Frosst P, Blom H J, Milos R, Goyette P, Sheppard C A, Matthews R G, Boers G J, den Heijer M, Kluijtmans L A, van den Heuvel L P
Nat Genet. 1995 May;10(1):111-3. doi: 10.1038/ng0595-111.
Hyperhomocysteinaemia has been identified as a risk factor for cerebrovascular, peripheral vascular and coronary heart disease. Elevated levels of plasma homocysteine can result from genetic or nutrient-related disturbances in the trans-sulphuration or re-methylation pathways for homocysteine metabolism. 5, 10-Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the predominant circulatory form of folate and carbon donor for the re-methylation of homocysteine to methionine. Reduced MTHFR activity with a thermolabile enzyme has been reported in patients with coronary and peripheral artery disease. We have identified a common mutation in MTHFR which alters a highly-conserved amino acid; the substitution occurs at a frequency of approximately 38% of unselected chromosomes. The mutation in the heterozygous or homozygous state correlates with reduced enzyme activity and increased thermolability in lymphocyte extracts; in vitro expression of a mutagenized cDNA containing the mutation confirms its effect on thermolability of MTHFR. Finally, individuals homozygous for the mutation have significantly elevated plasma homocysteine levels. This mutation in MTHFR may represent an important genetic risk factor in vascular disease.
高同型半胱氨酸血症已被确认为脑血管疾病、外周血管疾病和冠心病的一个风险因素。血浆同型半胱氨酸水平升高可能源于同型半胱氨酸代谢的转硫途径或再甲基化途径中与遗传或营养相关的紊乱。5,10-亚甲基四氢叶酸还原酶（MTHFR）催化5,10-亚甲基四氢叶酸还原为5-甲基四氢叶酸，5-甲基四氢叶酸是叶酸的主要循环形式，也是同型半胱氨酸再甲基化为甲硫氨酸的碳供体。在冠心病和外周动脉疾病患者中，已报道了具有热不稳定酶的MTHFR活性降低。我们在MTHFR中发现了一个常见突变，该突变改变了一个高度保守的氨基酸；这种替代在未选择的染色体中出现的频率约为38%。杂合或纯合状态的突变与淋巴细胞提取物中酶活性降低和热稳定性增加相关；含有该突变的诱变cDNA的体外表达证实了其对MTHFR热稳定性的影响。最后，该突变的纯合个体血浆同型半胱氨酸水平显著升高。MTHFR中的这种突变可能是血管疾病的一个重要遗传风险因素。
