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1

Homozygous MTHFR C677T gene mutation and recurrent stroke in an infant.  

PubMed

The role of homozygosity for the C677T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene as an independent risk factor for primary and recurrent stroke has been questioned, although recent data appear to be supportive. However, the association of homozygous C677T MTHFR mutation with silent brain infarctions in infancy has not been reported. The authors describe an 11-month-old male who had suffered a silent brain infarction followed by a symptomatic arterial stroke. The evaluation revealed mildly elevated homocysteine levels secondary to homozygous C677T alleles for MTHFR and iron deficiency anemia. An extensive evaluation for other causes of infarction was negative. We suggest that the mother's homozygous MTHFR status played a role in the early onset of stroke and that iron deficiency anemia may have contributed to the recurrence. The patient was treated with anticoagulation therapy, folic acid, and iron supplementation and has not had a recurrent event during 3 years of follow-up. This case provides further evidence that homozygous MTHFR mutation is a predisposing factor for early and recurrent pediatric stroke, including silent infarcts, especially in the presence of other risk factors. PMID:16814086

Garoufi, Anastasia J; Prassouli, Alexia A; Attilakos, Achilleas V; Voudris, Konstantinos A; Katsarou, Eustathia S

2006-07-01

2

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

PubMed

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

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

2008-09-01

3

Association between the methylene tetrahydrofolate reductase gene C677T mutation and colchicine unresponsiveness in Behcet's disease  

PubMed Central

Purpose Behcet’s disease (BD) is a multisystemic immunoinflammatory disorder characterized by mucocutaneous, ocular, vascular, and central nervous system manifestations. The common methylene tetrahydrofolate reductase (MTHFR) gene C677T mutation is a known risk factor for thrombosis. The aim of this study was to investigate the MTHFR gene C677 mutation in patients with BD and evaluate if there was an association with clinical features, especially thrombosis, in a relatively large cohort of patients with BD. Methods The study included 318 patients with BD and 207 healthy controls. Genomic DNA was isolated and genotyped using PCR-based restriction fragment length polymorphism assay for the MTHFR gene C677T mutation. Results The genotype and allele frequencies of the C677T mutation showed a statistically significant difference between BD patients and controls (p=0.003 and p=0.001, respectively). There was also a significant association between C677T alteration and response to colchicine in BD patients (p=0.046). Conclusions The results of this study showed that there was a high association between the MTHFR gene C677T mutation and BD. Stratification analysis according to clinical features for this disease did not reveal an association except response to colchicine that was shown to be influenced by the MTHFR C677T mutation.

Yigit, Serbulent; Kalkan, Goknur; Rustemoglu, Aydin; Inanir, Ahmet; Gul, Ulker; Pancar, Gunseli Sefika; Akkanet, Songul; Ates, Omer

2012-01-01

4

Methylenetetrahydrofolate reductase gene C677T mutation and plasma homocysteine level in Behçet's disease  

Microsoft Academic Search

Objective The aim of this study was to assess whether homozygosity for the 5, 10-methylenetetrahydrofolate reductase (MTHFR) C677T mutation and plasma homocysteine concentration are related to deep vein thrombosis in Behçet's disease (BD) patients. Methods Forty BD patients (23 males, 17 females; mean age 40.2±8.4 years) and 60 healthy controls (HC) (34 males, 26 females; mean age 41.6±6.9 years) were

Abdullah Canataroglu; Kahraman Tanriverdi; Tamer Inal; Gulsah Seydaoglu; Didem Arslan; Suleyman Ozbek; Fikri Baslamisli

2003-01-01

5

Homozygous C677T mutation in the MTHFR gene as an independent risk factor for multiple small-artery occlusions  

Microsoft Academic Search

Introduction: Hyperhomocysteinemia is an independent risk factor for cerebrovascular disease and the homozygous C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene can induce hyperhomocysteinemia. However, the association between this 677TT genotype and ischemic stroke still remains controversial. Therefore, we carried out this study to determine whether the MTHFR TT genotype is associated with certain subtypes of ischemic stroke. Materials and

B. O Choi; N. K Kim; S. H Kim; M. S Kang; S Lee; J. Y Ahn; O. J Kim; D Oh

2003-01-01

6

C677T mutation in the 5,10-MTHFR gene and risk of Down syndrome in Italy  

Microsoft Academic Search

The C677T polymorphism of the MTHFR gene has been associated to maternal risk of Down syndrome, due to the detection of an higher prevalence of the T allele among mothers of children with trisomy 21, compared to control mothers. In order to confirm this association, we studied the presence of the C677T in 64 mothers of Down syndrome children and

Liborio Stuppia; Valentina Gatta; Anna Rita Gaspari; Ivana Antonucci; Elisena Morizio; Giuseppe Calabrese; Giandomenico Palka

2002-01-01

7

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

8

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

9

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

10

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

11

Methylenetetrahydrofolate reductase C677T mutation and nonalcoholic fatty liver disease.  

PubMed

A mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is known as one of the causes of hyperhomocyteinemia. The oxidation products of homocysteine can initiate lipid peroxidation, which has a central role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We aimed to assess the possible role of the MTHFR C677T mutation in the progression of simple steatosis to an advanced form of NAFLD. Thirty-four patients with NAFLD diagnosed by histologic analysis and 282 healthy controls were included in the study. The discrimination of nonalcoholic steatohepatitis (NASH) from another NAFLD was made by NAFLD activity score (NAS), and a NAS>or=5 was considered NASH. Patients with either NASH or nonalcoholic fatty liver (NAFL) and controls were evaluated for frequency of the MTHFR C677T mutation. The frequency of the MTHFR C677T mutation was 53.5% (CT, 44.7%; TT, 8.9%) in controls and 41.5% (CT, 37.7%; TT, 3.8%) in patients (odds ratio [OR], 0.62; 95% confidence interval [CI], 0.34-1.12). There was no statistical difference in the frequency of this genotype between patients with NAFL and those with NASH (36% [CT, 28%; TT, 8%] vs 46.4% [CT, 46.4; TT, 0%]; OR, 0.65; 95% CI, 0.22-1.96). According to this study, the MTHFR C677T mutation does not seem to be a risk factor for the progression of NAFL to NASH. PMID:17356914

Serin, Ender; Güçlü, Mustafa; Ataç, F Belgin; Verdi, Hasibe; Kayaselçuk, Fazilet; Ozer, Birol; Bilezikçi, Banu; Yilmaz, U?ur

2007-03-14

12

Hyperhomocysteinemia increases the risk of venous thrombosis independent of the C677T mutation of the methylenetetrahydrofolate reductase gene in selected Brazilian patients  

Microsoft Academic Search

Fasting total homocysteine (tHcy) and the methylenetetrahydrofolate reductase (MTHFR) C677T mutation were evaluated in 91 patients with venous thromboembolism and without acquired thrombophilia, and in 91 age-matched and sex-matched controls. Hyperhomocysteinemia was detected in 11 patients (12.1%) and in two controls (2.2%), yielding an odds ratio (OR) for venous thrombosis of 6.1 (95% confidence interval (CI), 1.3-28.4). After excluding 21

V. M. Morelli; D. M. Lourenco; V. D'Almeida; R. F. Franco; F. Miranda; M. A. Zago; M. A. E. Noguti; E. Cruz; J. Kerbauy

13

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

PubMed

We have investigated the incidence of the C677T and A1298C methylene tetrahydrofolate reductase (MTHFR) gene single nucleotide polymorphisms (SNPs) in the South Indian Tamil Nadu population with a total number of 72 individuals. The MTHFR genotyping was performed using the polymerase chain reaction followed by restriction enzyme analysis. Homozygosity for the MTHFR A1298C SNP was detected in 15.3% (11/72) of the individuals tested, and 47.2% (34/72) were heterozygous for this SNP. Homozygosity for the C677T MTHFR SNP was detected in 1.38%(1/72), and the frequency of the C677T heterozygotes was 18.1%(13/72). When we analyzed the combined frequency of the two SNPs, the frequency of double heterozygosity was19.6%, and the frequency of double homozygosity was completely absent among the study group. The 'C' allele frequency for MTHFR A1298C was 0.389, and the 'T' allele frequency for C677T mutation was 0.104. Out of the 72 individuals included in the study, 52 were acute myocardial infarction (AMI) patients and 20 were healthy individuals with no documented history of heart disease. The results of this study indicate that the MTHFR A1298C SNP is more prevalent among the Tamilians when compared to the MTHFR C677T SNP, suggesting a possible role of MTHFR A1298C in the pathogenesis of heart diseases. PMID:15351230

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

2004-10-01

14

Mutations C677T and A1298C of the 5,10-methylenetetrahydrofolate reductase gene and fasting plasma homocysteine levels are not associated with the increased risk of venous thromboembolic disease.  

PubMed

Mild hyperhomocysteinemia is associated with homozygosity for the thermolabile variant of 5,10-methylenetetrahydrofolate reductase (MTHFR) and could increase the risk of venous thromboembolic disease (VTD). Recently, the second A1298C mutation of the MTHFR gene was described. The present study aimed to analyze both mutations of the MTHFR gene and plasma homocysteine levels in subjects with VTD. The study groups comprised 146 patients with VTD and 100 healthy subjects. There were no statistical differences in carrier frequency and allelic frequency for both A1298C and C677T mutations, nor were there any differences encountered between subjects with VTD and controls in either plasma homocysteine levels or according to C677T or A1298C genotypes of MTHFR. In our VTD patients and controls, neither MTHFR 677CT/1298CC nor MTHFR 677TT/1298CC combined genotypes were observed; double heterozygotes (A1298C/C677T) were represented only in 11% of VTD patients, and in 15% of the controls. In conclusion, the polymorphisms C677T and A1298C of MTHFR and fasting plasma homocysteine levels do not seem to be significant risk factors for venous thromboembolic disease. PMID:12138370

Domagala, T B; Adamek, L; Nizankowska, E; Sanak, M; Szczeklik, A

2002-07-01

15

Methylenetetrahydrofolate Reductase C677T Mutation and Nonalcoholic Fatty Liver Disease  

Microsoft Academic Search

A mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is known as one of the causes of hyperhomocyteinemia. The\\u000a oxidation products of homocysteine can initiate lipid peroxidation, which has a central role in the pathogenesis of nonalcoholic\\u000a fatty liver disease (NAFLD). We aimed to assess the possible role of the MTHFR C677T mutation in the progression of simple\\u000a steatosis to an

Ender Serin; Mustafa Güçlü; F Belgin Ataç; Hasibe Verdi; Fazilet Kayaselçuk; Birol Özer; Banu Bilezikçi; U?ur Y?lmaz

2007-01-01

16

Prevalence of the C677T Methylenetetra- hydrofolate Reductase Mutation in Thai Patients with Deep Vein Thrombosis  

Microsoft Academic Search

We investigated the prevalence of a genetic variation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene (C677T) using polymerase chain reaction techniques in a sample of 500 general Thai population and among 40 unselected Thai patients with an objectively confirmed history of deep vein thrombosis (DVT). The prevalence of the mutated homozygous and heterozygous C677T MTHFR genotype in the group of 500

Pantep Angchaisuksiri; Sarinee Pingsuthiwong; Thanyachai Sura; Katcharin Aryuchai; Manisa Busabaratana; Vichai Atichartakarn

2000-01-01

17

Population Study of Frequency of Methylenetetrahydrofolate Reductase C677T Gene Polymorphism in Yakutia  

Microsoft Academic Search

The enzyme methylenetetrahydrofolate reductase (MTHFR) catalyzes synthesis of 5'-methylenehydrofolate, which is the methyl donor for the conversion of homocysteine to methionine. According to the numerous literature data, polymorphic variant of the MTHFR-encoding gene, C677T, is associated with hyperhomocysteinemia, vascular pathologies, neural tube defects, dementia, perinatal mortality, mental disorders, long-term neurodegenerative disorders, lens displacement, arachnodactyly, and venous thromboses. The present study

M. G. Spiridonova; V. A. Stepanov; N. R. Maximova; V. P. Puzyrev

2004-01-01

18

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

19

Methylenetetrahydrofolate reductase C677T gene polymorphism and colorectal cancer risk: A case-control study  

PubMed Central

We designed a case-control study to determine the plasma homocysteine (Hcy) level and evaluate the potential role of the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in colorectal cancer (CRC). Total Hcy was quantified using the fluorescence polarization immunoassay (FPIA) on the IMx analyzer. Genomic DNA was analyzed by the real-time polymerase chain reaction (RT-PCR). The plasma levels of Hcy in the CRC group (12.63±3.11 ?mol/l) were significantly higher compared with those in the control group (10.87±2.42 ?mol/l; P<0.05). The frequency of the MTHFR 677TT genotype in CRC patients was markedly high. The MTHFR 677TT genotype was significantly correlated with an increased risk of CRC (odds ratio, 1.671; 95% confidence interval, 1.094–2.553; P=0.018). This study suggests that the MTHFR C677T polymorphism indicates susceptibility to CRC and is correlated with CRC pathogenesis, suggesting that the homozygous variant MTHFR C677T polymorphism is a candidate risk factor for CRC.

YIN, GUANCHENG; MING, HANXIN; ZHENG, XIAO; XUAN, YI; LIANG, JIANWEI; JIN, XING

2012-01-01

20

COMBINED MARGINAL FOLATE AND RIBOFLAVIN STATUS AFFECT HOMOCYSTEINE METHYLATION IN CULTURED IMMORTALIZED LYMPHOCYTES FROM PERSONS HOMOZYGOUS FOR THE MTHFR C677T MUTATION  

Technology Transfer Automated Retrieval System (TEKTRAN)

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the methyl donor for the synthesis of methionine from homocysteine. A common C677T mutation in the MTHFR gene renders the enzyme 50% less active than the wild-type enzym...

21

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

22

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

PubMed

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 combined MTHFR C677T and A1298C polymorphisms in DNA samples from spontaneously aborted embryos (foetal death between sixth and twentieth week after conception) and adult controls using solid-phase minisequencing technique. There was a significant odds ratio of 14.2 (95% CI 1.78-113) in spontaneously aborted embryos comparing the prevalence of one or more 677T and 1298C alleles vs the wild type combined genotype (677CC/1298AA), indicating that the MTHFR polymorphisms may have a major impact on foetal survival. Combined 677CT/1298CC, 677TT/1298AC or 677TT/1298CC genotypes, which contain three or four mutant alleles, were not detected in any of the groups, suggesting complete linkage disequilibrium between the two polymorphisms. The present finding of high prevalence of mutated MTHFR genotypes in spontaneously aborted embryos emphasises the potential protective role of periconceptional folic acid supplementation. PMID:11938441

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

2002-02-01

23

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

24

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

25

Methylenetetrahydrofolate Reductase C677T and A1298C Mutations in Women with Recurrent Spontaneous Abortions in the Northwest of Iran  

PubMed Central

Introduction. Recurrent spontaneous abortion (RSA) is a significant obstetrical complication that may occur during pregnancy. Various studies in recent years have indicated that two common mutations (C677T and A1298C) of the methylenetetrahydrofolate reductase (MTHFR) gene are risk factor for RSA. This study was carried out to determine the influence of (C677T and A1298C) of the methylenetetrahydrofolate reductase (MTHFR) gene mutations with RSA. Materials and Methods. A total of 139 women were included in this study: 89 women with two or more consecutive miscarriages and 50 healthy controls. Total genomic DNA was isolated from blood leukocytes. To determine the frequency of the two common C677T and A1298C MTHFR gene mutations in the patients and controls, we used two methods, amplification refractory mutation system-PCR and PCR-restriction fragment length polymorphism. Results. There is no significant difference in the prevalence of 677T/T genotype among women with RSA and healthy controls (P = 0.285). Also no statistically significant difference in the frequency of A1298C MTHFR gene mutation was detected between the two groups (P = 0.175 ). Conclusion. In conclusion, the results indicate that the Amplification Refractory Mutation System-PCR method was in complete concordance with the results obtained by standard PCR-restriction fragment length polymorphism method. The results also show no significant difference in MTHFR C677T/A1298C genotype distribution among the two groups; therefore, further studies on larger population and other genetic variants to better understand the pathobiology of RSA are needed.

Poursadegh Zonouzi, Ahmad; Chaparzadeh, Nader; Asghari Estiar, Mehrdad; Mehrzad Sadaghiani, Mahzad; Farzadi, Laya; Ghasemzadeh, Alieh; Sakhinia, Masoud; Sakhinia, Ebrahim

2012-01-01

26

Association of MTHFR C677T and A1298C gene polymorphisms with hypertension  

PubMed Central

Objectives To check for the association of genetic polymorphisms related to the methylenetetrahydrofolate reductase (MTHFR) gene namely C677T and A1298C with hypertension in Saudi affected subjects from Qassim region. Subjects and methods Participants included 123 Saudi hypertensive cases (83 males and 40 females) in addition to 250 (142 males and 108 females) unrelated healthy controls from the same locality. Their age mean ±SD was 50.93 ± 15.43 years. For all subjects, DNA was extracted followed by real-time PCR amplifications for characterization of genotypes and alleles related to MTHFR C677T and A1298C gene polymorphisms Results Total cases showed significantly higher carriage rate for the mutant allele 677T compared to controls (40.7% vs. 26%, OR=1.9, 95% CI= 1.2–3.1) with a lower frequency of the wild type 677CC genotype (59.3% vs. 74%, p=0.004). The same was observed among cases-subgroups of hypertension associated with obesity with a notably higher odds ratio (OR=2.6, 95% CI=1.3–5.01, p=0.004). Total cases showed also significantly higher frequency of mutant 1298 C allele carriage rate compared to controls (59.3% vs. 42.4%, OR=1.98, 95% CI= 1.3–3.1) with a lower frequency of the normal AA genotype (40.7% vs. 57.6%, p=0.003). The same was observed among cases-subgroups of hypertension associated with both diabetes and obesity and among cases of hypertension with obesity, also with higher odds ratio (OR=2.6 and 2.2 respectively). Conclusion This work showed that genetic polymorphisms related to the MTHFR gene are associated with the risk of hypertension particularly when accompanied with obesity and diabetes among Saudi subjects.

Alghasham, Abdullah; Settin, Ahmad A; Ali, Ahmad; Dowaidar, Moataz; Ismail, Hisham

2012-01-01

27

Pediatric stroke and methylenetetrahydrofolate reductase polymorphisms: an examination of C677T and A1298C mutations.  

PubMed

Although rare in children, stroke is becoming increasingly recognized as an important cause of morbidity and mortality with an annual incidence of approximately 3 per 100,000 per year. While several studies have documented the underlying mechanisms and pathogenesis related to stroke in adults, including genetic and acquired prothrombotic conditions, the data available on similar conditions in children is limited. Evidence suggests that mutations in methylenetetrahydrofolate reductase (MTHFR) appear to be linked with hyperhomocysteinemia (HHC) and cerebral-thrombotic events in children. While the C677T common missense mutation is the best-characterized MTHFR polymorphism, another common missense mutation, A1298C also exists. A recent study of children demonstrated that the homozygous form of C677T polymorphism occurred two-times as often in those with stroke versus healthy controls. In our retrospective chart review of 33 children seen at Children's Hospital of Orange County from January 1, 2000 to September 30, 2003 with the diagnosis of stroke, we examined both the C677T and A1298C polymorphisms for occurrence and type. In the subset (n=21), which excluded those with a confounding disorder, we observed a significant increase in the frequency of A1298C and C677T homozygosity (0.25 [p=0.01] and 0.20 [p=0.100], respectively); expected rate: (0.06 and 0.08, respectively). Our observed rates of heterozygosity for both MTHFR mutations (0.35 and 0.40, respectively) were consistent with expected rates (0.28 and 0.38, respectively). In all subjects, homocysteine (HC) levels were normal. The results of our study suggest that mutations in MTHFR are associated with pediatric stroke. However, additional studies are required to confirm our findings and to determine if this relationship is causal. PMID:16282888

Rook, James L; Nugent, Diane J; Young, Guy

2005-11-01

28

The relationship between C677T methylenetetrahydrofolate reductase gene polymorphism and retinopathy in type 2 diabetes: a meta-analysis  

Microsoft Academic Search

The association between retinopathy in type 2 diabetes [diabetic retinopathy (DR)] and the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene has been investigated in several case-control studies. These studies rendered contradictory results, some indicating that the polymorphism is associated with the risk of developing DR whereas others concluded there is no association. To shed light on these inconclusive findings,

Elias Zintzaras; Dimitrios Z. Chatzoulis; Costas H. Karabatsas; Ioannis Stefanidis

2005-01-01

29

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

30

Methylenetetrahydrofolate Reductase Gene Variant (MTHFR C677T) and Migraine: A Case Control Study and Meta-analysis  

PubMed Central

Background Migraine is a common disorder that often coexists with depression. While a functional polymorphism in methyleneterahydrofolate reductase gene (MTHFR C677T) has been implicated in depression; the evidence to support an association of MTHFR with migraine has been inconclusive. We aim to investigate the effect of this variant on propensity for migraine and to perform a systematic review and meta-analysis of studies of MTHFR and migraine to date. Methods Individuals with migraine (n = 447) were selected from the Depression Case Control (DeCC) study to investigate the association between migraine and MTHFR C677T single nucleotide polymorphism (SNP) rs1801133 using an additive model compared to non-migraineurs adjusting for depression status. A meta-analysis was performed and included 15 studies of MTHFR and migraine. Results MTHFR C677T polymorphism was associated with migraine with aura (MA) (OR 1.31, 95% CI 1.01-1.70, p = 0.039) that remained significant after adjusting for age, sex and depression status. A meta-analysis of 15 case-control studies showed that T allele homozygosity is significantly associated with MA (OR = 1.42; 95% CI, 1.10-1.82) and total migraine (OR = 1.37; 95% CI, 1.07-1.76), but not migraine without aura (OR = 1.16; 95% CI, 0.36-3.76). In studies of non-Caucasian population, the TT genotype was associated with total migraine (OR= 3.46; 95% CI, 1.22-9.82), whereas in studies of Caucasians this variant was associated with MA only (OR = 1.28; 95% CI, 1.002-1.63). Conclusions MTHFR C677T is associated with MA in individuals selected for depression study. A meta-analysis of 15 studies supports this association and demonstrated effects across ethnic groups.

2011-01-01

31

The 5, 10 methylenetetrahydrofolate reductase C677T mutation and risk of fetal loss: a case series and review of the literature  

PubMed Central

Background The true relationship between methylenetetrahydrofolate reductase C677T homozygosity and risk of recurrent spontaneous abortion is unknown, and it is unclear if women with these mutations should be anticoagulated during pregnancy. Objectives We report a series of 8 patients with this issue and review the current literature. Methods 8 patients (3 of whom were actively pregnant) were referred with histories of spontaneous fetal loss; hypercoaguability work-ups revealed each were homozygous for the MTHFR C677T mutation without other thrombophilias. Results In the 3 women who have conceived, treatment with LMW heparin during pregnancy led to two full-term births and one additional pregnancy without complication. For the 5 who have not, we recommended treatment with LMW heparin upon conception. Conclusion We provide evidence to support the relationship between MTHFR C677T mutations and recurrent fetal loss, and to suggest that anticoagulation of these patients during pregnancy can lead to a successful pregnancy outcome.

Altomare, Ivy; Adler, Alan; Aledort, Louis M

2007-01-01

32

A newborn case with perinatal-lethal Gaucher disease due to R463H homozygosity complicated by C677T homozygosity in the MTHFR gene.  

PubMed

Perinatal-lethal Gaucher disease is very rare and is considered a variant of type 2 Gaucher disease that occurs in the neonatal period. The most distinct features of perinatal-lethal Gaucher disease are non-immune hydrops fetalis, in utero fetal demise and neonatal distress. In some cases without hydrops, neurological signs occur in the first week of life and lead to death within 3 months. Less common signs of the disease are hepatosplenomegaly, ichthyosis, arthrogryposis and facial dysmorphy. We describe a preterm neonate with Gaucher disease homozygous for R463H mutation in GBA gene who showed severe neurologic signs in addition to refractory thrombocytopenia, hepatosplenomagaly, direct hyperbilirubinemia, facial dysmorphy and ichthyosiform skin abnormalities in addition to having thrombosis in portal and splenic veins possibly due to homozygosity for C677T mutation in MTHFR gene. To the best of our knowledge, this is the first case homozygous for the GBA R463H mutation resulting in Gaucher disease with a concomitant homozygous MTHFR C677T mutation. PMID:21823541

Akdag, Arzu; O?uz, Serife Suna; Ezgü, Fatih; Erdeve, Omer; Ura?, Nurdan; Dilmen, U?ur

2011-01-01

33

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.

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

2000-01-01

34

The 5, 10 methylenetetrahydrofolate reductase C677T mutation and risk of fetal loss: a case series and review of the literature  

Microsoft Academic Search

BACKGROUND: The true relationship between methylenetetrahydrofolate reductase C677T homozygosity and risk of recurrent spontaneous abortion is unknown, and it is unclear if women with these mutations should be anticoagulated during pregnancy. OBJECTIVES: We report a series of 8 patients with this issue and review the current literature. METHODS: 8 patients (3 of whom were actively pregnant) were referred with histories

Ivy Altomare; Alan Adler; Louis M Aledort

2007-01-01

35

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

36

The Frequency of A1298C and C677T Polymorphisms of the Methylentetrahydrofolate Gene in Turkish Patients with Rheumatoid Arthritis: Relationship with Methotrexate Toxicity.  

PubMed

The C677T and A1298C polymorphisms of methylenetatrahydrofolate reductase (MTHFR) gene are reported to have a relationship to methotrexate (MTX) metabolism, with conflicting results. The aim of this study was to determine the frequency of MTHFR C677 T and A1298C gene polymorphisms in a group of Turkish RA patients and evaluate its association with MTX toxicity.Sixty-four patients with RA and 31 control subjects with a mean age of 48.7 ±12.5 and 46.2 ± 13.4 years, were enrolled to the study. Demographic characteristics were obtained and MTX-related adverse effects were recorded in the patient group. The A1298C and C677T polymorphisms of the MTHFR gene were analyzed and the distribution of genotypes according side effects, were determined.The frequency of MTHFR C677T and A1298C polymorphisms were similar in the patient and control groups. Folic acid supplementation with a mean dose of 5mg folic acid/week, was present in all patients. Thirty-six of the 64 patients showed adverse effects to MTX treatment, and MTX had been discontinued in 12 (18.8%) patients due to side effects and/or inefficacy. MTHFR C677T and A1298C gene polymorphisms were found to be similar in patients with and without MTX-related adverse events.In conclusion, A1298C and C677T polymorphisms in the MTHFR gene, were not related with MTX-related toxicity in RA patients receiving folate supplementation. Further studies are needed to illuminate the polymorphisms in other enzymes that might be responsible from the MTX toxicity in patients suffering from RA. PMID:22046205

Ta?ba?, Ozgür; Borman, P?nar; Gürhan Karabulut, Halil; Tükün, Ajlan; Yorganc?o?lu, Rezan

2011-10-14

37

The Frequency of A1298C and C677T Polymorphisms of the Methylentetrahydrofolate Gene in Turkish Patients with Rheumatoid Arthritis: Relationship with Methotrexate Toxicity  

PubMed Central

The C677T and A1298C polymorphisms of methylenetatrahydrofolate reductase (MTHFR) gene are reported to have a relationship to methotrexate (MTX) metabolism, with conflicting results. The aim of this study was to determine the frequency of MTHFR C677 T and A1298C gene polymorphisms in a group of Turkish RA patients and evaluate its association with MTX toxicity. Sixty-four patients with RA and 31 control subjects with a mean age of 48.7 ±12.5 and 46.2 ± 13.4 years, were enrolled to the study. Demographic characteristics were obtained and MTX-related adverse effects were recorded in the patient group. The A1298C and C677T polymorphisms of the MTHFR gene were analyzed and the distribution of genotypes according side effects, were determined. The frequency of MTHFR C677T and A1298C polymorphisms were similar in the patient and control groups. Folic acid supplementation with a mean dose of 5mg folic acid/week, was present in all patients. Thirty-six of the 64 patients showed adverse effects to MTX treatment, and MTX had been discontinued in 12 (18.8%) patients due to side effects and/or inefficacy. MTHFR C677T and A1298C gene polymorphisms were found to be similar in patients with and without MTX-related adverse events. In conclusion, A1298C and C677T polymorphisms in the MTHFR gene, were not related with MTX-related toxicity in RA patients receiving folate supplementation. Further studies are needed to illuminate the polymorphisms in other enzymes that might be responsible from the MTX toxicity in patients suffering from RA.

Tasbas, Ozgur; Borman, P?nar; Gurhan Karabulut, Halil; Tukun, Ajlan; Yorganc?oglu, Rezan

2011-01-01

38

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

39

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

40

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 Muñoz-Valle; M Vazquez del Mercado; I P Dávalos

2011-01-01

41

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

42

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

43

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

PubMed

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

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

2011-12-07

44

The C677T Polymorphism of the Methylenetetrahydrofolate Reductase Gene Is Associated with Idiopathic Ischemic Stroke in the Young Mexican-Mestizo Population  

Microsoft Academic Search

Background and Purpose: Previous studies have demonstrated that a common polymorphism in the gene encoding 5,10-methylenetetrahydrofolate reductase (MTHFR) is associated with an increased risk for stroke. However, this relation remains controversial. Our aim was to investigate the possible association between the C677T polymorphism in the MTHFR gene and idiopathic ischemic stroke in the young Mexican-Mestizo population. Methods: One hundred seventy-eight

Irma Isordia-Salas; Fernando Barinagarrementería-Aldatz; Alfredo Leaños-Miranda; Gabriela Borrayo-Sánchez; Jorge Vela-Ojeda; Jaime García-Chávez; Isabel Ibarra-González; Abraham Majluf-Cruz

2010-01-01

45

Molecular analysis of factor V Leiden, factor V Hong Kong, factor II G20210A, methylenetetrahydrofolate reductase C677T, and A1298C mutations related to Turkish thrombosis patients.  

PubMed

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 chain reaction-based restriction enzyme analysis was carried out to screen these mutations, and single-strand conformation analysis was established to identify variations using the primers selected for restriction enzyme analysis studies. As a result, a significant relationship was determined among FV Leiden, FII G20210A, and thrombosis. The FV Hong Kong mutation was observed in only 2 patients with pulmonary vein thrombosis who are FV Leiden/FV Hong Kong compound heterozygous for FV gene. MTHFR C677T and A1298C were equally distributed in the patient group compared with the control group. All named mutations were also identified with single-strand conformation analysis, but a new variant/polymorphism during studies was not found. Because some inherited abnormalities are associated with thromboembolic disorders, determining the mutations and gene-to-gene interactions in patients with thrombosis history has a great impact on diagnosis and treatment of these diseases. PMID:17911197

Dölek, Bilgen; Eraslan, Serpil; Ero?lu, Sevim; Kesim, Belgin Eroglu; Ulutin, Turgut; Yalçiner, Altan; Laleli, Yahya R; Gözükirmizi, Nermin

2007-10-01

46

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

47

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

48

Strong association of methylenetetrahydrofolate reductase gene C677T polymorphism with hypertension and hypertension-in-pregnancy in Chinese: a meta-analysis  

Microsoft Academic Search

Attempts to associate methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism with hypertension have been extensively evaluated, but mostly in Caucasians. We therefore meta-analysed this polymorphism in association with hypertension and hypertension-in-pregnancy (HIP) among Chinese subjects. A random-effects model was applied irrespective of between-study heterogeneity, which was evaluated by subgroup and meta-regression analyses. Study quality was assessed in duplicate. Publication bias was

W-Q Niu; Y-G You; Y Qi

2012-01-01

49

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

50

Interaction of MTHFR C677T and A1298C, and MTR A2756G gene polymorphisms in breast cancer risk in a population in Northeast Brazil.  

PubMed

Polymorphisms in genes encoding enzymes of folate metabolism are a focus of breast cancer risk studies due of the role of these enzymes in DNA methylation, synthesis, and repair. MTHFR, encoding for 5,10-methylenetetrahydrofolate reductase, is one of the most studied genes in this regard, but findings are controversial, and the majority of studies have analyzed polymorphisms individually. In this case control study, we examined the combination of the polymorphisms MTHFR C677T and A1298C with MTR A2756G, where MTR, methionine synthase, is an important enzyme of the folate cycle in the methylation pathway. One hundred and forty-two patients with breast cancer and controls were included and the genotypes were determined using PCR-RFLP. In the population studied, individuals carrying the polymorphic allele in the heterozygous state for both enzymes, MTHFR C677T and MTR A2756G, had an increased risk [odds ratio, OR=2.77 (95% confidence interval, CI=1.19-6.52)] for disease, compared to those with the wild genotype. In addition, individuals carrying the MTR 2756 genotype AG had an increased risk when this was combined with the MTHFR 1298 genotype CC [OR=5.13 (95% CI=0.87-38.82)]. No significant results were found from the analyses associating the MTHFR C677T and A1298C genotypes. However, when stratifying the patients by age (50 years old as the cut-off), patients over 50 years old had greater risk, with the presence of both MTHFR polymorphisms in the heterozygous state [OR=5.33 (95% CI=1.42-21.03)]. This study points out the importance of the interactions between the MTHFR C677T, MTHFR A1298C and MTR A2756G polymorphisms, and also highlights the relevance of the MTR A2756G polymorphism and age in breast cancer risk. PMID:23155246

de Cássia Carvalho Barbosa, Rita; da Costa, Débora Menezes; Cordeiro, Denise Ellen Francelino; Vieira, Ana Patricia Freitas; Rabenhorst, Silvia Helena Barem

2012-11-01

51

Association of homocysteine and methylene tetrahydrofolate reductase (MTHFR C677T) gene polymorphism with coronary artery disease (CAD) in the population of North India  

PubMed Central

The implications of the methylene tetrahydrofolate reductase (MTHFR) gene and the level of homocysteine in the pathogenesis of coronary artery disease (CAD) have been extensively studied in various ethnic groups. Our aim was to discover the association of MTHFR (C677T) polymorphism and homocysteine level with CAD in north Indian subjects. The study group consisted of 329 angiographically proven CAD patients, and 331 age and sex matched healthy individuals as controls. MTHFR (C677T) gene polymorphism was detected based on the polymerase chain reaction and restriction digestion with HinfI. Total homocysteine plasma concentration was measured using immunoassay. T allele frequency was found to be significantly higher in patients than in the control group. We found significantly elevated levels of mean homocysteine in the patient group when compared to the control group (p = 0.00). Traditional risk factors such as diabetes, hypertension, smoking habits, a positive family history and lipid profiles (triglyceride, total cholesterol, HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol), were found significantly associated through univariate analysis. Furthermore, multivariable logistics regression analysis revealed that CAD is significantly and variably associated with diabetes, hypertension, smoking, triglycerides and HDL-cholesterol. Our findings showed that MTHFR C677T polymorphism and homocysteine levels were associated with coronary artery disease in the selected population.

2010-01-01

52

MTHFR C677T polymorphisms are associated with aberrant methylation of the IGF-2 gene in transitional cell carcinoma of the bladder  

PubMed Central

The purpose of this study was to determine the relationship between methylation status of the insulin-like growth factor 2 (IGF-2) gene and methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphisms in bladder transitional cell carcinoma tissues in a Chinese population. The polymorphisms of the folate metabolism enzyme gene MTHFR were studied by restrictive fragment length polymorphism (RFLP). PCR-based methods of DNA methylation analysis were used to detect the CpG island methylation status of the IGF-2 gene. The association between the methylation status of the IGF-2 gene and clinical characteristics, as well as MTHFR C677T polymorphisms, was analyzed. Aberrant hypomethylation of the IGF-2 gene was found in 68.3% bladder cancer tissues and 12.4% normal bladder tissues, respectively, while hypomethylation was not detected in almost all normal bladder tissues. The hypomethylation rate of the IGF-2 gene in cancer tissues was significantly higher in patients with lymph node metastasis than in those without lymph node metastasis (46.3% vs 17.2%, P = 0.018). No association was found between aberrant DNA methylation and selected factors including sex, age, tobacco smoking, alcohol consumption and green tea consumption. After adjusting for potential confounding variables the variant allele of MTHFR C677T was found to be associated with hypomethylation of the IGF-2 gene. Compared with wildtype CC, the odds ratio was 4.33 (95% CI=1.06-10.59) for CT and 4.95 (95% CI=1.18-12.74) for TT. MTHFR 677 CC and CT genotypes might be one of the reasons that cause abnormal hypomethylation of the IGF-2 gene, and the aberrant CpG island hypomethylation of the IGF-2 gene may contribute to the genesis and progression of bladder transitional cell carcinoma.

Cheng, Huan; Deng, Zhonglei; Wang, Zengjun; Zhang, Wei; Su, Jiantang

2012-01-01

53

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

PubMed

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

Geçene, Muharrem; Tuncay, Figen; Borman, P?nar; Yücel, Dogan; Senes, Mehmet; Y?lmaz, Behice Kaniye

2012-12-18

54

Investigation of MTHFR C677T Gene Polymorphism, Biochemical and Clinical Parameters in Turkish Migraine Patients: Association with Allodynia and Fatigue.  

PubMed

We investigated whether there is any relationship between biochemical and clinical parameters of migraine and methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism, associated with the migraine subtypes, symptoms, and gender. A total of 150 migraine patients with and without aura (MA and MO) and 107 non-sufferers were included in the study. Biochemical and clinical parameters were measured and genetic analysis was performed. The MTFHR C677T genotype was significantly higher in the migraine group (p = 0.000). The CT genotype frequency of individuals with a family history of migraine was significantly higher (p = 0.025). This genotype frequency was higher in patients who suffer from compression, allodynia, fatigue, and sleeplessness (p = 0.027, 0.023, 0.006, and 0.05, respectively). Homocysteine and total cholesterol levels were significantly higher in the migraine group than the control group (p = 0.007 and 0.010, respectively). However, the other biochemical and clinical parameters did not differ from each other (p > 0.05), with only attack frequency being significantly higher in the MO group (p = 0.005). While the folate and HDL levels were significantly higher in females (p = 0.001 and 0.000, respectively), the homocysteine and triglyceride levels were significantly higher in males (p = 0.000 for each one). BMIs were significantly lower in the control than the migraine group (p = 0.021); however, an association between the C677T variant and BMI was not found (p = 0.787) in the migraine group. An association between the MTHFR C667T polymorphism and migraine susceptibility was found. Additional studies including genetic, clinic, and biochemical parameters should be conducted to better understand the disease. PMID:23975093

Bahadir, Anzel; Eroz, Recep; Dikici, Suber

2013-08-22

55

C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene: effect on methotrexate-related toxicity in adult acute lymphoblastic leukaemia.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme involved in folate metabolism. Two polymorphisms, C677T and A1298C, were described leading to reduced enzyme activity. Methotrexate (MTX) is an antifolate agent of consolidation and maintenance therapy of acute lymphoblastic leukaemia (ALL). Despite its clinical success, MTX can be associated with serious toxicities resulting in treatment interruption or discontinuation, impacting disease outcome. There is evidence that MTX toxicity can be affected by polymorphisms in genes encoding for drug-metabolizing enzymes such as MTHFR. Therefore, we aimed to investigate the influence of MTHFR C677T and A1298C polymorphisms on the frequency of MTX-related toxicity, disease outcome and patients' survival. MTHFR polymorphisms were assessed in 50 adult patients with de novo ALL using real-time PCR. Patients were followed-up for the development of haematologic and/or nonhaematologic toxicity and assessment of clinical outcome. Frequency of C677T polymorphisms was 42% for TT, 24% for CT and 34% for CC; A1298C polymorphisms were 28, 6 and 66% for CC, AC and AA, respectively. MTX therapy was significantly associated with neutropaenia, hepatic and gastrointestinal toxicities, unfavourable response at day 14 of induction therapy, increased relapse and mortality rates and shorter survival in patients with 677 TT genotype than in those with CC and CT, whereas 1298 CC genotype patients had lower frequency of neutropaenia, hepatic toxicity and relapse than in those with AA and AC. Our study suggests MTHFR polymorphism as an attractive predictor of MTX-related toxicity in adult ALL, considering it a potential prognostic factor influencing disease outcome. PMID:23183238

Eissa, Deena Samir; Ahmed, Tamer Mohamed

2013-03-01

56

The methylenetetrahydrofolate reductase C677T mutation induces cell-specific changes in genomic DNA methylation and uracil misincorporation: A possible molecular basis for the site-specific cancer risk modification  

PubMed Central

The C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with a decreased risk of colon cancer while it may increase the risk of breast cancer. This polymorphism is associated with changes in intracellular folate cofactors, which may affect DNA methylation and synthesis via altered one-carbon transfer reactions. We investigated the effect of this mutation on DNA methylation and uracil misincorporation and its interaction with exogenous folate in further modulating these biomarkers of one-carbon transfer reactions in an in vitro model of the MTHFR 677T mutation in HCT116 colon and MDA-MB-435 breast adenocarcinoma cells. In HCT116 cells, the MTHFR 677T mutation was associated with significantly increased genomic DNA methylation when folate supply was adequate or high; however, in the setting of folate insufficiency, this mutation was associated with significantly decreased genomic DNA methylation. In contrast, in MDA-MB-435 cells, the MTHFR 677T mutation was associated with significantly decreased genomic DNA methylation when folate supply was adequate or high and with no effect when folate supply was low. The MTHFR 677T mutation was associated with a nonsignificant trend toward decreased and increased uracil misincorporation in HCT116 and MDA-MB-435 cells, respectively. Our data demonstrate for the first time a functional consequence of changes in intracellular folate cofactors resulting from the MTHFR 677T mutation in cells derived from the target organs of interest, thus providing a plausible cellular mechanism that may partly explain the site-specific modification of colon and breast cancer risks associated with the MTHFR C677T mutation.

