-related tumor syndromes. PMID:17427195

Buxbaum, Joseph D; Cai, Guiqing; Chaste, Pauline; Nygren, Gudrun; Goldsmith, Juliet; Reichert, Jennifer; Anckarsäter, Henrik; Rastam, Maria; Smith, Christopher J; Silverman, Jeremy M; Hollander, Eric; Leboyer, Marion; Gillberg, Christopher; Verloes, Alain; Betancur, Catalina

2007-06-01

369

Heterozygosity Loss at 22q and Lack of INI1 Gene Mutation in Gastrointestinal Stromal Tumor  

Microsoft Academic Search

Objectives: Gastrointestinal stromal tumor (GIST) is characterized by KIT or PDGFRA gene mutation. Although chromosomal losses of 22q are frequent in GIST, it is unclear which tumor suppressor genes might be inactivated in association with such losses. The INI1 gene, located at 22q11.23, is a tumor suppressor gene that is frequently altered in malignant rhabdoid tumor. Methods: To elucidate the

Hidetaka Yamamoto; Kenichi Kohashi; Masazumi Tsuneyoshi; Yoshinao Oda

2011-01-01

370

Novel mutation of the notch3 gene in arabic family with CADASIL  

PubMed Central

Mutations in the NOTCH3 gene are responsible for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), an adult onset hereditary angiopathy leading to ischemic stroke, vascular dementia and psychiatric disorders. All mutation of NOTCH3 described so far are striking stereotyped leading to the gain or loss of cystiene residue in a given epidermal growth factor (EGF), like repeat. We report an Arabic family affected with CADASIL mutation, G1790 C, in Exon 11 of the NOTCH3 gene. This is the first novel mutation reported in Arabic CADASIL patients. This finding confirms that mutations in NOTCH3 are associated with the pathogenesis of CADASIL across different ethnic background. PMID:22053260

Bohlega, Saeed

2011-01-01

371

Inferring the Temporal Order of Cancer Gene Mutations in Individual Tumor Samples  

PubMed Central

The temporal order of cancer gene mutations in tumors is essential for understanding and treating the disease. Existing methods are unable to infer the order of mutations that are identified at the same time in individual tumor samples, leaving the heterogeneity of the order unknown. Here, we show that through a complex network-based approach, which is based on the newly defined statistic –carcinogenesis information conductivity (CIC), the temporal order in individual samples can be effectively inferred. The results suggest that tumor-suppressor genes might more frequently initiate the order of mutations than oncogenes, and every type of cancer might have its own unique order of mutations. The initial mutations appear to be dedicated to acquiring the function of evading apoptosis, and some order constraints might reflect potential regularities. Our approach is completely data-driven without any parameter settings and can be expected to become more effective as more data will become available. PMID:24586626

Guo, Jun; Guo, Hanliang; Wang, Zhanyi

2014-01-01

372

A frameshift mutation in exon 2 of the phenylalanine hydroxylase gene linked to RFLP haplotype 1.  

PubMed

A deletion of a single base in codon 55 (exon 2) of the phenylalanine hydroxylase (PAH) gene has been identified by direct DNA sequencing of 94 phenylketonuria (PKU) chromosomes. This mutation alters the reading frame so that a stop signal (TAA) is generated in codon 60 of the PAH gene. Haplotype analysis revealed that all PKU alleles showing the codon 55 frameshift mutation exhibited haplotype 1. In our panel of DNA probes 13% of all mutant haplotype 1 alleles carry this particular mutation. Patients who were compound heterozygotes for this deletion and R408W in exon 12, or the splice mutation in intron 12, were affected by severe PKU. Thus, the clinical data provide additional evidence that haplotype 1 PKU alleles carry molecular defects which confer a null phenotype. In addition, we were able to show that the newly detected mutation occurs on alleles of different ethnic background. PMID:1682235

Eigel, A; Dworniczak, B; Kalaydjieva, L; Horst, J

1991-10-01

373

Distribution of Gene Mutations Associated with Familial Normosmic Idiopathic Hypogonadotropic Hypogonadism  

PubMed Central

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

Gurbuz, Fatih; Kotan, L. Damla; Mengen, Eda; S?klar, Zeynep; Berberoglu, Merih; Dokmetas, Sebila; K?l?cl?, Mehmet Fatih; Guven, Ayla; Kirel, Birgul; Saka, Nurcin; Poyrazoglu, Sukran; Cesur, Yasar; Dogan, Murat; Ozen, Samim; Ozbek, Mehmet Nuri; Demirbilek, Huseyin; Kekil, M. Burcu; Temiz, Fatih; Onenli Mungan, Neslihan; Yuksel, Bilgin; Topaloglu, Ali Kemal

