Goyette P, Christensen B, Rosenblatt D S, Rozen R
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
Am J Hum Genet. 1996 Dec;59(6):1268-75.
Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, a methyl donor in the conversion of homocysteine to methionine. Patients with severe MTHFR deficiency have hyperhomocysteinemia, hypomethioninemia, and a range of neurological and vascular findings with a variable age at onset. We have previously described nine mutations in patients with severe MTHFR deficiency. A mild form of MTHFR deficiency, associated with a thermolabile enzyme, has been proposed as a genetic risk factor for cardiovascular disease and for neural tube defects. We have shown that a common missense mutation (an alanine-to-valine substitution) encodes this thermolabile variant. We now report an additional five mutations causing severe MTHFR deficiency and an analysis of genotype (alanine/valine status) and enzyme thermolability in 22 patients with this inborn error of metabolism. Six of these patients have four mutations in the MTHFR gene-two rare mutations causing severe deficiency and two mutations for the common alanine-to-valine mutation that results in thermolability. Even in severe MTHFR deficiency, the thermolabile variant is frequently observed, and there is a strong relationship between the presence of this variant and increased enzyme thermolability.
亚甲基四氢叶酸还原酶（MTHFR）催化5-甲基四氢叶酸的合成，5-甲基四氢叶酸是同型半胱氨酸转化为蛋氨酸过程中的甲基供体。严重MTHFR缺乏症患者有高同型半胱氨酸血症、低蛋氨酸血症，以及一系列神经系统和血管方面的表现，发病年龄各不相同。我们之前曾描述过严重MTHFR缺乏症患者中的9种突变。一种与热不稳定酶相关的轻度MTHFR缺乏症已被认为是心血管疾病和神经管缺陷的遗传风险因素。我们已经表明，一种常见的错义突变（丙氨酸到缬氨酸的替换）编码了这种热不稳定变体。我们现在报告另外5种导致严重MTHFR缺乏症的突变，并对22例患有这种先天性代谢错误的患者进行了基因型（丙氨酸/缬氨酸状态）和酶热稳定性分析。其中6例患者在MTHFR基因中有4种突变——2种导致严重缺乏症的罕见突变和2种导致热不稳定的常见丙氨酸到缬氨酸突变。即使在严重MTHFR缺乏症中，也经常观察到热不稳定变体，并且这种变体的存在与酶热稳定性增加之间存在密切关系。