Sohn, Kyoung-Jin; Jang, Hyeran; Campan, Mihaela; Weisenberger, Daniel J.; Dickhout, Jeffrey; Wang, Yi-Cheng; Cho, Robert C.; Yates, Zoe; Lucock, Mark; Chiang, En-Pei; Austin, Richard C.; Choi, Sang-Woon; Laird, Peter W.; Kim, Young-In

2009-01-01

57

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; Celebiler, Ozhan; Erdim, Melike; Akarsu, Nurten; Elçio?lu, Nursel H

58

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 11.62±3.43 ?mol/L, while tHcy level was significantly higher in patients with deep vein thrombosis as compared to the control group, 15.19±3.63 ?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.

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

2013-01-01

59

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.

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

2012-01-01

60

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

PubMed Central

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

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

2012-01-01

61

Role of C677T and A1298C MTHFR, A2756G MTR and -786 C/T eNOS Gene Polymorphisms in Atrial Fibrillation Susceptibility  

PubMed Central

Background Hyperhomocysteinemia has been suggested to play a role in the NonValvular Atrial Fibrillation (NVAF) pathogenesis. Polymorphisms in genes coding for homocysteine (Hcy) metabolism enzymes may be associated with hyperhomocysteinemia and NVAF. Methodologies 456 NVAF patients and 912 matched controls were genotyped by an electronic microchip technology for C677T and A1298C MTHFR, A2756G MTR, and -786C/T eNOS gene polymorphisms. Hcy was determined by an immunoassay method. Principal Findings The genotype distribution of the four polymorphisms as well as genotype combinations did not differ in patients and controls. Hcy was higher in patients than in controls (15.2, 95%CI 14.7–15.7 vs 11.3, 95%CI 11.0–11.6 µmol/L; p<0.0001). In both populations, a genotype-phenotype association (p<0.0001) between Hcy and C677T MTHFR polymorphism was observed; in controls a significant (p?=?0.029) association between tHcy and ?786C/T eNOS polymorphism was also observed. At the multivariate analysis the NVAF risk significantly increased in the upper quartiles of Hcy compared to the lowest: OR from 2.8 (1.68–4.54 95%CI) in Q2 to 12.9 (7.96–21.06 95%CI) in Q4. Conclusions Our data demonstrated the four polymorphisms, although able, at least in part, to affect Hcy, were not associated with an increased risk of NVAF per se or in combination.

Giusti, Betti; Gori, Anna Maria; Marcucci, Rossella; Sestini, Ilaria; Saracini, Claudia; Sticchi, Elena; Gensini, Francesca; Fatini, Cinzia; Abbate, Rosanna; Gensini, Gian Franco

2007-01-01

62

Evaluation of C677T and A1298C polymorphisms of the MTHFR gene as maternal risk factors for Down syndrome and congenital heart defects.  

PubMed

Abnormal folate/homocysteine metabolism due to polymorphisms in genes involved in this pathway has been implicated as an etiologic factor in Down syndrome (DS). This case-control study aimed to evaluate the effect of maternal C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) as risk factors for the development of DS and congenital heart defects (CHD). The distribution of these genotypic variants was similar between mothers of children with DS (n = 239) and control mothers of normal children (n = 197), but the combined genotypes 677CT or TT and 1298AA increased the risk of having offspring with DS (OR = 1.99; 95% CI 1.11-3.55). The presence of the 677T allele in case mothers resulted in a 2.07-fold higher odds of CHD in the offspring (P < 0.01). Among the 57 mothers of CHD-affected children with DS who carried the MTHFR 677CT or TT genotypes and did not have periconceptional folic acid intake, we observed a 2.26-fold increased odds (95% CI 1.25-4.09) of having any CHD-affected child with DS. Our results show that MTHFR genetic polymorphisms may be involved in the etiology of DS in our population when controlling for age. We noted a borderline significant association for the C677T polymorphism (P = 0.05). Maternal 677T allele may be associated with an increased occurrence of CHD in children with DS and we anticipate that women who carry this polymorphism would benefit from periconceptional folic acid supplementation. (c) 2009 Wiley-Liss, Inc. PMID:19725133

Brandalize, Ana Paula Carneiro; Bandinelli, Eliane; dos Santos, Pollyanna Almeida; Roisenberg, Israel; Schüler-Faccini, Lavínia

2009-10-01

63

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

64

Effect of the methylenetetrahydrofolate reductase gene C677T polymorphism on C-erbB-2 methylation status and its association with cancer.  

PubMed

Methylation abnormalities of cancer-related genes are recognized to play an important role in carcinogenesis. Methylenetetrahydrofolate reductase (MTHFR) regulates DNA methylation by affecting synthesis of S-adenosylmethionine, which is a universal methyl donor for methylation reactions. MTHFR gene polymorphisms that affect enzymatic activity may be associated with DNA methylation and cancer susceptibility. In the present study, we investigated the MTHFR C677T polymorphism in 247 cancer patients and 100 healthy subjects using PCR-RFLP, as well as the methylation status of the CpG island in the promoter region of the C-erbB-2 oncogene in 247 tumor and matched adjacent tissue samples using methylation-specific PCR. The results revealed that the methylation rate of the C-erbB-2 gene was significantly lower in the tumor tissues than in the matched adjacent tissues (43.3 vs. 69.2%, P=0.000). No correlation was observed between the methylation patterns of C-erbB-2 in tumor tissues and the clinicopathological characteristics of the patients. The frequency of the MTHFR gene 677 T allele was significantly higher in cancer patients than in the healthy subjects, and the combined variant genotypes (677CT+TT) significantly increased the risk of developing cancer (OR=1.619, 95% CI 1.012-2.588, P=0.043). Among the cancer patients, the methylation rate of the C-erbB-2 gene was higher in indi-viduals with the CC genotype than in those with the CT/TT genotype (50.0 vs. 39.4%). This difference was not significant (P=0.103). However, a significant difference was found in patients with breast cancer (P=0.008). In conclusion, the C-erbB-2 promoter CpG island was hypomethylated in cancer patients, and the MTHFR 677 CT/TT genotype increased the risk of developing the disease. Moreover, in breast cancer patients, the MTHFR gene C677T polymorphism had an effect on the methylation status of the C-erbB-2 gene. PMID:21475826

Jin, Zhonggan; Lu, Qing; Ge, Danhong; Zong, Ming; Zhu, Qinghui

65

Strong association of methylenetetrahydrofolate reductase gene C677T polymorphism with hypertension and hypertension-in-pregnancy in Chinese: a meta-analysis.  

PubMed

Attempts to associate methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism with hypertension have been extensively evaluated, but mostly in Caucasians. We therefore meta-analysed this polymorphism in association with hypertension and hypertension-in-pregnancy (HIP) among Chinese subjects. A random-effects model was applied irrespective of between-study heterogeneity, which was evaluated by subgroup and meta-regression analyses. Study quality was assessed in duplicate. Publication bias was weighed using Egger's test and funnel plot. Data on 20 qualified studies totalling 4461 Chinese subjects were meta-analysed. In overall allelic/genotypic models, carriers of 677T or 677TT were consistently at significantly increased risk of developing hypertension and HIP. No between-study heterogeneity was identified for all genetic models, with the exception for contrast of allele 677T versus 677C in hypertension association studies (P=0.03), and the dominant contrast in HIP association studies (P=0.025). Both the subgroup and meta-regression analyses indicated that study design was a potential source of between-study heterogeneity. Funnel plot and Egger's test suggested no evidence of publication bias. Taken together, our results supported the notion that carriers of 677T or 677TT were at significantly increased risk of developing hypertension and HIP, but indicated caution in interpreting this result, because the study design made marginal significant contribution to the heterogeneity. PMID:21346782

Niu, W-Q; You, Y-G; Qi, Y

2011-02-24

66

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

67

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

68

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

69

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

70

MTHFR gene polymorphisms and outcome of methotrexate treatment in patients with rheumatoid arthritis: analysis of key polymorphisms and meta-analysis of C677T and A1298C polymorphisms.  

PubMed

Association of two key variants mapping to the MTHFR gene (C677T (rs1801133) and A1298C (rs1801131)) with response to methotrexate (MTX) remains controversial. We investigated these and other markers spanning the gene as predictors of MTX efficacy and adverse events in a UK rheumatoid arthritis (RA) patient cohort and performed a meta-analysis of the two key variants using all published data. The tagging single nucleotide polymorphisms (SNPs) were genotyped in 309 patients with well-defined outcomes to MTX treatment and 17 studies were included in the meta-analysis. No association of the SNPs tested was detected with MTX efficacy or toxicity in our UK cohort. After combining our data with previous studies by meta-analysis, the random effects pooled odds ratios (OR) for both C677T and A1298C showed no association with efficacy or toxicity for either of the SNPs (efficacy: OR=1.05 (95% confidence interval (CI) 0.83-1.32) and OR=0.81 (95% CI 0.53-1.24), respectively; toxicity: OR=1.38 (95% CI 0.90-2.12) and OR=1.19 (95% CI 0.80-1.78), respectively). The available evidence suggests that the MTHFR C677T and A1298C gene polymorphisms are not reliable predictors of response to MTX treatment in RA patients. PMID:21931346

Owen, S A; Lunt, M; Bowes, J; Hider, S L; Bruce, I N; Thomson, W; Barton, A

2011-09-20

71

Genetic susceptibility of methylenetetrahydrofolate reductase (MTHFR) gene C677T, A1298C, and G1793A polymorphisms with risk for bladder transitional cell carcinoma in men  

Microsoft Academic Search

We performed a case–control study of 158 bladder transitional cell carcinoma (TCC) cases and 316 controls to investigate the\\u000a association between methylenetetrahydrofolate reductase (MTHFR) C677T, A1298G, and G1793A polymorphisms and bladder cancer\\u000a susceptibility by polymerase chain reaction restriction fragment length polymorphism (PCR-RLFP) technique. The controls were\\u000a frequency-matched to the cases by age (±5 years), ethnicity, and smoking status. We also measured

Nayyer Shafiei; Shiva Safarinejad

72

Genetic susceptibility of methylenetetrahydrofolate reductase (MTHFR) gene C677T, A1298C, and G1793A polymorphisms with risk for bladder transitional cell carcinoma in men.  

PubMed

We performed a case-control study of 158 bladder transitional cell carcinoma (TCC) cases and 316 controls to investigate the association between methylenetetrahydrofolate reductase (MTHFR) C677T, A1298G, and G1793A polymorphisms and bladder cancer susceptibility by polymerase chain reaction restriction fragment length polymorphism (PCR-RLFP) technique. The controls were frequency-matched to the cases by age (± 5 years), ethnicity, and smoking status. We also measured serum levels of total homocysteine (tHcy), folate, and vitamin B12. It was found that the 1298AC (odds ratio, OR = 3.74; 95% confidence interval, CI = 2.34-5.47; P = 0.001) and 1298CC (OR = 3.46, 95% CI = 2.37-5.52; P = 0.001) genotypes of MTHFR A1298C were significantly associated with increased risk of bladder TCC. The MTHFR C677T and G1793A polymorphisms were not associated with bladder TCC. After stratification for grade and stage, we observed that the 677TT (OR = 4.47, 95% CI = 2.74-6.72; P = 0.001) and MTHFR 1298CC (OR = 4.78, 95% CI = 2.82-6.89; P = 0.001) genotypes of MTHFR were associated with increased risk of muscle-invasive bladder TCC. We also found that the MTHFR 677CT+1298AA genotypes were associated with an approximately 70% reduction in risk of bladder cancer (OR = 0.31; 95% CI = 0.15-0.68) compared to the combined referent genotype. There were 8 haplotypes and 16 haplotype genotypes based on these three variants. When we used the haplotypes and assumed that the 677T, 1298C, and 1793G alleles were risk alleles, the adjusted odds ratios increased as the number of risk alleles increased: 1.00 for 0-1 variant, 1.88 (1.4-2.7) for any two risk alleles and 2.07 (1.6-2.8) for any three risk alleles. Serum tHcy levels were significantly higher in carriers of the 677T, 1298C, and 1793G alleles compared to noncarriers (all P < 0.01). There was no significant correlation between serum levels of tHcy and folate and bladder cancer risk. Further studies in larger samples size and different ethnicity are required to confirm our findings. PMID:21046286

Safarinejad, Mohammad Reza; Shafiei, Nayyer; Safarinejad, Shiva

2010-10-29

73

Evaluation of C677T polymorphism of the methylenetetra hydrofolate reductase gene and its association with levels of serum homocysteine, folate, and vitamin B12 as maternal risk factors for Down syndrome  

PubMed Central

AIMS AND OBJECTIVE: Evaluation of C677T polymorphisms of the methylenetetra hydrofolate reductase (MTHFR) gene and its association with level of serum homocysteine, folate, and vitamin B12 as possible maternal risk factors for Down syndrome. DESIGN: This was a case–control study. MATERIAL AND METHODS Fifty-two mothers (mean age 27.6 years) with babies having free trisomy 21 of North Indian ethnicity and 52 control nonlactating mothers (mean age 24.9 years) of same ethnicity attending services of genetic lab for bloodletting for other causes were enrolled after informed written consent. Fasting blood was collected and was used for determination of plasma homocysteine, vitamin B12, and folate (serum and RBC), and for PCR amplification of the MTHFR gene. RESULTS: The prevalence of MTHFR C677T polymorphism in north Indian mothers of babies with trisomy 21 Down syndrome was 15.38% compared to 5.88 % in controls. The difference between two groups was not statistically significant (P = 0.124). Low serum folate was demonstrated in 34.62% of cases vs. 11.54% in controls, which was significant (P = 0.005). Low RBC folate was found in 30.7% of cases versus 11.53% in controls, which was not significant (P = 0.059), when analyzed independently. But on multiple regression analysis the difference was statistically significant. Low serum vitamin B12 was found in 42.31% of cases versus 34.62% in controls, which was not significant (P = 0.118). The mean serum homocysteine in cases was 10.35 ± 0.68 while controls were 9.02 ± 0.535. CONCLUSION: Serum levels of folate were low in cases. The RBC folate levels were comparable in both groups. However the combined serum folate and RBC folate were low in cases compared to control groups. Homocysteine levels in our study were higher in Down syndrome mothers compared to controls; however high-serum level of Homocysteine had no association with MTHFR polymorphism. No association of serum vitamin B12 with MTHFR polymorphism in occurrence of Down syndrome births was found. Peri- or preconceptional folate supplementation may therefore lead to a decline in DS births, if supported by larger studies.

Mohanty, Pankaj K.; Kapoor, Seema; Dubey, Anand P.; Pandey, Sanjeev; Shah, Renuka; Nayak, Hemant K.; Polipalli, Sunil K.

2012-01-01

74

Common C677T Polymorphism in the Methylenetetrahydrofolate Reductase Gene Increases the Risk for Deep Vein Thrombosis in Patients with Predisposition of Thrombophilia  

Microsoft Academic Search

The alanine\\/valine (A\\/V) gene polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR), one of the key enzymes catalyzing remethylation of homocysteine, has been reported and the VV genotype is associated with increased plasma homocysteine levels as a result of the reduced activity and increased thermolability of this enzyme. Although previous studies have suggested that the VV genotype is a risk factor for arterial

Hironobu Fujimura; Tomio Kawasaki; Toshiyuki Sakata; Hideo Ariyoshi; Hisao Kato; Morito Monden; Toshiyuki Miyata

2000-01-01

75

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

76

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

77

A common mutation in methylenetetrahydrofolate reductase gene is not a major risk of coronary artery disease or myocardial infarction  

Microsoft Academic Search

A common mutation (C677?T) in methylenetetrahydrofolate (MTHFR) gene, involved in the metabolism of homocysteine, has been suggested to play a role in increasing cardiovascular disease risk. We determined the frequency of C677?T genotypes and alleles in 155 Caucasian patients with angiographically documented coronary artery disease (CAD) and in 155 age and sex matched normal Caucasian individuals. DNA was extracted from

Ramon Brugada; A. J Marian

1997-01-01

78

Genetic Polymorphisms in MTHFR (C677T, A1298C), MTR (A2756G) and MTRR (A66G) Genes Associated With Pathological Characteristics of Prostate Cancer in the Ecuadorian Population.  

PubMed

INTRODUCTION:: The methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR) and MTR reductase (MTRR) enzymes act in the folate metabolism, which is essential in methylation and synthesis of nucleic acids. The single nucleotide polymorphisms, MTHFR C677T, A1298C, MTR A2756G and MTRR A66G, cause alteration in the homocysteine levels and reduced enzymatic activity that generates deficiency in the assimilation of folates associated with DNA damage; that is, why it is important to know if the single nucleotide polymorphisms are associated with the pathological characteristics and development of prostate cancer, through a case-control retrospective study. METHODS:: DNA was extracted from 110 healthy and 104 affected men. The genotypes were determined by means of the polymerase chain reaction-restriction fragment length polymorphism and confirmed with genomic sequencing. RESULTS:: We found significant association between the genotypes of the MTHFR C677T polymorphism: C/T (odds ratio [OR] = 2.2; 95% confidence interval [CI] = 1.3-3.9; P = 0.008) and C/T + T/T (OR = 2.2; 95% CI = 1.3-3.9; P = 0.009) with the risk of prostate cancer development, and a slight association with MTRR A66G. Regarding pathological characteristics, we found significant risk between the C/T + T/T genotypes and the Gleason score (7-10) of poorly differentiated carcinoma (OR = 5.2; 95% CI = 1.7-16.2; P = 0.007). On the other hand, a significant association between A1298C, A66G, and A2756G with the pathological characteristics was not found (P > 0.05). CONCLUSIONS:: The MTHFR C677T polymorphism has significant effects on susceptibility to prostate cancer in Ecuadorian population, especially with the Gleason grade. PMID:23459165

López-Cortés, Andrés; Jaramillo-Koupermann, Gabriela; Muñoz, María J; Cabrera, Alejandro; Echeverría, Carolina; Rosales, Felipe; Vivar, Nicolás; Paz-Y-Miño, César

2013-03-01

79

Prevalence of methylenetetrahydrofolate reductase C677T polymorphism in eastern Uttar Pradesh  

PubMed Central

AIM: This study was aimed to evaluate the 5, 10-methylenetetrahydrofolate reductase (MTHFR) C677T mutation in eastern Uttar Pradesh population. MATERIALS AND METHODS: Polymerase chain reaction (PCR) using specific primers followed by amplicon digestion by Hinf I restriction enzyme was used for MTHFR C677T polymorphism analysis. Total 250 subjects were analyzed. RESULTS: The CC genotype was found in 192 subjects, followed by CT in 56 subjects and TT in 2 subject. Genotype frequencies of CC, CT and TT were 0.768, 0.224 and 0.008, respectively. The frequency of C allele was found to be 0.88 and that of T allele was 0.12. CONCLUSION: It is evident from the results of the present study that the percentage of homozygous genotype (CC) is highest in the target population.

Rai, Vandana; Yadav, Upendra; Kumar, Pradeep

2012-01-01

80

Association of MTHFR C677T polymorphism with susceptibility to migraine in the Chinese population.  

PubMed

A number of genes have been implicated in the pathogenesis of migraine, a common neurological disorder also in China. However, data on association of genetic variations with migraine susceptibility among Chinese, which might be different from people of other ethnic background, are still scarce. We have therefore investigated the association of polymorphisms in four genes, MTHFR C677T, ACE I/D, MAOA T941G and TNF-? G252A, which are considered to be with risk of migraine. A case-control study including a cohort of 151 migraine cases and 137 ethnically matched controls was conducted. The genotypes of each polymorphism followed the Hardy-Weinberg equilibrium in the two groups. Genotypic distribution of MTHFR C677T was significantly different with higher frequency of allele T in the migraine cohort as compared with that in controls (OR=1.686, 95%CI: 1.175-2.420, P=0.004). No difference was found between migraine with aura (MA) patients and controls, but T allele frequency was significantly higher in migraine without aura (MO) than in controls (OR=1.744, 95% CI: 1.202-2.532, P=0.003). No difference in genotypic and allelic distributions was observed between migraine patients and controls for the other polymorphisms, including ACE I/D, MAOA T941G, and TNF-? G252A. Our data suggested that MTHFR C677T polymorphism plays a role in Chinese migraine susceptibility, especially in MO. PMID:23811028

An, Xing-Kai; Lu, Cong-Xia; Ma, Qi-Lin; Zhang, Xiao-Rong; Burgunder, Jean-Marc; Lin, Qing; Qu, Hong-Li

2013-06-27

81

Association between MTHFR polymorphism (C677T) with nonfamilial colorectal cancer.  

PubMed

The enzyme 5,10-methylene-tetrahydrofolate reductase (MTHFR) is linked to DNA methylation, synthesis, and repair. C677T is one of the most important polymorphisms in the MTHFR gene. The single nucleotide polymorphism C677T has been found to be associated with decreased enzyme activity and plasma folate, and thus may play a crucial role in the etiology of colorectal cancer. This decrease was observable in people with either high or low folate status. We aimed to test the hypothesis that the C677T genotype is involved in colorectal cancer. Using pyrosequencing, we analyzed the MTHFR genotypes in 234 colorectal cancer patients and 257 matched controls. We examined the polymorphisms in MTHFR and folate intake in relation to risk of colon cancer in an Iranian population-based case-control study. Our finding revealed that the CC, CT, and TT genotypes of MTHFR among the colorectal cancer patients were 50%, 29.1%, and 20.9%, respectively. On the other hand, we could find 29.5% of 677CC, 46% of 677CT and 24.5% of 677TT in the controls. A decreased risk of colon cancer for participants with wild-type genotype was observed. Interestingly, this association was stronger at higher levels of folate intake. Our study corroborates previous findings of an inverse association of the MTHFR 677TT genotype with colorectal cancer, in particular at high levels of folate. PMID:20066895

Haghighi, Mahdi Montazer; Radpour, Ramin; Mahmoudi, Touraj; Mohebbi, Seyed Reza; Vahedi, Mohsen; Zali, Mohammad Reza

2009-01-01

82

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

83

Thermolabile Methylenetetrahydrofolate Reductase C677T Polymorphism and Homocysteine Are Risk Factors for Coronary Artery Disease in Moroccan Population  

PubMed Central

Increased plasma total homocysteine (tHcy) levels have been shown to be a risk factor for coronary artery disease (CAD). The common methylenetetrahydrofolate reductase C677T (MTHFR C677T) polymorphism has been reported to be a strong predictor of mild hyperhomocysteinaemia (HHcy). We assessed whether this mutation was associated with increased risk of CAD and plasma levels of tHcy. We also evaluated interactions between this polymorphism, mild elevated tHcy levels and conventional risk factors of CAD. Method. Using PCR-RFLP analysis, we studied the frequency of the C677T genotypes and its effect on CAD and on tHcy concentrations in 400 subjects without and with CAD angiographically confirmed. There were 210 subjects with CAD and 190 subjects without CAD. Results. The frequencies of the C677T genotypes were 53% (59.5% in controls versus 48.1% in cases), 34.8% (32.1 in controls versus 37.1 in cases), and 11.8% (8.4% in controls versus 14.8% in cases), respectively, for 677CC, 677CT, and 677TT. The genotype frequencies were significantly different between case and control groups (P < .05). The 677T allele enhances the risk of CAD associated to HHcy (P < .01). In multivariate analysis models, MTHFR C677T polymorphism effect on CAD was masked by other risk factors. HHcy was only and independently influenced by MTHFR polymorphism and smoking habits, and it is a strong predictor of CAD independently of conventional risk factors. Conclusion. Our data suggest that HHcy is strongly and independently associated to CAD risk increase; and MTHFR C677T polymorphism and smoking habits were the main predictors of tHcy levels. The CAD risk increase is mainly associated with mild HHcy in 677TT, whereas in 677CT and 677CC it is mainly associated with the conventional risk factors.

Bennouar, Nawal; Allami, Abdellatif; Azeddoug, Houssine; Bendris, Abdenbi; Laraqui, Abdelilah; El Jaffali, Amal; El Kadiri, Nizar; Benzidia, Rachid; Benomar, Anwar; Fellat, Seddik; Benomar, Mohamed

2007-01-01

84

MTHFR C677T polymorphism is associated with hyperlipidemia in women with polycystic ovary syndrome  

PubMed Central

CONTEXT: Women with polycystic ovary syndrome (PCOS) are prone for coronary artery disease (CAD), and hyperhomocysteinemia is an independent risk factor for CAD. MTHFR deficiency is the most common cause of hyperhomocysteinemia, thereby provoking a possible association between PCOS and MTHFR C677T polymorphism. AIMS: The aim of this study was to investigate an association of MTHFR C677T polymorphism with PCOS. SETTINGS AND DESIGN: 92 women with PCOS (Rotterdam criteria) and 95 age-matched controls were compared with respect to MTHFR C677T polymorphism. The 2 genotypes (CC and CT) obtained were compared with clinical and laboratory parameters in women with PCOS. MATERIALS AND METHODS: In a case-control study, clinical, biochemical, hormonal and genetic analysis (PCR-RFLP of peripheral leucocytes) was carried out on all women with PCOS as well as controls. STATISTICAL ANALYSIS: Student “t” test for quantitative and Chi-square test for nominal variables was used. For estimation of risk, odds ratio and 95% confidence interval were calculated. RESULTS: The odds ratio of bearing a heterozygous genotype (CT) was 1.32 in women with PCOS as compared to controls (P = 0.48). No homozygous mutation (TT) was found in the study population. Serum cholesterol was more in heterozygous (CT) genotype (215.48 ± 25.56 mg/dl) as compared to normal (CC) genotype (203.29 ± 16.35 mg/dl) in women with PCOS (P = 0.01). Similarly, serum triglyceride was more in heterozygous (CT) genotype (95.86 ± 37.34 mg/dl) as compared to normal (CC) genotype (82.36 ± 20.88 mg/dl) in women with PCOS (P = 0.04). CONCLUSIONS: Although not statistically significant, there is a slightly higher prevalence of heterozygous (CT) genotype in women with PCOS. MTHFR C677T polymorphism when present may confer an increased susceptibility to develop hyperlipidemia in women with PCOS. More prospective studies are needed to confirm whether this hyperlipidemia due to MTHFR C677T polymorphism clinically manifests into CAD in long term in women with PCOS.

Jain, Madhu; Pandey, Priyanka; Tiwary, Narendra K; Jain, Shuchi

2012-01-01

85

[Genetic thrombophilic defects (Factor V Leiden, prothrombin G20210A, MTHFR C677T) in women with recurrent fetal loss].  

PubMed

Maternal thrombophilia (inherited and acquired) has recently been identified as a major cause of thrombembolism, but it may also contribute to adverse pregnancy outcomes and recurrent pregnancy loss. To determine the association of specific inherited thrombophilias and recurrent fetal loss (RFL), three gene mutations (Factor V Leiden, prothrombin G20210A, MTHFR C677T) were investigated. The prevalence of the thrombophilic markers was compared in 156 women with history of fetal loss in different trimester of pregnancy and 80 matched controls. At least one thrombophilic defect was found in 28.2% of total study group women compared with 16.2% in controls (p=0.06; OR-2.02) and in 50% of women with RFL in third trimester (p=0.008; OR-5.15). Factor V Leiden was more common in the group of women with fetal loss in third trimester (37.5%) compared to the controls (6.2%) (p=0.002; OR-9.0). Presence of FVL was associated with a significant increased risk for RFL in second and third trimester (OR-6.25; P<0.001) and significant protection for RFL in first trimester (OR-0.16; P<0.001). Mutation prothrombin G20210A or MTHFR C677T was more common in group of women with fetal loss in first trimester compared to the controls (28.3% vs. 11.2% respectively; p=0.009; OR-3.11). The presence of either of these mutations was associated with no significant increased risk for RFL in first trimester (OR-2.5). Genetic thrombophilic defects are common in women with RFL and are associated with late fetal loss. This association is manifest by FVL rather than total number of defects involved. PMID:18333414

Kovacheva, K; Ivanov, P; Konova, E; Simeonova, M; Komsa-Penkova, R

2007-01-01

86

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

87

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

88

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

89

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

90

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

91

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 Stenkjær; Bente L. Langdahl

2005-01-01

92

MTHFR polymorphic variant C677T is associated to vascular complications in sickle-cell disease.  

PubMed

Vaso-occlusion is a determinant for most signs and symptoms of sickle-cell anemia (SCA). The mechanisms involved in the pathogenesis of vascular complications in SCA remain unclear. It is known that genetic polymorphisms associated with thrombophilia may be potential modifiers of clinical features of SCA. The genetic polymorphisms C677T and A1298C relating to the enzyme methylenetetrahydrofolate reductase (MTHFR), a clotting Factor V Leiden mutation (1691G?A substitution of Factor V Leiden), and the mutant prothrombin 20210A allele were analyzed in this study. The aim was to find possible correlations with vascular complications and thrombophilia markers in a group of SCA patients in Pernambuco, Brazil. The study included 277 SCA patients, divided into two groups: one consisting of 177 nonconsanguineous SCA patients who presented vascular manifestations of stroke, avascular necrosis, leg ulcers, priapism, and acute chest syndrome (group 1); and the other consisting of 100 SCA patients without any reported vascular complication (group 2). Molecular tests were done using either polymerase chain reaction (PCR) restriction fragment length polymorphism or allele-specific PCR techniques. Comparisons between the groups were made using the ?(2) test. The 677 CT and TT genotypes showed a significant risk of vascular complications (p=0.015). No significant associations between the groups were found when samples were analyzed for the MTHFR A1298C allele (p=0.913), Factor V G1691 (p=0.555), or prothrombin G20210A mutation (p=1.000). The polymorphism MTHFR C677T seemed to be possibly predictive for the development of some vascular complications in SCA patients among this population. PMID:22924497

Hatzlhofer, Betânia L D; Bezerra, Marcos André C; Santos, Magnun N N; Albuquerque, Dulcinéia M; Freitas, Elizabete M; Costa, Fernando F; Araújo, Aderson S; Muniz, Maria Tereza C

2012-08-27

93

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.

Gong, Fangqi; Zhu, Weihua; Fu, Songling

2013-01-01

94

Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism and Age at Onset of Schizophrenia: No Consistent Evidence for an Association in the Nordic Population  

PubMed Central

Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in metabolic pathways of importance for nucleotide synthesis and methylation of DNA, membranes, proteins and lipids. The MTHFR gene includes a common polymorphism (rs1801133 or C677T), which is associated with enzyme activity. The T-allele of the C677T polymorphism has been associated with earlier age at onset of schizophrenia in a Scandinavian population, although no association was found in replication attempts in other populations. Extending the study to five Nordic samples consisting of 2,198 patients with schizophrenia, including the original Scandinavian samples, there was no significant association between MTHFR C677T polymorphism and age at onset in schizophrenia. The present results do not suggest that the investigated MTHFR polymorphism has any significant influence on age at onset of schizophrenia in the Nordic population. © 2012 Wiley Periodicals, Inc.

Saetre, Peter; Grove, Jakob; B?rglum, Anders D; Mors, Ole; Werge, Thomas; Andreassen, Ole A; Vares, Maria; Agartz, Ingrid; Terenius, Lars; Jonsson, Erik G

2012-01-01

95

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

PubMed

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

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

2010-03-01

96

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

PubMed Central

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

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

2012-01-01

97

Methylenetetrahydrofolate C677T polymorphism and pre-eclamptic Egyptian women  

Microsoft Academic Search

Thrombosis of the maternal spiral arteries can be one of the causative events in pre-eclampsia disease, it has been suggested that the C677T polymorphism may also play a role in the pathogenesis of pre-eclampsia.

Zakia Mahdy Ibrahim; Mohamed Abd Elhamid Metawie; Ahmed Mohamed El-Baz; Mohamed Ahmed El-Bahie

98

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

99

Effect of the Methylenetetrahydrofolate Reductase C677T Polymorphism on Chemosensitivity of Colon and Breast Cancer Cells to 5Fluorouracil and Methotrexate  

Microsoft Academic Search

Background: Although single nucleotide polymorphisms may be potentially important pharmacogenetic determi- nants of cancer therapy, functional evidence regarding their relevance is currently lacking. The C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with changes in cellular composition of folates. We hypothesized that this polymorphism may modulate the cytotoxic effect of 5-fluorouracil (5FU) and methotrexate (MTX), two commonly used

Kyoung-Jin Sohn; Ruth Croxford; Zoe Yates; Mark Lucock; Young-In Kim

100

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

Microsoft Academic Search

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

Lin Zhang; Rui-Xing Yin; Wan-Ying Liu; Lin Miao; Dong-Feng Wu; Lynn Htet Htet Aung; Xi-Jiang Hu; Xiao-Li Cao; Jin-Zhen Wu; Shang-Ling Pan

2010-01-01

101

Prevalence of the polymorphism MTHFR A1298C and not MTHFR C677T is related to chromosomal aneuploidy in Brazilian Turner Syndrome patients  

Microsoft Academic Search

Background: Dysfunctions in the folate metabolism can result in DNA hypom- ethylation and abnormal chromosome segregation. Two common polymor- phisms of this enzyme (C677T and A1298C) reduce its activity, but when associated with aneuploidy studies the results are confl icting. The objective of the present study is to analyze the MTHFR gene polymorphisms in women with Turner Syndrome and in

Kelly Cristina de Oliveira; Bianca Bianco; Ieda T. N. Verreschi; Alexis Dourado Guedes; Bianca Borsato Galera; Marcial Francis Galera; Caio P. Barbosa; Monica Vannucci Nunes Lipay

2008-01-01

102

Influence of the MTHFR C677T polymorphism on MRI hyperintensity volume and cognition in geriatric depression  

PubMed Central

Objective The 5,10-methylenetetrahydrofolate reductase gene (MTHFR) has been linked to unipolar major depressive disorder (MDD) and MRI hyperintensities. We examined the relationship between the MTHFR C677T polymorphism (C677T) and a) geriatric depression, b) MRI hyperintense lesion volume, and c) neurocognitive test performance. Design Cross-sectional. Setting Duke University Medical Center. Participants Depressed (N=178) and comparison (N=85) elderly subjects. Measurements Subjects had blood drawn to assess MTHFR genotype, were imaged by MRI to determine their white (WML) and gray (GML) matter hyperintense lesion volume, and assessed using a comprehensive neurocognitive battery evaluating multiple domains of function. Linear regression models were fit to test the effect of genotype, a depression by genotype interaction, and an age by genotype interaction on both hyperintense lesion volume measures and neurocognitive task performance. Results The MTHFR C677T genotype by age interaction term was significantly associated with MRI WML volume (p=0.0175), however this relationship was no longer statistically significant when WML volumes underwent a log transformation to produce a more normal distribution. The 677T allele was neither more frequent in depressed subjects nor associated with either gray matter hyperintensity volume or neurocognitive test performance. Conclusions MTHFR genotype affects the relationship between age and WML volume, where individuals who carry the 677T allele exhibit greater WML volume by age, although this relationship should be verified given the failure to replicate the finding using transformed WML volumes. Genotype was not related to GML volume, cognitive function, or presence of depression, although demographic differences could account for this negative finding.

Hong, Edmund D.; Taylor, Warren D.; McQuoid, Douglas R.; Potter, Guy G.; Payne, Martha E.; Ashley-Koch, Allison; Steffens, David C.

2009-01-01

103

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

PubMed

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

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

2008-01-19

104

Methylenetetrahydrofolate reductase C677T polymorphism in patients with lung cancer in a Korean population  

Microsoft Academic Search

Background  This study was designed to investigate an association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism\\u000a and the risk of lung cancer in a Korean population.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  We conducted a large-scale, case-control study involving 3938 patients with newly diagnosed lung cancer and 1700 healthy controls.\\u000a Genotyping was performed with peripheral blood DNA for MTHFR C677T polymorphisms. Statistical significance was estimated by\\u000a logistic regression

Lian-Hua Cui; Min-Ho Shin; Hee Nam Kim; Hye-Rim Song; Jin-Mei Piao; Sun-Seog Kweon; Jin-Su Choi; Woo-Jun Yun; Young-Chul Kim; In-Jae Oh; Kyu-Sik Kim

2011-01-01

105

Effect of MTHFR C677T genotype on survival in type 2 diabetes patients with end-stage diabetic nephropathy  

Microsoft Academic Search

Background. The MTHFR C677T single nucleotide polymorphism TT genotype is associated with increased levels of plasma homocysteine and possibly an effect on cardiovascular mortality. We evaluated the effect of C677T genotype on mortality in a large end-stage renal disease (ESRD) cohort. Methods. C677T genotype was determined in 439 Caucasians with end-stage diabetic nephropathy (DNP) (cases) recruited from 30 dialysis centres

Carsten A. Boger; Mike Stubanus; Thomas Haak; Angela K. Gotz; Johanna Christ; Ute Hoffmann; A. J. Riegger; Bernhard K. Kramer

2006-01-01

106

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

2013-06-28

107

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

PubMed

Down's 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 fourteen mothers (with DS children and controls), mostly from the eastern states of India, were genotyped for the two above-mentioned SNPs. Significant association with both of these SNPs were detected, more specifically, in the mothers of DS children homozygous for the polymorphic alleles 677 T and 1298 C. The relative risk of T (C677T) and C (A1298C) homozygosity in mothers for DS-affected pregnancy was 7 (OR 7.67, 95% CI 1.67-35.08, P=0.003) and 4 (OR 4.40, 95% CI 1.45-13.26, P=0.008), respectively. Moreover, all 677TT mothers studied were less than 31 years of age, whereas no correlation with maternal age was observed for A1298C genotypes. Interestingly, all of the young 677TT mothers had either a first- or secondborn child with DS. Thus, this study reports that young Indian mothers with TT genotypes are genetically predisposed to nondisjunction due to abnormal folate metabolism. PMID:16489479

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

2006-02-18

108

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; Jørn Schneede; Helga Refsum; Stein Emil Vollset

2001-01-01

109

Methylenetetrahydrofolate reductase C677T polymorphism in patients with lung cancer in a Korean population  

PubMed Central

Background This study was designed to investigate an association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and the risk of lung cancer in a Korean population. Methods We conducted a large-scale, case-control study involving 3938 patients with newly diagnosed lung cancer and 1700 healthy controls. Genotyping was performed with peripheral blood DNA for MTHFR C677T polymorphisms. Statistical significance was estimated by logistic regression analysis. Results The MTHFR C677T frequencies of CC, CT, and TT genotypes were 34.5%, 48.5%, and 17% among lung cancer patients, and 31.8%, 50.7%, and 17.5% in the controls, respectively. The MTHFR 677CT and TT genotype showed a weak protection against lung cancer compared with the homozygous CC genotype, although the results did not reach statistical significance. The age- and gender-adjusted odds ratio (OR) of overall lung cancer was 0.90 (95% confidence interval (CI), 0.77-1.04) for MTHFR 677 CT and 0.88 (95% CI, 0.71-1.07) for MTHFR 677TT. However, after stratification analysis by histological type, the MTHFR 677CT genotype showed a significantly decreased risk for squamous cell carcinoma (age- and gender-adjusted OR, 0.78; 95% CI, 0.64-0.96). The combination of 677 TT homozygous with 677 CT heterozygous also appeared to have a protection effect on the risk of squamous cell carcinoma. We observed no significant interaction between the MTHFR C677T polymorphism and age and gender or smoking habit. Conclusions This is the first reported study focusing on the association between MTHFR C677T polymorphisms and the risk of lung cancer in a Korean population. The T allele was found to provide a weak protective association with lung squamous cell carcinoma.