2012-01-01

374

A Mutation in the Mitochondrial Fission Gene Dnm1l Leads to Cardiomyopathy  

PubMed Central

Mutations in a number of genes have been linked to inherited dilated cardiomyopathy (DCM). However, such mutations account for only a small proportion of the clinical cases emphasising the need for alternative discovery approaches to uncovering novel pathogenic mutations in hitherto unidentified pathways. Accordingly, as part of a large-scale N-ethyl-N-nitrosourea mutagenesis screen, we identified a mouse mutant, Python, which develops DCM. We demonstrate that the Python phenotype is attributable to a dominant fully penetrant mutation in the dynamin-1-like (Dnm1l) gene, which has been shown to be critical for mitochondrial fission. The C452F mutation is in a highly conserved region of the M domain of Dnm1l that alters protein interactions in a yeast two-hybrid system, suggesting that the mutation might alter intramolecular interactions within the Dnm1l monomer. Heterozygous Python fibroblasts exhibit abnormal mitochondria and peroxisomes. Homozygosity for the mutation results in the death of embryos midway though gestation. Heterozygous Python hearts show reduced levels of mitochondria enzyme complexes and suffer from cardiac ATP depletion. The resulting energy deficiency may contribute to cardiomyopathy. This is the first demonstration that a defect in a gene involved in mitochondrial remodelling can result in cardiomyopathy, showing that the function of this gene is needed for the maintenance of normal cellular function in a relatively tissue-specific manner. This disease model attests to the importance of mitochondrial remodelling in the heart; similar defects might underlie human heart muscle disease. PMID:20585624

Ashrafian, Houman; Docherty, Louise; Leo, Vincenzo; Towlson, Christopher; Neilan, Monica; Steeples, Violetta; Lygate, Craig A.; Hough, Tertius; Townsend, Stuart; Williams, Debbie; Wells, Sara; Norris, Dominic; Glyn-Jones, Sarah; Land, John; Barbaric, Ivana; Lalanne, Zuzanne; Denny, Paul; Szumska, Dorota; Bhattacharya, Shoumo; Griffin, Julian L.; Hargreaves, Iain; Fernandez-Fuentes, Narcis; Cheeseman, Michael; Watkins, Hugh; Dear, T. Neil

2010-01-01

375

Novel missense mutations in the FOXC2 gene alter transcriptional activity.  

PubMed

Mutations in the FOXC2 gene that codes for a forkhead transcription factor are associated with primary lymphedema that usually develops around puberty. Associated abnormalities include distichiasis and, very frequently, superficial and deep venous insufficiency. Most mutations reported so far either truncate the protein or are missense mutations in the forkhead domain causing a loss of function. The haplo-insufficient state is associated with lymphatic hyperplasia in mice as well as in humans. We analyzed the FOXC2 gene in 288 patients with primary lymphedema and found 11 pathogenic mutations, of which 9 are novel. Of those, 5 were novel missense mutations of which 4 were located outside of the forkhead domain. To examine their pathogenic potential we performed a transactivation assay using a luciferase reporter construct driven by FOXC1 response elements. We found that the mutations outside the forkhead domain cause a gain of function as measured by luciferase activity. Patient characteristics conform to previous reports with the exception of distichiasis, which was found in only 2 patients out of 11. FOXC2 mutations causing lymphedema-distichiasis syndrome reported thus far result in haplo-insufficiency and lead to lymphatic hyperplasia. Our results suggest that gain-of-function mutations may also cause lymphedema. One would expect that in this case, lymphatic hypoplasia would be the underlying abnormality. Patients with activating mutations might present with Meige disease. PMID:19760751

van Steensel, M A M; Damstra, R J; Heitink, M V; Bladergroen, R S; Veraart, J; Steijlen, Peter M; van Geel, M

2009-12-01

376

Analysis of gene mutations in children with cholestasis of undefined etiology  

PubMed Central

Introduction The discovery of genetic mutations in children with inherited syndromes of intrahepatic cholestasis allows for diagnostic specificity despite similar clinical phenotypes. Here, we aimed to determine whether mutation screening of target genes can assign a molecular diagnosis in children with idiopathic cholestasis. Methods DNA samples were obtained from 51 subjects with cholestasis of undefined etiology and surveyed for mutations in the genes SERPINA1, JAG1, ATP8B1, ABCB11, and ABCB4 by a high-throughput gene chip. Then, the sequence readouts for all five genes were analyzed for mutations and correlated with clinical phenotypes. Healthy subjects served as controls. Results Sequence analysis of the genes identified 14 (or 27%) subjects with missense, nonsense, deletion, and splice site variants associated with disease phenotypes based on the type of mutation and/or biallelic involvement in the JAG1, ATP8B1, ABCB11, or ABCB4 genes. These patients had no syndromic features and could not be differentiated by biochemical markers or histopathology. Among the remaining subjects, 10 (or ~20%) had sequence variants in ATP8B1 or ABCB11 that involved only one allele, 8 had variants not likely to be associated with disease phenotypes, and 19 had no variants that changed amino acid composition. Conclusion Gene sequence analysis assigned a molecular diagnosis in 27% of subjects with idiopathic cholestasis based on the presence of variants likely to cause disease phenotypes. PMID:20683201

