A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase

@article{Frosst1995ACG,
  title={A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase},
  author={Phyllis D Frosst and Henk J Blom and Renate Milos and P. Goyette and Christal A. Sheppard and Rowena G. Matthews and Godfried H. J. Boers and Martin den Heijer and Leo A. J. Kluijtmans and L. P. van den Heuve and Rima Rozen},
  journal={Nature Genetics},
  year={1995},
  volume={10},
  pages={111-113}
}
Hyperhomocysteinaemia has been identified as a risk factor for cerebrovascular, peripheral vascular and coronary heart disease1–4. Elevated levels of plasma homocysteine can result from genetic or nutrient-related disturbances in the trans-sulphuration or re-methylation pathways for homocysteine metabolism1,5–7. 5,10-Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetra-hydrofolate, the predominant circulatory form of folate and… Expand
Correlation of a common mutation in the methylenetetrahydrofolate reductase gene with plasma homocysteine in patients with premature coronary artery disease.
TLDR
Individuals with the homozygous mutant genotype had higher plasma homocysteine, particularly when plasma folate was below the median value, and this genetic-environmental interaction is proposed to be a risk factor for CAD. Expand
Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease.
TLDR
It is concluded that heterozygosity for CBS deficiency does not appear to be involved in premature cardiovascular disease, however, a frequent homozygous mutation in the MTHFR gene is associated with a threefold increase in risk for prematurely cardiovascular disease. Expand
A1298C methylenetetrahydrofolate reductase mutation and coronary artery disease: relationships with C677T polymorphism and homocysteine/folate metabolism
TLDR
The hypothesis that MTHFR genotypes may interfere with coronary artery disease risk only when an unbalanced nutritional status leads to raised total plasma homocysteine levels is emphasized. Expand
Association of Methylenetetrahydrofolate Reductase Gene Polymorphism With Carotid Arterial Wall Thickening and Myocardial Infarction Risk in NIDDM
TLDR
As a step to understanding the pathophysiological role of the 677C-»T mutation in the MTHFR gene in the development of vascular disease in diabetes, the effect of the mutation on carotid atherosclerosis assessed by high-resolution ultrasound B-mode imaging is examined. Expand
Molecular Biology of Methylenetetrahydrofolate Reductase (MTHFR): Interrelationships with Folic Acid, Homocysteine and Vascular Disease
TLDR
The influence of the genotype on disease risk is dependent on nutritional status (folate level), as well as on the number of other more traditional risk factors present in the study group, supporting the multifactorial nature of cardiovascular disease. Expand
Methylenetetrahydrofolate Reductase C677T Mutation, Plasma Homocysteine, and Folate in Subjects From Northern Italy With or Without Angiographically Documented Severe Coronary Atherosclerotic Disease: Evidence for an Important Genetic-Environmental Interaction
TLDR
The MTHFR C677T mutation is rather common, but it does not appear to be associated per se to CAD, and a genetic-environmental interaction may contribute to the vascular risk by elevating tHcy when folate status is low. Expand
Investigations of a common genetic variant in betaine-homocysteine methyltransferase (BHMT) in coronary artery disease.
TLDR
The study suggests that the Q allele of the R239Q mutation may decrease the risk of CAD and that this variant warrants additional investigation of its relationship with the development of CAD as well as other homocysteine-dependent disorders. Expand
A common mutation in methylenetetrahydrofolate reductase gene is not a major risk of coronary artery disease or myocardial infarction.
TLDR
The MTHFR TT genotype is not a major genetic risk factor for predisposition to CAD and its thrombotic complications in this population of Caucasian patients. Expand
Polymorphism (C677T) in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene: A preliminary study on north Indian men
TLDR
No significant association was found between C677T mutation and CAD severity and the lack of statistical significance could be due to the small sample size studied, hence a larger study including various ethnic groups is warranted. Expand
Common mutation in methylenetetrahydrofolate reductase. Correlation with homocysteine metabolism and late-onset vascular disease.
TLDR
The genotype dependence of the folate-homocysteine correlation suggests that homozygotes for this mutation may have both an exaggerated hyperhomocysteinemic response to folic acid depletion and a better response tofolic acid therapy. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 27 REFERENCES
Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency.
TLDR
Seven novel mutations in this gene are characterized: six missense mutations and a 5' splice-site defect that activates a cryptic splice site in the coding sequence that is associated with extremely low activity and onset of symptoms within the 1st year of age. Expand
Hyperhomocysteinemia: an independent risk factor for vascular disease.
TLDR
Hyperhomocysteinemia is an independent risk factor for vascular disease, including coronary disease, and in most instances is probably due to cystathionine beta-synthase deficiency. Expand
Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease.
TLDR
The thermostability of lymphocyte MTHFR is determined in 212 patients with proven coronary artery disease and in 202 controls without clinical evidence of atherosclerotic vascular disease and it is concluded that thermolabile MTHfr is a variant of MTH FR deficiency which is inherited as an autosomal recessive trait. Expand
Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase.
TLDR
Evidence of a hitherto undescribed mutant MTHF reductase is provided in two patients with intermediate homocysteinemia, suggesting that a moderate deficiency of MTHf reduct enzyme might be associated with vascular disorders in adult life. Expand
Thermolabile Defect of Methylenetetrahydrofolate Reductase in Coronary Artery Disease
TLDR
Using discriminant function analysis, thermolabile methylenetetrahydrofolate reductase was predictive of angiographically proven coronary artery stenosis and the traditional risk factors - age, sex, diabetes, smoking, hypercholesterolemia, and hypertension - were not significant. Expand
Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification
TLDR
Two mutations were identified in MTHFR–deficient patients: a missense mutation in a residue conserved in bacterial enzymes, and a nonsense mutation (Arg to Ter) that results in homocysteine methylation to methionine. Expand
Thermolabile 5,10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia.
TLDR
In 28% of the hyperhomocysteinemic patients with premature vascular disease, abnormal homocysteine metabolism could be attributed to thermolabile MTHFR. Expand
Methylenetetrahydrofolate Reductase in Cultured Human Cells. II. Genetic and Biochemical Studies of Methylenetetrahydrofolate Reductase Deficiency
TLDR
The data suggest that in CP and WMa there is a mutationally induced structural defect in the aporeductase as the basis for the observed alteration in thermostability, presumably reflecting reduced ability to bind the FAD cofactor. Expand
Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease.
TLDR
It is concluded that this condition predisposes to the development of premature occlusive arterial disease, causing intermittent claudication, renovascular hypertension, and ischemic cerebrovascular disease. Expand
Crystal structures of recombinant human dihydrofolate reductase complexed with folate and 5-deazafolate.
TLDR
It is proposed that this 1-A overlap of the binding sites for folate's pteridine ring and the dihydronicotinamide ring of NADPH accelerates the reduction of both folate and 7,8-dihydrofolate by simultaneously binding substrate and cofactor with a sub van der Waals separation that is optimal for hydride transfer. Expand
...
1
2
3
...