2011-01-01

110

MTHFR C677T and A1298C polymorphisms were associated with bladder cancer risk and disease progression: a meta-analysis.  

PubMed

Epidemiological studies have investigated that functional polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene may play an essential role in bladder carcinogenesis, but the association between these single-nucleotide polymorphisms in the MTHFR gene and the susceptibility of bladder cancer (BC) was inconsistent in previous studies. The objective of this current study was to conduct an update analysis investigating the association between three polymorphisms in the MTHFR gene and the risk of BC. We performed a meta-analysis of 13 publications involving an association between BC and MTHFR gene three polymorphisms (C677T, A1298C, and G1793A). We assessed the strength of the association, using odds ratios (ORs) with 95% confidence intervals (CIs). On one hand, we found that the C677T polymorphism was associated with increased BC risk among Asians, however, with decreased BC risk among a mixed population. Interestingly, BC patients who carried the T-allele (TT+TC) had a higher percentage than the individuals who carried the CC genotype (OR=1.38, 95% CI=1.13-1.69, p=0.002). On the other hand, the A1298C polymorphism may increase BC risk among Asians and Africans, but played a decreased association among Europeans. Results from the current update analysis suggested that the C677T and A1298C polymorphisms in the MTHFR gene were associated with BC risk and disease progression. PMID:23578207

You, Wu; Li, Zuo; Jing, Chen; Qian-Wei, Xing; Yu-Ping, Zhang; Weng-Guang, Li; Hua-Lei, Li

2013-04-11

111

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

112

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

113

Homocysteine and MTHFR C677T polymorphism in children and adolescents with psychotic and mood disorders.  

PubMed

Background : High level of homocysteine (Hcy) is risk factor of schizophrenia and mood disorders. Aim: The aim was to detect a serum level of Hcy, examine the associations between the level of Hcy, methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism and clinical properties for patients with schizophrenia, mood disorders and in a control group. Material and methods: There were 88 patients with schizophrenia, 28 with affective disorders and 94 from the control group. The Hamilton Anxiety Scale (HAM-A) was performed to study anxiety, the Hamilton Depression Scale (HAM-D) to study depression and the Brief Psychiatric Rating Scale (BPRS) to study severity of schizophrenia. The level of Hcy was stated by isocratic high-performance liquid chromatography (HPLC) system with fluorometric detection. DNA isolation from venous blood was performed by the phenol-chloroform method. Results: The levels of B12 vitamin and folic acid were within normal limits for all the patients. The average level of Hcy was 11.94 ± 5.6 ?mol/l for patients with schizophrenia and 11.65 ± 3.3 ?mol/l for patients with affective disorders, vs. 6.80 ± 2.93 ?mol/l in a control group. The highest level of Hcy has been observed in patients with an episodic-recurrent course of schizophrenia, paranoid schizophrenia-continuous, particularly in patients with CT genotype (r = - 0.58; P < 0.01). In the given diagnostic groups, the highest level of anxiety was observed. Conclusions: The level of Hcy is higher in the blood of a heterozygotic person who becomes ill with schizophrenia, and the process of the illness is more serious and with more typical affective disorders. PMID:23586533

Kevere, Laura; Purvina, Santa; Bauze, Daiga; Zeibarts, Marcis; Andrezina, Raisa; Piekuse, Linda; Brekis, Edgars; Purvins, Indulis

2013-04-16

114

MTHFR C677T and A1298C polymorphisms: diet, estrogen, and risk of colon cancer.  

PubMed

5,10-methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism, diverting metabolites toward methylation reactions or nucleotide synthesis. Using data from an incident case-control study (1608 cases and 1972 controls) we investigated two polymorphisms in the MTHFR gene, C677T and A1298C, and their associations with risk of colon cancer. All of the combined genotypes were evaluated separately, and the 1298AA/677CC (wild-type/wild-type) group was considered the reference group. Among both men and women, the 677TT/1298AA (variant/wild-type) genotype was associated with a small reduction in risk [men: odds ratio (OR), 0.7, 95% confidence interval (CI), 0.5-1.0; women: OR, 0.8, 95% CI, 0.5-1.2]. However, the 677CC/1298CC (wild-type/variant) genotype was associated with a statistically significant lower risk among women (OR, 0.6; 95% CI, 0.4-0.9) but not men. When the polymorphisms were considered individually, for A1298C a significant risk reduction associated with the homozygous variant CC genotype was seen among women only (OR, 0.6; 95% CI, 0.5-0.9), and nonstatistically significant reduced risks were observed for the variant 677 TT genotypes among both men and women. Stratification by nutrient intakes showed inverse associations with higher intakes of folate, vitamin B(2), B(6), B(12), and methionine among women with the MTHFR 677CC/1298AA genotypes, but not those with 677TT/1298AA. We observed opposite risk trends for both MTHFR variants, depending on whether women used hormone-replacement therapy or not (P for interaction = <.01). In summary, this study supports recent findings that the MTHFR A1298C polymorphism may be a predictor of colon cancer risk and have functional relevance. The possible interaction with hormone-replacement therapy warrants additional investigation. PMID:14973104

Curtin, Karen; Bigler, Jeannette; Slattery, Martha L; Caan, Bette; Potter, John D; Ulrich, Cornelia M

2004-02-01

115

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

PubMed

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

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

2009-02-14

116

Association Between C677T Polymorphism of Methylene Tetrahydrofolate Reductase and Congenital Heart Disease: Meta-Analysis of 7697 Cases and 13 125 Controls.  

PubMed

Background- Association between the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and congenital heart disease (CHD) is contentious. Methods and Results- We compared genotypes between CHD cases and controls and between mothers of CHD cases and controls. We placed our results in context by conducting meta-analyses of previously published studies. Among 5814 cases with primary genotype data and 10 056 controls, there was no evidence of association between MTHFR C677T genotype and CHD risk (odds ratio [OR], 0.96 [95% confidence interval, 0.87-1.07]). A random-effects meta-analysis of all studies (involving 7697 cases and 13 125 controls) suggested the presence of association (OR, 1.25 [95% confidence interval, 1.03-1.51]; P=0.022) but with substantial heterogeneity among contributing studies (I(2)=64.4%) and evidence of publication bias. Meta-analysis of large studies only (defined by a variance of the log OR <0.05), which together contributed 83% of all cases, yielded no evidence of association (OR, 0.97 [95% confidence interval, 0.91-1.03]) without significant heterogeneity (I(2)=0). Moreover, meta-analysis of 1781 mothers of CHD cases (829 of whom were genotyped in this study) and 19 861 controls revealed no evidence of association between maternal C677T genotype and risk of CHD in offspring (OR, 1.13 [95% confidence interval, 0.87-1.47]). There was no significant association between MTHFR genotype and CHD risk in large studies from regions with different levels of dietary folate. Conclusions- The MTHFR C677T polymorphism, which directly influences plasma folate levels, is not associated with CHD risk. Publication biases appear to substantially contaminate the literature with regard to this genetic association. PMID:23876493

Mamasoula, Chrysovalanto; Prentice, R Reid; Pierscionek, Tomasz; Pangilinan, Faith; Mills, James L; Druschel, Charlotte; Pass, Kenneth; Russell, Mark W; Hall, Darroch; Töpf, Ana; Brown, Danielle L; Zelenika, Diana; Bentham, Jamie; Cosgrove, Catherine; Bhattacharya, Shoumo; Riveron, Javier Granados; Setchfield, Kerry; Brook, J David; Bu'lock, Frances A; Thornborough, Chris; Rahman, Thahira J; Doza, Julian Palomino; Tan, Huay L; O'Sullivan, John; Stuart, A Graham; Blue, Gillian; Winlaw, David; Postma, Alex V; Mulder, Barbara J M; Zwinderman, Aelko H; van Engelen, Klaartje; Moorman, Antoon F M; Rauch, Anita; Gewillig, Marc; Breckpot, Jeroen; Devriendt, Koen; Lathrop, G Mark; Farrall, Martin; Goodship, Judith A; Cordell, Heather J; Brody, Lawrence C; Keavney, Bernard D

2013-07-22

117

Methylenetetrahydrofolate reductase polymorphism C677T is a protective factor for pediatric acute lymphoblastic leukemia in the Chinese population: a meta-analysis.  

PubMed

Two polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, C677T and A1298C, were hypothesized to decrease the risk of acute lymphoblastic leukemia (ALL). Studies examining the associations between these two polymorphisms and ALL susceptibility drew inconsistent results. To obtain a reliable conclusion in a Chinese population, we carried out a meta-analysis. In total, 11 studies on C677T polymorphism (1597 cases and 2295 controls) and 10 studies on A1298C polymorphism (1553 cases and 2224 controls) were included in the meta-analysis. We found a significant association between the 677T variant and reduced ALL risk in Chinese children (Dominant model: odds ratio [OR(FE)]=0.73, 95% confidence interval [CI]: 0.63-0.86, p<0.01). Heterogeneity between the studies in the children subgroup was weak and vanished after excluding one study deviating from HWE in the control group (p>0.1). In the adult subgroup, there was no significant association between the C677T variant and ALL risk (Dominant model: OR(RE)=0.88, 95% CI: 0.45-1.72, p=0.72). Significant heterogeneity was found in the adult subgroup in all the genetic model tests (p<0.1). The A1298C polymorphism had an effect on ALL risk neither in adults (Dominant model: OR(FE)=0.95, 95% CI: 0.71-1.27, p=0.72) nor in children (Dominant model: OR(FE)=1.02, 95% CI: 0.87-1.21, p=0.77). No significant heterogeneity between studies on A1298C polymorphism was found in the meta-analysis (p>0.1). The results showed that there was a protective effect of the MTHFR C677T variant on ALL risk in Chinese children. PMID:23061880

Wang, Haigang; Meng, Lujing; Zhao, Lixia; Wang, Jiali; Liu, Xinchun; Mi, Wenjie

2012-10-12

118

The Methylenetetrahydrofolate Reductase C677T Polymorphism Influences Risk of Esophageal Cancer in Chinese.  

PubMed

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

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

2013-01-01

119

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

PubMed Central

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

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

2011-01-01

120

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.

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

121

A literature review of MTHFR (C677T and A1298C polymorphisms) and cancer risk.  

PubMed

5,10-Methlenetetrahydrofolate reductase (MTHFR) is one of the most important enzymes for folate metabolism. This enzyme is mapped on chromosome 1, which is located at the end of the short arm (1p36.3). The C677T and A1298C are MTHFR polymorphisms that decrease in vitro MTHFR enzyme activity. Folate metabolism plays a key role in cell metabolism. These reactions are associated with purine-pyrimidine synthesis: DNA, RNA, and protein methylation. Polymorphism is also a factor in biodiversity, and be affected by ethnic heritage and geographic locale. In the case of unknown outcomes, not only should all geographical regions be investigated to ascertain biodiversity, but all populations as well to fully understand the variations in the effect. PUBMED was searched from January 2006 to December 2011 to develop an investigatory pursuit strategy. MTHFR, cancer, C677T, A1298C, and polymorphisms were key words used to focus the search. The literature review included all published relevant cancer types and MTHFR polymorphisms for that 5 years period. All selected polymorphisms data for cancer types was listed in tables for easy access and retrieval. PMID:23076526

Izmirli, Muzeyyen

2012-10-19

122

Prenatal Exposure to Maternal Depressed Mood and the MTHFR C677T Variant Affect SLC6A4 Methylation in Infants at Birth  

PubMed Central

Background Prenatal and early postnatal exposure to maternal depression may “program” childhood behavior via epigenetic processes such as DNA methylation. Methylenetetrahydro-folate reductase (MTHFR) is an important enzyme in the generation of methyl groups for DNA methylation. The common MTHFR C677T variant is associated with depression in men and non-pregnant women, and with global changes in DNA methylation. This study investigated the effect of maternal MTHFR C677T genotype on antenatal maternal mood, and their impact on the gene-specific methylation in pregnant women and their newborn infants. The methylation status of SLC6A4, which encodes the transmembrane serotonin transporter, and BDNF, which encodes brain derived neurotrophic factor, were assessed because of their potential role in behaviour. Methods/Principal Findings Depressed mood was assessed by the Edinburgh Postnatal Depression Scale (EPDS) and the Hamilton Rating Scale for Depression (HAM-D) in women (n?=?82, all taking folate) during the 2nd and 3rd trimesters of pregnancy. The methylation status of SLC6A4 and BDNF were assessed in 3rd trimester maternal peripheral leukocytes and in umbilical cord leukocytes collected from their infants at birth. Women with the MTHFR 677TT genotype had greater 2nd trimester depressed mood (p<0.05). Increased 2nd trimester maternal depressed mood (EPDS scores) was associated with decreased maternal and infant SLC6A4 promoter methylation (p<0.05), but had no effect on BDNF promoter methylation. Conclusions These findings show that the MTHFR C677T variant is associated with greater depressed mood during pregnancy. We further showed that prenatal exposure to maternal depressed mood affects gene-specific DNA methylation patterns. These findings support the concept that alterations in epigenetic processes may contribute to developmental programming of behaviour by maternal depression.

Devlin, Angela M.; Brain, Ursula; Austin, Jehannine; Oberlander, Tim F.

2010-01-01

123

Association between MTHFR C677T and A1298C, and MTRR A66G polymorphisms and susceptibility to schizophrenia in a Syrian study cohort.  

PubMed

The folate-homocystiene metabolic pathway has been shown to be involved in the susceptibility for developing schizophrenia by several studies. In the present study we investigated the role of three common polymorphisms of the folate-homocysteine metabolic pathway in an Arab population from Syria consisting of 85 schizophrenic patients and 126 healthy controls. The studied polymorphisms included the MTHFR C677T and A1298C, and MTRR A66G, all of which result into amino acid changes, and were previously shown to yield decreased enzymatic activity and alter plasma homocysteine concentration. While MTHFR C677T and A1298C polymorphisms were not previously studied in an Arab population with respect to the susceptibility for developing schizophrenia, the MTRR A66G was not previously investigated in any population around the world. Our results indicated a strong association between MTHFR A1298C and schizophrenia. The variant C allele frequency was significantly higher in the patients group (40% vs 29.4%, OR=1.6, 95% CI (1.06-2.41), p=0.023). A statistically significant association was found for MTHFR 677TT genotype under the recessive model in the male patients subgroup (OR=2.6, 95% CI (1.04-6.5), p=0.036), and MTHFR 677CT genotype under the overdominant model in the total patients group (OR=0.52 95% CI (0.29-0.92), p=0.024). No statistically significant association was found for MTRR A66G polymorphism on an individual basis. However, a borderline association was found for the CC/GG (C677T/A66G) compound genotype (OR=2.24, 95% CI (0.97-5.15), p=0.053). Our results support the hypothesis of association between schizophrenia and folate-homocystiene metabolic pathway genes. PMID:22813657

Lajin, Bassam; Alhaj Sakur, Amir; Michati, Roula; Alachkar, Amal

2012-04-26

124

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

PubMed Central

AIMS—To 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).?METHOD—Prospective 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 polymerase chain reaction with restriction enzyme product digestion and factor VIII by one stage automated clotting assay.?RESULTS—Plasma homocysteine (patients: median 12.4 µmol/l, controls: median 11.6 µmol OR = 1.05, p=0.20), factor VIII (patients: median = 115 U/dl, controls: median = 113 U/dl), and vWF (patients: median = 115 U/dl, controls: median = 108 U/dl) were not statistically higher in patients than in controls. Five CRVO patients and seven controls were homozygous for the MTHFR C677T mutation. One control was heterozygous for the factor II G20210A mutation.?CONCLUSION—This study has not identified new risk factors for CRVO.??

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

2001-01-01

125

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

126

Influence of Methylenetetrahydrofolate Reductase C677T, A1298C, and G80A Polymorphisms on the Survival of Pediatric Patients with Acute Lymphoblastic Leukemia  

PubMed Central

The influence of genic polymorphisms involved in metabolism of chemotherapeutic agents as the methotrexate (MTX) has been studied mainly in acute lymphoblastic leukemia (ALL) of childhood. Advances in treatment may be attributed to identification of prognostic factors added to chemotherapy protocol. The aim of this study was to analyze the association of the C677T, A1298C, and G80A polymorphisms on MTHFR gene and on the overall survival of pediatric patients (n = 126) with lymphoblastic leukemia treated with MTX according to the Brazilian protocol in 187 months. The C677T and G80A polymorphisms were genotyped by PCR-RFLP and A1298C polymorphism by allele-specific PCR. We observed that ALL patients presented rate (dead/alive) of 0.36 for the 677CC genotype, corresponding also to lower overall survival (P = 0.0013); on the other hand, the 677TT genotype showed a better survival (98%). Thus, we believe that patients with 80AA genotype presented a small reduction in MTX plasma level, suggesting that ALL children, carrying the 80AA genotype, showed a high toxicity to MTX (P < 0.0001).

de Deus, Dayse Maria Vasconcelos; de Lima, Elker Lene Santos; Seabra Silva, Rafaela Maria; Leite, Edinalva Pereira; Cartaxo Muniz, Maria Tereza

2012-01-01

127

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.

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

2012-01-01

128

Hyperhomocysteinemia and Methylenetetrahydrofolate Reductase C677T Polymorphism in Cerebral Veno-sinus Thrombosis.  

PubMed

There is limited data on the role of hyperhomocysteinemia as a risk factor for cerebral veno-sinus thrombosis (CVT) in Indians. We examined the association between plasma homocysteine (Hcy), methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, and CVT in 185 patients with aseptic CVT (puerperal 80 and nonpuerperal 105) and 248 healthy controls (puerperal 67 and nonpuerperal 181). Fasting Hcy was higher in patients compared to controls (20.25 ± 5.97 vs 9.81 ± 5.19 ?mol/L, P < .001) and associated with 4.54-fold (95% confidence interval [CI]: 2.74-7.53) increase in risk of CVT. Risk was higher in puerperal (odds ratio [OR]: 8.7, 95% CI: 2.73-26.91) compared to nonpuerperal CVT (OR: 3.82, 95% CI: 2.09-6.96). Plasma Hcy was higher in MTHFR 677TT compared to 677CT and 677CC genotypes (34.44 ± 32.8 vs 25.81 ± 33.3 vs 18.50 ± 23.7 ?mol/L, respectively, P < .001), but the risk associated with MTHFR 677TT was insignificant (OR: 1.91, 95% CI: 0.53-7.06). We conclude that hyperhomocysteinemia is a risk marker for Indian patients with aseptic CVT. MTHFR 677TT genotype is not linked with CVT but is a determinant of plasma Hcy. PMID:23172871

Bharatkumar, Venkata Pinnelli; Nagaraja, Dindagur; Christopher, Rita

2012-11-21

129

The prognostic significance of genetic polymorphisms (Methylenetetrahydrofolate Reductase C677T, Methionine Synthase A2756G, Thymidilate Synthase tandem repeat polymorphism) in multimodally treated oesophageal squamous cell carcinoma  

PubMed Central

The present study retrospectively examined the correlation between the outcome of patients with locally advanced oesophageal squamous cell carcinoma (cT3-4 cN0-1 cM0) after multimodal treatment (radiochemotherapy±surgical resection), and the presence of genetic polymorphisms in genes involved in folate metabolism. In total, 68 patients who took part in a prospective multicentric trial received 5-fluorouracil (FU)-based radiochemotherapy, optionally followed by surgery. DNA was extracted from pretherapeutic tumour biopsies and was subsequently genotyped for common genetic polymorphisms of three genes (MTHFR C677T, MTR A2756G, TS tandem repeat polymorphism) involved in folate metabolism and potentially in sensitivity to 5-FU-based chemotherapy. The genotypes were correlated with tumour response to polychemotherapy, radiochemotherapy and with overall survival. Tumours with the MTR wild-type genotype (2756AA) showed a median survival time of 16 months, whereas tumours with an MTR variant genotype (2756AG/2756GG) showed a median survival time of 42 months (P=0.0463). No prognostic impact could be verified for the genotypes of the MTHFR genes and the TS gene. Among tumours treated with radiochemotherapy and subsequent resection, MTR variant genotype showed higher histopathological response rate than tumours with MTR wild-type genotype (P=0.0442). In contrast, no significant relationship between clinically determined tumour regression after polychemotherapy and polymorphisms of the three genes under analysis was observed. In conclusion, pretherapeutic determination of the MTR A2756G polymorphism may predict survival of multimodally treated oesophageal squamous cell carcinomas. Determination of MTHFR C677T and TS tandem repeat polymorphism has no predictive value.

Sarbia, M; Stahl, M; von Weyhern, C; Weirich, G; Puhringer-Oppermann, F

2006-01-01

130

Livedoid vasculopathy associated with combined prothrombin G20210A and factor V (Leiden) heterozygosity and MTHFR C677T homozygosity.  

PubMed

Livedoid vasculopathy (LV) is an occlusive thrombotic disease of lower extremities. A 34-year-old woman presented with 4-year history of recurrent necrotic and painful lesions with violaceous and purpuric border on both legs. Initial treatment with hydroxychloroquine, dapsone and prednisone were unsuccessful. Skin biopsy showed inflammatory infiltrate with epidermal necrosis. Prothrombin G20210A and factor V-Leiden heterozygosity, and MTHFR C677T homozygosity with hyperhomocysteinemia were confirmed. LV diagnosis was made; acetylsalicylic acid, folic acid, vitamin B12, and prednisone treatement resulted in complete healing. This is the first report on coexistence of prothrombin G20210A, factor V-Leiden, and homozygous MTHFR C677T with hyperhomocysteinemia in LV. PMID:18360788

Irani-Hakime, Noha A; Stephan, Farid; Kreidy, Raghid; Jureidini, Isabelle; Almawi, Wassim Y

2008-03-23

131

Mutations and Polymorphisms in Genes Affecting Hemostasis Proteins and Homocysteine Metabolism in Children with Arterial Ischemic Stroke  

Microsoft Academic Search

Background: The pathogenesis of thrombosis in childhood seems to be multifactorial implicating genetic and environmental factors. Aim: To compare the distributions of mutations\\/polymorphisms in genes affecting hemostasis (factor V Leiden – FVL, FV H1298R-FVR2, FII 20210A, b-Fib 455G>A, FXIII V34L, PAI-1 4G, HPA-1b) or homocysteine metabolism (MTHFR C677T, MTHFR A1298C) among 90 children with arterial ischemic stroke (AIS) and 103

A. Komitopoulou; H. Platokouki; Z. Kapsimali; H. Pergantou; E. Adamtziki; S. Aronis

2006-01-01

132

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

133

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

134

Population distribution of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C risk alleles for methotrexate toxicity in Israel.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) is a central regulatory enzyme in the folate pathway. Two non-synonymous single nucleotide polymorphisms in MTHFR, C677T (rs1801133) and A1298C (rs1801131) have been associated with reduced MTHFR enzyme activity. These polymorphisms, especially C677T, appear to be linked with methotrexate-related toxicity, particularly hepatotoxicity; thus, pretreatment identification of individuals carrying these polymorphisms may be of clinical relevance. The purpose of this study was to determine the frequency and distribution of MTHFR polymorphic variants, known to functionally impair MTHFR activity, in the highly heterogeneous Israeli population. MTHFR genotyping was carried out in the representatives of three major demographic groups in Israel by PCR-restriction fragment length polymorphism and high-resolution melting. The relative distribution of variant alleles 677T and 1298C was found to be similar in individuals of Jewish, Druze and Arab Moslem descent (p = 0.09). However, Ashkenazi Jews displayed a 1.9-fold higher frequency of variant 677T and a 1.8-fold lower frequency of variant 1298C compared to non-Ashkenazi Jews (p < 0.001). Distinct differences in the relative frequencies of both polymorphisms were also found between Ashkenazi Jews and Druze (p < 0.01 for C677T, p < 0.01 for A1298C) or Ashkenazi Jews and Arab Moslem (p < 0.01 for C677T, p < 0.05 for A1298C). These data underscore the importance of geographic genetic analysis for a better understanding of human pharmacotherapy and personalized medicine. PMID:22847291

Efrati, Edna; Elkin, Hela; Nahum, Sagi; Krivoy, Norberto

2012-07-31

135

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

136

Methylenetetrahydrofolate reductase C677T polymorphism in patients with gastric and colorectal cancer in a Korean population  

PubMed Central

Background This study was designed to investigate an association between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and the risk of gastric and colorectal cancer in the Korean population. Methods We conducted a population-based large-scale case-control study involving 2,213 patients with newly diagnosed gastric cancer, 1,829 patients with newly diagnosed colorectal cancer, and 1,700 healthy controls. Genotyping was performed with peripheral blood DNA for MTHFR C677T polymorphisms. The statistical significance was estimated by logistic regression analysis. Results The MTHFR C677T frequencies of CC, CT, and TT genotypes were 35.2%, 47.5%, and 17.3% among stomach cancer, 34%, 50.5%, and 15.5% in colorectal cancer, and 31.8%, 50.7%, and 17.5% in the controls, respectively. The MTHFR 677TT genotype showed a weak opposite association with colorectal cancer compared to the homozygous CC genotype [adjusted age and sex odds ratio (OR) = 0.792, 95% confidence interval (CI) = 0.638-0.984, P = 0.035]. Subjects with the MTHFR 677CT showed a significantly reduced risk of gastric cancer compared whose with the 677CC genotype (age- and sex-adjusted OR = 0.810; 95% CI = 0.696-0.942, P = 0.006). We also observed no significant interactions between the MTHFR C677T polymorphism and smoking or drinking in the risk of gastric and colorectal cancer. Conclusions The T allele was found to provide a weak protective association with gastric cancer and colorectal cancer.

2010-01-01

137

Risk of colorectal cancer associated with the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in the Kashmiri population.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism and is involved in DNA synthesis, DNA repair and DNA methylation. The two common functional polymorphisms of MTHFR, 677 C?T and 1298 A?C, have been shown to impact various diseases, including cancer. The 677 C?T polymorphism has been widely investigated in different cancers and has been implicated as a risk factor for the development of various cancers. We investigated MTHFR C677T genotype frequency in colorectal cancer cases in the Kashmiri population and correlated this information with the known clinicopathological characters of colorectal cancer, in a case-control study. Eighty-six colorectal cancer cases were studied for MTHFR C677T polymorphism, compared to 160 controls taken from the general population, employing the PCR-RFLP technique. We found the frequency of the three different genotypes of MTHFR in our ethnic Kashmir population, i.e., CC, CT and TT, to be 68.6, 20.9 and 10.4% among colorectal cancer cases and 75.6, 16.9 and 7.5% among the general control population, respectively. There was a significant association between the MTHFR TT genotype and colorectal cancer in the higher age group. We conclude that the MTHFR C677T polymorphism slightly increases the risk for colorectal cancer development in our ethnic Kashmir population. PMID:21732284

Sameer, A S; Shah, Z A; Nissar, S; Mudassar, S; Siddiqi, M A

2011-06-21

138

Methylenetetrahydrofolate reductase polymorphisms, C677T and A1298C, are associated with methotrexate-related toxicities in Korean patients with rheumatoid arthritis  

Microsoft Academic Search

We investigated associations between the methylenetetrahydrofolate reductase (MTHFR) polymorphisms C677T and A1298C and methotrexate\\u000a (MTX)-related toxicities in Korean patients with rheumatoid arthritis (RA) taking MTX. One hundred sixty-seven patients with\\u000a RA were enrolled in a cross-sectional study and genotyped for the single-nucleotide polymorphisms C677T and A1298C in MTHFR.\\u000a Alleles, genotypes, and haplotypes of the C677T and A1298C polymorphisms were not

Jung-Yoon Choe; Hwajeong Lee; Hyun-Young Jung; Sung-Hoon Park; Sang-Cheol Bae; Seong-Kyu Kim

139

Leber Hereditary Optic Neuropathy: Do Folate Pathway Gene Alterations Influence the Expression of Mitochondrial DNA Mutation?  

PubMed Central

Background: Leber hereditary optic neuropathy (LHON) is an inherited form of bilateral optic atrophy leading to the loss of central vision. The primary cause of vision loss is mutation in the mitochondrial DNA (mtDNA), however, unknown secondary genetic and/or epigenetic risk factors are suggested to influence its neuropathology. In this study folate gene polymorphisms were examined as a possible LHON secondary genetic risk factor in Iranian patients. Methods: Common polymorphisms in the MTHFR (C677T and A1298C) and MTRR (A66G) genes were tested in 21 LHON patients and 150 normal controls. Results: Strong associations were observed between the LHON syndrome and C677T (P= 0.00) and A66G (P= 0.00) polymorphisms. However, no significant association was found between A1298C (P =0.69) and the LHON syndrome. Conclusion: This is the first study that shows MTHFR C677T and MTRR A66G polymorphisms play a role in the etiology of the LHON syndrome. This finding may help in the better understanding of mechanisms involved in neural degeneration and vision loss by LHON and hence the better treatment of patients.

Aleyasin, A; Ghazanfari, M; Houshmand, M

2010-01-01

140

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

PubMed

Genetic and environmental factors interact in determining the risk of venous thromboembolism (VTE). The risk associated with the polymorphic variants G1691A of factor V (Factor V Leiden, FVL), G20210A of prothrombin (PT20210A) and C677T of methylentetrahydrofolate reductase (C677T MTHFR) genes has been investigated in many studies. We performed a pooled analysis of case-control and cohort studies investigating in adults the association between each variant and VTE, published on Pubmed, Embase or Google through January 2010. Authors of eligible papers, were invited to provide all available individual data for the pooling. The Odds Ratio (OR) for first VTE associated with each variant, individually and combined with the others, were calculated with a random effect model, in heterozygotes and homozygotes (dominant model for FVL and PT20210A; recessive for C677T MTHFR). We analysed 31 databases, including 11,239 cases and 21,521 controls. No significant association with VTE was found for homozygous C677T MTHFR (OR: 1.38; 95 % confidence intervals [CI]: 0.98-1.93), whereas the risk was increased in carriers of either heterozygous FVL or PT20210 (OR = 4.22; 95 % CI: 3.35-5.32; and OR = 2.79;95 % CI: 2.25-3.46, respectively), in double heterozygotes (OR = 3.42; 95 %CI 1.64-7.13), and in homozygous FVL or PT20210A (OR = 11.45; 95 %CI: 6.79-19.29; and OR: 6.74 (CI 95 % 2.19-20.72), respectively). The stratified analyses showed a stronger effect of FVL on individuals ? 45 years (p value for interaction = 0.036) and of PT20210A in women using oral contraceptives (p-value for interaction = 0.045). In this large pooled analysis, inclusive of large studies like MEGA, no effect was found for C677T MTHFR on VTE; FVL and PT20210A were confirmed to be moderate risk factors. Notably, double carriers of the two genetic variants produced an impact on VTE risk significantly increased but weaker than previously thought. PMID:23900608

Simone, Benedetto; De Stefano, Valerio; Leoncini, Emanuele; Zacho, Jeppe; Martinelli, Ida; Emmerich, Joseph; Rossi, Elena; Folsom, Aaron R; Almawi, Wassim Y; Scarabin, Pierre Y; den Heijer, Martin; Cushman, Mary; Penco, Silvana; Vaya, Amparo; Angchaisuksiri, Pantep; Okumus, Gulfer; Gemmati, Donato; Cima, Simona; Akar, Nejat; Oguzulgen, Kivilcim I; Ducros, Véronique; Lichy, Christoph; Fernandez-Miranda, Consuelo; Szczeklik, Andrzej; Nieto, José A; Torres, Jose Domingo; Le Cam-Duchez, Véronique; Ivanov, Petar; Cantu-Brito, Carlos; Shmeleva, Veronika M; Stegnar, Mojka; Ogunyemi, Dotun; Eid, Suhair S; Nicolotti, Nicola; De Feo, Emma; Ricciardi, Walter; Boccia, Stefania

2013-07-31

141

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

142

Prevalence of hyperhomocysteinemia and the MTHFR C677T polymorphism in patients with arterial and venous thrombosis from North Western Russia.  

PubMed

Conflicting data from Western European and USA population studies led us to investigate hyperhomocysteinemia (HHcy), the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms and thrombotic disease in North Western Russia. Plasma total homocysteine (tHcy) levels, MTHFR C677T genotype, selected life style determinants and haemostatic factor activity were determined in patients with arterial (n = 33), venous (n = 40), arterial + venous (n = 11) thrombosis and healthy controls (n = 30). We found raised median tHcy levels in all patient groups vs. controls (p < 0.05), with odds ratios (95% CI) for vascular disease among patients with HHcy (defined as > 15 micromol/l) of 3.9 (0.6 - 14.3), 4.8 (1.2 - 18.8) and 15.8 (2.8 - 87.3) respectively. tHcy levels were a function of MTHFR C677T genotype, and all patients with tHcy levels > 30 micromol/l had the MTHFR C677T homozygous substitution. Elevated tHcy levels (p < 0.05) were identified in smokers and coffee drinkers, with the degree of elevation dependent on MTHFR C677T genotype. Of the studied haemostatic parameters increased factor VIII activity and vWF antigen and activity was observed in HHcy subjects. We conclude that HHcy and MTHFR C677T genotype are positively associated with arterial and venous thrombotic disease in the population of North Western Russia. PMID:14698652

Shmeleva, Veronika M; Kapustin, Sergey I; Papayan, Ludmila P; Sobczy?ska-Malefora, Agata; Harrington, Dominic J; Savidge, Geoffrey F

2003-01-01

143

Quantitative assessment of the association between MTHFR C677T polymorphism and colorectal cancer risk in East Asians.  

PubMed

A great number of studies regarding the association between MTHFR C677T polymorphism and risk of colorectal cancer (CRC) in East Asians were published, but the results were inconsistent. Thus, a meta-analysis was performed to investigate the association. PubMed, Embase, and CBM databases were searched for eligible publications. Pooled odds ratios (ORs) with 95 % confidence intervals (95 % CIs) were calculated using random or fixed effect models. Finally, 24 case-control studies with a total of 7,230 CRC cases and 9,285 controls were included. Meta-analyses of a total of 24 studies showed there was a statistically significant association between MTHFR C677T polymorphism and decreased CRC risk in East Asians under four genetic models (T versus C, OR = 0.92, 95 % CI 0.85-0.99; TT versus CC, OR = 0.80, 95 % CI 0.69-0.94; TT versus CT/CC, OR = 0.82, 95 % CI 0.71-0.95; TT/CT versus CC, OR = 0.92, 95 % CI 0.86-0.98). The cumulative meta-analyses for the allele contrast (T versus C), homozygote (TT versus CC), dominant (TT/CT versus CC), and recessive (TT versus CT/CC) models all showed a trend of more obvious association as information accumulated by year. Subgroup analyses by country further identified this association in Korea and Japan. This meta-analysis suggests that MTHFR C677T polymorphism is associated with decreased risk of colorectal cancer in East Asians, and MTHFR 677T variant has a protective effect on colorectal cancer. PMID:22890827

Zhong, Shan; Yang, Jia-He; Liu, Kai; Jiao, B H; Chang, Zhi-Jie

2012-08-15

144

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

145

Cardiometabolic risk and the MTHFR C677T variant in children treated with second-generation antipsychotics  

PubMed Central

Second-generation antipsychotics (SGAs) are increasingly being used to treat children with a variety of psychiatric illnesses. Metabolic syndrome (MetS), a risk factor for cardiovascular disease, is a side-effect of SGA-treatment. We conducted a cross-sectional study and assessed the association of the methylenetetrahydrofolate reductase (MTHFR) C677T variant with features of MetS in SGA-treated (n=105) and SGA–naïve (n=112) children. We targeted the MTHFR C677T variant, because it is associated with risk for cardiovascular disease, and features of MetS in adults without psychiatric illness. MetS in children is based on the presence of any three of the following: waist circumference ?90th percentile for age and sex; plasma triglyceride ?1.24?mmol?l?1; plasma high-density lipoprotein-cholesterol ?1.03?mmol?l?1; systolic or diastolic blood pressure ?90th percentile for age, sex, and height; and fasting glucose ?5.6?mmol?l?1. We found that 15% of SGA-treated children had MetS compared with 2% of SGA-naïve children (OR 8.113, P<0.05). No effect of the MTHFR C677T variant on psychiatric diagnosis was observed. The MTHFR 677T allele was associated (P<0.05) with MetS (OR 5.75, 95% CI= 1.18–28.12) in SGA-treated children. Models adjusted for duration of SGA treatment, ethnicity, sex, age and use of other medications revealed a positive relationship between the MTHFR 677T allele and diastolic blood pressure Z-scores (P=0.001) and fasting plasma glucose (P<0.05) in SGA-treated children. These findings illustrate the high prevalence of MetS in SGA-treated children and suggest metabolic alterations associated with the MTHFR C677T variant may have a role in the development of MetS features in SGA-treated children.

Devlin, A M; Ngai, Y F; Ronsley, R; Panagiotopoulos, C

2012-01-01

146

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

PubMed

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

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

2012-04-26

147

Modulator effects of the methylenetetrahydrofolate reductase C677T polymorphism on response to vitamin B12 therapy and homocysteine metabolism.  

PubMed

In this study, our aim was to investigate the association of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism on the vitamin B12 therapy response in 95 patients with vitamin B12 deficiency and 92 healthy control subjects using vitamin B12, plasma total homocysteine (tHcy), and folate as the main measure of outcome. MTHFR C677T genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism techniques. There were no differences in the distribution of MTHFR genotypes in the cases versus the controls. Mean concentrations of plasma tHcy and B12 vitamin were 18.84 ?M and 142.47 pg/mL in patients with TT (10.5%) genotypes. Furthermore, mean concentrations of B12 vitamin after cobalamin therapy were 697.62, 656.64, and 488.76 pg/mL in patients with the CC, CT, and TT genotypes, respectively. The MTHFR 677 TT genotype has decreasing effect in B12 vitamin and increasing effect in tHcy. In comparison with the patients having CC and CT genotypes, patients with the TT genotype had a lower response to vitamin B12 therapy. PMID:22084937

Sensoy, Nazli; ?oysal, Yasemin; Kahraman, Ahmet; Do?an, Nurhan; Imirzalio?lu, Necat

2011-11-15

148

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and susceptibility to diabetic nephropathy in Chinese type 2 diabetic patients: a meta-analysis.  

PubMed

The association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and diabetic nephropathy (DN) or diabetes mellitus (DM) risk has been widely reported, but the results are still debatable. To investigate the role of MTHFR C677T polymorphism on DM or DN, 13 separate studies in the Chinese population on the relation between MTHFR C677T polymorphism and DM or DN were analyzed by a meta-analysis. Five genetic models were used to estimate the association between MTHFR C677T polymorphism and the risk of DM or DN. Overall, our meta-analysis for DN versus healthy controls produced significant results for all genetic contrasts except for the co-dominant model (allele contrast: OR?=?2.24, 95%CI: 1.88-2.65, p?C677T polymorphism might influence DN risk, but not for DM in the Chinese population. PMID:23822721

Chang, Wei-wei; Zhang, Liu; Yao, Ying-shui; Su, Hong; Jin, Yue-long; Chen, Yan

2013-07-03

149

Folate intake and the MTHFR C677T genotype influence choline status in young Mexican American women?  

PubMed Central

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

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

2009-01-01

150

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

PubMed Central

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

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

2013-01-01

151

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

PubMed

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

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

2012-12-11

152

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

153

Association between Methylenetetrahydrofolate Reductase C677T Polymorphism and Bone Mineral Density: The Dong-gu Study and the Namwon Study  

PubMed Central

The purpose of this study was to examine the association between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and bone mineral density (BMD). Two large cohort studies were performed: the Dong-gu Study (3,621 men and 5,409 women) and the Namwon Study (3,703 men and 5,672 women). We assessed lumbar spine and femoral neck BMD by dual-energy X-ray absorptiometry. Genotypes were determined by real-time polymerase chain reaction. Multiple linear regression analysis was performed to evaluate the association between MTHFR C677T and BMD, adjusting for age, weight and height. The MTHFR C677T genotype frequencies for CC, CT, and TT genotypes were 34.5, 48.7, and 16.8%, respectively, in the Dong-gu Study and 33.6, 49.2, and 17.2%, respectively, in the Namwon Study. There are no significant differences between the MTHFR C677T genotype and the BMD at the lumbar spine and femoral neck in men or women in both cohorts.

Shin, Min-Ho; Choi, Jin-Su; Rhee, Jung-Ae; Lee, Young-Hoon; Nam, Hae-Sung; Jeong, Seul-Ki; Park, Kyeong-Soo; Kim, Hye-Yeon; Ryu, So-Yeon; Choi, Seong-Woo; Song, Hye-Rim; Kim, Hee Nam; Cauley, Jane A.