Miethke, Alexander; Liu, Cong; Kauffmann, Gregory; Moyer, Katie; Zhang, Kejian; Bezerra, Jorge A.

2014-01-01

377

Recombination and spontaneous mutation at the major cluster of resistance genes in lettuce (Lactuca sativa).  

PubMed Central

Two sets of overlapping experiments were conducted to examine recombination and spontaneous mutation events within clusters of resistance genes in lettuce. Multiple generations were screened for recombinants using PCR-based markers flanking Dm3. The Dm3 region is not highly recombinagenic, exhibiting a recombination frequency 18-fold lower than the genome average. Recombinants were identified only rarely within the cluster of Dm3 homologs and no crossovers within genes were detected. Three populations were screened for spontaneous mutations in downy mildew resistance. Sixteen Dm mutants were identified corresponding to spontaneous mutation rates of 10(-3) to 10(-4) per generation for Dm1, Dm3, and Dm7. All mutants carried single locus, recessive mutations at the corresponding Dm locus. Eleven of the 12 Dm3 mutations were associated with large chromosome deletions. When recombination could be analyzed, deletion events were associated with exchange of flanking markers, consistent with unequal crossing over; however, although the number of Dm3 paralogs was changed, no novel chimeric genes were detected. One mutant was the result of a gene conversion event between Dm3 and a closely related homolog, generating a novel chimeric gene. In two families, spontaneous deletions were correlated with elevated levels of recombination. Therefore, the short-term evolution of the major cluster of resistance genes in lettuce involves several genetic mechanisms including unequal crossing over and gene conversion. PMID:11157000

Chin, D B; Arroyo-Garcia, R; Ochoa, O E; Kesseli, R V; Lavelle, D O; Michelmore, R W

2001-01-01

378

Mutational landscape of gingivo-buccal oral squamous cell carcinoma reveals new recurrently-mutated genes and molecular subgroups  

PubMed Central

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

Maitra, Arindam; Biswas, Nidhan K.; Amin, Kishore; Kowtal, Pradnya; Kumar, Shantanu; Das, Subrata; Sarin, Rajiv; Majumder, Partha P.; Bagchi, I; Bairagya, B. B.; Basu, A.; Bhan, M. K.; Chaturvedi, P.; Das, D.; D'Cruz, A.; Dhar, R.; Dutta, D.; Ganguli, D.; Gera, P.; Gupta, T.; Mahapatra, S.; Mujawar, M. H. K.; Mukherjee, S.; Nair, S.; Nikam, S.; Nobre, M.; Patil, A.; Patra, S.; Rama-Gowtham, M.; Rao, T. S.; Roy, B.; Roychowdhury, B.; Sarkar, D.; Sarkar, S.; Sarkar-Roy, N.; Sutradhar, D.

2013-01-01

379

Phenotype variability and neonatal diabetes in a large family with heterozygous mutation of the glucokinase gene.  

PubMed

Monogenic diabetes caused by mutations in the glucokinase gene (GCK-MODY) is usually characterized by a mild clinical phenotype. The clinical course of diabetes may be, however, highly variable. The authors present a child with diabetes manifesting with ketoacidosis during the neonatal period, born in a large family with ten members bearing a heterozygous p.Gly223Ser mutation in GCK. DNA sequencing and multiplex ligation-dependent probe amplification were used to confirm GCK mutation and exclude other de novo mutations in other known genes associated with monogenic diabetes. Continuous glucose monitoring (CGM) was used to assess daily glycemic profiles. At the onset of diabetes the child had hyperglycemia 765 mg/dl with pH 7.09. Her glycated hemoglobin level was 8.6% (70.5 mmol/mol). The C-peptide level was below normal range (<0.5 pmol/ml) at onset, and the three- and 6-month follow-up examinations. Current evaluation at age 3 still showed unsatisfactory metabolic control with HbA1c level equal to 8.1% (65.0 mmol/mol). CGM data showed glucose concentrations profile similar to poorly controlled type 1 diabetes. The patient was confirmed to be heterozygous for the p.Gly223Ser mutation and did not show any point mutations or deletions within other monogenic diabetes genes. Other family members with p.Gly223Ser mutation had retained C-peptide levels and mild diabetes manageable with diet (five individuals), oral hypoglycemizing agents (five patients), or insulin (one patient). This mutation was absent within all healthy family members. Heterozygous mutations of the GCK gene may result in neonatal diabetes similar to type 1 diabetes, the cause of such phenotype variety is still unknown. The possibility of other additional, unknown mutations seems to be the most likely explanation for the unusual presentation of GCK-MODY. PMID:21437567

Borowiec, Maciej; Mysliwiec, Malgorzata; Fendler, Wojciech; Antosik, Karolina; Brandt, Agnieszka; Malecki, Maciej; Mlynarski, Wojciech

2011-09-01

380

Identification of photoreceptor genes affected by PRPF31 mutations associated with autosomal dominant retinitis pigmentosa.  

PubMed

Several ubiquitously expressed genes encoding pre-mRNA splicing factors have been associated with autosomal dominant retinitis pigmentosa (adRP), including PRPF31, PRPF3 and PRPF8. Molecular mechanisms by which defects in pre-mRNA splicing factors cause photoreceptor degeneration are not clear. To investigate the role of pre-mRNA splicing in photoreceptor gene expression and function, we have begun to search for photoreceptor genes whose pre-mRNA splicing is affected by mutations in PRPF31. Using an immunoprecipitation-coupled-microarray method, we identified a number of transcripts associated with PRPF31-containing complexes, including peripherin/RDS, FSCN2 and other photoreceptor-expressed genes. We constructed minigenes to study the effects of PRPF31 mutations on the pre-mRNA splicing of these photoreceptor specific genes. Our experiments demonstrated that mutant PRPF31 significantly inhibited pre-mRNA splicing of RDS and FSCN2. These observations suggest a functional link between ubiquitously expressed and retina-specifically expressed adRP genes. Our results indicate that PRPF31 mutations lead to defective pre-mRNA splicing of photoreceptor-specific genes and that the ubiquitously expressed adRP gene, PRPF31, is critical for pre-mRNA splicing of a subset of photoreceptor genes. Our results provide an explanation for the photoreceptor-specific phenotype of PRPF31 mutations. PMID:17350276

Mordes, Daniel; Yuan, Liya; Xu, Lili; Kawada, Mariko; Molday, Robert S; Wu, Jane Y

2007-05-01

381

A bacterial model for expression of mutations in the human ornithine transcarbamylase (OTC) gene  

SciTech Connect

OTC is a mitochondrial enzyme catalyzing the formation of citrulline from carbamyl phosphate and ornithine. X-linked deficiency of OTC is the most prevalent genetic defect of ureagenesis. Mutations and polymorphisms in the OTC gene identified in deficient patients have indicated the occurrence of many family-specific, unique alleles. Due to the low frequency of recurrent mutations, distinguishing between deleterious mutations and polymorphisms is difficult. Using a human OTC gene containing plasmid driven by a tac promoter, we have devised a simple and efficient method for expressing mutations in the mature human OTC enzyme. To demonstrate this method, PCR engineered site-directed mutagenesis was employed to generated cDNA fragments which contained either the R151Q or R277W known mutations found in patients with neonatal and late-onset OTC deficiency, respectively. The normal allele for each mutation was also generated by an identical PCR procedure. Digestion with Bgl II- and Sty I-generated mutant and normal replacement cassettes containing the respective mutant and wild type sequences. Upon transformation of JM109 E.coli cells, OTC enzymatic activity was measured at log and stationary phases of growth using a radiochromatographic method. The R141Q mutation abolished enzymatic activity (<0.02% of normal), whereas the R277W mutation expressed partial activity (2.3% of normal). In addition, a PCR-generated mutation, A280V, resulted in 73% loss of catalytic activity. This OTC expression system is clinically applicable for distinguishing between mutations and polymorphisms, and it can be used to investigate the effects of mutations on various domains of the OTC gene.

Tuchman, M.; McCann, M.T.; Qureshi, A.A. [Univ. of Minnesota, Mineapolis (United States)

1994-09-01

382

Characterization of Usher syndrome type I gene mutations in an Usher syndrome patient population.  