2013-01-01

154

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

155

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

156

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and nonsyndromic orofacial clefts susceptibility in a southern Chinese population.  

PubMed

Nonsyndromic orofacial clefts (NSOC) are one of the most common congenital anomalies in humans. Great efforts have been taken to unravel its genetic background. Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme in folate metabolism and two of its functional polymorphisms, MTHFR C677T and MTHFR A1298C, might be associated with NSOC susceptibility. The aim of the present study was to investigate their associations with risks of NSOC in a southern Chinese population. We found that MTHFR 677 TT and 677 CT/TT were associated with increased risk of cleft lip with or without cleft palate; meanwhile, MTHFR 1298 AC and 1298 AC/CC had protective effects against cleft lip with or without cleft palate. In further stratified analysis, we found that MTHFR 677 CT contributed to elevated risk of cleft lip only, as did MTHFR 677 CT/TT. On the contrary, MTHFR 1298 AC and 1298 AC/CC appeared to be protective against cleft lip with cleft palate. These results suggested that these two polymorphisms were involved in the development of NSOC in a southern Han Chinese population. PMID:21612398

Han, Yue; Pan, Yongchu; Du, Yifei; Tong, Na; Wang, Meilin; Zhang, Zhengdong; Wan, Linzhong; Wang, Lin

2011-05-25

157

Association between 5,10-methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and conotruncal heart defects.  

PubMed

Reports related some polymorphisms of the 5,10-methylenetetrahydrofolate reductase (MTHFR) to folate-dependent neural tube defects. In view of the common origin of the cells involved both in neural tube closure and heart septation, we analyzed the MTHFR C677T and A1298C polymorphisms in mothers of children with conotruncal heart defect (CD) and in their offspring to evaluate the association between the MTHFR genotype and the risk of CD. We genotyped 103 Italian mothers with CD offspring, 200 control mothers, 103 affected children and their fathers by restriction fragment length polymorphism analysis. No increased risk was observed for the prevalence of the 677TT genotype by itself in affected children and in their mothers. The combined maternal 677TT/1298AA and 677CC/1298CC genotypes have odds ratio of 1.73 and 1.85, respectively. The prevalence of 1298CC genotype in the affected children gives odds ratio of 1.90, that becomes 2.31 for the 677CC/1298CC genotype. However, none of the odds ratios was statistically significant. We observed a higher frequency of the 677T allele in Italy than in other European countries. No association has been demonstrated between the 677TT MTHFR genotype and CD. PMID:12705333

Storti, Simona; Vittorini, Simona; Iascone, Maria R; Sacchelli, Monica; Collavoli, Anita; Ripoli, Andrea; Cocchi, Guido; Biagini, Andrea; Clerico, Aldo

2003-03-01

158

The MTHFR C677T and DeltaDNMT3B C-149T polymorphisms confer different risks for right- and left-sided colorectal cancer.  

PubMed

Etiological risk factors for proximal (right-sided) colon cancers may be different to those of distal colon and rectal (left-sided) cancers if these tumors develop along distinct pathways. The CpG Island Methylator Phenotype (CIMP+) occurs in approximately 15% of colorectal cancers (CRC) and predominantly in the proximal colon. CIMP+ tumors have frequent methylation of gene promoter regions and increased tissue folate levels. The aim here was to determine whether polymorphisms in 2 genes involved in cellular methyl group metabolism were associated with different risks for right- and left-sided CRC. This population-based case-control study involved 859 incident cases of CRC and 973 sex and age-matched controls. Information on dietary folate and alcohol intake was obtained from food frequency questionnaires and information on the anatomical site of tumors from pathology reports. DNA was collected using FTA cards and genotyping performed for the MTHFR C677T and DeltaDNMT3B C-149T polymorphisms. The MTHFR 677 T allele was associated with increased risk for proximal colon cancer (adjusted odds ratio, AOR = 1.29) but decreased risk for distal cancers (AOR = 0.87). The increased risk for proximal cancers was especially pronounced in older individuals (AOR = 1.49) and those with a low folate diet (AOR = 1.67) or high alcohol consumption (AOR = 1.90). The DeltaDNMT3B-149 TT genotype was protective against proximal colon cancers (AOR = 0.65), but showed no association with the risk of distal colon and rectal cancers (AOR = 1.02). Epidemiological studies on dietary and genetic risk factors for CRC should take into account these may confer different risks for right- and left-sided tumors. PMID:19326430

Iacopetta, Barry; Heyworth, Jane; Girschik, Jennifer; Grieu, Fabienne; Clayforth, Cassandra; Fritschi, Lin

2009-07-01

159

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

PubMed Central

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

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

2011-01-01

160

The methylenetetrahydrofolate reductase C677T polymorphism is a major determinant of coffee-induced increase of plasma homocysteine: a randomized placebo controlled study.  

PubMed

Some methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms are associated with hyperhomocysteinemia. Trials have shown a plasma homocysteine raising effect of coffee. We determined the effect of a daily intake of 600 ml coffee and a supplementation of 200 microg folic acid or placebo on plasma homocysteine (tHcy) with respect to the MTHFR C677T and A1298C polymorphisms. One hundred and twenty healthy, non-smoking men (22%) and women (78%) aged 29-65 years, took part in a controlled, randomized, blinded study with two intervention periods: i) a coffee-free period of three weeks, ii) 600 ml coffee/day and a supplement of 200 microg folic acid/d or placebo for four weeks. The results showed that tHcy at baseline was significantly higher for the 677TT genotype group compared to the 677CC genotype group (p=0.0045) and that this group responded with significantly larger increase in tHcy upon coffee exposure than the 677CC and 677CT genotype groups (p=0.0045 and p=0.0041, respectively). Supplementation with 200 microg folic acid compared to placebo reduced the tHcy increasing effect of coffee in the 677TT genotype group. The A1298C polymorphism did not affect tHcy concentration significantly at any stage in the study. In conclusion, the homocysteine increasing effect of coffee is particularly seen in individuals with the homozygous 677TT genotype. Supplementation with 200 microg folic acid/d decreases this tHcy increment. PMID:15138617

Strandhagen, Elisabeth; Zetterberg, Henrik; Aires, Nibia; Palmér, Mona; Rymo, Lars; Blennow, Kaj; Landaas, Sverre; Thelle, Dag S

2004-06-01

161

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

PubMed

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

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

2010-03-01

162

Meta- and Pooled Analyses of the Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism and Colorectal Cancer: A HuGE-GSEC Review  

PubMed Central

Worldwide, over 1 million cases of colorectal cancer (CRC) were reported in 2002, with a 50% mortality rate, making CRC the second most common cancer in adults. Certain racial/ethnic populations continue to experience a disproportionate burden of CRC. A common polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene has been associated with a lower risk of CRC. The authors performed both a meta-analysis (29 studies; 11,936 cases, 18,714 controls) and a pooled analysis (14 studies; 5,068 cases, 7,876 controls) of the C677T MTHFR polymorphism and CRC, with stratification by racial/ethnic population and behavioral risk factors. There were few studies on different racial/ethnic populations. The overall meta-analysis odds ratio for CRC for persons with the TT genotype was 0.83 (95% confidence interval (CI): 0.77, 0.90). An inverse association was observed in whites (odds ratio = 0.83, 95% CI: 0.74, 0.94) and Asians (odds ratio = 0.80, 95% CI: 0.67, 0.96) but not in Latinos or blacks. Similar results were observed for Asians, Latinos, and blacks in the pooled analysis. The inverse association between the MTHFR 677TT polymorphism and CRC was not significantly modified by smoking status or body mass index; however, it was present in regular alcohol users only. The MTHFR 677TT polymorphism seems to be associated with a reduced risk of CRC, but this may not hold true for all populations.

Taioli, E.; Garza, M. A.; Ahn, Y. O.; Bishop, D. T.; Bost, J.; Budai, B.; Chen, K.; Gemignani, F.; Keku, T.; Lima, C. S. P.; Le Marchand, L.; Matsuo, K.; Moreno, V.; Plaschke, J.; Pufulete, M.; Thomas, S. B.; Toffoli, G.; Wolf, C. R.; Moore, C. G.; Little, J.

2009-01-01

163

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and colorectal cancer: the Fukuoka Colorectal Cancer Study.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating folate metabolism, which affects DNA synthesis and methylation. This study investigated the relation of MTHFR C677T and A1298C polymorphisms to colorectal cancer in a case-control study in Fukuoka, Japan. The subjects comprised 685 incident cases of histologically confirmed colorectal adenocarcinomas and 778 community controls selected randomly in the study area. The genotype was determined by the PCR-RFLP method using genomic DNA extracted from buffy coat. Alcohol use was ascertained by in-person interview. Statistical adjustment was made for gender, age class, area, and alcohol use. The MTHFR 677TT genotype was associated with a statistically significant decrease in the risk with an adjusted odds ratio of 0.69 (95% confidence interval 0.51-0.93) compared with the 677CC and 677CT combined, and the decrease was most evident in individuals with no alcohol consumption. While the A1298C polymorphism showed no measurable association with the overall risk of colorectal cancer, the 1298CC genotype was associated with a statistically significant increase in the risk when alcohol consumption was high, and was also associated with an approximately 2-fold increase in the risk of each of proximal and distal colon cancer. The findings add to evidence that individuals with the MTHFR 677TT genotype have a decreased risk of colorectal cancer in the absence of folate depletion, suggesting a protective role of folate by ensuring a sufficient thymidylate pool for DNA synthesis. Because very few individuals had the 1298CC genotype, the findings regarding the A1298C polymorphism need careful interpretation and confirmation in larger studies. PMID:15546509

Yin, Guang; Kono, Suminori; Toyomura, Kengo; Hagiwara, Tomoko; Nagano, Jun; Mizoue, Tetsuya; Mibu, Ryuichi; Tanaka, Masao; Kakeji, Yoshihiro; Maehara, Yoshihiko; Okamura, Takeshi; Ikejiri, Koji; Futami, Kitaroh; Yasunami, Yohichi; Maekawa, Takafumi; Takenaka, Kenji; Ichimiya, Hitoshi; Imaizumi, Nobutoshi

2004-11-01

164

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. Lacasaña-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

165

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

166

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

167

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

PubMed

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 and 6243 controls for A1298C). The summary odds ratio (OR) of head and neck cancer was 0.92 (95% CI: 0.76-1.11) for MTHFR 677 TT and 0.68 (95% CI: 0.37-1.26) for MTHFR 1298 CC. The OR of lung cancer was 1.22 [95% confidence interval (CI): 0.95-1.55] for MTHFR 677 TT and 1.07 (95% CI: 0.83-1.38) for MTHFR 1298 CC. Results from the meta-analysis of three studies on C677T stratified according to dietary folate intake showed an increased risk for individuals with low folate intake (OR = 1.37, 95% CI: 0.92-2.06 for head and neck and OR = 1.28, 95% CI: 0.97-1.68 for lung) versus high folate intake (OR = 0.85, 95% CI: 0.63-1.16 for head and neck, and OR = 0.94, 95% CI: 0.79-1.12 for lung). Despite the lack of formal statistical significance, these findings are consistent with the hypothesis that folate play a role in lung and head/neck carcinogenesis, and show the need to incorporate data on folate intake when interpreting results of MTHFR polymorphisms in relation to cancer risk. PMID:18789576

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

2008-09-11

168

Meta- and pooled analyses of the methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and gastric cancer risk: a huge-GSEC review.  

PubMed

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 controls for C677T and seven studies, 1,223 cases and 2,015 controls for A1298C; pooled analyses: nine studies, 1,540 cases and 2,577 controls for C677T and five studies, 1,146 cases and 1,549 controls for A1298C). An increased risk was found for MTHFR 677 TT in the meta-analysis (odds ratio (OR) = 1.52, 95% confidence interval (CI): 1.31, 1.77) and pooled analysis (OR = 1.49, 95% CI: 1.14, 1.95). No association resulted for MTHFR 1298 CC (meta-OR = 0.94, 95% CI: 0.65, 1.35; pooled OR = 0.90, 95% CI: 0.69, 1.34). Results from the pooled analysis of four studies on C677T stratified according to folate levels showed an increased risk for individuals with low (OR = 2.05, 95% CI: 1.13, 3.72) versus high (OR = 0.95, 95% CI: 0.54, 1.67) folate levels. Overall, these findings support the hypothesis that folate plays a role in gastric carcinogenesis. PMID:18162478

Boccia, Stefania; Hung, Rayjean; Ricciardi, Gualtiero; Gianfagna, Francesco; Ebert, Matthias P A; Fang, Jing-Yuan; Gao, Chang-Ming; Götze, Tobias; Graziano, Francesco; Lacasaña-Navarro, Marina; Lin, Dongxin; López-Carrillo, Lizbeth; Qiao, You-Lin; Shen, Hongbing; Stolzenberg-Solomon, Rachael; Takezaki, Toshiro; Weng, Yu-Rong; Zhang, Fang Fang; van Duijn, Cornelia M; Boffetta, Paolo; Taioli, Emanuela

2007-12-27

169

Methylenetetrahydrofolate reductase polymorphisms, C677T and A1298C, are associated with methotrexate-related toxicities in Korean patients with rheumatoid arthritis.  

PubMed

We investigated associations between the methylenetetrahydrofolate reductase (MTHFR) polymorphisms C677T and A1298C and methotrexate (MTX)-related toxicities in Korean patients with rheumatoid arthritis (RA) taking MTX. One hundred sixty-seven patients with RA were enrolled in a cross-sectional study and genotyped for the single-nucleotide polymorphisms C677T and A1298C in MTHFR. Alleles, genotypes, and haplotypes of the C677T and A1298C polymorphisms were not associated with specific MTX toxicities. However, among RA patients with the 1298CC genotype, the proportion who experienced at least one toxicity was significantly greater than the proportion of patients with 1298AA who did (P = 0.043). In addition, the proportion of patients with the 677C/1298A haplotype who experienced toxicity was greater than the proportion of those with 677C/1298C who did (P = 0.032, odds ratio = 2.085, 95% confidence interval 1.058-4.106). In this study, MTHFR polymorphisms were associated with MTX toxicities in Korean patients with RA. Further study for association of MTHFR polymorphisms with MTX toxicities should be needed in larger RA population. PMID:21773884

Choe, Jung-Yoon; Lee, Hwajeong; Jung, Hyun-Young; Park, Sung-Hoon; Bae, Sang-Cheol; Kim, Seong-Kyu

2011-07-21

170

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

171

Hypercoagulable State and Methylenetetra- hydrofolate Reductase (MTHFR) C677T Mutation in Patients with Beta-Thalassemia Major in Kuwait  

Microsoft Academic Search

Introduction: Patients with thalassemia major often present with a hypercoagulable state, the pathogenesis of which is still not understood. Materials and Methods: This study evaluates the risk factors for hypercoagulability in 50 ?-thalassemia major patients and 50 healthy controls. Fasting total homocysteine, protein C (PC), protein S (PS), antithrombin (AT), activated protein C resistance (APCR) and lupus anticoagulant (LA) were

Nada Y. Mustafa; Rajaa Marouf; Salah Al-Humood; Suad M. Al-Fadhli; Olusegun Mojiminiyi

2010-01-01

172

MTHFR C677T and A1298C polymorphisms and cervical carcinoma susceptibility: meta-analyses based on 4,421 individuals.  

PubMed

MTHFR polymorphisms have been implicated as risk factors for several cancers. Studies have conducted on the associations of MTHFR polymorphisms with cervical carcinoma risk and have generated inconclusive results. The aim of the present study was to increase power demonstrating the possible relations. Meta-analyses examining the association between MTHFR C677T and A1298C polymorphisms and cervical carcinoma risk were performed. Separate analyses on ethnicity and source of controls were also implemented. Eligible studies were identified for the period up to Dec 2011. Eleven case-control studies containing 1859 cases and 2562 controls regarding MTHFR C677T polymorphisms were selected, of which four studies containing 461 cases and 832 controls described A1298C polymorphisms. For the overall data, no associations of MTHFR C677T polymorphisms with cervical carcinoma were observed (TT vs CC: OR = 1.07; 95 %CI = 0.73-1.58; dominant model: OR = 0.89; 95 %CI = 0.66-1.18; recessive model: OR = 1.13; 95 %CI = 0.84-1.52). In the subgroup analysis by ethnicity, MTHFR 677T allele was associated with decreased cervical cancer susceptibility among Caucasians (TT vs CC: OR = 0.65; 95 %CI = 0.45-0.93; dominant model: OR = 0.70; 95 %CI = 0.58-0.86) but not Asians. As for A1298C polymorphism, no marked associations of A1298C genetic variation with cervical cancer risk were observed (CC vs AA: OR = 1.01; 95 %CI = 0.60-1.73; dominant model: OR = 1.17; 95 %CI = 0.91-1.49; recessive model: OR = 0.99; 95 %CI = 0.60-1.63). Collectively, the results of the present study suggest that MTHFR 677T allele might play a preventive role for cervical carcinoma among Caucasians. A1298C polymorphisms might exert little effect on cervical cancerigenesis. PMID:22711309

Zhuo, Wen-Lei; Zhang, Liang; Ling, Jun-Jun; Zhu, Yi; Chen, Zheng-Tang

2012-06-19

173

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

PubMed

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 analyzed by PCR-RFLP analysis, and fasting serum homocysteine was measured with ELISA. The frequency of MTHFR 677T/T (30.0 vs 7.0%) and 1298C/C (13.5 vs 4.0%) genotypes was significantly higher in patients. While it was similar among patients and controls (P = 0.095), higher homocysteine was seen with the T/T (but not 1298A/C and 1298C/C) genotype among patients and controls compared with non-T/T carriers (P < 0.05), and in patients vs controls. Higher prevalence of MTHFR 677T/T was seen in late (P < 0.05) and early-late (P < 0.001) RPL, while higher prevalence of 1298C/C genotype was seen only in early-late RPL (P < 0.001), and the prevalence of double heterozygotes was statistically not significant between patients and controls (P = 0.10; odds ratio = 2.73). Logistic regression analysis showed that, after adjusting for all variables, homozygosity for MTHFR C677T was associated with late (P < 0.001), and combined early-late (P < 0.001), while homozygosity for A1298C was associated only with combined early-late (P = 0.026), as was secondary-level education, which was associated with early (P = 0.005), late (P = 0.026) and combined early-late (P = 0.004) abortions. Homozygosity for MTHFR C677T (late and early-late) and A1298C (early-late) are risk factor for RPLs, irrespectively of total homocysteine levels. PMID:16452733

Mtiraoui, N; Zammiti, W; Ghazouani, L; Braham, N Jmili; Saidi, S; Finan, R R; Almawi, W Y; Mahjoub, T

2006-02-01

174

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

175

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 Jørgensen; LLN Husemoen

2004-01-01

176

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

PubMed

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

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

2011-09-06

177

MTHFR C677T and MTR A2756G polymorphisms and the homocysteine lowering efficacy of different doses of folic acid in hypertensive Chinese adults  

PubMed Central

Background This study aimed to investigate if the homocysteine-lowering efficacy of two commonly used physiological doses (0.4 mg/d and 0.8 mg/d) of folic acid (FA) can be modified by individual methylenetetrahydrofolate reductase (MTHFR) C677T and/or methionine synthase (MTR) A2756G polymorphisms in hypertensive Chinese adults. Methods A total of 480 subjects with mild or moderate essential hypertension were randomly assigned to three treatment groups: 1) enalapril only (10 mg, control group); 2) enalapril-FA tablet [10:0.4 mg (10 mg enalapril combined with 0.4 mg of FA), low FA group]; and 3) enalapril-FA tablet (10:0.8 mg, high FA group), once daily for 8 weeks. Results After 4 or 8 weeks of treatment, homocysteine concentrations were reduced across all genotypes and FA dosage groups, except in subjects with MTR 2756AG /GG genotype in the low FA group at week 4. However, compared to subjects with MTHFR 677CC genotype, homocysteine concentrations remained higher in subjects with CT or TT genotype in the low FA group (P < 0.05 for either of these genotypes) and TT genotype in the high FA group (P < 0.05). Furthermore, subjects with TT genotype showed a greater homocysteine-lowering response than did subjects with CC genotype in the high FA group (mean percent reduction of homocysteine at week 8: CC 10.8% vs. TT: 22.0%, P = 0.005), but not in the low FA group (CC 9.9% vs. TT 11.2%, P = 0.989). Conclusions This study demonstrated that MTHFR C677T polymorphism can not only affect homocysteine concentration at baseline and post-FA treatment, but also can modify therapeutic responses to various dosages of FA supplementation.

2012-01-01

178

Influence of Methylenetetrahydrofolate Reductase C677T Polymorphism on the Risk of Lung Cancer and the Clinical Response to Platinum-Based Chemotherapy for Advanced Non-Small Cell Lung Cancer: An Updated Meta-Analysis.  

PubMed

Purpose: Methylenetetrahydrofolate reductase (MTHFR) has been implicated in lung cancer risk and response to platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC). However, the results are controversial. We performed meta-analysis to investigate the effect of MTHFR C677T polymorphism on lung cancer risk and response to platinum-based chemotherapy in advanced NSCLC. Materials and Methods: The databases of PubMed, Ovid, Wanfang and Chinese Biomedicine were searched for eligible studies. Nineteen studies on MTHFR C677T polymorphism and lung cancer risk and three articles on C677T polymorphism and response to platinum-based chemotherapy in advanced NSCLC, were identified. Results: The results indicated that the allelic contrast, homozygous contrast and recessive model of the MTHFR C677T polymorphism were associated significantly with increased lung cancer risk. In the subgroup analysis, the C677T polymorphism was significantly correlated with an increased risk of NSCLC, with the exception of the recessive model. The dominant model and the variant T allele showed a significant association with lung cancer susceptibility of ever smokers. Male TT homozygote carriers had a higher susceptibility, but the allelic contrast and homozygote model had a protective effect in females. No relationship was observed for SCLC in any comparison model. In addition, MTHFR 677TT homozygote carriers had a better response to platinum-based chemotherapy in advanced NSCLC in the recessive model. Conclusion: The MTHFR C677T polymorphism might be a genetic marker for lung cancer risk or response to platinum- based chemotherapy in advanced NSCLC. However, our results require further verification. PMID:24142642

Zhu, Ning; Gong, Yi; He, Jian; Xia, Jingwen; Chen, Xiaodong

2013-11-01

179

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

Microsoft Academic Search

This study aimed to determine the relation between methylene-tetrahydrofolate reductase (MTHFR) gene polymorphism and lung\\u000a cancer risk and the frequency of this polymorphism. The study involved 64 lung cancer patients (the study group) with definitive\\u000a diagnosis and 61 noncancerous subjects (the control group). MTHFR C677T and A1298C mutation analysis was made using DNA isolated\\u000a from peripheric blood and multiplex PCR

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

2011-01-01

180

Heterogeneity in the prevalence of methylenetetrahydrofolate reductase gene polymorphisms in women of different ethnic groups  

Microsoft Academic Search

Objective To determine the prevalence of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms in women of different ethnic groups and to relate these common mutations to plasma homocysteine, red cell folate, and serum folate. Design A one-time fasting blood sample was obtained for MTHFR genotype (C677T and A1298C) determinations (n=433). Serum folate, red cell folate, and homocysteine analyses were performed in nonfolic

Setareh Torabian Esfahani; Edward A Cogger; Marie A Caudill

2003-01-01

181

Homocysteinemia is inversely correlated with platelet count and directly correlated with sE- and sP-selectin levels in females homozygous for C677T methylenetetrahydrofolate reductase.  

PubMed

Plasma homocysteine levels depend in part on the molecular nature of the methylenetetrahydrofolate reductase (MTHFR) and on blood folate intake. Little has been reported on platelet counts in the presence of hyperhomocysteinemia and MTHFR polymorphisms, with the exception of delayed platelet recovery in homozygous MTHFR C677T subjects after treatment with methotrexate for ovarian cancer. The aim of this investigation was to evaluate the possibility of a link between the platelet count and plasma homocysteine levels in different MTHFR variants in 165 female patients. Determinations of plasma homocysteine levels were by ELISA and of MTHFR polymorphisms (A1298C and C677T) were by inverse hybridization. Serum P- and E-selectin concentrations were obtained by ELISA. An inverse correlation (R=-0.88, P<0.001) was observed between blood platelet counts and plasma homocysteine levels in the women homozygous for MTHFR C677T. This correlation did not depend on pregnancy or other variables reported. Serum concentrations of sE- and sP-selectin, markers of endothelial and platelet activation, were significantly and positively correlated with homocysteine levels. These findings suggest that homocysteine affects platelet numbers in women with MTHFR C677T possibly consequent to endothelial and platelet activation. PMID:16011963

Rongioletti, Mauro; Baldassini, Mauro; Papa, Fabrizio; Capoluongo, Ettore; Rocca, Bianca; Cristofaro, Raimondo De; Salvati, Giuseppina; Larciprete, Giovanni; Stroppolo, Annalisa; Angelucci, Piero Antonio; Cirese, Elio; Ameglio, Franco

182

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; Søren Risom Kristensen; Kim Brixen; Leif Mosekilde

2005-01-01

183

MTHFR variants reduce the risk of G:C->A:T transition mutations within the p53 tumor suppressor gene in colon tumors.  

PubMed

5,10-Methylene-tetrahydrofolate reductase (MTHFR) is a key enzyme in folate-mediated 1-carbon metabolism. Reduced MTHFR activity has been associated with genomic DNA hypomethylation. Methylated cytosines at CpG sites are easily mutated and have been implicated in G:C-->A:T transitions in the p53 tumor suppressor gene. We investigated 2 polymorphisms in the MTHFR gene (C677T and A1298C) and their associations with colon tumor characteristics, including acquired mutations in Ki-ras and p53 genes and microsatellite instability (MSI). The study population comprised 1248 colon cancer cases and 1972 controls, who participated in a population-based case-control study and had been analyzed previously for MSI, acquired mutations in Ki-ras, p53, and germline MTHFR polymorphisms. Multivariable-adjusted odds ratios are presented. Overall, MTHFR genotypes were not associated with MSI status or the presence of any p53 or Ki-ras mutation. Individuals with homozygous variant MTHFR genotypes had a significantly reduced risk of G:C-->A:T transition mutations within the p53 gene, yet, as hypothesized, only at CpG-associated sites [677TT vs. 677CC (referent group) OR = 0.4 (95% CI: 0.1-0.8) for CpG-associated sites; OR = 1.5 (0.7-3.6) for non-CpG associated sites]. Genotypes conferring reduced MTHFR activity were associated with a decreased risk of acquired G:C-->A:T mutations within the p53 gene occurring at CpG sites. Consistent with evidence on the phenotypic effect of the MTHFR C677T variant, we hypothesize that this relation may be explained by modestly reduced genomic DNA methylation, resulting in a lower probability of spontaneous deamination of methylated cytosine to thymidine. These results suggest a novel mechanism by which MTHFR polymorphisms can affect the risk of colon cancer. PMID:16177213

Ulrich, C M; Curtin, K; Samowitz, W; Bigler, J; Potter, J D; Caan, B; Slattery, M L

2005-10-01

184

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

185

Methylenetetrahydrofolate reductase gene mutations as risk factors for sudden hearing loss.  

PubMed

Sudden hearing loss (SHL) can be caused by vascular disorders favoring impaired cochlear perfusion. Several inherited prothrombotic risk factors have been considered in the pathogenesis of vascular impairment, and the possible role of genetic alterations has recently been suggested. Methylenetetrahydrofolate reductase (MTHFR) gene mutations at nucleotides 677 and 1298 cause reduced MTHFR enzyme activity, which leads to increased homocysteine and reduced serum folate levels that are known to be involved in vascular impairment. We studied the relationship between SHL and MTHFR C677T and A1298C gene polymorphisms in 67 patients with SHL and 134 controls. Wild-type MTHFR CC677/AA1298 was significantly more frequent in the controls (P = .05), and gene mutations were significantly more frequent in the patients (P = .001; P = .001 for trend). Fifty-three patients (79.1%) and 56 controls (41.8%) (P = .012) had a double mutation (homozygosis 677TT or 1298CC; compound heterozygosis for both polymorphisms). Homocysteine levels were significantly higher and serum folate levels significantly lower in the patients than in the controls (P < .0001). These data suggest that MTHFR gene polymorphisms may be involved in the pathogenesis of SHL. PMID:16275406

Capaccio, Pasquale; Ottaviani, Francesco; Cuccarini, Valeria; Ambrosetti, Umberto; Fagnani, Enrico; Bottero, Alessandro; Cenzuales, Salvatore; Cesana, Bruno Mario; Pignataro, Lorenzo

186

ACE I/D and MTHFR C677T polymorphisms are significantly associated with type 2 diabetes in Arab ethnicity: a meta-analysis.  

PubMed

In this meta-analysis study, SNPs were investigated for their association with type 2 diabetes (T2D) in both Arab and Caucasian ethnicities. A total of 55 SNPs were analyzed, of which 11 fulfilled the selection criteria, and were used for analysis. It was found that TCF7L2 rs7903146 was significantly associated with a pooled OR of 1.155 (95%C.I.=1.059-1.259), p<0.0001 and I(2)=78.30% among the Arab population, whereas among Caucasians, the pooled OR was 1.45 (95%C.I.=1.386-1.516), p<0.0001 and I(2)=77.20%. KCNJ11 rs5219 was significantly associated in both the populations with a pooled OR of 1.176(1.092-1.268), p<0.0001 and I(2)=32.40% in Caucasians and a pooled OR of 1.28(1.111-1.475), p=0.001 among Arabs. The ACE I/D polymorphism was found to be significantly associated with a pooled OR of 1.992 (95%C.I.=1.774-2.236), p<0.0001 and I(2)=83.20% among the Arab population, whereas among Caucasians, the pooled OR was 1.078 (95%C.I.=0.993-1.17), p=0.073 and I(2)=0%. Similarly, MTHFR C677T polymorphism was also found to be significantly associated among Arabs with a pooled OR of 1.924 (95%C.I.=1.606-2.304), p<0.0001 and I(2)=27.20%, whereas among Caucasians, the pooled OR was 0.986 (95%C.I.=0.868-1.122), p=0.835 and I(2)=0%. Meanwhile PPARG-2 Pro12Ala, CDKN2A/2B rs10811661, IGF2BP2 rs4402960, HHEX rs7923837, CDKAL1 rs7754840, EXT2 rs1113132 and SLC30A8 rs13266634 were found to have no significant association with T2D among Arabs. In conclusion, it seems from this study that both Arabs and Caucasians have different SNPs associated with T2D. Moreover, this study sheds light on the profound necessity for further investigations addressing the question of the genetic components of T2D in Arabs. PMID:23458876

Al-Rubeaan, Khalid; Siddiqui, Khalid; Saeb, Amr T M; Nazir, Nyla; Al-Naqeb, Dhekra; Al-Qasim, Sara

2013-02-28

187

Ramifications of four concurrent thrombophilic mutations and one hypofibrinolytic mutation.  

PubMed

A kindred was examined in which the 48-year-old white female proband with three deep venous thrombosis-pulmonary emboli events had four thrombophilic and one hypofibrinolytic mutations, and in which her 14-year-old asymptomatic daughter had four thrombophilic mutations. The proband was heterozygous for the G1691A factor V Leiden, G20210A prothrombin, and platelet glycoprotein IIIa PL A1/A2 mutations, had high factor VIII (221%), and was homozygous for the 4G4G plasminogen activator inhibitor-1 gene mutation, with high plasminogen activator inhibitor activity (23.7 U/mL). Her 14-year-old daughter was homozygous for the G1691A factor V Leiden and platelet glycoprotein IIb-IIIa PL A2/A2 mutations, compound heterozygous for the C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) mutations, and heterozygous for the G20210A prothrombin mutation, a combination with an estimated likelihood of 1.6 x 10(-7). In 247 white healthy controls, there was no V Leiden homozygosity and no V Leiden-prothrombin gene compound heterozygosity. Heterozygosity for the V Leiden and prothrombin gene mutations was 3.2% and 4.1%, respectively. Homozygosity for the platelet glycoprotein IIb-IIIa PL A2A2, PAI-1 gene 4G4G, and C677T MTHFR mutations was 3.2%, 22.7%, and 12%, respectively. The proband will receive anticoagulation therapy for life. Beyond aspirin, avoidance of exogenous estrogens, and enoxaparin prophylaxis during pregnancy, it is not known whether the proband's daughter should have lifelong anticoagulation therapy, or only after her first thrombotic event. PMID:15497023

Glueck, Charles J; Goldenberg, Naila; Wang, Ping; Aregawi, Dawit

2004-10-01

188

No association with the 5,10-methylenetetrahydrofolate reductase gene and major depressive disorder: results of the depression case control (DeCC) study and a meta-analysis.  

PubMed

Unipolar major depressive disorder (MDD) is a complex disorder thought to result from multiple genes in combination with environmental and developmental components. The 5,10-methylenetetrahydrofolate reductase gene (MTHFR) has been implicated in MDD in a meta-analysis of association studies and is within a linkage region suggested by a recent study of affected sib pairs. A single base mutation in the MTHFR gene (C677T) results in the production of a mildly dysfunctional thermolabile enzyme. The MTHFR 677TT genotype, and to a lesser extent the 677CT genotype, is associated with a significant elevation in the circulating concentrations of homocysteine and a decrease in serum folate concentrations. This may parallel a similar reduction in 5-methyltetrahydrofolate in the CNS, leading to a potential reduction in monoamine neurotransmitter function and an elevated risk of depressive disorder. To test the hypothesis that the MTHFR C677T polymorphism is involved in the predisposition to MDD, we conducted an association study of 1,222 patients with recurrent MDD and 835 control subjects. This allows 99% power to detect an effect of the size reported in the study of Bjelland et al. 2003, however no significant differences in genotype or allele frequencies between depressive patients and controls were observed. This was the case in the sample as a whole, and when females and males were considered separately. Our findings suggest that the MTHFR C677T polymorphism is not involved in the etiology of clinically significant recurrent MDD. PMID:18165972

Gaysina, D; Cohen, S; Craddock, N; Farmer, A; Hoda, F; Korszun, A; Owen, M J; Craig, I W; McGuffin, P

2008-09-01

189

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

190

A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells  

PubMed Central

A common mutation (C677T) in the gene encoding for methylenetetrahydrofolate reductase (MTHFR) (5-methyltetrahydrofolate:(acceptor) oxidoreductase, EC 1.7.99.5), a key regulatory enzyme in one-carbon metabolism, results in a thermolabile variant of the MTHFR enzyme with reduced activity in vitro. In the present study we used a chromatographic method for folate analysis to test the hypothesis that this mutation would be associated with altered distribution of red blood cell (RBC) folates. An alteration was found as manifested by the presence of formylated tetrahydrofolate polyglutamates in addition to methylated derivatives in the RBCs from homozygous mutant individuals. 5-Methyltetrahydrofolate polyglutamates were the only folate form found in RBCs from individuals with the wild-type genotype. Existence of formylated folates in RBCs only from individuals with the thermolabile MTHFR is consistent with the hypothesis that there is in vivo impairment in the activity of the thermolabile variant of MTHFR and that this impairment results in an altered distribution of RBC folates.

Bagley, Pamela J.; Selhub, Jacob

1998-01-01

191

Methylenetetrahydrofolate reductase gene polymorphisms in 13 Chinese ethnic populations.  

PubMed

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

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

2008-04-01

192

C677T (thermolabile alanine\\/valine) polymorphism in methylenetetrahydrofolate reductase (MTHFR): its frequency and impact on plasma homocysteine concentration in different European populations  

Microsoft Academic Search

A common polymorphism has been described in the methylenetetrahydrofolate reductase (MTHFR) gene, substituting an alanine (A) for a valine (V), where the V allele results in a thermolabile enzyme with reduced activity. This polymorphism is easily detectable by PCR amplification and digestion with HinfI restriction enzyme. We describe the use of the MADGE high throughput genotyping system for rapid typing

Vilmundur Gudnason; David Stansbie; Jeff Scott; Ann Bowron; Viviane Nicaud; Steve Humphries

1998-01-01

193

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

194

5,10-Methylenetetrahydrofolate Reductase Gene Variants and Congenital Anomalies: A HuGE Review  

Microsoft Academic Search

The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism. The MTHFR gene is located on chromosome 1 (1p36.3), and two common alleles, the C677T (thermolabile) allele and the A1298C allele, have been described. The population frequency of C677T homozygosity ranges from 1% or less among Blacks from Africa and the United States to 20% or more among Italians and

Lorenzo D. Botto; Quanhe Yang

2000-01-01

195

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.

Madjunkova, Svetlana; Volk, Marija; Peterlin, Borut

2012-01-01

196

Deep vein thrombosis after bunionectomy: a case report of two genetic mutations.  

PubMed

Deep venous thrombosis after foot and ankle surgery is a serious complication that can have potentially life-threatening complications, such as pulmonary embolus. Genetic mutations have been reported in the published data to cause an increased risk of developing deep vein thrombosis. Two such genetic mutations are the methylenetetrahydrofolate reductase gene variant C677T and the 4G/5G polymorphism of the plasminogen activator inhibitor gene. This case report presents a female patient who developed a postoperative deep vein thrombosis after hallux valgus reconstruction. A hypercoagulable panel revealed the 2 mentioned genetic mutations. We hope this case study will highlight the importance of ascertaining all patient risk factors and the relation to perioperative deep vein thrombosis prophylaxis. PMID:21741861

Peterson, Kyle S; Mendicino, Robert W; Catanzariti, Alan R; Saltrick, Karl R

2011-07-13

197

Polymorphisms in the CBS gene and homocysteine, folate and vitamin B12 levels: association with polymorphisms in the MTHFR and MTRR genes in Brazilian children.  

PubMed

Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR) and cystathionine beta-synthase (CBS) genes, involved in the intracellular metabolism of homocysteine (Hcy), can result in hyperhomocysteinemia. The objective of this study was to evaluate prevalence estimates of CBS T833C, G919A and the insertion of 68-bp (844ins68) polymorphisms and their correlation with Hcy, folate and B(12) in 220 children previously genotyped for MTHFR C677T, A1298C, and MTRR A66G. The prevalence of heterozygote children for 844ins68 was 19.5%. The T833C CBS mutation was identified in association with 844ins68 in all the carriers of the insertion. Genotyping for CBS G919A mutation showed that all the children presented the GG genotype. Analysis of Hcy, B(12) and folate, according to the combination of the different genotypes of the C677T and A1298C MTHFR, A66G MTRR, and 844ins68 CBS showed that the 677TT/1298AA/68WW genotype is associated with an increase in Hcy, when compared to the 677CC/1298AC/68WW (P = 0.033) and the 677CT/1298AA/68WW genotypes (P = 0.034). Since B(12) and folate were not different between these groups, a genetic interaction between diverse polymorphisms probably influences Hcy. Our results emphasize the role of genetic interactions in Hcy levels. PMID:18792976

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

2008-10-15

198

Association study between methylenetetrahydrofolate reductase gene polymorphisms and Graves' disease.  

PubMed

5,10-Methylenetetrahydrofolate reductase (MTHFR) catalyzes the metabolism of folate and nucleotides, which are essential for DNA synthesis and methylation. It is highly polymorphic, and its variant genotypes result in lower enzymatic activity and higher plasma homocysteine. Previous studies have provided evidence that a high prevalence of MTHFR gene polymorphisms is frequently detected in patients with autoimmune disease, suggesting a novel genetic association with autoimmune disorders. However, the genetic association between MTHFR and Graves' disease (GD), one of the most common autoimmune diseases, has not been studied. Here, we designed a clinic-based case-control study including 199 GD cases and 235 healthy controls to examine the associations between three common MTHFR polymorphisms (i.e., C677T, A1298C, and G1793A) and GD. Surprisingly, logistic regression analysis shows MTHFR 677CT?+?TT genotypes are associated with an approximately 42% reduction in the risk of GD in women (adjusted OR?=?0.58, 95% CI?=?0.3-0.9), compared to the CC genotype, indicating a significant protective effect of 677CT?+?TT genotypes. Our result provides epidemiological evidence that MTHFR mutation (C677T) protects women from GD. The protective effect, possibly obtained by influencing DNA methylation, should be confirmed in a large number of cohorts. PMID:20941748

Mao, Renfang; Fan, Yihui; Zuo, Lulu; Geng, Dongfeng; Meng, Fantao; Zhu, Jing; Li, Qiang; Qiao, Hong; Jin, Yan; Bai, Jing; Fu, Songbin

2010-10-01

199

MTHFR gene polymorphisms in bladder cancer in the Turkish population.  