PubMed

Usher syndrome type I (USH1), the most severe form of this syndrome, is characterized by profound congenital sensorineural deafness, vestibular dysfunction, and retinitis pigmentosa. At least seven USH1 loci, USH1A-G, have been mapped to the chromosome regions 14q32, 11q13.5, 11p15, 10q21-q22, 21q21, 10q21-q22, and 17q24-25, respectively. Mutations in five genes, including MYO7A, USH1C, CDH23, PCDH15 and SANS, have been shown to be the cause of Usher syndrome type 1B, type 1C, type 1D, type 1F and type 1G, respectively. In the present study, we carried out a systematic mutation screening of these genes in USH1 patients from USA and from UK. We identified a total of 27 different mutations; of these, 19 are novel, including nine missense, two nonsense, four deletions, one insertion and three splicing defects. Approximatelly 35-39% of the observed mutations involved the USH1B and USH1D genes, followed by 11% for USH1F and 7% for USH1C in non-Acadian alleles and 7% for USH1G. Two of the 12 MYO7A mutations, R666X and IVS40-1G > T accounted for 38% of the mutations at that locus. A 193delC mutation accounted for 26% of CDH23 (USH1D) mutations, confirming its high frequency. The most common PCDH15 (USH1F) mutation in this study, 5601-5603delAAC, accounts for 33% of mutant alleles. Interestingly, a novel SANS mutation, W38X, was observed only in the USA cohort. The present study suggests that mutations in MYO7A and CDH23 are the two major components of causes for USH1, while PCDH15, USH1C, and SANS are less frequent causes. PMID:15660226

Ouyang, Xiao Mei; Yan, Denise; Du, Li Lin; Hejtmancik, J Fielding; Jacobson, Samuel G; Nance, Walter E; Li, An Ren; Angeli, Simon; Kaiser, Muriel; Newton, Valerie; Brown, Steve D M; Balkany, Thomas; Liu, Xue Zhong

2005-03-01

383

Mutations in Gcr1, a Transcriptional Activator of Saccharomyces Cerevisiae Glycolytic Genes, Function as Suppressors of Gcr2 Mutations  

PubMed Central

The Saccharomyces cerevisiae GCR1 and GCR2 genes affect expression of most of the glycolytic genes. Evidence for Gcr1p/Gcr2p interaction has been presented earlier and is now supported by the isolation of mutations in Gcr1p suppressing gcr2, as assessed by growth and enzyme assay. Four specific mutation sites were identified. Together with use of the two-hybrid system of FIELDS and SONG, they show that Gcr1p in its N-terminal half has a potential transcriptional activating function as well as elements for interaction with Gcr2p, which perhaps acts normally to expose an otherwise cryptic activation domain on Gcr1p. Complementation of various gcr1 mutant alleles and results with the two-hybrid system also indicate that Gcr1p itself normally functions as an oligomer. PMID:7713414

Uemura, H.; Jigami, Y.

1995-01-01

384

Mutation analysis of the phenylalanine hydroxylase gene using heteroduplex analysis with synthetic DNA constructs.  

PubMed

Using heteroduplex analysis generated with synthetic PCR-amplifiable DNA we have screened the PKU populations of southwest England and Wales, western Scotland, and southeast and central England for mutations in exons 3, 7 and 12 of the phenylalanine hydroxylase (PAH) gene. The technique characterized three mutations in exon 12, two in exon 3 and five in exon 7. Altogether over 370 PKU chromosomes were screened. In all geographical regions exon 12 mutations (R408W, IVS12nt1g- > a and Y414C) accounted for about 40% of mutant chromosomes. Exon 3 mutations (principally I65T) were found on between 9 and 12% of mutant alleles and exon 7 mutations accounted for a further 5-7%. Heteroduplex analysis is rapid, simple and safe and three constructs covering three exons can identify between 55 and 60% of mutations in various PKU populations of the UK. PMID:7766958

Tyfield, L A; Stephenson, A; Bidwell, J L; Wood, N A; Cockburn, F; Harvie, A; Smith, I

1994-12-01

385

Spectrum of rhodopsin gene mutations in Chinese patients with retinitis pigmentosa  

PubMed Central

Purpose This study was to analyze the spectrum and frequency of rhodopsin gene (RHO) mutations in Chinese patients with retinitis pigmentosa (RP). Methods Patients were given physical examinations, and blood samples were collected for DNA extraction. The RHO mutations were screened with direct sequencing. Results Eight heterozygous nucleotide changes were detected in eight of 300 probands with RP, including six novel mutations and two known mutations. p.R21C, p.C110S, p.G182V, p.C187G, c.409–426delGTGGTGGTGTGTAAGCCC, and p.P347L were found in six autosomal dominant families. p.T92I and p.Y178C were found in two isolated cases. Conclusions The results reveal the spectrum and frequency of RHO mutations in Chinese patients with different forms of RP and demonstrate that RHO mutations account for a high proportion of autosomal dominant RP (adRP) cases.

Yang, Guoxing; Xie, Shipeng; Feng, Na; Yuan, Zhifeng; Zhang, Minglian

2014-01-01

386

Heteroduplex analysis of the dystrophin gene: Application to point mutation and carrier detection  

SciTech Connect

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.

Prior, T.W.; Papp, A.C.; Snyder, P.J.; Sedra, M.S.; Western, L.M.; Bartolo, C.; Mendell, J.R. [Ohio State Univ., Columbus, OH (United States); Moxley, R.T. [Univ. of Rochester Medical Center, NY (United States)

1994-03-01

387

Mutations of 3c and spike protein genes correlate with the occurrence of feline infectious peritonitis.  

PubMed

The genes encoding accessory proteins 3a, 3b, 3c, 7a and 7b, the S2 domain of the spike (S) protein gene and the membrane (M) protein gene of feline infectious peritonitis virus (FIPV) and feline enteric coronavirus (FECV) samples were amplified, cloned and sequenced. For this faeces and/or ascites samples from 19 cats suffering from feline infectious peritonitis (FIP) as well as from 20 FECV-infected healthy cats were used. Sequence comparisons revealed that 3c genes of animals with FIP were heavily affected by nucleotide deletions and point mutations compared to animals infected with FECV; these alterations resulted either in early termination or destruction of the translation initiation codon. Two ascites-derived samples of cats with FIP which displayed no alterations of ORF3c harboured mutations in the S2 domain of the S protein gene which resulted in amino acid exchanges or deletions. Moreover, changes in 3c were often accompanied by mutations in S2. In contrast, in samples obtained from faeces of healthy cats, the ORF3c was never affected by such mutations. Similarly ORF3c from faecal samples of the cats with FIP was mostly intact and showed only in a few cases the same mutations found in the respective ascites samples. The genes encoding 3a, 3b, 7a and 7b displayed no mutations linked to the feline coronavirus (FCoV) biotype. The M protein gene was found to be conserved between FECV and FIPV samples. Our findings suggest that mutations of 3c and spike protein genes correlate with the occurrence of FIP. PMID:25150756

Bank-Wolf, Barbara Regina; Stallkamp, Iris; Wiese, Svenja; Moritz, Andreas; Tekes, Gergely; Thiel, Heinz-Jürgen

2014-10-10

388

A novel fibrillin 1 gene mutation leading to marfan syndrome with minimal cardiac features.  

PubMed

Marfan syndrome is an autosomal dominant disorder of the connective tissue, characterized by early development of thoracic aortic aneurysms and/or dissections, accompanied by ocular and/or skeletal involvement, and is caused by mutations in the fibrillin 1 (FBN1) gene. We report on a patient with ectopia lentis and a nonprogressive aortic root dilatation who presented with a novel mutation affecting a conserved cysteine residue present in a calcium-binding epidermal growth factor-like domain of FBN1 (ENSP00000325527, p.Cys538Phe; Chr15:48,805,751 G>T), as revealed by complete sequencing of the FBN1 gene exons and flanking sequences. Identification of the mutation led to genetic screening of apparently asymptomatic family members, allowing the detection of characteristic ocular phenotypes in the absence of typical cardiac Marfan features. This finding stresses the importance of genetic screening of asymptomatic relatives for FBN1 gene mutation carriers. PMID:25337071

Martínez-Quintana; Rodríguez-González; Garay-Sánchez; Tugores

2014-08-01

389

A Novel Fibrillin 1 Gene Mutation Leading to Marfan Syndrome with Minimal Cardiac Features  

PubMed Central

Marfan syndrome is an autosomal dominant disorder of the connective tissue, characterized by early development of thoracic aortic aneurysms and/or dissections, accompanied by ocular and/or skeletal involvement, and is caused by mutations in the fibrillin 1 (FBN1) gene. We report on a patient with ectopia lentis and a nonprogressive aortic root dilatation who presented with a novel mutation affecting a conserved cysteine residue present in a calcium-binding epidermal growth factor-like domain of FBN1 (ENSP00000325527, p.Cys538Phe; Chr15:48,805,751 G>T), as revealed by complete sequencing of the FBN1 gene exons and flanking sequences. Identification of the mutation led to genetic screening of apparently asymptomatic family members, allowing the detection of characteristic ocular phenotypes in the absence of typical cardiac Marfan features. This finding stresses the importance of genetic screening of asymptomatic relatives for FBN1 gene mutation carriers.