PubMed

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

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

2011-01-01

200

Methylenetetrahydrofolate Reductase Gene Polymorphisms in Children with Attention Deficit Hyperactivity Disorder  

PubMed Central

Objective: The purpose of this study was to evaluate the relationship between 5,10- methylenetetrahydrofolate reductase (MTHFR) polymorphisms and Attention Deficit Hyperactivity Disorder (ADHD) in a sample of Turkish children. Study Design: MTHFR gene polymorphisms were assessed in 40 patients with ADHD and 30 healty controls. Two mutations in the MTHFR gene were investigated using polymerase chain reactions and restriction fragment length polymorphisms. Results: Although there were no statistically significant differences in genotype distributions of the C677T alleles between the ADHD and the control groups (p=0,678) but the genotypic pattern of the distributions of the A1298C alleles was different between the ADHD patients and the controls (p=0,033). Conclusions: Preliminary data imply a possible relationship between A1298C MTHFR polymorphisms and the ADHD.

Gokcen, Cem; Kocak, Nadir; Pekgor, Ahmet

2011-01-01

201

Maternal gene polymorphisms involved in folate metabolism and risk of Down syndrome offspring: a meta-analysis  

Microsoft Academic Search

Studies investigating the association between gene polymorphisms involved in homocysteine\\/folate metabolism and Down syndrome\\u000a (DS) have reported contradictory or inconclusive results. A meta-analysis of 11 case–control studies relating MTHFR C677T,\\u000a MTHFR A1298C and MTRR A66G gene polymorphisms to the maternal risk of DS was carried out. For MTHFR C677T polymorphism the\\u000a heterogeneity between studies was significant (P = 0.03) and the random

Elias Zintzaras

2007-01-01

202

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

203

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

PubMed Central

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

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

2012-01-01

204

Two cousins with neonatal stroke, PAI-1 4G variant and MTHFR A1298C mutation.  

PubMed

The authors describe 2 female cousins with neonatal stroke. One was heterozygous for the plasminogen activator inhibitor-1 4G variant and compound heterozygous for the A1298C and C677T methylenetetrahydrofolate reductase mutations. Her cousin was homozygous for the plasminogen activator inhibitor-1 4G variant and heterozygous for the methylenetetrahydrofolate reductase A1298C and factor V Leiden mutations. PMID:17641264

Golomb, Meredith R; Heiny, Mark; Garg, Bhuwan P

2007-06-01

205

Case-control Study of methylenetetrahydrofolate reductase mutations and hyperhomocysteinemia and risk of stroke.  

PubMed

The association of factor V-Leiden and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C mutations with stroke was investigated in 118 patients with stroke and 120 control subjects. MTHFR 677TT (P < .001) and 1298CC (P < .001), but not factor V-Leiden (P = .179), genotypes were associated with stroke. The C677T but not A1298C MTHFR mutation was associated with elevated homocysteine levels in patients and control subjects. In addition to hypertension, the significant predictors for stroke were MTHFR 677CT and TT and A1298CC genotypes, together with hyperhomocysteinemia, indicating a synergistic effect of MTHFR mutations with elevated homocysteine and other risk factors in pathogenesis of stroke. PMID:19717029

Almawi, Wassim Y; Khan, Abdulmajeed; Al-Othman, Sara S; Bakhiet, Moiz

206

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

PubMed

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

Arslan, Sulhattin; Manduz, Sinasi; Epöztürk, Kür?at; Karahan, O?uz; Akkurt, Ibrahim

2010-11-16

207

Cerebral sinus venous thrombosis in a subject with thyrotoxicosis and MTHFR gene polymorphism.  

PubMed

We report a case of cerebral venous thrombosis (CVT) due to tyrotoxicosis in a patient with methylenetetrahydro-folate-reductase (MTHFR) gene polymorphism C677T, (genotype 677TT), in which discontinuation of intravenous heparin was followed by clinical and radiological worsening despite warfarin treatment. We discuss the relationship between CVT, MTHFR hyperthiroidism and anticoagulant therapy. PMID:18941937

Strada, Laura; Gandolfo, Carlo; Del Sette, Massimo

2008-10-21

208

Mutations and polymorphisms in gonadotropin genes  

Microsoft Academic Search

Mutations in gonadotropin genes are extremely rare. Only one case of inactivating human luteinizing hormone (LH) ? mutation exists in the literature, a male with absence of Leydig cells, lack of spontaneous puberty and infertility. A total of four cases of inactivating mutation of the follicle-stimulating hormone ? (FSH?) gene (two female and two male) are known. The phenotype of

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

1999-01-01

209

Functional inference of methylenetetrahydrofolate reductase gene polymorphisms on enzyme stability as a potential risk factor for Down syndrome in Croatia.  

PubMed

Understanding the biochemical structure and function of the methylenetetrahydrofolate reductase gene (MTHFR) provides new evidence in elucidating the risk of having a child with Down syndrome (DS) in association with two common MTHFR polymorphisms, C677T and A1298C. The aim of this study was to evaluate the risk for DS according to the presence of MTHFR C677T and A1298C polymorphisms as well as the stability of the enzyme configuration. This study included mothers from Croatia with a liveborn DS child (n=102) or DS pregnancy (n=9) and mothers with a healthy child (n=141). MTHFR C677T and A1298C polymorphisms were assessed by PCR-RFLP. Allele/genotype frequencies differences were determined using chi square test. Odds ratio and the 95% confidence intervals were calculated to evaluate the effects of different alleles/genotypes. No statistically significant differences were found between the frequencies of allele/genotype or genotype combinations of the MTHFR C677T and A1298C polymorphisms in the case and the control groups. Additionally, the observed frequencies of the stable (677CC/1298AA, 677CC/1298AC, 677CC/1298CC) and unstable (677CT/1298AA, 677CT/1298AC, 677TT/1298AA) enzyme configurations were not significantly different. We found no evidence to support the possibility that MTHFR polymorphisms and the stability of the enzyme configurations were associated with risk of having a child with DS in Croatian population. PMID:20592453

Vranekovi?, Jadranka; Babi? Bozovi?, Ivana; Starcevi? Cizmarevi?, Nada; Bureti?-Tomljanovi?, Alena; Risti?, Smiljana; Petrovi?, Oleg; Kapovi?, Miljenko; Brajenovi?-Mili?, Bojana

2010-01-01

210

The androgen receptor gene mutations database.  

PubMed

The androgen receptor gene mutations database is a comprehensive listing of mutations published in journals and meetings proceedings. The majority of mutations are point mutations identified in patients with androgen insensitivity syndrome. Information is included regarding the phenotype, the nature and location of the mutations, as well as the effects of the mutations on the androgen binding activity of the receptor. The current version of the database contains 149 entries, of which 114 are unique mutations. The database is available from EMBL (NetServ@EMBL-Heidelberg.DE) or as a Macintosh Filemaker file (mc33001@musica.mcgill.ca). PMID:7937057

Patterson, M N; Hughes, I A; Gottlieb, B; Pinsky, L

1994-09-01

211

The Human Gene Mutation Database: 2008 update  

Microsoft Academic Search

The Human Gene Mutation Database (HGMD®) 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

212

Mutations in the human factor XII gene.  

PubMed

The factor XII gene from 31 unrelated factor XII-deficient patients from Germany, Switzerland, and Austria was screened for mutations at the genomic level. Several novel mutations were detected and their absence in a control group of 74 healthy unrelated individuals was checked. Most changes are in the serine protease domain affecting the catalytic triad His-393-Asp-442-Ser-544; two missense mutations, R398Q (arginine 398 to glutamine; gene bank accession no. U71276) and L395M (leucine 395 to methionine; gene bank accession no. U71277), are close to the active site histidine at position 393. Another mutation detected in a cross-reacting material (CRM)-positive female with a history of three abortions affects the active site aspartic acid by changing it to asparagine (D442N; gene bank accession no. U71275). The novel mutation G570R (glycine 570 to arginine; gene bank accession no. U71274) giving rise to a CRM-positive phenotype is located next to Cys571, which forms a vital disulfide bridge. Two mutations are causing reading frame shifts: one single basepair deletion in exon 12 [exon 12: 10590(DelC); gene bank accession no. U71278] and one acceptor splice site mutation [exon 14: 11397(G --> A); gene bank accession no. L43615]. The putative regulatory mutation exon 1:-8 (g --> c) in the upstream region of the gene is associated with an aberrant Taq I restriction site allele in intron B of the gene (gene bank accession no. X80393). PMID:9354665

Schloesser, M; Zeerleder, S; Lutze, G; Halbmayer, W M; Hofferbert, S; Hinney, B; Koestering, H; Lämmle, B; Pindur, G; Thies, K; Köhler, M; Engel, W

1997-11-15

213

Tyrosinase Gene Mutations Causing Oculocutaneous Albinisms  

Microsoft Academic Search

Since the first report of a mutation in the tyrosinase gene that causes tyrosinase-negative oculocutaneous albinism (OCA), more than 25 alleles with a different mutation in patients with three types of OCA, i.e., tyrosinase-negative OCA (type IA), yellow-mutant OCA (type IB), and temperature sensitive OCA (type ITS), have been found in several laboratories. The mutated alleles are presently classified into

Yasushi Tomita

1993-01-01

214

Serum Homocysteine, MTHFR Gene Polymorphism, and Carotid Intimal-Medial Thickness in NIDDM Subjects  

Microsoft Academic Search

We assessed the contribution of serum homocysteine levels, an independent risk factor for vascular disease, and of the methylenetetrahydrofolate reductase (MTHFR) C677T mutation to the variability of carotid intimal-medial thickness (IMT) in patients with non–insulin-dependent diabetes mellitus (NIDDM). Ninety-five patients (33 males and 62 females, mean age 53 ± 10 years) without nephropathy or other vascular complications were enrolled. Fasting

Alfredo Mazza; Corradino Motti; Angela Nulli; Anna Pastore; Felicita Andreotti; Vincenzo Ammaturo; Pasquale Bianco; Elena Santoro; Giorgio Federici; Claudio Cortese

1999-01-01

215

A microarray approach for identifying mutated genes  

Microsoft Academic Search

This study was performed to evaluate if microarray technology can identify genes using their transcriptionally defective mutant alleles. Three barley (Hordeum vulgare L.) mutant strains, xantha-h57, xantha-f27 and xantha-g28, with mutations in the genes encoding the three subunits of the chlorophyll biosynthetic enzyme magnesium chelatase, were used in a reconstruction experiment. The mutation xantha-h57 prevents transcription of Xantha-h mRNA. Microarrays

Shakhira Zakhrabekova; C. Gamini Kannangara; Diter von Wettstein; Mats Hansson

2002-01-01

216

Association of MTHFR gene polymorphisms with breast cancer survival  

Microsoft Academic Search

BACKGROUND: Two functional single nucleotide polymorphisms (SNPs) in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, C677T and A1298C, lead to decreased enzyme activity and affect chemosensitivity of tumor cells. We investigated whether these MTHFR SNPs were associated with breast cancer survival in African-American and Caucasian women. METHODS: African-American (n = 143) and Caucasian (n = 105) women, who had incident breast cancer

Damali N Martin; Brenda J Boersma; Tiffany M Howe; Julie E Goodman; Leah E Mechanic; Stephen J Chanock; Stefan Ambs

2006-01-01

217

B-vitamin intake, metabolic genes, and colorectal cancer risk (United States)  

Microsoft Academic Search

Objective: This population-based case–control study was designed to investigate the interrelationships between polymorphisms in the methylenetetrahydrofolate (MTHFR C677T and A1298C) gene and other genes (MTR A2756G; MTRR A66G and CBS 844ins68), intake of B-vitamins and colorectal cancer risk (CRC). Methods: We interviewed 727 CRC cases of Japanese, Caucasian, or Native Hawaiian origin and 727 controls matched on sex, age, and

Loïc Le Marchand; Timothy Donlon; Jean H. Hankin; Laurence N. Kolonel; Lynne R. Wilkens; Ann Seifried

2002-01-01

218

Mutation update for the PORCN gene.  

PubMed

Mutations in the PORCN gene were first identified in Goltz-Gorlin syndrome patients in 2007. Since then, several reports have been published describing a large variety of genetic defects resulting in the Goltz-Gorlin syndrome, and mutations or deletions were also reported in angioma serpiginosum, the pentalogy of Cantrell and Limb-Body Wall Complex. Here we present a review of the published mutations in the PORCN gene to date and report on seven new mutations together with the corresponding clinical data. Based on the review we have created a Web-based locus-specific database that lists all identified variants and allows the inclusion of future reports. The database is based on the Leiden Open (source) Variation Database (LOVD) software, and is accessible online at http://www.lovd.nl/porcn. At present, the database contains 106 variants, representing 68 different mutations, scattered along the whole coding sequence of the PORCN gene, and 12 large gene rearrangements, which brings up to 80 the number of unique mutations identified in Goltz-Gorlin syndrome patients. PMID:21472892

Lombardi, Maria Paola; Bulk, Saskia; Celli, Jacopo; Lampe, Anne; Gabbett, Michael T; Ousager, Lillian Bomme; van der Smagt, Jasper J; Soller, Maria; Stattin, Eva-Lena; Mannens, Marcel A M M; Smigiel, Robert; Hennekam, Raoul C

2011-06-21

219

MTHFR (677 and 1298) and IL6-174 G\\/C genes in pathogenesis of Alzheimer's and vascular dementia and their epistatic interaction  

Microsoft Academic Search

Genetic risk factors play an important role in the pathogenesis of Alzheimer disease (AD) and vascular dementia (VaD). In this case-control study, we examined C677T and A1298C (rs1801133 and rs1801131) polymorphism in the methylenetetrahydrofolate reductase (MTHFR) genes and their correlation with plasma levels of homocysteine (Hcy) in AD and VaD cases and evaluated the gene-gene interaction (epistasis) with IL-6-174 G\\/C

Nasim Mansoori; Manjari Tripathi; Kalpana Luthra; Rizwan Alam; Ramakrishnan Lakshmy; Subhadra Sharma; Subramanyam Arulselvi; Shama Parveen; Asok K. Mukhopadhyay

220

The androgen receptor gene mutations database.  

PubMed

The current version of the androgen receptor (AR) gene mutations database is described. We have added (if available) data on the androgen binding phenotype of the mutant AR, the clinical phenotype of the affected persons, the family history and whether the pathogenicity of a mutation has been proven. Exonic mutations are now listed in 5'-->3' sequence regardless of type and single base pair changes are presented in codon context. Splice site and intronic mutations are listed separately. The database has allowed us to substantiate and amplify the observation of mutational hot spots within exons encoding the AR androgen binding domain. The database is available from EML (ftp://www.ebi.ac.uk/pub/databases/androgen) or as a Macintosh Filemaker file (MC33@musica.mcgill.ca). PMID:8594566

Gottlieb, B; Trifiro, M; Lumbroso, R; Vasiliou, D M; Pinsky, L

1996-01-01

221

Haemochromatosis gene mutations in idiopathic dilated cardiomyopathy  

Microsoft Academic Search

BACKGROUNDTwo common mutations of the haemochromatosis associated gene (HFE) (cys282tyr (C282Y) and his63asp (H63D)) have been implicated in haemochromatosis and as modulators in cardiovascular disease.OBJECTIVETo investigate the role of these mutations in the pathogenesis of idiopathic dilated cardiomyopathy.DESIGN AND SETTINGCase–control and prospective cohort study of patients attending a cardiomyopathy unit in a tertiary referral cardiac centre.METHODS207 unrelated white patients with

N G Mahon; A S Coonar; S Jeffery; F Coccolo; J Akiyu; B Zal; R Houlston; G E Levin; C Baboonian; W J McKenna

2000-01-01

222

Mutational robustness of gene regulatory networks.  

PubMed

Mutational robustness of gene regulatory networks refers to their ability to generate constant biological output upon mutations that change network structure. Such networks contain regulatory interactions (transcription factor-target gene interactions) but often also protein-protein interactions between transcription factors. Using computational modeling, we study factors that influence robustness and we infer several network properties governing it. These include the type of mutation, i.e. whether a regulatory interaction or a protein-protein interaction is mutated, and in the case of mutation of a regulatory interaction, the sign of the interaction (activating vs. repressive). In addition, we analyze the effect of combinations of mutations and we compare networks containing monomeric with those containing dimeric transcription factors. Our results are consistent with available data on biological networks, for example based on evolutionary conservation of network features. As a novel and remarkable property, we predict that networks are more robust against mutations in monomer than in dimer transcription factors, a prediction for which analysis of conservation of DNA binding residues in monomeric vs. dimeric transcription factors provides indirect evidence. PMID:22295094

van Dijk, Aalt D J; van Mourik, Simon; van Ham, Roeland C H J

2012-01-25

223

Classification of Missense Mutations of Disease Genes  

PubMed Central

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

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

2008-01-01

224

Plasma Total Homocysteine Levels and Methylenetetrahydrofolate Reductase Gene Polymorphism in Patients with Type 2 Diabetes Mellitus  

Microsoft Academic Search

Background: Thrombotic episodes account for approximately 80% of deaths in type 2 diabetic patients. Hyperhomocysteinaemia is a well recognized independent risk factor for atherosclerosis and thromboembolism. Increased homocysteine levels may occur due to a number of factors including inherited gene polymorphism of methylenetetrahydrofolate reductase (MTHFR) C677T. Here, we evaluate plas- ma total homocysteine (tHcy) levels and frequency of the MTHFR

Anna L. Soares; Ana P. Fernandes; Jarbas E. Cardoso; Marinez O. Sousa; Marcelo C. Lasmar; Bethânia A. Novelli; Geralda F. Lages; Luci M. Dusse; Lauro M. Vieira; Bashir A. Lwaleed; Maria G. Carvalho

2009-01-01

225

Cerebral sinus venous thrombosis in a subject with thyrotoxicosis and MTHFR gene polymorphism  

Microsoft Academic Search

We report a case of cerebral venous thrombosis (CVT) due to tyrotoxicosis in a patient with methylenetetrahydro-folate-reductase\\u000a (MTHFR) gene polymorphism C677T, (genotype 677TT), in which discontinuation of intravenous heparin was followed by clinical\\u000a and radiological worsening despite warfarin treatment. We discuss the relationship between CVT, MTHFR hyperthiroidism and\\u000a anticoagulant therapy.

Laura Strada; Carlo Gandolfo; Massimo Del Sette

2008-01-01

226

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

Microsoft Academic Search

BackgroundHyperhomocysteinemia (>15 µmol\\/L) is highly prevalent in South Asian populations including Pakistan. In order to investigate the genetic determinants of this condition, we studied 6 polymorphisms in genes of 3 enzymes - methylenetetrahydrofolate reductase (MTHFR; C677T; A1298C), methionine synthase (MS; A2756G), cystathionine-?-synthase (CBS; T833C\\/844ins68, G919A) involved in homocysteine metabolism and investigated their interactions with nutritional and environmental factors in a

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

2012-01-01

227

Polymorphisms and haplotypes in methylenetetrahydrofolate reductase gene and head and neck squamous cell carcinoma risk  

Microsoft Academic Search

Functional polymorphisms in genes encoding enzymes involved in folate metabolism might modulate head and neck carcinoma risk\\u000a because folate participates in DNA methylation and synthesis. We therefore conducted a case–control study of 853 individuals\\u000a (322 head and neck cancer cases and 531 non-cancer controls) to investigate associations among MTHFR C677T and MTHFR A1298C polymorphisms and head and neck squamous cell

Ana Lívia Silva Galbiatti; Mariangela Torreglosa Ruiz; Juliana Olsen Rodrigues; Luiz Sérgio Raposo; José Victor Maníglia; Érika Cristina Pavarino; Eny Maria Goloni-Bertollo

228

Methylenetetrahydrofolate reductase gene polymorphisms in Turkish children with attention-deficit/hyperactivity disorder.  

PubMed

Attention-deficit/hyperactivity disorder (ADHD) is a common, multifactorial genetic disorder. The aim of the present study was to evaluate a possible association between 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and ADHD. There is evidence to suggest that MTHFR C677T and A1298C polymorphisms alter the function of the enzyme, causing reduced folate and increased homocysteine levels in plasma. Two polymorphisms of the MTHFR gene, C677T (rs1801133) and A1298C (rs1801131), were analyzed in a sample of 100 Diagnostic and Statistical Manual of Mental Disorders-IV-diagnosed ADHD and 300 healthy controls using a polymerase chain reaction-restriction fragment length polymorphism method. We did not find any association between MTHFR 677T allele, MTHFR 1298C allele, and ADHD. In addition, there was no genotype association between the MTHFR gene and ADHD (?(2)=1.711; df=2; p=0.425; ?(2)=2.946; df=2; p=0.229). Our data suggest that neither the MTHFR C677T polymorphism nor the MTHFR A1298C polymorphism was associated with ADHD in Turkish children. Thus, the MTHFR gene does not seem to play a role in the etiopathogenesis of ADHD in the cohort studied. PMID:21819229

Ergul, Emel; Sazci, Ali; Kara, Ihsan

2011-08-05

229

The androgen receptor gene mutations database.  

PubMed

The current version of the androgen receptor (AR) gene mutations database is described. The total number of reported mutations has risen from 212 to 272. We have expanded the database: (i) by adding a large amount of new data on somatic mutations in prostatic cancer tissue; (ii) by defining a new constitutional phenotype, mild androgen insensitivity (MAI); (iii) by placing additional relevant information on an internet site (http://www.mcgill.ca/androgendb/ ). The database has allowed us to examine the contribution of CpG sites to the multiplicity of reports of the same mutation in different families. The database is also available from EMBL (ftp.ebi.ac.uk/pub/databases/androgen) or as a Macintosh Filemaker Pro or Word file (MC33@musica,mcgill.ca) PMID:9016528

Gottlieb, B; Trifiro, M; Lumbroso, R; Pinsky, L

1997-01-01

230

The Neurological Presentation of Ceruloplasmin Gene Mutations  

Microsoft Academic Search

Aceruloplasminemia is an autosomal recessive disorder of iron metabolism resulting from mutations of the ceruloplasmin gene. To better define the neurological phenotype of aceruloplasminemia we reviewed reports of published cases and sought details of unpublished ones. We identified 32 published reports and 1 unpublished case. The age at diagnosis ranged from 16 to 71 years with a mean of 51.

Alisdair McNeill; Massimo Pandolfo; Jens Kuhn; Huifang Shang; Hiroaki Miyajima

2008-01-01

231

Candidate gene strategy reveals ENAM mutations.  

PubMed

Amelogenesis imperfecta (AI) is a genetically and phenotypically heterogeneous genetic disorder affecting tooth enamel without other non-oral syndromic conditions. Based on a review of the literature, the authors constructed a candidate-gene-based mutational analysis strategy. To test the strategy, they identified two Turkish families with hypoplastic enamel without any other non-oral syndromic phenotype. The authors analyzed all exons and exon/intron boundaries of the enamelin (ENAM) gene for family 1 and the DLX3 and ENAM genes for family 2, to identify the underlying genetic etiology. The analysis revealed 2 ENAM mutations (autosomal-dominant g.14917delT and autosomal-recessive g.13185-13186insAG mutations). A single T deletion in exon 10 is a novel deletional mutation (g.14917delT, c.2991delT), which is predicted to result in a frameshift with a premature termination codon (p.L998fsX1062). This result supports the use of a candidate-gene-based strategy to study the genetic basis for AI. PMID:19329462

Kang, H-Y; Seymen, F; Lee, S-K; Yildirim, M; Tuna, E Bahar; Patir, A; Lee, K-E; Kim, J-W

2009-03-01

232

From Gene Mutation to Protein Characterization  

ERIC Educational Resources Information Center

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

Moffet, David A.

2009-01-01

233

Association between polymorphisms in genes encoding methylenetetrahydrofolate reductase and the risk of Ménière's disease.  

PubMed

Folate metabolism is essential for cellular functioning. Despite extensive research on the roles of folate-metabolism-related gene polymorphisms in the pathophysiology of many diseases, such as cardiovascular disease, cancers, and sudden sensorineural hearing loss, little is known about their association with Ménière's disease (MD). The aim of this study was to investigate the effect of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms (C677T and A1298C) on the risk of MD in a Japanese population. We examined the C677T and A1298C (rs1801133 and rs1801131) polymorphisms in the MTHFR gene and compared them between 1946 adults (986 men and 960 women) participating in the National Institute for Longevity Sciences Longitudinal Study of Aging and 86 cases of MD. A multiple logistic regression was performed to obtain odds ratios (ORs) for the risk of MD regarding the MTHFR polymorphisms before (model 1) and after (model 2) adjustment for age and sex factors. The OR of MTHFR C677T for the risk of MD was 0.669 (95% confidence interval [CI], 0.479-0.934) in model 1 and 0.680 (95% CI, 0.484-0.954) in model 2. In contrast, the OR of MTHFR A1298C for the risk of MD was 1.503 (95% CI, 1.064-2.123) in model 1 and 1.505 (95% CI, 1.045-2.167) in model 2. Our results imply that the MTHFR C677T and A1298C polymorphisms are associated with the risk of MD. PMID:23484733

Huang, Yang; Teranishi, Masaaki; Uchida, Yasue; Nishio, Naoki; Kato, Ken; Otake, Hironao; Yoshida, Tadao; Sone, Michihiko; Sugiura, Saiko; Ando, Fujiko; Shimokata, Hiroshi; Nakashima, Tsutomu

2013-03-13

234

Multicentric origin of hemochromatosis gene (HFE) mutations.  

PubMed Central

Genetic hemochromatosis (GH) is believed to be a disease restricted to those of European ancestry. In northwestern Europe, >80% of GH patients are homozygous for one mutation, the substitution of tyrosine for cysteine at position 282 (C282Y) in the unprocessed protein. In a proportion of GH patients, two mutations are present, C282Y and H63D. The clinical significance of this second mutation is such that it appears to predispose 1%-2% of compound heterozygotes to expression of the disease. The distribution of the two mutations differ, C282Y being limited to those of northwestern European ancestry and H63D being found at allele frequencies>5%, in Europe, in countries bordering the Mediterranean, in the Middle East, and in the Indian subcontinent. The C282Y mutation occurs on a haplotype that extends mutation has arisen during the past 2,000 years. The H63D mutation is older and does not occur on such a large extended haplotype, the haplotype in this case extending mutations on new haplotypes. In Sri Lanka we have found H63D on three new haplotypes and have found C282Y on one new haplotype, demonstrating that these mutations have arisen independently on this island. These results suggest that the HFE gene has been the subject of selection pressure. These selection pressures could be due to infectious diseases, environmental conditions, or other genetic disorders such as anemia.

Rochette, J; Pointon, J J; Fisher, C A; Perera, G; Arambepola, M; Arichchi, D S; De Silva, S; Vandwalle, J L; Monti, J P; Old, J M; Merryweather-Clarke, A T; Weatherall, D J; Robson, K J

1999-01-01

235

The Wilson disease gene: Haplotypes and mutations  

SciTech Connect

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

Thomas, G.R.; Roberts, E.A.; Cox, D.W. [Hospital for Sick Children, Toronto (Canada); Walshe, J.M. [Middlesex Hospital, London (United Kingdom)

1994-09-01

236

The factor V Leiden mutation, high factor VIII, and high plasminogen activator inhibitor activity: etiologies for sporadic miscarriage.  

PubMed

We hypothesized that the thrombophilic G1691A factor V Leiden gene mutation was a common significant cause of sporadic first trimester miscarriage. We compared thrombophilia and hypofibrinolysis in 92 women (85 white, 5 black, 2 other) with 1 or more pregnancies and 1 miscarriage (143 live births, 92 miscarriages) (cases) and in 380 female controls (355 white, 21 black, 4 other) with 1 or more pregnancies and 0 miscarriages (964 live births). We used polymerase chain reaction techniques to characterize thrombophilic gene mutations (G1691A V Leiden [FV], G20210A prothrombin, C677T/A1298C MTHFR) and hypofibrinolytic gene mutations (plasminogen activator inhibitor [PAI-1] activity 4G4G). We carried out serologic measures of thrombophilia (homocysteine, anticardiolipin antibodies [ACLA] immunoglobulin G and immunoglobulin M, lupus anticoagulant, factor VIII, factor XI, protein C, total and free protein S, antithrombin III) and hypofibrinolysis (plasminogen activator inhibitor activity [PAI-Fx], lipoprotein[a]). Of the 380 controls, 6 (1.6%) had FV heterozygosity vs 12 heterozygous and 2 homozygous FV cases (15.2% [14/92]; P < .0001). Plasminogen activator inhibitor activity was high (> or =21.1 U/mL) in 21 (33%) of 63 cases vs 27 (18%) of 152 controls (P = .013). Factor VIII was high (>150%) in 15 (31%) of 48 cases vs 19 (18%) of 103 controls (P = .079). By logistic regression, with age and factor VIII (categorical [< or =150%, >150%]) as explanatory variables and group (cases, controls) as the dependent variable, after adjusting for age, high factor VIII was a significant predictor for miscarriage (odds ratio, 3.28; 95% confidence interval, 1.34-8.04; P = .01). There were no other group differences (P > .05) in measures of thrombophilia and hypofibrinolysis. After unexplained sporadic first trimester miscarriage, we suggest that measurements be done of the FV mutation, PAI-Fx, and factor VIII, etiologies for sporadic miscarriage. PMID:16154434

Glueck, Charles J; Pranikoff, Joel; Aregawi, Dawit; Haque, Mofiz; Zhu, Binghua; Tracy, Trent; Wang, Ping

2005-10-01

237

A meta-analysis of genotypes and haplotypes of methylenetetrahydrofolate reductase gene polymorphisms in acute lymphoblastic leukemia  

Microsoft Academic Search

A meta-analysis of case–control studies that investigated the association between the C677T and\\/or A1298C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and acute lymphoblastic leukemia (ALL) was carried out. Pooled odds ratios (OR) of various genetic contrasts of each polymorphism were estimated using random (RE) and fixed effects (FE) models. Pooled ORs for combined genotypes and haplotypes were estimated after

Elias Zintzaras; Theocharis Koufakis; Panayiotis D. Ziakas; Paraskevi Rodopoulou; Stavroula Giannouli; Michael Voulgarelis

2006-01-01

238

LEOPARD Syndrome: Clinical Features and Gene Mutations  

PubMed Central

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

Martinez-Quintana, E.; Rodriguez-Gonzalez, F.

2012-01-01

239

LEOPARD Syndrome: Clinical Features and Gene Mutations.  

PubMed

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

Martínez-Quintana, E; Rodríguez-González, F

2012-08-29

240

Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review.  

PubMed

Epidemiologic and mechanistic evidence suggests that folate is involved in colorectal neoplasia. Some polymorphic genes involved in folate metabolism--methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MTR A2756G), methionine synthase reductase (MTRR A66G), cystathionine beta-synthase (CBS exon 8, 68-base-pair insertion), and thymidylate synthase (TS enhancer region and 3' untranslated region)--have been investigated in colorectal neoplasia. For MTHFR C677T and A1298C, the variant allele is associated with reduced enzyme activity in vitro. For the other polymorphisms, functional data are limited and/or inconsistent. Genotype frequencies for all of the polymorphisms show marked ethnic and geographic variation. In most studies, MTHFR 677TT (10 studies, >4,000 cases) and 1298CC (four studies, >1,500 cases) are associated with moderately reduced colorectal cancer risk. In four of five genotype-diet interaction studies, 677TT subjects who had higher folate levels (or a "high-methyl diet") had the lowest cancer risk. In two studies, 677TT homozygote subjects with the highest alcohol intake had the highest cancer risk. Findings from six studies of MTHFR C677T and adenomatous polyps are inconsistent. There have been only one or two studies of the other polymorphisms; replication is needed. Overall, the roles of folate-pathway genes, folate, and related dietary factors in colorectal neoplasia are complex. Research priorities are suggested. PMID:14977639

Sharp, Linda; Little, Julian

2004-03-01

241

Mutation scanning of peach floral genes  

PubMed Central

Background Mutation scanning technology has been used to develop crop species with improved traits. Modifications that improve screening throughput and sensitivity would facilitate the targeted mutation breeding of crops. Technical innovations for high-resolution melting (HRM) analysis are enabling the clinic-based screening for human disease gene polymorphism. We examined the application of two HRM modifications, COLD-PCR and QMC-PCR, to the mutation scanning of genes in peach, Prunus persica. The targeted genes were the putative floral regulators PpAGAMOUS and PpTERMINAL FLOWER I. Results HRM analysis of PpAG and PpTFL1 coding regions in 36 peach cultivars found one polymorphic site in each gene. PpTFL1 and PpAG SNPs were used to examine approaches to increase HRM throughput. Cultivars with SNPs could be reliably detected in pools of twelve genotypes. COLD-PCR was found to increase the sensitivity of HRM analysis of pooled samples, but worked best with small amplicons. Examination of QMC-PCR demonstrated that primary PCR products for further analysis could be produced from variable levels of genomic DNA. Conclusions Natural SNPs in exons of target peach genes were discovered by HRM analysis of cultivars from a southeastern US breeding program. For detecting natural or induced SNPs in larger populations, HRM efficiency can be improved by increasing sample pooling and template production through approaches such as COLD-PCR and QMC-PCR. Technical advances developed to improve clinical diagnostics can play a role in the targeted mutation breeding of crops.

2011-01-01

242

Tyrosinase gene mutations causing oculocutaneous albinisms.  

PubMed

Since the first report of a mutation in the tyrosinase gene that causes tyrosinase-negative oculocutaneous albinism (OCA), more than 25 alleles with a different mutation in patients with three types of OCA, i.e., tyrosinase-negative OCA (type IA), yellow-mutant OCA (type IB), and temperature sensitive OCA (type ITS), have been found in several laboratories. The mutated alleles are presently classified into three types. The first and the second group of alleles, termed t- and y, produce tyrosinases with no enzyme activity and with very low activity, respectively. The third, termed ts, produces temperature-sensitive tyrosinase with very low activity at 35 degrees C, but with no activity at temperatures greater than 35 degrees C. Various combinations of these alleles result in tyrosinase-negative (t-/t-), yellow mutant (y/y, y/t-, y/ts), or temperature-sensitive (ts/t-, ts/ts) OCA. PMID:8433007

Tomita, Y

1993-02-01

243

Identifying Mutations in Duplicated Functions in Saccharomyces cererrisiae: Recessive Mutations in HMGCoA Reductase Genes  

Microsoft Academic Search

The two yeast genes for 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, HMGl and HMG2, each encode a functional isozyme. Although cells bearing null mutations in both genes are inviable, cells bearing a null mutation in either gene are viable. This paper describes a method of screening for recessive mutations in the HMGl gene, the gene encoding the majority of HMG-CoA reductase activity

Michael E. Basson; Robert L. Moore; Jules O'Rear; Jasper Rine

244

Genetic polymorphisms of methylenetetrahydrofolate reductase and promoter methylation of MGMT and FHIT genes in diffuse large B cell lymphoma risk in Middle East  

Microsoft Academic Search

Diffuse large B cell lymphoma (DLBCL) is one of the most common non-Hodgkin’s lymphoma types. Methylenetetrahydrofolate reductase\\u000a (MTHFR) balances the pool of folate coenzymes in one carbon metabolism of deoxyribonucleic acid (DNA) synthesis and methylation;\\u000a both are implicated in carcinogenesis of many types of cancer including lymphoma. Two common variants in the MTHFR gene (C677T\\u000a and A1298C) have been associated

Abdul K. Siraj; Muna Ibrahim; Maha Al-Rasheed; Rong Bu; Prashant Bavi; Zeenath Jehan; Jehad Abubaker; Walid Murad; Fouad Al-Dayel; Adnan Ezzat; Hassan El-Solh; Shahab Uddin; Khawla Al-Kuraya

2007-01-01

245

Mutations of the Prion Protein Gene  

Microsoft Academic Search

.   Prion diseases are inherited in 5–15 % of cases. They are classified according to changes in the prion protein gene (PRNP) or conventionally according to phenotype as Gerstmann-Sträussler-Scheinker disease (GSS), fatal familial insomnia (FFI),\\u000a or familial Creutzfeldt-Jakob disease (fCJD). Point mutations and insertions within PRNP form the genetic background. We report the results of a systematic analysis of over

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

2002-01-01

246

RNA Gene Finding with Biased Mutation Operators  

Microsoft Academic Search

The use of genetic algorithms for non-coding RNA gene finding has previously been investigated and found to be a potentially viable method for accelerating covariance-model-based database search relative to full dynamic-programming methods. The mutation operators in previous work chose new alignment insertion and deletion locations uniformly over the length of the model consensus sequence. Since the covariance models are estimated

Scott F. Smith

2007-01-01

247

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.

2012-01-01

248

The Bipolar Association Case-Control Study (BACCS) and meta-analysis: No association with the 5,10-Methylenetetrahydrofolate reductase gene and bipolar disorder.  

PubMed

Bipolar disorder (BD) is a complex genetic disease for which the underlying pathophysiology has yet to be fully explained. 5,10-Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme in folate-mediated one-carbon metabolism and folate deficiency can be associated with psychiatric symptoms. A single base variant in MTHFR gene (C677T) results in the production of a mildly dysfunctional thermolabile enzyme and has recently been implicated in BD. We conducted an association study of this polymorphism in 897 patients with bipolar I or bipolar II disorder, and 1,687 healthy control subjects. We found no evidence for genotypic or allelic association in this sample. We also performed a meta-analysis of our own, and all published data, and report no evidence for association. Our findings suggest that the MTHFR C677T polymorphism is not involved in the genetic etiology of clinically significant BD. PMID:20552676

Cohen-Woods, Sarah; Craig, Ian; Gaysina, Darya; Gray, Joanna; Gunasinghe, Cerisse; Craddock, Nick; Elkin, Amanda; Jones, Lisa; Kennedy, James; King, Nicole; Korszun, Ania; Knight, Jo; Owen, Michael; Parikh, Sagar; Strauss, John; Sterne, Abram; Tozzi, Federica; Perry, Julia; Muglia, Pierandrea; Vincent, John; McGuffin, Peter; Farmer, Anne

2010-10-01

249

PRKAR1A gene mutation in patients with cardiac myxoma  

Microsoft Academic Search

BackgroundPRKAR1A gene encodes the type 1A regulatory subunit of protein kinase A. The mutation of this gene causes Carney complex which is an autosomal dominant multiple neoplasia syndrome characterized by spotty pigmentations, endocrine overactivity and cardiac myxoma. We hypothesized that cardiac myxoma may be associated with PRKAR1A gene mutation and determined whether mutation in the PRKAR1A gene is the cause

T. Mabuchi; M. Shimizu; H. Ino; M. Yamguchi; H. Terai; N. Fujino; M. Nagata; K. Sakata; M. Inoue; T. Yoneda; H. Mabuchi

2005-01-01

250

Multi-susceptibility genes associated with the risk of the development stages of esophageal squamous cell cancer in Feicheng County  

PubMed Central

Background The purpose of this study was to evaluate the association of multi-genotype polymorphisms with the stepwise progression of esophageal squamous cell cancer (ESCC) and the possibility of predicting those at higher risk. Methods A total of 1,004 subjects were recruited from Feicheng County, China, between Jan. 2004 and Dec. 2007 and examined by endoscopy for esophageal lesions. These subjects included 270 patients with basal cell hyperplasia (BCH), 262 patients with esophageal squamous cell dysplasia (ESCD), 226 patients with ESCC, and 246 controls with Lugol-voiding area but diagnosed as having normal esophageal squamous epithelial cells by histopathology. The genotypes for CYP2E1 G1259C, hOGG1 C326G, MTHFR C677T, MPO G463A, and ALDH2 allele genes were identified in blood samples collected from all participants. Results The alleles ALDH2 and MTHFR C677T were critical for determining individual susceptibility to esophageal cancer. Compared to the ALDH 1*1 genotype, the ALDH 2*2 genotype was significantly associated with increased risks of BCH, ESCD, and ESCC. However, the TT genotype of MTHFR C677T only increased the risk of ESCC. Further analysis revealed that the combination of the high-risk genotypes 2*2/1*2 of ALDH 2 and TT/TC of MTHFR C677T increased the risk of BCH by 4.0 fold, of ESCD by 3.7 fold, and ESSC by 8.72 fold. The generalized odds ratio (ORG) of the two combined genotypes was 1.83 (95%CI: 1.55-2.16), indicating a strong genetic association with the risk of carcinogenic progression in the esophagus. Conclusions The study demonstrated that the genotypes ALDH2*2 and MTHFR 677TT conferred elevated risk for developing esophageal carcinoma and that the two susceptibility genotypes combined to synergistically increase the risk.

2011-01-01

251

Mutational analysis of the human MAOA gene.  