Martinez-Quintana; Rodriguez-Gonzalez; Garay-Sanchez; Tugores

2014-01-01

390

A common FGFR3 gene mutation is present in achondroplasia but not in hypochondroplasia  

SciTech Connect

Achondroplasia is the most common type of genetic dwarfism. It is characterized by disproportionate short stature and other skeletal anomalies resulting from a defect in the maturation of the chondrocytes in the growth plate of the cartilage. Recent studies mapped the achondroplasia gene on chromosome region 4p16.3 and identified a common mutation in the gene encoding the fibroblast growth factor receptor 3 (FGFR3). In an analysis of 19 achondroplasia families from a variety of ethnic backgrounds we confirmed the presence of the G380R mutation in 21 of 23 achondroplasia chromosomes studied. In contrast, the G380R mutation was not found in any of the 8 hypochondroplasia chromosomes studied. Futhermore, linkage studies in a 3-generation family with hypochondroplasia show discordant segregation with markers in the 4p16.3 region suggesting that at least some cases of hypochondroplasia are caused by mutations in a gene other than FGFR3. 27 refs., 2 figs.

Stoilov, I.; Kilpatrick, M.W.; Tsipouras, P. [Univ. of Connecticut Health Center, Farmington, CT (United States)

1995-01-02

391

Novel polymerase gamma (POLG1) gene mutation in the linker domain associated with parkinsonism  

PubMed Central

Background Mutations in the POLG1 gene have variable phenotypic presentations and a high degree of clinical suspicion is necessary for their recognition. Parkinsonism and ataxia are the most common movement disorders associated with POLG1 mutations but no phenotype-genotype correlation has been established. Case presentation We identified a male patient with progressive external ophthalmoplegia who also developed a progressive bradykinesia, rigidity and camptocormia in the third decade. Parkinsonism was partially responsive to dopaminegic replacement. His father and brother had reportedly similar clinical problems. Genetic analysis identified a novel mutation p.K512M in the POLG1 gene. Conclusion This report further expands the spectrum of POLG1-associated neurologic problems with the report of a novel mutation in the linker region of the gene, which are rarely associated with parkinsonism. PMID:23865558

2013-01-01

392

[Search for frequently encountered mutations in genes predisposing to breast cancer].  

PubMed

DNA of oncological patients, including Ashkenazi Jews and Slavs, living in St. Petersburg was collected, and the resultant collection was screened for three common mutations of genes BRCA1 and BRCA2 by means of heteroduplex analysis. The mutation 5382insC in exon 20 of the BRCA1 gene was found in four unrelated patients, including three Slavs and one Ashkenazi Jew, with a positive family history of breast cancer. The mutations 185delAG and 6174delT in the BRCA1 and BRCA2 genes, respectively, which are typical of Ashkenazi Jewish patients with breast cancer, were not found in the patients of either ethnicity living in St. Petersburg, although the 6174delT mutation was found in the control group of Ashkenazi Jews. A new 12-nucleotide duplication g.71741ins12nt found in intron 20 of the BRCA1 gene was described. The high frequency of the 5382insC mutation in the BRCA1 gene in patients with familial breast cancer in both St. Petersburg and Moscow indicates that Russian families with the history of breast cancer should be primarily tested for this mutation. PMID:11785296

Mandel'shtam, M Iu; Golubkov, V I; Lamber, E P; Shapiro, I M; Brezhneva, T V; Semiglazov, V F; Lipovetski?, B M; Hanson, K P; Ga?tskhoki, V S

2001-12-01

393

Four novel cases of permanent neonatal diabetes mellitus caused by homozygous mutations in the glucokinase gene.  

PubMed

Permanent neonatal diabetes mellitus (PNDM) caused by homozygous mutations in the glucokinase gene (GCK) is rare and only eight homozygous GCK mutations have been reported so far. Heterozygous GCK mutations cause maturity-onset diabetes of the young (MODY). We report four patients with growth retardation from two separate families (with three siblings in one family and one patient in another family) presenting with persistent hyperglycaemia within the first two days of life. We found one homozygous non-sense mutation (Q98X) in GCK in three siblings from one family and a homozygous missense GCK mutation (G261R) in one patient from another family. Both mutations have been identified previously in GCK-MODY in the heterozygous state. However, this is the first study to report the homozygous forms of these mutations in PNDM. We report four novel cases of PNDM caused by homozygous GCK mutations, including a non-sense mutation in exon 3 (Q98X) and a missense mutation in exon 7 (G261R). PMID:21518409

Bennett, Kate; James, Chela; Mutair, Angham; Al-Shaikh, Hala; Sinani, Aisha; Hussain, Khalid

2011-05-01

394

Mutations of the tyrosinase gene in Indo-Pakistani patients with type I (tyrosinase-deficient) oculocutaneous albinsm (OCA)  

SciTech Connect

Oculocutaneous albinism (OCA) is a group of autosomal recessive disorders characterized by deficient synthesis of melanin pigment. Type I (tyrosinase-deficient) OCA results from mutations of the tyrosinase gene (TYR gene) encoding tyrosinase, the enzyme that catalyzes the first two steps of melanin biosynthesis. Mutations of the TYR gene have been identified in a large number of patients, most of Caucasian ethnic origin, with various forms of type I OCA. The authors present an analysis of the TYR gene in eight Indo-Pakistani patients with type I OCA. The authors describe four novel TYR gene mutations and a fifth mutation previously observed in a Caucasian patient. 16 refs., 6 figs.