PubMed

The monoamine oxidases (MAO-A and MAO-B) are the enzymes primarily responsible for the degradation of amine neurotransmitters, such as dopamine, norepinephrine, and serotonin. Wide variations in activity of these isozymes have been reported in control humans. The MAOA and MAOB genes are located next to each other in the p11.3-11.4 region of the human X chromosome. Our recent documentation of an MAO-A-deficiency state, apparently associated with impulsive aggressive behavior in males, has focused attention of genetic variations in the MAOA gene. In the present study variations in the coding sequence of the MAOA gene were evaluated by RT-PCR, SSCP, and sequencing a mRNA or genomic DNA in 40 control males with > 100-fold variations of MAO-A activity, as measured in cultured skin fibroblasts. Remarkable conservation of the coding sequence was found with only 5 polymorphisms observed. All but one of these were in the third codon position and thus did not alter the deduced amino acid sequence. The one amino acid alteration observed, lys --> arg, was neutral and should not affect the structure of the protein. This study demonstrates high conservation of coding sequence in the human MAOA gene in control males, and provides primer sets which can be used to search genomic DNA for mutations in this gene in males with neuropsychiatric conditions. PMID:8678123

Tivol, E A; Shalish, C; Schuback, D E; Hsu, Y P; Breakefield, X O

1996-02-16

252

Mutational analysis of the human MAOA gene  

SciTech Connect

The monoamine oxidases (MAO-A and MAO-B) are the enzymes primarily responsible for the degradation of amine neurotransmitters, such as dopamine, norepinephrine, and serotonin. Wide variations in activity of these isozymes have been reported in control humans. The MAOA and MAOB genes are located next to each other in the p11.3-11.4 region of the human X chromosome. Our recent documentation of an MAO-A-deficiency state, apparently associated with impulsive aggressive behavior in males, has focused attention on genetic variations in the MAOA gene. In the present study, variations in the coding sequence of the MAOA gene were evaluated by RT-PCR, SSCP, and sequencing of mRNA or genomic DNA in 40 control males with >100-fold variations in MAOA activity, as measured in cultured skin fibroblasts. Remarkable conservation of the coding sequence was found, with only 5 polymorphisms observed. All but one of these were in the third codon position and thus did not alter the deduced amino acid sequence. The one amino acid alteration observed, lys{r_arrow}arg, was neutral and should not affect the structure of the protein. This study demonstrates high conservation of coding sequence in the human MAOA gene in control males, and provides primer sets which can be used to search genomic DNA for mutations in this gene in males with neuropsychiatric conditions. 47 refs., 1 fig., 2 tabs.

Tivol, E.A.; Shalish, C.; Schuback, D.E.; Breakefield, X.O. [Harvard Medical School, Boston, MA (United States); Hsu, Yun-Pung [VA Medical Center, West Roxbury, MA (United States)

1996-02-16

253

Combinatorial patterns of somatic gene mutations in cancer  

Microsoft Academic Search

Cancer is a complex process in which the abnormalities of many genes appear to be involved. The combinatorial patterns of gene mutations may reveal the functional relations between genes and path- ways in tumorigenesis as well as identify targets for treatment. We examined the patterns of somatic muta- tions of cancers from Catalog of Somatic Mutations in Cancer (COSMIC), a

Chen-Hsiang Yeang; Frank McCormick; Arnold Levine

2008-01-01

254

Ankyrin gene mutations in japanese patients with hereditary spherocytosis.  

PubMed

We studied mutations of the ankyrin-1 (ANK-1) gene of genomic DNA from Japanese patients with hereditary spherocytosis (HS). Forty-nine patients from 46 unrelated families were included in this study. Of these patients, 19 cases from 16 unrelated families had HS of autosomal-dominant inheritance, and 30 patients had non-autosomal-dominant HS. Fifteen mutations of the ANK-1 gene pathognomonic for HS were identified: 4 nonsense mutations, 7 frameshift mutations, and 4 abnormal splicing mutations. These 15 mutations have not been previously reported. The frameshift mutations were found from exon 1 to exon 26, corresponding particularly to the band 3-binding domain of ankyrin. The nonsense mutations, on the contrary, were present mostly at the 3'-terminal side, especially in the spectrin-binding domain and the regulatory domain. The patients with ankyrin gene mutations tended to be more anemic with a higher level of reticulocytosis than those without these mutations. Fifteen silent mutations of the ANK-1 gene, most of which have previously been detected in HS patients in Western populations, were also found. The allele frequency of these silent mutations in the HS patients was nearly identical to that in normal subjects. There was no difference between the Japanese and Western populations in the allele frequency of these gene polymorphisms in healthy subjects or HS patients. PMID:11372755

Nakanishi, H; Kanzaki, A; Yawata, A; Yamada, O; Yawata, Y

2001-01-01

255

[Development of the high-throughput fluorescence assay detecting SNPs in hemostasis and folate metabolism genes for clinical use].  

PubMed

Genetic predisposition of an individual patient should be taken in account to choose the proper treatment. Implementation to clinical practice requires the development of rapid, high-throughput, and easy assays intended to detect single nucleotide polymorphisms. A detection kit intended to identify the hemostasis and folate cycle gene mutations G20210A FII, G1691A FV, G10976A FVII, G103T FXIII, C807T ITGA2, T1565C ITGB3, 5G(-675)4G PAI, G(-455)A FGB, C677T and A1298C MTHFR, A2756G MTR, A66G MTRR was suggested in this work. The method is based on the polymerase chain reaction and subsequent melt curve analysis of the complexes of amplicons with specific probe. Three single nucleotide polymorphisms can be identified in one tube using our detection kit that increases the productivity of the analysis in the clinical use. Different types of biological samples (buccal epithelium, saliva, plasma, serum, and urogenital swabs) can be used as the initial material for DNA isolation and further analysis by the method developed in this work. PMID:23785789

Prasolova, M A; Shchepotina, E G; Dymshits, G M

2013-01-01

256

NOTCH3 gene mutations in subjects clinically suspected of CADASIL  

Microsoft Academic Search

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease due to mutations involving loss or gain of a cysteine residue in the NOTCH3 gene. A cluster of mutations around exons 3 and 4 was originally reported. Identification of pathogenic mutation is important for diagnostic confirmation of the disease, however genetic counselling and testing of

Lorena Mosca; Raffaella Marazzi; Alfonso Ciccone; Ignazio Santilli; Anna Bersano; Valeria Sansone; Enrico Grosso; Giorgia Mandrile; Daniela Francesca Giachino; Laura Adobbati; Elisabetta Corengia; Elio Agostoni; Anna Fiumani; Salvatore Gallone; Elio Scarpini; Mario Guidotti; Roberto Sterzi; Clara Ajmone; Alessandro Marocchi; Silvana Penco

2011-01-01

257

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

258

Clonal diversity of recurrently mutated genes in myelodysplastic syndromes  

PubMed Central

Recent studies suggest that most cases of myelodysplastic syndrome (MDS) are clonally heterogeneous, with a founding clone and multiple subclones. It is not known whether specific gene mutations typically occur in founding clones or subclones. We screened a panel of 94 candidate genes in a cohort of 157 patients with MDS or secondary acute myeloid leukemia (sAML). This included 150 cases with samples obtained at MDS diagnosis and 15 cases with samples obtained at sAML transformation (8 were also analyzed at the MDS stage). We performed whole-genome sequencing (WGS) to define the clonal architecture in eight sAML genomes and identified the range of variant allele frequencies (VAFs) for founding clone mutations. At least one mutation or cytogenetic abnormality was detected in 83% of the 150 MDS patients and 17 genes were significantly mutated (false discovery rate ?0.05). Individual genes and patient samples displayed a wide range of VAFs for recurrently mutated genes, indicating that no single gene is exclusively mutated in the founding clone. The VAFs of recurrently mutated genes did not fully recapitulate the clonal architecture defined by WGS, suggesting that comprehensive sequencing may be required to accurately assess the clonal status of recurrently mutated genes in MDS.

Walter, MJ; Shen, D; Shao, J; Ding, L; White, BS; Kandoth, C; Miller, CA; Niu, B; McLellan, MD; Dees, ND; Fulton, R; Elliot, K; Heath, S; Grillot, M; Westervelt, P; Link, DC; DiPersio, JF; Mardis, E; Ley, TJ; Wilson, RK; Graubert, TA

2013-01-01

259

PTEN gene mutations in colorectal cancers displaying microsatellite instability  

Microsoft Academic Search

To determine the relationship between the mutation of the PTEN gene and genomic instability in human colorectal cancer, we screened the PTEN gene in 32 colorectal cancers (eight cell lines and 24 tissues) displaying microsatellite instability (MSI) and 32 colorectal cancers (six cell lines and 26 tissues) displaying microsatellite stability (MSS). Of 64 samples, six frameshift mutations were identified in

Ki-Hyuk Shin; Young Jin Park; Jae-Gahb Park

2001-01-01

260

Conditional Lethal Amber Mutations in Essential Escherichia coli Genes  

Microsoft Academic Search

The essential genes of microorganisms encode biological functions important for survival and thus tend to be of high scientific interest. Drugs that interfere with essential functions are likely to be interesting candidates for antimicrobials. However, these genes are hard to study genetically because knockout mutations in them are by definition inviable. We recently described a conditional mutation system in Escherichia

Christopher D. Herring; Frederick R. Blattner

2004-01-01

261

Gene Mutations in Adult Japanese Patients With Dilated Cardiomyopathy  

Microsoft Academic Search

Background Some patients with dilated cardiomyopathy (DCM) have mutations of the genes that encode sarcomeric or cytoskeletal proteins of cardiomyocytes, but the prevalence of these mutations in Japan remains unclear. Methods and Results A group of 99 unrelated adult patients with DCM (familial n=27, sporadic n=72) were screened for the following genes: cardiac -myosin heavy chain, cardiac myosin-binding protein C

Masami Shimizu; Hidekazu Ino; Toshihiko Yasuda; Noboru Fujino; Katsuharu Uchiyama; Tomohito Mabuchi; Tetsuo Konno; Tomoya Kaneda; Takashi Fujita; Eiichi Masuta; Masahiro Katoh; Akira Funada; Hiroshi Mabuchi

2005-01-01

262

Mutations of the HFE gene among Turkish hereditary hemochromatosis patients  

Microsoft Academic Search

Since the discovery of the HFE gene, C282Y and H63D mutations have been reported as significantly correlated with clinically manifested hereditary hemochromatosis (HH). As the other genes involved in iron metabolism have been described, non-HFE cases of HH have been identified. Since in the general Turkish population, the C282Y mutation is not found and the H63D mutation is of high

Halis Simsek; Yasemin H. Balaban; Engin Yilmaz; Hale Sumer; Yahya Buyukasik; Cem Cengiz; Osman Ozcebe; Gulsen Hascelik; Gonca Tatar

2005-01-01

263

Hepatoblastoma and APC gene mutation in familial adenomatous polyposis.  

PubMed Central

BACKGROUND: Hepatoblastoma is a rare, rapidly progressive, usually fatal childhood malignancy, which if confined to the liver can be cured by radical surgical resection. An association between hepatoblastoma and familial adenomatous polyposis (FAP), which is due to germline mutation of the APC (adenomatous polyposis coli) gene, has been confirmed, but correlation with site of APC mutation has not been studied. AIM: To analyse the APC mutational spectrum in FAP families with hepatoblastoma as a possible basis to select kindreds for surveillance. PATIENTS: Eight patients with hepatoblastoma in seven FAP kindreds were compared with 97 families with identified APC gene mutation in a large Registry. METHODS: APC gene mutation was evaluated by RNase protection assay or in vitro synthesis protein assay. The chi 2 test and correlation were used for data analysis. RESULTS: APC gene mutation was identified in all seven FAP kindreds in which an at risk member developed hepatoblastoma. A male predominance was noted (six of eight), similar to literature cases (18 of 25, p < 0.01. Mutations were restricted to codons 141 to 1230, but no significant difference in site of mutation between pedigrees with and without hepatoblastoma was identified. CONCLUSIONS: Hepatoblastoma occurs primarily in boys in FAP kindreds and is associated with germline APC mutation in the 5' end of the gene. However, the site of APC mutation cannot be used to predict occurrence of this extracolonic cancer in FAP pedigrees.

Giardiello, F M; Petersen, G M; Brensinger, J D; Luce, M C; Cayouette, M C; Bacon, J; Booker, S V; Hamilton, S R

1996-01-01

264

Gender-specific association of methylenetetrahydrofolate reductase gene polymorphisms with sporadic amyotrophic lateral sclerosis.  

PubMed

Studies have revealed that elevated homocysteine levels can cause damage to motor neurons through multiple neurotoxic mechanisms, thus leading to the pathogenesis of amyotrophic lateral sclerosis (ALS). One way by which homocysteine levels are increased in the body is the consequence of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms. Therefore, to address this question, we studied the MTHFR C677T and A1298C polymorphisms in 437 sporadic ALS (SALS) and 439 healthy controls to learn whether they were associated with SALS. The overall SALS were not associated with MTHFR C677T and A1298C polymorphisms (?(2)=1.378; p=0.502; ?(2)=1.304; p=0.521, respectively). However, when we stratified results in terms of gender, we found that the MTHFR C677T polymorphism (?(2)=6.376; p=0.041), T677T genotype (?(2)=5.508; p=0.019; odds ratio [OR]=2.561; 95% confidence interval [CI]=1.142-5.744), C677C/A1298A (?(2)=5.216; p=0.022; OR=0.424, 95% CI=0.199-0.900), and T677T/A1298A (?(2)=6.639; p=0.010; OR=2.900; 95% CI=1.252-6.717) compound genotypes were associated with SALS in female patients only. Moreover, stratification of SALS according to the onset of disease indicated that there was no association between MTHFR C677T (?(2)=1.565; p=0.457; A1298C ?(2)=3.461; p=0.177) polymorphisms and overall spinal onset SALS. Further stratification analysis according to gender revealed that there was a remarkable association between MTHFR C677T (?(2)=9.728, p=0.008), T677T genotype (?(2)=7.820; p=0.005; OR=3.126; 95% CI=1.361-7.178) and T allele (?(2)=5.000; p=0.025; OR=1.711; 95% CI=1.067-2.745), and T677T/A1298A compound genotype (?(2)=9.108; p=0.003; OR=3.540; 95% CI=1.494-8.387) and spinal onset female SALS only. Likewise, there was also association between MTHFR A1298C polymorphism (?(2)=5.946; p=0.051) and the C1298C genotype (?(2)=5.282; p=0.022; OR=2.524; 95% CI=1.125-5.658), and the C677T/C1298C compound genotype (?(2)=7.155; p=0.007; OR=1.045; 95% CI=0.983-1.112) and bulbar onset SALS only in women. In conclusion, the evidence we provide here clearly shows that MTHFR C677T and A1298C polymorphisms are genetic risk factors for SALS in women in a gender-specific manner whether they are of spinal or bulbar onset. PMID:22385294

Sazci, Ali; Ozel, Mavi Deniz; Emel, Ergul; Idrisoglu, Halil Atilla

2012-03-02

265

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

266

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

PubMed

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

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

2011-10-01

267

G protein gene mutations in patients with multiple endocrinopathies.  

PubMed

Point mutations of G protein genes that result in the constitutive activation of G proteins have been described. Such mutations have been shown to occur in a number of endocrine diseases. We have examined tissues from patients having more than one organ affected by an endocrine disorder and patients having separate distinct endocrine diseases for G protein gene mutations. G protein genes encoding for Gs alpha and Gi2 alpha were examined for activating mutations at codons 201 and 227 (Gs alpha) and codons 179 and 205 (Gi2 alpha) using site-directed oligonucleotide hybridization and direct sequencing of tissue DNA amplified by polymerase chain reaction. Tissues from six patients were examined. The only mutation that was identified was at codon 201 of Gs alpha (gsp), which encoded a change from arginine to cysteine. Patient 1 had the mutation in a corticotroph adenoma, a chemodectoma, and a nodular hyperplastic adrenal gland. patient 2 had the mutation in an extraadrenal pheochromocytoma, but an adrenal gland with medullary hyperplasia was wild-type. Patient 3 had an aggressive corticotroph adenoma and developed Nelson's syndrome after bilateral adrenalectomy. The corticotroph adenoma was wild-type, but both hyperplastic adrenal glands had the mutation. Patient 4 had the mutation in a parathyroid adenoma and in two hyperplastic parathyroid glands. Patient 5 had the mutation in both a primary and a metastatic pheochromocytoma. Patient 6 had the mutation in a parathyroid adenoma and also in histologically normal thyroid and parathyroid tissue. Leukocyte DNA was examined from five patients and was found to be wild-type in all cases. We conclude that G protein gene mutations occur in a wider range of endocrine conditions than has been recognized hereto. In addition, the presence of gsp mutations in different endocrine disorders in the same patient is suggestive of a common underlying etiology. PMID:7745022

Williamson, E A; Johnson, S J; Foster, S; Kendall-Taylor, P; Harris, P E

1995-05-01

268

Crystallin gene mutations in Indian families with inherited pediatric cataract  

PubMed Central

Purpose Pediatric cataract is the most common form of treatable childhood blindness and is both clinically and genetically heterogeneous. Autosomal dominant and recessive forms of cataract have been reported to be caused by mutations in 22 different genes so far. Of the cataract mutations reported to date, about half the mutations occur in crystallins, a quarter of the mutations in connexins, and the remainder is evenly divided between intrinsic membrane proteins, intermediate filament proteins, and transcription factors. This study is aimed at identification of the spectrum and frequency of crystallin gene mutations in cataractous patients in an Indian population. Methods Genetic analysis was extended to screen the entire coding region of the CRYAA, CRYAB, CRYBA1, CRYBA4, CRYBB1, CRYBB2, CRYBB3, CRYGC, CRYGD, and CRYGS genes using single stranded conformational polymorphism (SSCP) analysis as a screening technique followed by direct sequencing of all subjects that displayed an electrophoretic shift. Results This report describes the first simultaneous mutation analysis of 10 crystallin genes in the same population, represented by 60 south Indian families. The analysis allowed the identification of causative mutations in 10 of the families (three novel and six reported). This includes six missense mutations (CRYAA-R12C, R21W, R54C, CRYAB- A171T, CRYGC-R168W, CRYGS- S39C), two nonsense mutations (CRYBB2- Q155X, CRYGD- R140X), and one splice mutation, which was identified in two families (CRYBA1-IVS3+1G>A). Conclusions Crystallin mutations are responsible for 16.6% of the inherited pediatric cataract in this population. As causative mutations have not been found in many of the families analyzed, this study suggests the presence of further novel genes or sequence elements involved in the pathogenesis of cataract in these families.

Devi, Ramachandran Ramya; Yao, Wenliang; Vijayalakshmi, Perumalsamy; Sergeev, Yuri V.; Sundaresan, Periasamy

2008-01-01

269

Clinical implications for BRCA gene mutation in breast cancer.  

PubMed

To investigate the mutations of BRCA1 and BRCA2 and determine whether clinic-pathological factors related to BRCA gene mutation. Mastectomy specimens from 360 breast cancers were enrolled and examined in the study. The relationship between BRCA gene mutation and clinic-pathological factors was evaluated. Overall, 280 patients were BRCA negative and 80 got BRCA gene mutation. Triple-negative breast cancers--i.e., breast cancers that do not express estrogen receptors (ER), progesterone receptors (PR) or human epidermal growth factor receptor 2 (HER2/neu)--was observed in 53.85% of the BRCA1 mutation patients, in 28.57% of the BRCA2 mutation cases, while 14.29% of BRCA negative patients. BRCA1 mutation patients got a heavy lymph node metastasis and higher nuclear grade tumors than the others (P = 0.004, 0.007). Furthermore, BRCA mutation was also found to be significantly related to ER, PR and HER2/neu status (P < 0.05). BRCA1 expression was not associated with breast cancer-specific survival in the triple-negative breast cancers (P = 0.742). After Cox regression, BRCA1 mutation was not shown to be an independent prognostic factor for breast cancer. These findings substantiated the possibility of tumors associated with BRCA1 mutations divided into two distinct groups, triple-negative and non-triple-negative groups requires further investigation. PMID:21691706

Xu, Jin; Wang, Baosheng; Zhang, Yanjun; Li, Ruihui; Wang, Yuehua; Zhang, Shaokun

2011-06-21

270

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

271

Common Familial Mediterranean Fever gene mutations in a Turkish cohort.  

PubMed

Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disorder with the responsible gene of MEFV which primarily affects Jewish, Armenian, Turkish and Arab populations. The FMF gene (MEFV) has recently been cloned to chromosome 16 p, which encodes pyrin. In the present study, we enrolled 2,067 unrelated patients with the suspicion of FMF in Middle Anatolia between the years 2006-2009 and identified the 12 MEFV mutations. DNA was amplified by PCR and subjected to reverse hybridization for the detection of MEFV gene mutations. Among the 2,067 patients, 866 (41.9%) were males and 1,201 (58.1%) were females. The mutations were homozygous in 176 (16.85%) patients, compound heterozygous in 314 (30.1%) patients, heterozygous in 546 (52.25%) patients and the other forms of mutations were found in 8 patients (0.76%). No mutation was detected in 1,023 (49.5%) patients. The most frequent mutations were M694V, M680I (G/C), E148Q and V726A. We could not find any significant differences between the two common mutations according to the gender. The high incidence of MEFV gene mutations in the Turkish population indicated that newborn screening may be discussed in the future. Because of the ethnic origin of Anatolia, larger serial analyses are necessary to investigate the rate and coexistence of these mutations. PMID:21153919

Dundar, Munis; Emirogullari, Elif Funda; Kiraz, Aslihan; Taheri, Serpil; Baskol, Mevlut

2010-12-14

272

Analysis of mutations in the SCH gene in schwannomas.  

PubMed

Schwannomas are benign tumors of cranial, spinal, and other nerve sheaths that develop sporadically or are inherited as part of neurofibromatosis type 2 (NF2). The NF2 gene (SCH) on chromosome 22 has recently been identified and shown to be inactivated by mutation and allele loss in some schwannomas. However, only limited regions in the SCH coding region were examined for mutations. We have extended these studies by screening virtually all coding sequences of the SCH gene (95% coverage) and adjacent splice site sequences for the presence of mutations in 48 schwannomas. All tumors (34 vestibular schwannomas and 14 schwannomas of other locations) were additionally characterized for allele loss on chromosome 22. By PCR-DGGE screening of the 16 known exons of the SCH gene, 22 mutations were found. Most of these give rise to a premature stop codon and are expected to result in the synthesis of a truncated gene product (schwannomin). Although there was no apparent hotspot for mutations, 16 of the 22 mutations occurred in the first eight exons or adjacent splice site sequences of the SCH gene. In several vestibular as well as other schwannomas loss of one SCH allele and mutational inactivation of the second allele were identified in the same tumor. Our data indicate that the SCH gene is implicated in the development of schwannomas of all locations in the nervous system. PMID:7529050

Bijlsma, E K; Merel, P; Bosch, D A; Westerveld, A; Delattre, O; Thomas, G; Hulsebos, T J

1994-09-01

273

Prevalence of Hemochromatosis Gene (HFE) Mutations in Greece  

Microsoft Academic Search

The frequencies of the hereditary hemochromatosis gene (HFE) mutations C282Y and H63D vary between different populations. There are a limited number of reports regarding the frequency of these mutations in populations of southeastern Europe. Two hundred and sixty-four adult individuals of Greek origin were examined for the C282Y and H63D mutations to determine the allele and genotype frequencies. The HFE

Dimitrios Papazoglou; Triada Exiara; Matthaios Speletas; Ioannis Panagopoulos; Efstratios Maltezos

2003-01-01

274

Diverse growth hormone receptor gene mutations in Laron syndrome  

SciTech Connect

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

Berg, M.A.; Francke, U. (Stanford Univ. School of Medicine, CA (United States)); Gracia, R.; Rosenbloom, A.; Toledo, S.P.A. (Univ. Autonoma, Madrid (Spain)); Chernausek, S. (Children's Hospital Medical Center, Cincinnati, OH (United States)); Guevara-Aguirre, J. (Institute of Endocrinology, Metabolism, and Reproduction, Quito (Ecuador)); Hopp, M. (Univ. of Witwatersrand, Johannesburg (South Africa)); Rosenbloom, A.; Argente, J. (Univ. of Florida, Gainesville (United States)); Toledo, S.P.A. (Univ. of Sao Paulo (Brazil))

1993-05-01

275

Gene Mutation May Help Predict Lung Cancer Survival in Nonsmokers  

MedlinePLUS

... please enable JavaScript. Gene Mutation May Help Predict Lung Cancer Survival in Nonsmokers Finding might offer doctors a ' ... 2013 Related MedlinePlus Pages Genes and Gene Therapy Lung Cancer THURSDAY, Sept. 12 (HealthDay News) -- Researchers say they' ...

276

Mutator phenotypes of yeast strains heterozygous for mutations in the MSH2 gene  

PubMed Central

Heterozygosity for germ-line mutations in the DNA mismatch repair gene MSH2 predisposes humans to cancer. Here we use a highly sensitive reporter to describe a spontaneous mutator phenotype in diploid yeast cells containing a deletion of only one MSH2 allele. We also identify five MSH2 missense mutations that have dominant mutator effects in heterozygous cells when expressed at normal levels from the natural MSH2 promoter. For example, a 230-fold mutator effect is observed in an MSH2/msh2 diploid strain in which Gly693, which is invariant in MutS homologs and involved in ATP hydrolysis, is changed to alanine. DNA binding data suggest that mismatch repair is suppressed by binding of a mutant Msh2–Msh6 heterodimer to a mismatch with subsequent inability to dissociate from the mismatch in the presence of ATP. A dominant mutator effect also is observed in yeast when Gly693 is changed to serine. An early onset colorectal tumor is heterozygous for the analogous Gly ? Ser mutation in hMSH2, and a second hMSH2 mutation was not found, suggesting that this missense mutation may predispose to cancer via a dominant mutator effect. The mutator effects of the deletion mutant and the Gly ? Ala missense mutant in yeast MSH2 are enhanced by heterozygosity for a missense mutation in DNA polymerase ? that reduces its proofreading activity but is not a mutator in the heterozygous state. The synergistic effects of heterozygosity for mutations in two different genes that act in series to correct replication errors may be relevant to cancer predisposition.

Drotschmann, Karin; Clark, Alan B.; Tran, Hiep T.; Resnick, Michael A.; Gordenin, Dmitry A.; Kunkel, Thomas A.

1999-01-01

277

EGF receptor gene mutations are common in lung cancers from  

Microsoft Academic Search

Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. In-frame deletions occur in exon 19, whereas point mutations occur frequently in codon 858 (exon 21). We found from sequencing the EGFR TK domain that 7 of 10 gefitinib-sensitive tumors had

William Pao; Vincent Miller; Maureen Zakowski; Jennifer Doherty; Katerina Politi; Inderpal Sarkaria; Bhuvanesh Singh; Robert Heelan; Valerie Rusch; Lucinda Fulton; Elaine Mardis; Doris Kupfer; Richard Wilson; Mark Kris; Harold Varmus

2004-01-01

278

Mutations including the promoter region of myocilin\\/TIGR gene  

Microsoft Academic Search

Mutations in the MYOC\\/TIGR gene are responsible for autosomal dominant primary open angle glaucoma (POAG). Almost all mutations responsible for POAG have been detected in the coding region (in particular at exon 3). By using the techniques of PCR, SSCP, automated sequencing and restriction analysis, we have studied 79 patients suffering from glaucoma. We have found five patients with sequence

Maria Saura; Montse Cabana; Carmen Ayuso; Diana Valverde

2005-01-01

279

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

280

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, ...

281

Ankyrin gene mutations in japanese patients with hereditary spherocytosis  

Microsoft Academic Search

We studied mutations of theankyrin-1 (ANK-1) gene of genomic DNA from Japanese patients with hereditary spherocytosis (HS). Forty-nine patients from 46 unrelated families\\u000a were included in this study. Of these patients, 19 cases from 16 unrelated families had HS of autosomal-dominant inheritance,\\u000a and 30 patients had non-autosomal-dominant HS. Fifteen mutations of theANK-1 gene pathognomonic for HS were identified: 4 nonsense

Hidekazu Nakanishi; Akio Kanzaki; Ayumi Yawata; Osamu Yamada; Yoshihito Yawata

2001-01-01

282

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

283

HFE gene mutations an Apulian population: Allele frequencies  

Microsoft Academic Search

Hereditary hemochromatosis (HH) is an autosomal recessive trait regarding iron metabolism frequently found in Caucasian populations. The C282Y mutation of the HFE gene, held responsible for HH, has been identified as the major genetic basis for the phenotypic expression of HH whereas two additional mutations of the HFE H63D and S65C gene appear to be associated with a milder form

A. Pietrapertosa; A. Vitucci; D. Campanale; A. Palma; R. Renni; G. Delios; N. Tannoia

2003-01-01

284

Microarray-based mutation detection in the dystrophin gene.  

PubMed

Duchenne and Becker muscular dystrophies (DMD and BMD) are X-linked recessive neuromuscular disorders caused by mutations in the dystrophin gene affecting approximately 1 in 3,500 males. The human dystrophin gene spans>2,200 kb, or roughly 0.1% of the genome, and is composed of 79 exons. The mutational spectrum of disease-causing alleles, including exonic copy number variations (CNVs), is complex. Deletions account for approximately 65% of DMD mutations and 85% of BMD mutations. Duplications occur in approximately 6 to 10% of males with either DMD or BMD. The remaining 30 to 35% of mutations consist of small deletions, insertions, point mutations, or splicing mutations, most of which introduce a premature stop codon. Laboratory analysis of dystrophin can be used to confirm a clinical diagnosis of DMD, characterize the type of dystrophin mutation, and perform prenatal testing and carrier testing for females. Current dystrophin diagnostic assays involve a variety of methodologies, including multiplex PCR, Southern blot analysis, multiplex ligation-dependent probe amplification (MLPA), detection of virtually all mutations-SSCP (DOVAM-S), and single condition amplification/internal primer sequencing (SCAIP); however, these methods are time-consuming, laborious, and do not accurately detect duplication mutations in the dystrophin gene. Furthermore, carrier testing in females is often difficult when a related affected male is unavailable. Here we describe the development, design, validation, and implementation of a high-resolution comparative genomic hybridization (CGH) microarray-based approach capable of accurately detecting both deletions and duplications in the dystrophin gene. This assay can be readily adopted by clinical molecular testing laboratories and represents a rapid, cost-effective approach for screening a large gene, such as dystrophin. PMID:18663755

Hegde, Madhuri R; Chin, Ephrem L H; Mulle, Jennifer G; Okou, David T; Warren, Stephen T; Zwick, Michael E

2008-09-01

285

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

PubMed

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

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

2010-08-27

286

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

PubMed Central

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

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

2010-01-01

287

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

288

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

PubMed Central

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.

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

2003-01-01

289

Pancreatic adenocarcinomas frequently show p53 gene mutations.  

PubMed Central

Thirty-four pancreatic adenocarcinomas were studied for the presence of p53 gene mutations by the single-strand conformation polymorphism method and by direct sequencing of PCR-amplified fragments. p53 protein expression was immunohistochemically evaluated using monoclonal PAb1801 and polyclonal CM1 antibodies. Mutations were detected in 14 cases. The transitions were six G to A and two A to G; the transversions were one C to G and two A to C; the remaining three were frameshift mutations. Immunostaining results were identical with both antibodies. Nuclear immunohistochemical p53-positive cells were found in nine p53 mutated cases and in 12 cases in which no mutation was detected. In most of these latter cases only a minority of cancer cells showed immunohistochemical positivity. Twenty-nine cases, including all p53 mutated cancers, were known to contain codon 12 Ki-ras gene mutations. Also in the light of the demonstrated cooperation of ras and p53 gene alterations in the transformation of cultured cells, our data suggest that p53 mutation is one of the genetic defects that may have a role in the pathogenesis of a proportion of pancreatic cancers. Images Figure 1 Figure 2 Figure 3 Figure 4

Scarpa, A.; Capelli, P.; Mukai, K.; Zamboni, G.; Oda, T.; Iacono, C.; Hirohashi, S.

1993-01-01

290

Preservation of duplicate genes by complementary, degenerative mutations.  

PubMed Central

The origin of organismal complexity is generally thought to be tightly coupled to the evolution of new gene functions arising subsequent to gene duplication. Under the classical model for the evolution of duplicate genes, one member of the duplicated pair usually degenerates within a few million years by accumulating deleterious mutations, while the other duplicate retains the original function. This model further predicts that on rare occasions, one duplicate may acquire a new adaptive function, resulting in the preservation of both members of the pair, one with the new function and the other retaining the old. However, empirical data suggest that a much greater proportion of gene duplicates is preserved than predicted by the classical model. Here we present a new conceptual framework for understanding the evolution of duplicate genes that may help explain this conundrum. Focusing on the regulatory complexity of eukaryotic genes, we show how complementary degenerative mutations in different regulatory elements of duplicated genes can facilitate the preservation of both duplicates, thereby increasing long-term opportunities for the evolution of new gene functions. The duplication-degeneration-complementation (DDC) model predicts that (1) degenerative mutations in regulatory elements can increase rather than reduce the probability of duplicate gene preservation and (2) the usual mechanism of duplicate gene preservation is the partitioning of ancestral functions rather than the evolution of new functions. We present several examples (including analysis of a new engrailed gene in zebrafish) that appear to be consistent with the DDC model, and we suggest several analytical and experimental approaches for determining whether the complementary loss of gene subfunctions or the acquisition of novel functions are likely to be the primary mechanisms for the preservation of gene duplicates. For a newly duplicated paralog, survival depends on the outcome of the race between entropic decay and chance acquisition of an advantageous regulatory mutation.Sidow 1996(p. 717) On one hand, it may fix an advantageous allele giving it a slightly different, and selectable, function from its original copy. This initial fixation provides substantial protection against future fixation of null mutations, allowing additional mutations to accumulate that refine functional differentiation. Alternatively, a duplicate locus can instead first fix a null allele, becoming a pseudogene.Walsh 1995 (p. 426) Duplicated genes persist only if mutations create new and essential protein functions, an event that is predicted to occur rarely.Nadeau and Sankoff 1997 (p. 1259) Thus overall, with complex metazoans, the major mechanism for retention of ancient gene duplicates would appear to have been the acquisition of novel expression sites for developmental genes, with its accompanying opportunity for new gene roles underlying the progressive extension of development itself.Cooke et al. 1997 (p. 362)

Force, A; Lynch, M; Pickett, F B; Amores, A; Yan, Y L; Postlethwait, J

1999-01-01

291

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.

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

292

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

293

Mutations in the AGXT2L2 gene cause phosphohydroxylysinuria.  

PubMed

Phosphohydroxylysinuria has been described in two patients with neurological symptoms, but the deficient enzyme or mutated gene has never been identified. In the present work, we tested the hypothesis that this condition is due to mutations in the AGXT2L2 gene, recently shown to encode phosphohydroxylysine phospholyase. DNA analysis from a third patient, without neurological symptoms, but with an extreme hyperlaxicity of the joints, shows the existence of two mutations, p. Gly240Arg and p.Glu437Val, both in the heterozygous state. Sequencing of cDNA clones derived from fibroblasts mRNA indicated that the two mutations were allelic. Both mutations replace conserved residues. The mutated proteins were produced as recombinant proteins in Escherichia coli and HEK293T cells and shown to be very largely insoluble, whereas the wild-type one was produced as a soluble and active protein. We conclude that phosphohydroxylysinuria is due to mutations in the AGXT2L2 gene and the resulting lack of activity of phosphohydroxylysine phospholyase in vivo. The finding that the nul alleles of p.Gly240Arg and p.Glu437Val are present at low frequencies in the European and/or North American population suggests that this condition is more common than previously thought. The diversity of the clinical symptoms described in three patients with phosphohydroxylysinuria indicates that this is most likely not a neurometabolic disease. PMID:23242558

Veiga-da-Cunha, Maria; Verhoeven-Duif, Nanda M; de Koning, Tom J; Duran, Marinus; Dorland, Bert; Van Schaftingen, Emile

2012-12-14

294

From minisatellites and genes: When do germinal mutations occur  

SciTech Connect

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

Mohrenweiser, H. [Lawrence Livermore National Lab., CA (United States)

1997-10-01

295

Activation of Developmentally Mutated Human Globin Genes by Cell Fusion  

NASA Astrophysics Data System (ADS)

Human fetal globin genes are not expressed in hybrid cells produced by the fusion of normal human lymphocytes with mouse erythroleukemia cells. In contrast, when lymphocytes from persons with globin gene developmental mutations (hereditary persistence of fetal hemoglobin) are used for these fusions, fetal globin is expressed in the hybrid cells. Thus, mutations of developmental origin can be reconstituted in vitro by fusing mutant lymphoid cells with differentiated cell lines of the proper lineage. This system can readily be used for analyses, such as globin gene methylation, that normally require large numbers of pure nucleated erythroid cells, which are difficult to obtain.

Papayannopoulou, Thalia; Enver, Tariq; Takegawa, Susumu; Anagnou, Nicholas P.; Stamatoyannopoulos, George

1988-11-01

296

Neurocognitive profiles in Duchenne muscular dystrophy and gene mutation site.  

PubMed

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

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

2011-11-01

297

A novel mutation of the fibrillin gene causing Ectopia lentis  

SciTech Connect

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

Loennqvist, L.; Kainulainen, K.; Puhakka, L.; Peltonen, L. (National Public Health Institute, Helsinki (Finland)); Child, A. (St. George's Hospital Medical School, London (United Kingdom)); Peltonen, L. (Duncan Guthrie Institute, Glasgow, Scotland (United Kingdom))

1994-02-01

298

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

2011-01-26

299

Nonsense mutations in the dihydrofolate reductase gene affect RNA processing  

SciTech Connect

Steady-state dihydrofolate reductase (dhfr) mRNA levels were decreased as a result of nonsense mutations in the dhfr gene. Thirteen DHFR-deficient mutants were isolated after treatment of Chinese hamster ovary cells with UV irradiation. The positions of most point mutations were localized by RNA heteroduplex mapping, the mutated regions were isolated by cloning or by enzymatic amplification, and base changes were determined by DNA sequencing. Two of the mutants suffered large deletions that spanned the entire dhfr gene. The remaining 11 mutations consisted of nine single-base substitutions, one double-base substitution, and one single-base insertion. All of the single-base substitutions took place at the 3' position of a pyrimidine dinucleotide, supporting the idea that UV mutagenesis proceeds through the formation of pyrimidine dimers in mammalian cells. Of the 11 point mutations, 10 resulted in nonsense codons, either directly or by a frameshift, suggesting that the selection method favored a null phenotype. An examination of steady-state RNA levels in cells carrying these mutations and a comparison with similar data from other dhfr mutants showed that translation termination mutations in any of the internal exons of the gene gave rise to a low-RNA phenotype, whereas missense mutations in these exons or terminations in exon 6 (the final exon) did not affect dhfr mRNA levels. Nuclear run-on experiments showed that transcription of the mutant genes was normal. The stability of mature dhfr mRNA also was not affected, since (i) decay rates were the same in wild-type and mutant cells after inhibition of RNA synthesis with actinomycin D and (ii) intronless minigene versions of cloned wild-type and nonsense mutant genes were expressed equally after stable transfection.

Urlaub, G.; Mitchell, P.J.; Ciudad, C.J.; Chasin, L.A. (Columbia Univ., New York, NY (USA))

1989-07-01

300

Novel PRKAR1A gene mutations in Carney Complex.  

PubMed

Carney complex is a syndrome that may include cardiac and mucocutaneous myxomas, spotting skin pigmentation, and endocrine lesions. Many patients with Carney complex have been shown to have a stop codon mutation in the PRKAR1A gene in the 17q22-24 region. Here we present the case of a 57 year-old man with multiple skin lesions and cardiac myxomas. Histology of the skin lesions showed lentigenous melanocytic hyperplasia and cutaneous myxomas, confirming the diagnosis of Carney complex. Lesional and control normal tissue from the patient were identified and sequenced for the PRKAR1A gene. A germline missense mutation was identified at exon 1A. This is the first report of this mutation, and one of the few reported missense mutation associated with Carney complex. This finding strengthens the argument that there are alternative ways in which the protein kinase A 1-alpha subunit plays a role in tumorigenesis. PMID:20606737

Pan, Lorraine; Peng, Lan; Jean-Gilles, J; Zhang, Ximin; Wieczorek, Rosemary; Jain, Shilpa; Levine, Vicki; Osman, Iman; Prieto, Victor G; Lee, Peng

2010-05-10

301

Novel PRKAR1A gene mutations in Carney Complex  

PubMed Central

Carney complex is a syndrome that may include cardiac and mucocutaneous myxomas, spotting skin pigmentation, and endocrine lesions. Many patients with Carney complex have been shown to have a stop codon mutation in the PRKAR1A gene in the 17q22-24 region. Here we present the case of a 57 year-old man with multiple skin lesions and cardiac myxomas. Histology of the skin lesions showed lentigenous melanocytic hyperplasia and cutaneous myxomas, confirming the diagnosis of Carney complex. Lesional and control normal tissue from the patient were identified and sequenced for the PRKAR1A gene. A germline missense mutation was identified at exon 1A. This is the first report of this mutation, and one of the few reported missense mutation associated with Carney complex. This finding strengthens the argument that there are alternative ways in which the protein kinase A 1-alpha subunit plays a role in tumorigenesis

Pan, Lorraine; Peng, Lan; Jean-Gilles, J; Zhang, Ximin; Wieczorek, Rosemary; Jain, Shilpa; Levine, Vicki; Osman, Iman; Prieto, Victor G; Lee, Peng

2010-01-01

302

[Homozygous germline mutation in MUTYH gene in familial adenomatous polyposis].  

PubMed

Recently, MUTYH mutations have been reported to predispose to the development of polyposis. However, polyposis caused by mutations in MUTYH has been characterized as an autosomal recessive hereditary disease, different from the autosomal dominant pattern observed in polyposis caused by APC mutations. We report a 41-year-old female consulting for anemia. Colonoscopy detected multiple sessile polyps and a cecal carcinoma. The patient was operated and in the surgical piece, the tumor invaded serosa and there was lymph node involvement. Approximately 100 polyps were found. The patient received 5-fluorouracil, as adjuvant therapy. The patient had a sister (of a total of 12 brothers) with a colorectal carcinoma. The genetic study identified a homozygous mutation of the MUTYH gene, called c.340T > C, that produces an amino acid change of tyrosine for histidine called p.Y114H. The sister with colorectal cancer was a heterozygous carrier of this mutation. PMID:23677194

Alvarez, Karin; de la Fuente, Marjorie; Orellana, Paulina; Wielandt, Ana María; Heine, Claudio; Suazo, Cristóbal; Kronberg, Udo; Carvallo, Pilar; López-Köstner, Francisco

2012-11-01

303

Common MEFV gene mutations in Turkish patients with Behcet's disease.  

PubMed

Behcet's disease (BD) is a chronic systemic inflammatory disorder whose etiology has not been fully established yet. The MEditerranean FeVer (MEFV) gene has been identified as the cause of Familial Mediterranean Fever (FMF). BD shows similarities with FMF, in terms of clinical findings and treatments, as well as their geographical and ethnic co-occurrence. In this study we investigated common MEFV gene mutation frequencies in Turkish patients with BD in an area of Turkey where both diseases are frequently encountered. We screened 207 BD patients who had no symptoms and family history for FMF and 200 healthy subjects for five common MEFV gene mutations (E148Q, M680I, M694V, V726A, P369S) and clinical features. Seventy-five patients were found to carry a single MEFV mutation, and six patients were compound heterozygous. The difference in the frequency of the MEFV mutation between the BD and control groups was statistically significant (p<0.001, odds ratio [OR] 2.74, 95% confidence interval [CI] 1.75-4.29). The frequencies of E148Q and M680I mutations were significantly higher in the BD group (p=0.001, p=0.046, respectively). The frequency of uveitis was significantly lower in patients with the mutation than in patients without the mutation (p=0.029, OR 0.54, 95% CI 0.30-0.98). There was no statistical significance between carriers and non-carriers with respect to gender and other manifestations of BD. The frequency of the MEFV mutation was significantly higher in patients with BD compared to the healthy control group. Based on our results, MEFV mutations appear to have a role in the pathogenesis of BD. PMID:23973724

Tasliyurt, Turker; Yigit, Serbulent; Rustemoglu, Aydin; Gul, Ulker; Ates, Omer

2013-08-22

304

Gene expression profile study in CFTR mutated bronchial cell lines  

Microsoft Academic Search

Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis conductance transmembrane regulator (CFTR).\\u000a Symptoms are pancreatic insufficiency, chronic obstructive lung disease, liver disease, chronic sinusitis and infertility\\u000a in male patients. The phenotypic variability may be explained only in part by the more than 1200 CFTR mutations, which are\\u000a grouped into six different classes, according to

M. R. D'Apice; F. Amati; F. Sangiuolo; A. Farcomeni; G. Chillemi; S. Bueno; A. Desideri; G. Novelli

2006-01-01

305

Mutation Analysis of the HFE Gene in Brazilian Populations  

Microsoft Academic Search

ABSTRACT: 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 Parakanã Indians. Allelic frequency of the mutation C. 845G(A (C282Y) was 1.4% in the Caucasian population, 1.1% in

Marcela F Agostinho; Valder R Arruda; Daniela S Basseres; Silvana Bordin; Manoel C. P Soares; Raimundo C Menezes; Fernando F Costa; Sara T. O Saad

1999-01-01

306

Mutation Analysis of the HFE Gene in Brazilian Populations  

Microsoft Academic Search

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-deriv ed subjects (from Northeast Brazil) and 75 Parakanã Indians. Allelic frequency of the mutation C. 845G6A (C282Y) was 1.4% in the Caucasian population, 1.1% in

Marcela F. Agostinho; Valder R. Arruda; Daniela S. Basseres; Silvana Bordin; Manoel C. P. Soares; Raimundo C. Menezes

1999-01-01

307

A complete mutation screen of the ADPKD genes by DHPLC  

Microsoft Academic Search

A complete mutation screen of the ADPKD genes by DHPLC.BackgroundGenetic analysis is a useful diagnostic tool in autosomal dominant polycystic kidney disease (ADPKD), especially when imaging results are equivocal. However, molecular diagnostics by direct mutation screening has proved difficult in this disorder due to genetic and allelic heterogeneity and complexity of the major locus, PKD1.MethodsA protocol was developed to specifically

Sandro Rossetti; Dominique Chauveau; Denise Walker; Anand Saggar-Malik; Christopher G. Winearls; Vicente E. Torres; Peter C. Harris

2002-01-01

308

Mutations of the HFE Gene and the Risk of Hepatocellular  

Microsoft Academic Search

The discovery of the C282Y and H63D point mutations in the hereditary hemochromatosis-associated HFE gene allows us to study the molecular basis of congenital and acquired iron overload disorders. In hereditary hemochromatosis an increased frequency of the C282Y and, to a lesser extent, of the H63D mutations has been established, but their role in other conditions associated with iron overload

Omar Racchi; Rosa Mangerini; Davide Rapezzi; Gian Franco Gaetani; Maria Teresa Nobile; Antonino Picciotto; Anna Maria Ferraris

309

Mutations of the HFE Gene in Patients With Hepatocellular Carcinoma  

Microsoft Academic Search

OBJECTIVE:Hepatocellular carcinoma (HCC) is a late consequence of severe liver disease. Patients with genetic hemochromatosis may be at risk for HCC, but limited information is available on the relationship of HCC and heterozygosity for the HFE gene mutations.METHODS:HFE mutations (C282Y and H63D) were assessed in 162 consecutive patients (131 men\\/31 women) with HCC. A total of 159 patients had cirrhosis.

Edmund Cauza; Markus Peck-Radosavljevic; Herbert Ulrich-Pur; Christian Datz; Michael Gschwantler; Maximilian Schöniger-Hekele; Franz Hackl; Claudia Polli; Susanne Rasoul-Rockenschaub; Christian Müller; Friedrich Wrba; Alfred Gangl; Peter Ferenci

2003-01-01

310

Polymorphisms in methylenetetrahydrofolate reductase gene ( MTHFR ) and the age of onset of sporadic colorectal adenocarcinoma  

Microsoft Academic Search

Background and aims  Evidence is accumulating for a role of folate in the aetiology of colorectal cancer (CRC). The methylenetetrahydrofolate reductase\\u000a (MTHFR) gene, involved in folate metabolism, is polymorphic in humans. Since it is unknown whether the MTHFR C677T and A1298C polymorphisms alter the risk for CRC, this was the aim of our study.\\u000a \\u000a \\u000a \\u000a Materials and methods  Genomic DNA from 102 sporadic

Carmen S. P. Lima; Helvia Nascimento; Luciana C. Bonadia; Maria T. Teori; Claudio S. R. Coy; Juvenal R. N. Góes; Fernando F. Costa; Carmen S. Bertuzzo

2007-01-01

311

Methylenetetrahydrofolate reductase gene polymorphisms association with the risk of follicular lymphoma: a meta-analysis.  

PubMed

To date, case-control studies on the association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and follicular lymphoma have provided controversial results. To clarify the effect of MTHFR polymorphisms on the risk of follicular lymphoma, a meta-analysis of all case-control studies was performed. The fixed effects and random effects model showed that the C677T polymorphism was associated with a risk of follicular lymphoma among Caucasian populations, and A1298C polymorphism was associated with a risk of follicular lymphoma among Asian populations. Our pooled data suggest evidence for a major role of MTHFR polymorphisms in the carcinogenesis of follicular lymphoma. PMID:23359274

Xu, Jing-Yan; Sun, Yun-Yu; Zhou, Min; Wang, Jing; Zhang, Qi-Guo; Xu, Xi-Hui; Zeng, Hui; Ouyang, Jian

2013-01-29

312

Mitochondrial DNA depletion and dGK gene mutations.  

PubMed

Mitochondrial DNA depletion syndrome is a clinically heterogeneous group of disorders characterized by a reduction in mitochondrial DNA copy number. The recent discovery of mutations in the deoxyguanosine kinase (dGK) gene in patients with the hepatocerebral form of mitochondrial DNA depletion syndrome prompted us to screen 21 patients to determine the frequency of dGK mutations, further characterize the clinical spectrum, and correlate genotypes with phenotypes. We detected mutations in three patients (14%). One patient had a homozygous GATT duplication (nucleotides 763-766), and another had a homozygous GT deletion (nucleotides 609-610); both mutations lead to truncated proteins. The third patient was a compound heterozygote for two missense mutations (R142K and E227K) that affect critical residues of the protein. These mutations were associated with variable phenotypes, and their low frequencies suggests that dGK is not the only gene responsible for mitochondrial DNA depletion in liver. The patient with the missense mutations had isolated liver failure and responded well to liver transplantation, which may be a therapeutic option in selected cases. PMID:12205643

Salviati, Leonardo; Sacconi, Sabrina; Mancuso, Michelangelo; Otaegui, David; Camaño, Pilar; Marina, Alberto; Rabinowitz, Simon; Shiffman, Rebecca; Thompson, Karen; Wilson, Claire M; Feigenbaum, Annette; Naini, Ali B; Hirano, Michio; Bonilla, Eduardo; DiMauro, Salvatore; Vu, Tuan H

2002-09-01

313

Gene mutations and molecularly targeted therapies in acute myeloid leukemia  

PubMed Central

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

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

2013-01-01

314

Simultaneous mutation scanning for gross deletions, duplications and point mutations in the DMD gene.  

PubMed

We have developed a technique to screen for gross deletions/duplications and point mutations using one streamlined approach. Fluorescent multiplex quantitative PCR is used to determine the copy number of each exon, followed by conformation sensitive capillary electrophoresis (CSCE) of the same PCR products on a multi-capillary genetic analyser. We have developed this technique to screen all 79 exons of one of the largest human genes currently known (dystrophin) using 12 multiplex PCR assays. A blind trial of 50 male and 50 female samples, in which 84 mutations had previously been found and characterized by other techniques, showed 100% sensitivity and specificity. We then applied this method to screen over 100 patient samples previously screened for deletions and duplications of 28 exons from the two hotspot regions. Our data show that combining a full deletion/duplication screen with CSCE will detect a mutation in 98% of Duchenne muscular dystrophy patients and 93% of Becker muscular dystrophy patients where the clinical diagnosis is certain. This technique is applicable to any gene and is particularly suited to mutation screening of large genes, decreasing the time taken for a complete gene screen for nearly all mutation types. PMID:17726484

Ashton, Emma J; Yau, Shu C; Deans, Zandra C; Abbs, Stephen J

2007-08-29

315

Prevalence of haemochromatosis gene mutations in Parkinson's disease  

PubMed Central

The aim of this study was to investigate a possible association between haemochromatosis (HFE) gene mutations and the prevalence of Parkinson's disease. The HFE gene encodes a protein that modulates iron absorption. Several studies have documented increased iron levels in the basal ganglia in patients with Parkinson's disease. In a study on patients with concurrent hereditary haemochromatosis and Parkinson's disease, abnormal deposition of iron in the basal ganglia was suggested as an inductor of Parkinson's disease. In this study, genotype frequencies of the HFE mutations C282Y, H63D and S65C were estimated in 388 patients with Parkinson's disease and compared with frequencies found in comparable studies. No significant differences were found in frequencies between the patients and comparable populations. This study does not indicate increased susceptibility to Parkinson's disease in HFE gene mutation carriers in Norway.

Aamodt, Anne Hege; Stovner, Lars Jacob; Thorstensen, Ketil; Lydersen, Stian; White, Linda R; Aasly, Jan O

2007-01-01

316

Fas and Fas ligand gene mutations in Hashimoto's thyroiditis.  

PubMed

To clarify whether Fas and Fas ligand (FasL) mutations are involved in the pathogenesis of Hashimoto's thyroiditis (HT), we examined the open reading frame of Fas and FasL in 21 cases. Mutations of Fas and FasL genes were detected in 8 (38.1%) and 1 (4.8%) of 21 cases, respectively. All but one of the Fas mutations were frameshift mutations, which affect the cytoplasmic region (death domain) known to be involved in apoptotic signal transduction and thus could be loss-of-function mutations. FasL mutation in one case was a 46-bp deletion from nucleotide 349 to 394, which corresponded to exon 2. Lack of exon 2 results in a frameshift, which generates a stop codon at residue 128. This mutant encodes the protein that contains only a part of the intracellular domain, thus the abnormal protein might not be expressed on the cell surface. The cells with Fas mutations were confined to the mantle zone and the germinal center, as determined by microdissection methods. These findings suggest that the cells with Fas mutations might accumulate in those areas and might be involved in the pathogenesis of Hashimoto's thyroiditis. PMID:12480911

Dong, Zhiming; Takakuwa, Tetsuya; Takayama, Hitoshi; Luo, Wen-Juan; Takano, Toru; Amino, Nobuyuki; Matsuzuka, Fumio; Aozasa, Katsuyuki

2002-12-01

317

Screening for mutations of the apolipoprotein B gene causing hypocholesterolemia  

Microsoft Academic Search

In this study we have performed analyses of apolipoprotein (apo) B at both the protein and gene level to search for mutations\\u000a of the apoB gene causing hypocholesterolemia among 71 Norwegian subjects. None of the subjects possessed apoB of abnormal\\u000a molecular weight as determined by SDS-polyacrylamide gel electrophoresis of lipoproteins in the 1.025 g\\/ml–1.063 g\\/ml density\\u000a range. Screening for mutations

T. P. Leren; Kari S. Bakken; Vigdis Hoel; Ingvar Hjermann; Kåre Berg

1998-01-01

318

Gene conversion: point-mutation heterozygosities lower heteroduplex formation.  

PubMed Central

The effects of heterozygosity on meiotic gene conversion characteristics have been studied in the fungus Ascobolus immersus. The non-Mendelian segregation patterns of seven white ascospore mutants of the b2 gene were established in the presence or the absence of additional neighbouring allelic mutations. These correspond to nine different double mutants with wild-type or pseudo-wild-type phenotypes, constituted by two +1, -1 frameshift mutations of complementary phases. When heterozygous, these double point mutations decrease, by an average of one third, the gene conversion frequencies of the mutants located on their right, toward the low conversion end of the gene. The decrease corresponds either to a reduction in all classes of non-Mendelian segregation (6:2, 5:3 and aberrant 4:4 asci) or to a reduction restricted to the single class of aberrant 4:4 asci. These modifications are explained by changes in hybrid DNA parameter values: frequencies of formation and modalities of distribution (asymmetric versus symmetric ratio). Besides the nature of the non-homology, point mutation versus deletion, which leads to quantitative differential effects, the region where the non-homology is located within the gene also appears to play an important role.

Nicolas, A; Rossignol, J L

1983-01-01

319

An inherited LMNA gene mutation in atypical Progeria syndrome.  

PubMed

Hutchinson-Gilford Progeria syndrome (HGPS) is a rare genetic disorder, characterized by several clinical features that begin in early childhood, recalling an accelerated aging process. The diagnosis of HGPS is based on the recognition of common clinical features and detection of the recurrent heterozygous c.1824C>T (p.Gly608Gly) mutation within exon 11 in the Lamin A/C encoding gene (LMNA). Besides "typical HGPS," several "atypical progeria" syndromes (APS) have been described, in a clinical spectrum ranging from mandibuloacral dysplasia to atypical Werner syndrome. These patients's clinical features include progeroid manifestations, such as short stature, prominent nose, premature graying of hair, partial alopecia, skin atrophy, lipodystrophy, skeletal anomalies, such as mandibular hypoplasia and acroosteolyses, and in some cases severe atherosclerosis with metabolic complications. APS are due in several cases to de novo heterozygous LMNA mutations other than the p.Gly608Gly, or due to homozygous BAFN1 mutations in Nestor-Guillermo Progeria syndrome (NGPS). We report here and discuss the observation of a non-consanguineous Moroccan patient presenting with atypical progeria. The molecular studies showed the heterozygous mutation c.412G>A (p.Glu138Lys) of the LMNA gene. This mutation, previously reported as a de novo mutation, was inherited from the apparently healthy father who showed a somatic cell mosaicism. PMID:22991222

Doubaj, Yassamine; De Sandre-Giovannoli, Annachiara; Vera, Esteves-Vieira; Navarro, Claire Laure; Elalaoui, Siham Chafai; Tajir, Mariam; Lévy, Nicolas; Sefiani, Abdelaziz

2012-09-18

320

MADM methods in solving group decision support system on gene mutations detection simulation  

Microsoft Academic Search

Detection of gene mutation is an activity that can provide contribution in the medical field. Detection of mutated gene is needed to avoid the diseases caused by them such as cancer. The detection of gene mutations can be performed by utilizing computer-based system. Group Decision Support System (GDSS) is a computer-based system that can be utilized in detecting human gene

Ermatita; Sri Hartati; Retantyo Wardoyo; Agus Harjoko

2010-01-01

321

Prothrombotic gene variants as risk factors of acute myocardial infarction in young women  

PubMed Central

Background Acute myocardial infarction (AMI) in young women represent an extreme phenotype associated with a higher mortality compared with similarly aged men. Prothrombotic gene variants could play a role as risk factors for AMI at young age. Methods We studied Factor V Leiden, FII G20210A, MTHFR C677T and beta-fibrinogen -455G>A variants by real-time PCR in 955 young AMI (362 females) and in 698 AMI (245 females) patients. The data were compared to those obtained in 909 unrelated subjects (458 females) from the general population of the same geographical area (southern Italy). Results In young AMI females, the allelic frequency of either FV Leiden and of FII G20210A was significantly higher versus the general population (O.R.: 3.67 for FV Leiden and O.R.: 3.84 for FII G20210A; p<0.001). Among AMI patients we showed only in males that the allelic frequency of the MTHFR C677T variant was significantly higher as compared to the general population. Such difference was due to a significantly higher frequency in AMI males of the MTHFR C677T variant homozygous genotype (O.R. 3.05). Discussion and conclusion Our data confirm that young AMI in females is a peculiar phenotype with specific risk factors as the increased plasma procoagulant activity of FV and FII. On the contrary, the homozygous state for the 677T MTHFR variant may cause increased levels of homocysteine and/or an altered folate status and thus an increased risk for AMI, particularly in males. The knowledge of such risk factors (that may be easily identified by molecular analysis) may help to improve prevention strategies for acute coronary diseases in specific risk-group subjects.

2012-01-01

322

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

PubMed Central

Background Hyperhomocysteinemia (>15 µmol/L) is highly prevalent in South Asian populations including Pakistan. In order to investigate the genetic determinants of this condition, we studied 6 polymorphisms in genes of 3 enzymes - methylenetetrahydrofolate reductase (MTHFR; C677T; A1298C), methionine synthase (MS; A2756G), cystathionine-?-synthase (CBS; T833C/844ins68, G919A) involved in homocysteine metabolism and investigated their interactions with nutritional and environmental factors in a Pakistani population. Methodology/Principal Findings In a cross-sectional survey, 872 healthy adults (355 males and 517 females; age 18–60 years) were recruited from a low-income urban population in Karachi. Fasting venous blood was obtained and assessed for plasma/serum homocysteine; folate, vitamin B12, pyridoxal phosphate and blood lead. DNA was isolated and genotyping was performed by PCR-RFLP (restriction-fragment-length- polymorphism) based assays. The average changes in homocysteine levels for MTHFR 677CT and TT genotypes were positive [?(SE ?), 2.01(0.63) and 16.19(1.8) µmol/L, respectively]. Contrary to MTHFR C677T polymorphism, the average changes in plasma homocysteine levels for MS 2756AG and GG variants were negative [?(SE ?), ?0.56(0.58) and ?0.83(0.99) µmol/L, respectively]. The average change occurring for CBS 844ins68 heterozygous genotype (ancestral/insertion) was ?1.88(0.81) µmol/L. The combined effect of MTHFR C677T, MS A2756G and CBS 844ins68 genotypes for plasma homocysteine levels was additive (p value <0.001). Odds of having hyperhomocysteinemia with MTHFR 677TT genotype was 10-fold compared to MTHFR 677CC genotype [OR (95%CI); 10.17(3.6–28.67)]. Protective effect towards hyperhomocysteinemia was observed with heterozygous (ancestral/insertion) genotype of CBS 844ins68 compared to homozygous ancestral type [OR (95% CI); 0.58 (0.34–0.99)]. Individuals with MTHFR 677CT or TT genotypes were at a greater risk of hyperhomocysteinemia in folate and vitamin B12 deficiencies and high blood lead (p value <0.05) level. Conclusions Gene polymorphism (especially MTHFR C677T transition), folate and vitamin B12 deficiencies, male gender and high blood lead level appear to be contributing towards the development of hyperhomocysteinemia in a Pakistani population.

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

2012-01-01

323

PTPN11 gene mutations: linking the Gln510Glu mutation to the “LEOPARD syndrome phenotype”  

Microsoft Academic Search

We describe the “LEOPARD syndrome (LS) phenotype” associated with the Gln510Glu mutation of the PTPN11 gene in two patients presenting with rapidly progressive severe biventricular obstructive hypertrophic cardiomyopathy and structural abnormalities of the mitral valve, facial anomalies, café-au-lait spots and multiple lentigines.

M. Cristina Digilio; Anna Sarkozy; Giuseppe Pacileo; Giuseppe Limongelli; Bruno Marino; Bruno Dallapiccola

2006-01-01

324

Analysis of mismatch repair gene mutations in Turkish HNPCC patients  

Microsoft Academic Search

Hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome) is caused by the inheritance of a mutant allele of a\\u000a DNA mismatch repair gene. We aimed to investigate types and frequencies of mismatch repair (MMR) gene mutations in Turkish\\u000a patients with HNPCC and to identify specific biomarkers for early diagnosis of their non-symptomatic kindred’s. The molecular\\u000a characteristics of 28 Turkish colorectal

Berrin Tunca; Monica Pedroni; Gulsah Cecener; Unal Egeli; Enrica Borsi; Abdullah Zorluoglu; Carmela Di Gregorio; Tuncay Yilmazlar; Omer Yerci; Maurizio Ponz de Leon

2010-01-01

325

Mutational analysis of X-linked adrenoleukodystrophy gene  

Microsoft Academic Search

X-linked adrenoleukodystrophy (ALD) is an inherited peroxisomal disorder characterized by progressive neurological dysfunction,\\u000a occasionally associated with adrenal insufficiency. The clinical thenotypes of ALD are quite variable, and include childhood\\u000a ALD, adult-onset ALD, adrenomyeloneuropathy, and Addison's disease only. Although the causative gene for ALD has been identified,\\u000a the physiological role of the gene product remains to be clarified. Despite many mutations

Hiroki Takano; Ryoko Koike; Osamu Onodera; Shoji Tsuji

2000-01-01

326

Absence of beta-tubulin gene mutation in gastric carcinoma  

Microsoft Academic Search

Background. Effective chemotherapy for advanced gastric cancer is yet to be established. Taxanes, novel anticancer drugs which bind to beta-tubulin and prevent disruption of microtubules, are newly approved and promising agents for advanced and recurrent gastric cancer. To predict the chemoresistance to a taxan in gastric cancer, we examined the genetic mutations of the beta-tubulin gene. Methods. Fifty pairs of

Naomi Urano; Yoshiyuki Fujiwara; Seiichi Hasegawa; Yasuo Miyoshi; Shinzaburo Noguchi; Shuji Takiguchi; Takushi Yasuda; Masahiko Yano; Morito Monden

2003-01-01

327

Discovery of induced point mutations in maize genes by TILLING  

Microsoft Academic Search

BACKGROUND: Going from a gene sequence to its function in the context of a whole organism requires a strategy for targeting mutations, referred to as reverse genetics. Reverse genetics is highly desirable in the modern genomics era; however, the most powerful methods are generally restricted to a few model organisms. Previously, we introduced a reverse-genetic strategy with the potential for

Bradley J Till; Steven H Reynolds; Clifford Weil; Nathan Springer; Chris Burtner; Kim Young; Elisabeth Bowers; Christine A Codomo; Linda C Enns; Anthony R Odden; Elizabeth A Greene; Luca Comai; Steven Henikoff

2004-01-01

328

Telomere stability genes are not mutated in osteosarcoma cell lines  

Microsoft Academic Search

Osteosarcoma (OS), the most common primary bone tumor in adolescents and young adults, is characterized by a high degree of chromosomal abnormalities. Because telomeres are important for maintaining chromosomal integrity, it is plausible that germ-line or somatic mutations in the genes responsible for stabilizing the telomere complex could contribute to OS. We performed bi-directional sequence analysis in five OS cell

Sharon A. Savage; Brian J. Stewart; Jason S. Liao; Lee J. Helman; Stephen J. Chanock

2005-01-01

329

Phenotypic spectrum associated with mutations of the mitochondrial polymerase   gene  

Microsoft Academic Search

Mutations in the gene coding for the catalytic subunit of the mitochondrial DNA (mtDNA) polymerase g (POLG1) have recently been described in patients with diverse clinical presentations, revealing a complex relationship between genotype and phenotype in patients and their families. POLG1 was sequenced in patients from different European diagnostic and research centres to define the phenotypic spectrum and advance understanding

Rita Horvath; Gavin Hudson; Gianfrancesco Ferrari; Nancy Futterer; Sofia Ahola; Eleonora Lamantea; Holger Prokisch; Hanns Lochmuller; Robert McFarland; V. Ramesh; Thomas Klopstock; Peter Freisinger; Fabrizio Salvi; Johannes A. Mayr; Rene Santer; Marketa Tesarova; Jiri Zeman; Bjarne Udd; Robert W. Taylor; Douglass Turnbull; Michael Hanna; Doreen Fialho; Anu Suomalainen; Massimo Zeviani; Patrick F. Chinnery

2006-01-01

330

Adapting mutations in genetic algorithms using gene flow principles  

Microsoft Academic Search

Bit mutation in genetic algorithms is usually done with a single fixed probability. Methods to adapt this probability have been suggested, but they operate at the genome level. This paper describes a gene level adaption scheme, based on allele frequencies, which gives a better escape from local optima.

Garrison W. Greenwood

2003-01-01

331

Frequency of the HFE Gene Mutations in Five Italian Populations  

Microsoft Academic Search

ABSTRACTGenetic hemochromatosis is an autosomal recessive disorder characterized by iron overload and a variety of clinical manifestations such as liver cirrhosis and arthropathy. It is the most common genetic disease of northern European populations. The principal gene responsible for hereditary hemochromatosis, designated HFE, is located on chromosome 6 in the HLA region. The single point mutation 845A, changing cysteine at

Giuseppina Candore; Vilma Mantovani; Carmela Rita Balistreri; Domenico Lio; Giuseppina Colonna-Romano; Vincenzo Cerreta; Ciriaco Carru; Luca Deiana; Giovanni Pes; Giuseppe Menardi; Laura Perotti; Valeria Miotti; Elena Bevilacqua; Antonio Amoroso; Calogero Caruso

2002-01-01

332

Inactivating mutations of caspase-8 gene in colorectal carcinomas  

Microsoft Academic Search

Background & Aims: There has been evidence that dysregulation of apoptosis is involved in the pathogenesis of cancer development. Caspase-8 is an initiation caspase that activates the caspase cascade during apoptosis. The aim of this study was to explore the possibility that mutation of the caspase-8 gene might be involved in the development of colorectal cancer. Methods: We analyzed the

Hong Sug Kim; Jong Woo Lee; Young Hwa Soung; Won Sang Park; Su Young Kim; Jong Heun Lee; Jik Young Park; Youg Gu Cho; Chang Jae Kim; Seong Whan Jeong; Suk Woo Nam; Sang Ho Kim; Jung Young Lee; Nam Jin Yoo; Sug Hyung Lee

2003-01-01

333

Inactivating mutations of CASPASE7 gene in human cancers  

Microsoft Academic Search

Caspase-7 is a caspase involved in the execution phase of apoptosis. To explore the possibility that the genetic alterations of CASPASE-7 might be involved in the development of human cancers, we analysed the entire coding region and all splice sites of human CASPASE-7 gene for the detection of somatic mutations in a series of human solid cancers, including carcinomas from

Young Hwa Soung; Jong Woo Lee; Hong Sug Kim; Won Sang Park; Su Young Kim; Jong Heun Lee; Jik Young Park; Yong Gu Cho; Chang Jae Kim; Yong Gyu Park; Suk Woo Nam; Seong Whan Jeong; Sang Ho Kim; Jung Young Lee; Nam Jin Yoo; Sug Hyung Lee

2003-01-01

334

Mutations in RNA Binding Protein Gene Cause Familial Dilated Cardiomyopathy  

PubMed Central

Objectives We sought to identify a novel gene for dilated cardiomyopathy (DCM). Background DCM is a heritable, genetically heterogeneous disorder that remains idiopathic in a majority of patients. Familial cases provide an opportunity to discover unsuspected molecular bases of DCM, enabling preclinical risk detection. Methods Two large families with autosomal dominant DCM were studied. Genome-wide linkage analysis was used to identify a disease locus, followed by fine mapping and positional candidate gene sequencing. Mutation scanning was then performed in 278 unrelated subjects with idiopathic DCM, prospectively identified at the Mayo Clinic. Results Overlapping loci for DCM were independently mapped to chromosome 10q25-q26. DNA sequencing of affected individuals in each family revealed distinct heterozygous missense mutations in exon 9 of RBM20, encoding RNA binding motif protein 20. Comprehensive coding sequence analyses identified missense mutations clustered within this same exon in six additional DCM families. Mutations segregated with DCM (composite logarithm of the odds score >11.49), were absent in 480 control samples, and altered residues within a highly conserved arginine/serine (RS)-rich region. Expression of RBM20 messenger RNA was confirmed in human heart tissue. Conclusions Our findings establish RBM20 as a DCM gene and reveal a mutation hotspot in the RS domain. RBM20 is preferentially expressed in the heart and encodes motifs prototypical of spliceosome proteins that regulate alternative pre-mRNA splicing, thus implicating a functionally distinct gene in human cardiomyopathy. RBM20 mutations are associated with young age at diagnosis, end-stage heart failure, and high mortality.

Brauch, Katharine M.; Karst, Margaret L.; Herron, Kathleen J.; de Andrade, Mariza; Pellikka, Patricia A.; Rodeheffer, Richard J.; Michels, Virginia V.; Olson, Timothy M.

2009-01-01

335

Molecular basis of iduronate-2-sulphatase gene mutations in patients with mucopolysaccharidosis type II (Hunter syndrome)  

Microsoft Academic Search

Mucopolysaccharidosis type II (Hunter syndrome) is an X linked lysosomal storage disorder resulting from heterogeneous mutations in the iduronate-2-sulphatase (IDS) gene. To detect IDS gene mutations, direct sequencing of IDS cDNA fragments coupled with assays on IDS genomic amplicons was applied to 18 unrelated patients with MPS II. Seventeen mutations were detected from the 18 patients including seven missense mutations

Peining Li; Amy B Bellows; Jerry N Thompson

1999-01-01

336

Mutation analysis of BRCA1 and BRCA2 genes in Iranian high risk breast cancer families  

Microsoft Academic Search

Purpose: Germline mutations in either BRCA1 or BRCA2 genes are responsible for the majority of hereditary breast and ovarian cancers. At present, over thousand distinct BRCA1 and BRCA2 mutations have been identified. Specific mutations are found to be common within particular populations, resulting from genetic founder effects. To investigate the contribution of germline mutations in these two genes to inherited

Andrea Pietschmann; Parvin Mehdipour; Morteza Atri; Wera Hofmann; S. Said Hosseini-Asl; Siegfried Scherneck; Stefan Mundlos; Hartmut Peters

2005-01-01

337

Mutation analysis of the Ras pathway genes NRAS , HRAS , KRAS and BRAF in glioblastomas  

Microsoft Academic Search

Aberrant activation of Ras signaling is a common finding in human glioblastomas. To determine the contribution of Ras gene mutations to this aberration, we screened 94 glioblastomas for mutations in the three Ras family genes NRAS, KRAS and HRAS. All tumors were additionally analyzed for mutations in BRAF, which encodes a Ras-regulated serine\\/threonine kinase with oncogenic properties. Mutation analysis of

Christiane B. Knobbe; Julia Reifenberger; Guido Reifenberger

2004-01-01

338

Multidrug resistance decreases with mutations of melanosomal regulatory genes.  

PubMed

Whereas resistance to chemotherapy has long impeded effective treatment of metastatic melanoma, the mechanistic basis of this resistance remains unknown. One possible mechanism of drug resistance is alteration of intracellular drug distribution either by drug efflux or sequestration into intracellular organelles. Melanomas, as well as primary melanocytes from which they arise, have intracellular organelles, called melanosomes, wherein the synthesis and storage of the pigment melanin takes place. In this study, comparisons of congenic cells with and without functional molecules regulating melanosome formation show that sensitivity to the chemotherapeutic agent cis-diaminedichloroplatinum II (cis-platin) significantly increases with the mutation of genes regulating melanosome formation, concomitant disruption of melanosome morphology, and loss of mature melanosomes. Absence of the melanosomal structural protein gp100/Pmel17 causes increased cis-platin sensitivity. Independent mutations in three separate genes that regulate melanosome biogenesis (Dtnbp1, Pldn, Vps33a) also result in increased cis-platin sensitivity. In addition, a mutation of the gene encoding the integral melanosomal protein tyrosinase, resulting in aberrant melanosome formation, also causes increased cis-platin sensitivity. Furthermore, sensitivity to agents in other chemotherapeutic classes (e.g., vinblastine and etoposide) also increased with the mutation of Pldn. In contrast, a mutation in another melanosomal regulatory gene, Hps1, minimally affects melanosome biogenesis, preserves the formation of mature melanosomes, and has no effect on cis-platin or vinblastine response. Together, these data provide the first direct evidence that melanosomal regulatory genes influence drug sensitivity and that the presence of mature melanosomes likely contributes to melanoma resistance to therapy. PMID:19155314

Xie, Tong; Nguyen, Thuyen; Hupe, Melanie; Wei, Maria L

2009-01-20

339

Methylenetetrahydrofolate reductase gene, homocysteine and coronary artery disease: the A1298C polymorphism does matter. Inferences from a case study (Madeira, Portugal).  

PubMed

Elevated levels of plasma homocysteine, an independent risk factor and a strong predictor of mortality in patients with coronary artery disease (CAD), can result from nutritional deficiencies or genetic errors, including methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms. The contribution of these polymorphisms in the development of CAD remains controversial. We analysed the impact of MTHFR C677T and A1298C on fasting homocysteine and CAD in 298 CAD patients proved by angiography and 510 control subjects from the Island of Madeira (Portugal). After adjustment for other risk factors, plasma homocysteine remained independently correlated with CAD. Serum homocysteine was significantly higher in individuals with 677TT and 1298AA genotypes. There was no difference in the distribution of MTHFR677 genotypes between cases and controls but a significant increase in 1298AA prevalence was found in CAD patients. In spite of the clear effect of C677T mutation on elevated homocysteine levels we only found an association between 1298AA genotype and CAD in this population. The simultaneous presence of 677CT and 1298AA genotypes provides a significant risk of developing the disease, while the 1298AC genotype, combined with 677CC, shows a significant trend towards a decrease in CAD occurrence. The data shows an independent association between elevated levels of homocysteine and CAD. Both MTHFR polymorphisms are associated with increased fasting homocysteine (677TT and 1298AA genotypes), but only the 1298AA variant shows an increased prevalence in CAD group. Odds ratio seem to indicate that individuals with the MTHFR 1298AA genotype and the 677CT/1298AA compound genotype had a 1.6-fold increased risk for developing CAD suggesting a possible association of MTHFR polymorphisms with the risk of CAD in Madeira population. PMID:18384842

Freitas, Ana I; Mendonça, Isabel; Guerra, Graça; Brión, Maria; Reis, Roberto P; Carracedo, Angel; Brehm, António

2008-04-01

340

Analysis of helicase gene mutations in Japanese Werner’s syndrome patients  

Microsoft Academic Search

The profile of helicase gene mutations was studied in 89 Japanese Werner’s syndrome (WRN) patients by examining the previously\\u000a described mutations 1– 4 as well as a new mutation found during this study, designated mutation 5. Of 178 chromosomes (89\\u000a patients), 89 chromosomes (50%) had mutation 4, 11 (6.2%) chromosomes had mutation 1, and two chromosomes (1.1%) contained\\u000a mutation 5.

Makaoto Goto; Osamu Imamura; Junro Kuromitsu; Takehisa Matsumoto; Yukako Yamabe; Yoshiki Tokutake; Noriyuki Suzuki; Brian Mason; Dennis Drayna; Minoru Sugawara; Masanobu Sugimoto; Yasuhiro Furuichi

1997-01-01

341

Mutations of the tyrosinase gene produce autosomal recessive ocular albinism  

SciTech Connect

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

King, R.A.; Summers, C.G.; Oetting, W.S. [Univ. of Minnesota, Minneapolis, MN (United States)] [and others

1994-09-01

342

FLCN gene-mutated renal cell neoplasms: mother and daughter cases with a novel germline mutation.  

PubMed

Birt-Hogg-Dubé syndrome is a familial genodermatosis, of which patients frequently develop renal neoplasms, fibrofolliculomas and pneumatocele. Here, we report a mother and daughter with renal neoplasms surgically resected (69 and 46 years-of-age at surgery, respectively). The mother's tumor was diagnosed as an unclassified type renal cell carcinoma associated with microscopic tumorous nodules, whereas the daughter's tumor was a hybrid oncocytic/chromophobe tumor. The germline mutation analysis of the responsible gene, FCLN (the folliculin gene), showed a deletion of 18 bp in exon 5 (c.332_349del/p.H111_Q116del), predicting an alteration of the amino acid sequence of "HPSHPQ" replaced by a single amino acid, "L". This is a novel germline mutation of the FCLN gene that has not been previously reported. PMID:22211584

Nagashima, Yoji; Furuya, Mitsuko; Gotohda, Hiroko; Takagi, Seiji; Hes, Ondrej; Michal, Michal; Grossmann, Petr; Tanaka, Reiko; Nakatani, Yukio; Kuroda, Naoto

2011-12-29

343

Mutational analysis of the human MAOA gene  

Microsoft Academic Search

The monoamine oxidases (MAO-A and MAO-B) are the enzymes primarily responsible for the degradation of amine neurotransmitters, such as dopamine, norepinephrine, and serotonin. Wide variations in activity of these isozymes have been reported in control humans. The MAOA and MAOB genes are located next to each other in the p11.3-11.4 region of the human X chromosome. Our recent documentation of

E. A. Tivol; C. Shalish; D. E. Schuback; X. O. Breakefield; Yun-Pung Hsu

1996-01-01

344

Association between MTHFR Gene Polymorphisms and the Risk of Autism Spectrum Disorders: A Meta-Analysis.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) is essential for DNA biosynthesis and the epigenetic process of DNA methylation, and its gene polymorphisms have been implicated as risk factors for birth defects, neurological disorders, and cancers. However, reports on the association of MTHFR polymorphisms with autism spectrum disorders (ASD) are inconclusive. Therefore, we investigated the relationship of the MTHFR polymorphisms (C677T and A1298C) and the risk of ASD by meta-analysis. Up to December 2012, eight case-control studies involving 1672 patients with ASD and 6760 controls were included for meta-analysis. The results showed that the C677T polymorphism was associated with significantly increased ASD risk in all the comparison models [T vs. C allele (frequency of allele): odds ratio (OR)?=?1.42, 95% confidence interval (CI): 1.09-1.85; CT vs. CC (heterozygote): OR?=?1.48, 95% CI: 1.09-2.00; TT vs. CC (homozygote): OR?=?1.86, 95% CI: 1.08-3.20; CT+TT vs. CC (dominant model): OR?=?1.56, 95% CI: 1.12-2.18; and TT vs. CC+CT (recessive model): OR?=?1.51, 95% CI: 1.02-2.22], whereas the A1298C polymorphism was found to be significantly associated with reduced ASD risk but only in a recessive model (CC vs. AA+AC: OR?=?0.73, 95% CI: 0.56-0.97). In addition, we stratified the patient population based on whether they were from a country with food fortification of folic acid or not. The meta-analysis showed that the C677T polymorphism was found to be associated with ASD only in children from countries without food fortification. Our study indicated that the MTHFR C677T polymorphism contributes to increased ASD risk, and periconceptional folic acid may reduce ASD risk in those with MTHFR 677C>T polymorphism. Autism Res 2013, ??: ??-??. © 2013 International Society for Autism Research, Wiley Periodicals, Inc. PMID:23653228

Pu, Danhua; Shen, Yiping; Wu, Jie

2013-05-01

345

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

346

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.