Tripathi, R.K.; Droetto, S.; Strunk, K.M.; Holmes, S.A.; Spritz, R.A. (Univ. of Wisconsin, Madison, WI (United States)); Bundey, S.; Musarella, M.A.

1993-12-01

395

The Phenotype of a Germline Mutation in PIGA: The Gene Somatically Mutated in Paroxysmal Nocturnal Hemoglobinuria  

PubMed Central

Phosphatidylinositol glycan class A (PIGA) is involved in the first step of glycosylphosphatidylinositol (GPI) biosynthesis. Many proteins, including CD55 and CD59, are anchored to the cell by GPI. Loss of CD55 and CD59 on erythrocytes causes complement-mediated lysis in paroxysmal nocturnal hemoglobinuria (PNH), a disease that manifests after clonal expansion of hematopoietic cells with somatic PIGA mutations. Although somatic PIGA mutations have been identified in many PNH patients, it has been proposed that germline mutations are lethal. We report a family with an X-linked lethal disorder involving cleft palate, neonatal seizures, contractures, central nervous system (CNS) structural malformations, and other anomalies. An X chromosome exome next-generation sequencing screen identified a single nonsense PIGA mutation, c.1234C>T, which predicts p.Arg412?. This variant segregated with disease and carrier status in the family, is similar to mutations known to cause PNH as a result of PIGA dysfunction, and was absent in 409 controls. PIGA-null mutations are thought to be embryonic lethal, suggesting that p.Arg412? PIGA has residual function. Transfection of a mutant p.Arg412? PIGA construct into PIGA-null cells showed partial restoration of GPI-anchored proteins. The genetic data show that the c.1234C>T (p.Arg412?) mutation is present in an affected child, is linked to the affected chromosome in this family, is rare in the population, and results in reduced, but not absent, biosynthesis of GPI anchors. We conclude that c.1234C>T in PIGA results in the lethal X-linked phenotype recognized in the reported family. PMID:22305531

Johnston, Jennifer J.; Gropman, Andrea L.; Sapp, Julie C.; Teer, Jamie K.; Martin, Jodie M.; Liu, Cyndi F.; Yuan, Xuan; Ye, Zhaohui; Cheng, Linzhao; Brodsky, Robert A.; Biesecker, Leslie G.

2012-01-01

396

Mutation analysis of pre-mRNA splicing genes in Chinese families with retinitis pigmentosa  

PubMed Central

Purpose Seven genes involved in precursor mRNA (pre-mRNA) splicing have been implicated in autosomal dominant retinitis pigmentosa (adRP). We sought to detect mutations in all seven genes in Chinese families with RP, to characterize the relevant phenotypes, and to evaluate the prevalence of mutations in splicing genes in patients with adRP. Methods Six unrelated families from our adRP cohort (42 families) and two additional families with RP with uncertain inheritance mode were clinically characterized in the present study. Targeted sequence capture with next-generation massively parallel sequencing (NGS) was performed to screen mutations in 189 genes including all seven pre-mRNA splicing genes associated with adRP. Variants detected with NGS were filtered with bioinformatics analyses, validated with Sanger sequencing, and prioritized with pathogenicity analysis. Results Mutations in pre-mRNA splicing genes were identified in three individual families including one novel frameshift mutation in PRPF31 (p.Leu366fs*1) and two known mutations in SNRNP200 (p.Arg681His and p.Ser1087Leu). The patients carrying SNRNP200 p.R681H showed rapid disease progression, and the family carrying p.S1087L presented earlier onset ages and more severe phenotypes compared to another previously reported family with p.S1087L. In five other families, we identified mutations in other RP-related genes, including RP1 p. Ser781* (novel), RP2 p.Gln65* (novel) and p.Ile137del (novel), IMPDH1 p.Asp311Asn (recurrent), and RHO p.Pro347Leu (recurrent). Conclusions Mutations in splicing genes identified in the present and our previous study account for 9.5% in our adRP cohort, indicating the important role of pre-mRNA splicing deficiency in the etiology of adRP. Mutations in the same splicing gene, or even the same mutation, could correlate with different phenotypic severities, complicating the