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

2012-01-01

347

A mutation in the enamelin gene in a mouse model.  

PubMed

Amelogenesis imperfecta is an inherited disorder affecting tooth enamel formation. We previously isolated a mouse strain with an amelogenesis imperfecta phenotype (ATE1 mice) from a dominant ethylnitrosourea screen and mapped the disease-causing defect to a 9-cM region of mouse chromosome 5. In the current study, we tested the hypothesis that there is a mutation in enamelin (ENAM) or ameloblastin (AMBN), both of which are located within the linkage region, by sequencing these two candidate genes. Analysis of our data shows that the amelogenesis imperfecta phenotype is linked to a C > T transition in exon 8 of the enamelin gene. The mutation predicts a C826T transition, which is present in the enamelin transcript and changes the glutamine (Gln) codon at position 176 into a premature stop codon (Gln176X). Conversely, no mutation could be detected in the ameloblastin gene. These results define the ATE1 mice as a model for local hypoplastic autosomal-dominant amelogenesis imperfecta (AIH2), which is caused by enamelin truncation mutations in humans. PMID:17652207

Seedorf, H; Klaften, M; Eke, F; Fuchs, H; Seedorf, U; Hrabe de Angelis, M

2007-08-01

348

PEN-2 gene mutation in a familial Alzheimer's disease case.  

PubMed

Genetic evidence indicates a central role of cerebral accumulation of beta-amyloid (Abeta) in the pathogenesis of Alzheimer's disease (AD). Beside presenilin 1 and 2, three other recently discovered proteins (Aph 1, PEN 2 and nicastrin) are associated with gamma-secretase activity, the enzymatic complex generating Abeta. Alterations in genes encoding these proteins were candidates for a role in AD. The PEN 2 gene was examined for unknown mutations and polymorphisms in sporadic and familial Alzheimer patients. Samples from age-matched controls (n=253), sporadic AD (SAD, n=256) and familial AD (FAD, n=140) were screened with DHPLC methodology followed by sequencing. Scanning the gene identified for the first time a missense mutation (D90N) in a patient with FAD. Three intronic polymorphisms were also identified, one of which had a higher presence of the mutated allele in AD subjects carrying the allele epsilon4 of apolipoprotein E than controls. The pathogenic role of the PEN-2 D90N mutation in AD is not clear, but the findings might lead to new studies on its functional and genetic role. PMID:16170650

Sala Frigerio, C; Piscopo, P; Calabrese, E; Crestini, A; Malvezzi Campeggi, L; Civita di Fava, R; Fogliarino, S; Albani, D; Marcon, G; Cherchi, R; Piras, R; Forloni, G; Confaloni, A

2005-03-16

349

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

PubMed

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

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

2010-06-08

350

Meta-analysis of Genetic Studies in Ischemic Stroke: Thirty-two Genes Involving Approximately 18 000 Cases and 58 000 Controls  

Microsoft Academic Search

with ischemic stroke were identified for factor V Leiden Arg506Gln (OR, 1.33; 95% CI, 1.12-1.58), methylenetetrahydrofolate reductase C677T (OR, 1.24; 95% CI, 1.08-1.42), prothrombin G20210A (OR, 1.44; 95% CI, 1.11-1.86), and angiotensin-converting enzyme insertion\\/deletion (OR, 1.21; 95% CI, 1.08-1.35). These were also the most investigated candidate genes, including 4588, 3387, 3028, and 2990 cases, respectively. No statistically significant association with

Juan P. Casas; Aroon D. Hingorani; Leonelo E. Bautista; Pankaj Sharma

2004-01-01

351

Transposon-induced nuclear mutations that alter chloroplast gene expression  

SciTech Connect

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

Barkan, A.

1992-01-01

352

Calpain 3 gene mutations: genetic and clinico-pathologic findings in limb-girdle muscular dystrophy  

Microsoft Academic Search

Mutations in the calpain 3 gene have been proven to be responsible for limb-girdle muscular dystrophy (LGMD) type 2A. To determine the incidence and genotypes of the calpain 3 (p94) gene mutations in Japanese LGMD patients, we sequenced the gene in 80 patients with clinical characteristics of autosomal recessive or sporadic LGMD. We identified 13 distinct pathogenic mutations in 21

Jonghee Chae; Narihiro Minami; Yuko Jin; Masahiro Nakagawa; Kumiko Murayama; Fumie Igarashi; Ikuya Nonaka

2001-01-01

353

Frequent Mutation of the p53 Gene in Human Esophageal Cancer  

Microsoft Academic Search

Sequence alterations in the p53 gene have been detected in human tumors of the brain, breast, lung, and colon, and it has been proposed that p53 mutations spanning a major portion of the coding region inactivate the tumor suppressor function of this gene. To our knowledge, neither transforming mutations in oncogenes nor mutations in tumor suppressor genes have been reported

M. C. Hollstein; R. A. Metcalf; J. A. Welsh; R. Montesano; C. C. Harris

1990-01-01

354

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

355

Heterogeneous AVPR2 gene mutations in congenital nephrogenic diabetes insipidus  

SciTech Connect

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

Wildin, R.S.; Antush, M.J.; Bennett, R.L.; Schoof, J.M.; Scott, C.R. (Univ. of Washington, Seattle, WA (United States))

1994-08-01

356

Mutations in SOHLH1 gene associate with nonobstructive azoospermia.  

PubMed

In a previous study, we found SOHLH1 (spermatogenesis and oogenesis-specific basic helix-loop-helix 1) as the first testis-specific basic helix-loop-helix transcription factor essential for spermatogonial differentiation. SOHLH1 therefore represents an excellent candidate gene for testicular failure such as nonobstructive azoospermia (NOA). We analyzed whether there were mutations in the SOHLH1 gene in 96 Korean patients with NOA. The sequence analysis discovered three novel variations: one intronic variant (c.346-1G>A), and two nonsynonymous exonic variants (c.91T>C and c.529C>A) with known single nucleotide polymorphisms (SNPs), which included six intronic variants, two synonymous, and two nonsynonymous variants. We examined the consequences of mutations in SOHLH1 using in vivo and in vitro assays. Analysis of transcripts from minigenes carrying the c.346-1G>A revealed that splicing site variation leads to the partial deletion at a cryptic splicing site within exon 4. This deletion results in SOHLH1 with a truncated bHLH domain. Transient transfection assay showed that the SOHLH1 mutant with the truncated domain disrupted the transcriptional activity of KIT promoter, whereas two missense mutations harboring either p.Arg37Gln or p.Pro269Ser did not have a significant effect on its transactivation. Our findings indicate that a splice-acceptor site mutation that probably causes a nonfunctional SOHLH1 protein results in nonobstructive azoospermia by the lack of normal spermatogenesis. PMID:20506135

Choi, Youngsok; Jeon, Sanghyun; Choi, Mikyung; Lee, Min-ho; Park, Miseon; Lee, Dong Ryul; Jun, Kyu-Yeon; Kwon, Youngjoo; Lee, Ok-Hee; Song, Seung-Hun; Kim, Ji-Young; Lee, Kyung-Ah; Yoon, Tae Ki; Rajkovic, Aleksandar; Shim, Sung Han

2010-07-01

357

Mutational analysis of the BRAF gene in human tumor cells.  

PubMed

Genes of the RAF family, which mediate cellular responses to growth signals, encode kinases that are regulated by RAS and participate in the RAS, RAF, mitogen/extracellular signal-regulated kinase, extracellular signal-regulated kinase and mitogen-activated protein kinase pathway. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation, it may provide possible diagnostic and therapeutic targets in human malignant tumors. We analyzed exon 15 of the BRAF gene for mutations in 58 lung, 12 breast, six kidney, 14 cervical, four endometrial and 10 ovarian carcinoma cell lines by PCR-SSCP and direct sequencing. The T1796A transversion was found in one (2.9%) of 34 small cell lung carcinoma and one (8.3%) of 12 breast carcinoma cell lines, resulting in a valine-to-glutamate substitution at residue 599 (V599E). One (4.2%) of 24 non-small cell lung carcinoma cell line showed the C1786G transversion, leading to a leucine-to-valine substitution at residue 596 (L596V). No BRAF point mutations were found in any of the other cell lines examined. Our present results suggest that BRAF may not be a frequent target of mutations involved in the pathogenesis of human lung, breast, kidney, cervical, endometrial and ovarian carcinomas. PMID:18397470

Ueda, Masatsugu; Toji, Eisaku; Nunobiki, Osamu; Izuma, Shinji; Okamoto, Yoshiaki; Torii, Kiyo; Noda, Sadamu

2008-05-01

358

Mutational analysis of the GALT gene in filipino patients.  

PubMed

Classic galactosemia is an inherited metabolic disorder due to mutations in the galactose-1-phosphate uridyltransferase (GALT) gene. This study describes the results of the GALT gene analysis of four unrelated Filipino patients with Classic Galactosemia. DNA extracted from dried blood spots and peripheral blood of the patients, age one month to two and a half years, underwent PCR-amplification with subsequent bidirectional sequencing of all eleven exons with their flanking intronic regions following standard protocols. Clinical data of these patients were reviewed. The patients presented with jaundice, hepatomegaly, diarrhea, vomiting, poor feeding and seizures during their neonatal period. They were diagnosed with elevated blood galactose and galactose-1-phosphate and absent GALT activity. Four missense mutations were found wherein two were previously reported (p.V168L and p.A345D) and two were novel (p.L116P and p.M178R). The most frequent mutation in our cohort is p.V168L. This study suggests that GALT mutations are ethnic-specific and that galactosemia is a heterogeneous disorder at the molecular level. The importance of early detection, immediate and proper medical management and genetic counseling of the patients and their families cannot be overemphasized. PMID:24045215

Estrada, Sylvia C; Canson, Daffodil M; Silao, Catherine Lynn T

2013-08-09

359

Spontaneous Mutation in the Escherichia Coli Laci Gene  

PubMed Central

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

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

1991-01-01

360

Mutational analysis of ATP7B gene in Egyptian children with Wilson disease: 12 novel mutations  

Microsoft Academic Search

The aim of this work was to study the mutations within ATP7B in Egyptian children with Wilson disease and to evaluate any potential correlation between genotype and phenotype in this\\u000a cohort. The study consisted of 48 children with Wilson disease from 32 independent families. The 21 exons of the ATP7B gene were amplified in a thermal cycler. Direct sequencing of

Tawhida Y. Abdelghaffar; Solaf M. Elsayed; Ezzat Elsobky; Bettina Bochow; Janine Büttner; Hartmut Schmidt

2008-01-01

361

Mutations and expressions of the tropomyosin gene and the troponin C gene of Caenorhabditis elegans.  

PubMed

How does muscle gene mutation affect the muscle structure and function of an animal? Mutant animals of the tropomyosin and troponin C genes of Caenorhabditis elegans show Pat (paralyzed, arrested elongation at twofold) phenotypes together with abnormal muscle filament assembly. We present evidence that the mutation sites of lev-11 gene was in the tropomyosin gene, tmy-1 and that of pat-10 was in the troponin C gene, tnc-1, of the worm, respectively. The lev-11 (st557) mutation occurred at the splice donor site of exon 1 and results in translation termination. Although the gene product from heterozygous (+/st557) animal was not detected, our result could be the reason for the Pat phenotype of this mutation. The lev-11(x12) mutation, isolated as an allele of levamisole resistance, occurred in exon 7 and results in amino acid substitution at 234 from Glu to Lys. This substitution give a charge change from - to + at this point which is common in three isoforms. There may be functional importance of this region for molecular interaction of the tropomyosin. Mutation site of pat-10(st575) was Asp64 to Asn and Trp153 to termination in the troponin C. The first mutation site was in the second calcium binding site and the second mutation raised the deletion of H helix in the troponin C. Both might affect the calcium binding or the retaining of the conformation for its function. Results presented here will be useful to understand the interaction site between the tropomyosin and troponin complex. PMID:9113409

Kagawa, H; Takuwa, K; Sakube, Y

1997-02-01

362

Unverricht-Lundborg disease: homozygosity for a new splicing mutation in the cystatin B gene.  

PubMed

Unverricht-Lundborg disease is the most common form of progressive myoclonic epilepsy (PME). It is due to cystatin B gene (CSTB) mutations. Several mutations in CSTB gene have been published, but few in homozygosity. We describe a patient with a new splicing alteration. Mutation Gln22Gln leads to abnormal splicing and partial inclusion of intronic sequence. This is one of the few cases of homozygosity for a non-classic mutation and adds to mutational heterogeneity of CSTB. PMID:22154554

Pinto, Eugénia; Freitas, Joel; Duarte, Ana Joana; Ribeiro, Isaura; Ribeiro, Diogo; Lima, J Lopes; Chaves, João; Amaral, Olga

2011-12-10

363

TGFBI gene mutations in Brazilian patients with corneal dystrophy  

Microsoft Academic Search

PurposeTo investigate the transforming growth factor beta-induced gene (TGFBI) mutations in Brazilian patients with corneal dystrophy and to evaluate the phenotype–genotype correlation in these patients.MethodsA total of 11 unrelated families were studied. The diagnosis of corneal dystrophy was based on clinical and histopathological findings. Genomic DNA was extracted from peripheral blood leucocytes, and exons 4 and 12 of the TGFBIgene

H P Solari; M P Ventura; A B A Perez; J M F Sallum; M N Burnier; R Belfort

2007-01-01

364

Mutational analysis of the BRAF gene in human tumor cells  

Microsoft Academic Search

Genes of the RAF family, which mediate cellular responses to growth signals, encode kinases that are regulated by RAS and\\u000a participate in the RAS, RAF, mitogen\\/extracellular signal-regulated kinase, extracellular signal-regulated kinase and mitogen-activated\\u000a protein kinase pathway. As BRAF is a serine\\/threonine kinase that is commonly activated by somatic point mutation, it may\\u000a provide possible diagnostic and therapeutic targets in human

Masatsugu Ueda; Eisaku Toji; Osamu Nunobiki; Shinji Izuma; Yoshiaki Okamoto; Kiyo Torii; Sadamu Noda

2008-01-01

365

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

366

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

367

Tau gene mutation in familial progressive subcortical gliosis  

Microsoft Academic Search

Familial forms of frontotemporal dementias are associated with mutations in the tau gene. A kindred affected by progressive subcortical gliosis (PSG), a rare form of presenile dementia, has genetic linkage to chromosome 17q21-22 (refs. 1,2, 3). This kindred (PSG-1) is included in the 'frontotemporal dementias and Parkinsonism linked to chromosome 17' group along with kindreds affected by apparently different forms

M. G. Spillantini; R. A. Crowther; S. G. Chen; P. Parchi; M. Tabaton; D. J. Lanska; W. R. Markesbery; K. C. Wilhelmsen; D. W. Dickson; R. B. Petersen; M. Goedert; P. Gambetti

1999-01-01

368

Oncological implications of RET gene mutations in Hirschsprung's disease  

Microsoft Academic Search

Background—Germline mutations of the RET proto-oncogene identical to those found in the tumour predisposition syn- drome multiple endocrine neoplasia type 2A (MEN2A), were detected in 2.5-5% of sporadic and familial cases of Hirschs- prung's disease. Some patients with Hir- schsprung's disease may therefore be exposed to a highly increased risk of tumours. Aims—To define clinical use of RET gene testing

R. H. Sijmons; R. M. W. Hofstra; F. A. Wijburg; T. P. Links; R. P. Zwierstra; A. Vermey; D. C. Aronson; G. Tan-Sindhunata; G. J. Brouwers-Smalbraak; S. M. Maas; C. H. C. M. Buys

1998-01-01

369

Frequencies in the Japanese Population of HFE Gene Mutations  

Microsoft Academic Search

We studied the frequencies of C282Y and H63Dmutations in the HFE gene, thought to be responsible forhereditary hemochromatosis (HH), in 504 chromosomesobtained from 252 unrelated Japanese. Allele-specific PCR and PCRrestriction fragment lengthpolymorphism methods revealed that the C282Y mutationwas not found and the H63D mutation was low in frequency(at only 0.99%) compared with data from European people. Since most HH is

Tetsuro Sohda; Junichi Yanai; Hidenobu Soejima; Kazuo Tamura

1999-01-01

370

Frequent Mutations of Fas Gene in Thyroid Lymphoma1  

Microsoft Academic Search

Fas (Apo-1\\/CD95) is a cell-surface receptor involved in cell death signaling through binding of Fas ligand. Mutation of the Fas gene results in accumulation of lymphoid cells and thus might contribute to lym- phomagenesis. Thyroid lymphoma (TL) is supposed to arise from active lymphoid cells formed in the preceding autoimmune chronic lymphocytic thyroiditis (CLTH). We examined the open reading frame

Tetsuya Takakuwa; Zhiming Dong; Hitoshi Takayama; Fumio Matsuzuka; Shigekazu Nagata; Katsuyuki Aozasa

2001-01-01

371

Mutations in the Pericentrin (PCNT) Gene Cause Primordial Dwarfism  

Microsoft Academic Search

Fundamental processes influencing human growth can be revealed by studying extreme short stature. Using genetic linkage analysis, we find that biallelic loss-of-function mutations in the centrosomal pericentrin (PCNT) gene on chromosome 21q22.3 cause microcephalic osteodysplastic primordial dwarfism type II (MOPD II) in 25 patients. Adults with this rare inherited condition have an average height of 100 centimeters and a brain

Anita Rauch; Christian T. Thiel; Detlev Schindler; Ursula Wick; Yanick J. Crow; Arif B. Ekici; Anthonie J. van Essen; Timm O. Goecke; Lihadh Al-Gazali; Krystyna H. Chrzanowska; Christiane Zweier; Han G. Brunner; Kristin Becker; Cynthia J. Curry; Bruno Dallapiccola; Koenraad Devriendt; Arnd Dörfler; Esther Kinning; André Megarbane; Peter Meinecke; Robert K. Semple; Stephanie Spranger; Annick Toutain; Richard C. Trembath; Egbert Voss; Louise Wilson; Raoul Hennekam; Francis de Zegher; Helmuth-Günther Dörr; André Reis

2008-01-01

372

Mutational analysis of the adeno-associated virus rep gene.  

PubMed Central

The replication (rep) gene of the human parvovirus adeno-associated virus (AAV) is a pleiotropic effector of numerous viral functions and experts profound effects on cellular transformation. Of the four Rep proteins, the primarily nuclear Rep78 and Rep68 direct AAV DNA replication, trans activation of the capsid (cap) gene promoter, and inhibition of cellular proliferation mediated by various oncogenes. In an initial attempt to define functional domains in Rep78, we have constructed a comprehensive set of XhoI linker insertion and deletion mutations in the rep gene. Each of the mutant genes has been expressed in cell culture and assayed for the following functions: (i) nuclear localization, (ii) AAV DNA replication, (iii) trans activation of the AAV capsid gene transcription promoter, and (iv) suppression of cellular transformation mediated by the adenovirus E1a and an activated ras oncogene pair. Modest disruptions in the normal conformation of Rep78 inactivated its AAV DNA replication function and trans activation of the cap gene promoter. Linker insertion mutations in the amino-terminal one-third of the protein inactivated Rep78's ability to suppress oncogene-mediated cellular transformation. The transformation suppression domains are not limited to the amino-terminal regions, however, since deletions throughout the protein altered its suppression capabilities. A putative nuclear localization signal that is essential for each of the above functions was found in the Rep proteins. These results provide a preliminary screening of the functional domains in the AAV Rep proteins and pave the way for more subtle mutational analysis. Images

Yang, Q; Kadam, A; Trempe, J P

1992-01-01

373

Kinetochore KMN network gene CASC5 mutated in primary microcephaly.  

PubMed

Several genes expressed at the centrosome or spindle pole have been reported to underlie autosomal recessive primary microcephaly (MCPH), a neurodevelopmental disorder consisting of an important brain size reduction present since birth, associated with mild-to-moderate mental handicap and no other neurological feature nor associated malformation. Here, we report a mutation of CASC5 (aka Blinkin, or KNL1, or hSPC105) in MCPH patients from three consanguineous families, in one of which we initially reported the MCPH4 locus. The combined logarithm of odds score of the three families was >6. All patients shared a very rare homozygous mutation of CASC5. The mutation induced skipping of exon 18 with subsequent frameshift and truncation of the predicted protein. CASC5 is part of the KMN network of the kinetochore and is required for proper microtubule attachment to the chromosome centromere and for spindle-assembly checkpoint (SAC) activation during mitosis. Like MCPH gene ASPM, CASC5 is upregulated in the ventricular zone (VZ) of the human fetal brain. CASC5 binds BUB1, BUBR1, ZWINT-1 and interestingly it binds to MIS12 through a protein domain which is truncated by the mutation. CASC5 localized at the equatorial plate like ZWINT-1 and BUBR1, while ASPM, CEP152 and PCTN localized at the spindle poles in our patients and in controls. Comparison of primate and rodent lineages indicates accelerated evolution of CASC5 in the human lineage. Our data provide strong evidence for CASC5 as a novel MCPH gene, and underscore the role of kinetochore integrity in proper volumetric development of the human brain. PMID:22983954

Genin, Anne; Desir, Julie; Lambert, Nelle; Biervliet, Martine; Van Der Aa, Nathalie; Pierquin, Genevieve; Killian, Audrey; Tosi, Mario; Urbina, Montse; Lefort, Anne; Libert, Frederick; Pirson, Isabelle; Abramowicz, Marc

2012-09-13

374

Somatic mutations in the transcriptional corepressor gene BCORL1 in adult acute myelogenous leukemia  

PubMed Central

To further our understanding of the genetic basis of acute myelogenous leukemia (AML), we determined the coding exon sequences of ? 18 000 protein-encoding genes in 8 patients with secondary AML. Here we report the discovery of novel somatic mutations in the transcriptional corepressor gene BCORL1 that is located on the X-chromosome. Analysis of BCORL1 in an unselected cohort of 173 AML patients identified a total of 10 mutated cases (6%) with BCORL1 mutations, whereas analysis of 19 AML cell lines uncovered 4 (21%) BCORL1 mutated cell lines. The majority (87%) of the mutations in BCORL1 were predicted to inactivate the gene product as a result of nonsense mutations, splice site mutation, or out-of-frame insertions or deletions. These results indicate that BCORL1 by genetic criteria is a novel candidate tumor suppressor gene, joining the growing list of genes recurrently mutated in AML.

Li, Meng; Collins, Roxane; Jiao, Yuchen; Ouillette, Peter; Bixby, Dale; Erba, Harry; Vogelstein, Bert; Kinzler, Kenneth W.

2011-01-01

375

A substitution mutation in the myosin binding protein C gene in ragdoll hypertrophic cardiomyopathy.  

PubMed

Familial hypertrophic cardiomyopathy (HCM) is a primary myocardial disease with a prevalence of 1 in 500 in human beings. Causative mutations have been identified in several sarcomeric genes, including the cardiac myosin binding protein C (MYBPC3) gene. Heritable HCM also exists in a large-animal model, the cat, and we have previously reported a mutation in the MYBPC3 gene in the Maine coon breed. We now report a separate mutation in the MYBPC3 gene in ragdoll cats with HCM. The mutation changes a conserved arginine to tryptophan and appears to alter the protein structure. The ragdoll is not related to the Maine coon and the mutation identified is in a domain different from that of the previously identified feline mutation. The identification of two separate mutations within this gene in unrelated breeds suggests that these mutations occurred independently rather than being passed on from a common founder. PMID:17521870

Meurs, Kathryn M; Norgard, Michelle M; Ederer, Martina M; Hendrix, Kristina P; Kittleson, Mark D

2007-05-22

376

Clinical and Neuropathological Features of the Arctic APP Gene Mutation Causing Early-Onset Alzheimer Disease  

Microsoft Academic Search

Background: A majority of mutations within the - amyloid region of the amyloid precursor protein (APP) gene cause inherited forms of intracerebral hemor- rhage. Most of these mutations may also cause cognitive impairment, but the Arctic APP mutation is the only known intra--amyloid mutation to date causing the more typical clinical picture of Alzheimer disease. Objective: To describe features of

Hans Basun; Nenad Bogdanovic; Martin Ingelsson; Ove Almkvist; Jan Naslund; Karin Axelman; Thomas D. Bird; David Nochlin; Gerard D. Schellenberg; Lars-Olof Wahlund; Lars Lannfelt

2008-01-01

377

Epidermal growth factor receptor gene mutations in atypical adenomatous hyperplasias of the lung  

Microsoft Academic Search

Activating epidermal growth factor receptor (EGFR) gene mutations are frequently detected in lung adenocarcinomas, especially adenocarcinomas with a nonmucinous bronchioloalveolar carcinoma component. EGFR-mutated lung adenocarcinomas respond well to EGFR tyrosine kinase inhibitors. We previously found that most (88%) pure nonmucinous bronchioloalveolar carcinomas (adenocarcinoma in situ) already harbor EGFR mutations, indicating that the mutations are an early genetic event in the

Yuji Sakuma; Shoichi Matsukuma; Mitsuyo Yoshihara; Yoshiyasu Nakamura; Haruhiko Nakayama; Yoichi Kameda; Eiju Tsuchiya; Yohei Miyagi

2007-01-01

378

Mutational analysis of the amyloid precursor protein gene in Japanese familial Alzheimer's disease kindreds  

Microsoft Academic Search

We sequenced the entire coding region of the amyloid precursor protein (APP) genes of 11 unrelated patients with Japanese familial Alzheimer's disease (FAD) in order to determine the exact frequency of known APP gene mutations and to search for novel mutations responsible for FAD. Three out of 11 (27.3%) FAD patients showed the known Val to Ile mis-sense mutation at

Hiroto Fujigasaki; Satoshi Naruse; Kiyotoshi Kaneko; Hideto Hirasawa; Shoji Tsuji; Tadashi Miyatake

1994-01-01

379

A new Thr49Pro transthyretin gene mutation associated with leptomeningeal amyloidosis  

Microsoft Academic Search

Leptomeningeal amyloidosis is a rare central nervous system manifestation of systemic amyloidosis from transthyretin (TTR) mutation. Ten TTR gene mutations associated with this condition have been described. We report the clinical, radiological, and pathological features of a case of leptomeningeal amyloidosis from a novel Thr49Pro TTR gene mutation. A 53 year-old man presented with recurrent episodes of transient aphasia and

Kazuma Nakagawa; Sarah I. Sheikh; Matija Snuderl; Matthew P. Frosch; Steven M. Greenberg

2008-01-01

380

Spectrum of mutations in the Fanconi anaemia group G gene, FANCG\\/XRCC9  

Microsoft Academic Search

FANCG was the third Faconi anaemia gene identified and proved to be identical to the previously cloned XRCC9 gene. We present the pathogenic mutations and sequence variants we have so far identified in a panel of FA-G patients. Mutation screening was performed by PCR, single strand conformational polymorphism analysis and protein truncation tests. Altogether 18 mutations have been determined in

Ilja Demuth; Marcin Wlodarski; Alex J Tipping; Neil V Morgan; Johan P de Winter; Michaela Thiel; Sonja Gräsl; Detlev Schindler; Alan D D'Andrea; Cigdem Altay; Hülya Kayserili; Adriana Zatterale; Jürgen Kunze; Wolfram Ebell; Christopher G Mathew; Hans Joenje; Karl Sperling; Martin Digweed

2000-01-01

381

Prognostic significance of p53 gene mutations in squamous cell carcinoma of the lung.  

PubMed

The aim of the present study was to analyze the prevalence and clinical importance of p53 gene mutations in surgically treated squamous cell lung carcinoma. Sixty patients were included. Fifty-one patients in stages I to IIIa were submitted to radical resection. Twenty-five samples tested positive for the p53 immunohistochemistry assay, and were analyzed for p53 gene mutations. Eleven mutations were found. Patients harboring p53 gene mutations suffered a higher incidence of recurrence and a higher mortality rate. Disease-free interval and overall survival were shorter for patients with mutated p53 gene (p=0.03 and p=0.005, respectively). PMID:9683822

Sánchez-Pernaute, A; Torres, A; Iniesta, P; Hernando, F; Gómez, A; González, O; De Juan, C; Pérez-Aguirre, E; Maestro, M L; López-Asenjo, J A; Benito, M; Balibrea, J L

382

BSE Case Associated with Prion Protein Gene Mutation  

PubMed Central

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

Richt, Jurgen A.; Hall, S. Mark

2008-01-01

383

Molecular Basis of Human CD36 Gene Mutations  

PubMed Central

CD36 is a transmembrane glycoprotein of the class B scavenger receptor family. The CD36 gene is located on chromosome 7 q11.2 and is encoded by 15 exons. Defective CD36 is a likely candidate gene for impaired fatty acid metabolism, glucose intolerance, atherosclerosis, arterial hypertension, diabetes, cardiomyopathy, Alzheimer disease, and modification of the clinical course of malaria. Contradictory data concerning the effects of antiatherosclerotic drugs on CD36 expression indicate that further investigation of the role of CD36 in the development of atherosclerosis may be important for the prevention and treatment of this disease. This review summarizes current knowledge of CD36 gene structure, splicing, and mutations and the molecular, metabolic, and clinical consequences of these phenomena.

Rac, Monika Ewa; Safranow, Krzysztof; Poncyljusz, Wojciech

2007-01-01

384

Novel CFTR gene mutation in a patient with CBAVD.  

PubMed

We report a novel mutation detected in a 33 year old Chinese man with congenital bilateral absence of the vas deferens (CBAVD), a past history of pulmonary meliodosis infection and a past history of bronchiolitis obliterans organising pneumonia. A novel splice site mutation in intron 6b (1001+5 G-->A) in the homozygous state was identified, and was predicted to lead to inefficient splicing. He was also homozygous at all intragenic and flanking polymorphic markers. Quantitative realtime PCR analysis showed that there were 2 copies of the CFTR gene present, ruling out the possibility of a deletion, and strongly suggesting the possibility of uniparental isodisomy involving at least a part of chromosome 7. PMID:17398169

Goh, Denise L M; Zhou, Youyou; Chong, Samuel S; Ngiam, Nicola S P; Goh, Daniel Y T

2007-03-29

385

Optimal control of gene mutation in DNA replication.  

PubMed

We propose a molecular-level control system view of the gene mutations in DNA replication from the finite field concept. By treating DNA sequences as state variables, chemical mutagens and radiation as control inputs, one cell cycle as a step increment, and the measurements of the resulting DNA sequence as outputs, we derive system equations for both deterministic and stochastic discrete-time, finite-state systems of different scales. Defining the cost function as a summation of the costs of applying mutagens and the off-trajectory penalty, we solve the deterministic and stochastic optimal control problems by dynamic programming algorithm. In addition, given that the system is completely controllable, we find that the global optimum of both base-to-base and codon-to-codon deterministic mutations can always be achieved within a finite number of steps. PMID:22454557

Yu, Juanyi; Li, Jr-Shin; Tarn, Tzyh-Jong

2012-01-22

386

Simultaneous mutation detection of three homoeologous genes in wheat by High Resolution Melting analysis and Mutation Surveyor®  

Microsoft Academic Search

BACKGROUND: TILLING (Targeting Induced Local Lesions IN Genomes) is a powerful tool for reverse genetics, combining traditional chemical mutagenesis with high-throughput PCR-based mutation detection to discover induced mutations that alter protein function. The most popular mutation detection method for TILLING is a mismatch cleavage assay using the endonuclease CelI. For this method, locus-specific PCR is essential. Most wheat genes are

Chongmei Dong; Kate Vincent; Peter Sharp

2009-01-01

387

Four novel and three recurrent mutations of the BTK gene and pathogenic effects of putative splice mutations  

Microsoft Academic Search

X-linked agammaglobulinemia is caused by mutations in the human BTK gene, leading to recurrent pyogenic infections. We describe four novel and three known BTK-mutations in seven patients from seven (six Thai and one Burmese) families. All but one were sporadic cases. Patients 1 and 2 had recurrent mutations in exon 10 (R288W) and exon 17 (R562W), respectively. Patient 3, a previously healthy

Duangrurdee Wattanasirichaigoon; Suwat Benjaponpitak; Chonnamet Techasaensiri; Wasu Kamchaisatian; Pakit Vichyanond; Sucheela Janwityanujit; Lulin Choubtum; Sayomporn Sirinavin

2006-01-01

388

Influence of missense mutation and silent mutation of LH?-subunit gene in Japanese patients with ovulatory disorders  

Microsoft Academic Search

The frequency of variant LH? containing two point mutations (T986–C and T1008–C) and its relationship to reproductive disorders differ widely between ethnic groups. In a Japanese population, variant luteinizing hormone (LH) correlates with ovulatory disorders. Here we examined the relationship between two missense mutations and five silent mutations (C894–T, G1018–C, C1036–A, C1098-T and C1423–T) in the LH? gene, and ovulatory

Kentaro Takahashi; Kenji Karino; Haruhiko Kanasaki; Hiroko Kurioka; Tomoya Ozaki; Toshie Yonehara; Kohji Miyazaki

2003-01-01

389

Horizontal gene transfer and mutation: Ngrol genes in the genome of Nicotiana glauca  

PubMed Central

Ngrol genes (NgrolB, NgrolC, NgORF13, and NgORF14) that are similar in sequence to genes in the left transferred DNA (TL-DNA) of Agrobacterium rhizogenes have been found in the genome of untransformed plants of Nicotiana glauca. It has been suggested that a bacterial infection resulted in transformation of Ngrol genes early in the evolution of the genus Nicotiana. Although the corresponding four rol genes in TL-DNA provoked hairy-root syndrome in plants, present-day N. glauca and plants transformed with Ngrol genes did not exhibit this phenotype. Sequenced complementation analysis revealed that the NgrolB gene did not induce adventitious roots because it contained two point mutations. Single-base site-directed mutagenesis at these two positions restored the capacity for root induction to the NgrolB gene. When the NgrolB, with these two base substitutions, was positioned under the control of the cauliflower mosaic virus 35S promoter (P35S), transgenic tobacco plants exhibited morphological abnormalities that were not observed in P35s-RirolB plants. In contrast, the activity of the NgrolC gene may have been conserved after an ancient infection by bacteria. Discussed is the effect of the horizontal gene transfer of the Ngrol genes and mutations in the NgrolB gene on the phenotype of ancient plants during the evolution of N. glauca.

Aoki, Seishiro; Syono, Kunihiko

1999-01-01

390

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

Code of Federal Regulations, 2013 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,â Mutation Research,...

2013-07-01

391

Novel MEK1 Mutation Identified by Mutational Analysis of Epidermal Growth Factor Receptor Signaling Pathway Genes in Lung Adenocarcinoma  

Microsoft Academic Search

Genetic lesions affecting a number of kinases and other elements within the epidermal growth factor receptor (EGFR) signaling pathway have been implicated in the pathogenesis of human non-small-cell lung cancer (NSCLC). We performed mutational profiling of a large cohort of lung adenocarcino- mas to uncover other potential somatic mutations in genes of this pathway that could contribute to lung tumorigenesis.

Dhananjay Chitale; Ben Golas; Michael D. McLellan; Yumi Kasai; Elaine R. Mardis; Richard K. Wilson; David Solit; Ross Levine; Kathrin Michel; Roman K. Thomas; Valerie W. Rusch; Marc Ladanyi; William Pao

392

Screening for mutations in Spanish families with myotonia. Functional analysis of novel mutations in CLCN1 gene.  

PubMed

Myotonia congenita is an inherited muscle disorder caused by mutations in the CLCN1 gene, a voltage-gated chloride channel of skeletal muscle. We have studied 48 families with myotonia, 32 out of them carrying mutations in CLCN1 gene and eight carry mutations in SCN4A gene. We have found 26 different mutations in CLCN1 gene, including 13 not reported previously. Among those 26 mutations, c.180+3A>T in intron 1 is present in nearly one half of the Spanish families in this series, the largest one analyzed in Spain so far. Although scarce data have been published on the frequency of mutation c.180+3A>T in other populations, our data suggest that this mutation is more frequent in Spain than in other European populations. In addition, expression in HEK293 cells of the new missense mutants Tyr137Asp, Gly230Val, Gly233Val, Tyr302His, Gly416Glu, Arg421Cys, Asn567Lys and Gln788Pro, demonstrated that these DNA variants are disease-causing mutations that abrogate chloride currents. PMID:22094069

Mazón, María J; Barros, Francisco; De la Peña, Pilar; Quesada, Juan F; Escudero, Adela; Cobo, Ana M; Pascual-Pascual, Samuel I; Gutiérrez-Rivas, Eduardo; Guillén, Encarna; Arpa, Javier; Eraso, Pilar; Portillo, Francisco; Molano, Jesús

2011-11-16

393

Adaptive evolution by mutations in the FLO11 gene  

PubMed Central

In nature, Saccharomyces yeasts manifest a number of adaptive responses to overcome adverse environments such as filamentation, invasive growth, flocculation and adherence to solid surfaces. Certain Saccharomyces wild yeasts, namely “flor yeasts,” have also acquired the ability to form a buoyant biofilm at the broth surface. Here we report that mutations in a single gene, identified as FLO11, separate these “floating” yeasts from their nonfloating relatives. We have determined that the capability to form a self-supporting biofilm at the liquid surface is largely dependent on two changes in the FLO11 gene. First, we identified a 111-nt deletion within a repression region of the FLO11 promoter that significantly increases FLO11 gene expression. Secondly, we found rearrangements within the central tandem repeat domain of the coding region that yield a more hydrophobic Flo11p variant. Together, these mutations result in dramatic increase in cell surface hydrophobicity, which in turn confers these yeasts the ability to float by surface tension, an adaptive mechanism to gain direct access to oxygen within oxygen-poor liquid environments.

Fidalgo, Manuel; Barrales, Ramon R.; Ibeas, Jose I.; Jimenez, Juan

2006-01-01

394

Polymorphism analysis of MTHFR, factor II, and factor V genes in the Pomeranian population of Espirito Santo, Brazil.  

PubMed

Pomeranian populations worldwide immigrated originally from the north of Europe, and because of their preferential marriage, religion, and cultural habits, they show little or no reproductive mixing with local populations. Methylenetetrahydrofolate reductase gene (MTHFR) C677T, Factor V Leiden, and Factor II G20210A polymorphisms are linked to augmented clotting and their frequencies may vary according to population ethnicity. We aimed to assess the frequencies of these thrombophilic alleles in the Pomeranian population residing in Espirito Santo and compare with the general population of the Espirito Santo state, Brazil. A total of 200 individuals were analyzed. The intrapopulation fixation index of the MTHFR C677T polymorphism was 0.03736. The observed heterozygosity was 0.44 and 0.4 for the general and Pomeranian populations, respectively. According to the chi-square test, both populations are in Hardy-Weinberg equilibrium. Four polymorphic alleles were detected for Factor II (2.02%) and 8 for Factor V (4.81%). Our results show that there is gene flow between the general and the Pomeranian population of Espirito Santo, which should no longer be considered an isolated population. PMID:21919702

Stur, Elaine; Silveira, Amanda Nunes; Selvatici, Livia Serra; Alves, Lyvia Neves Rebello; de Vargas Wolfgramm, Eldamária; Tovar, Thaís Tristão; De Nadai Sartori, Mariana Penha; de Paula, Flavia; Louro, Iuri Drumond

2011-09-15

395