van der Put N M, van den Heuvel L P, Steegers-Theunissen R P, Trijbels F J, Eskes T K, Mariman E C, den Heyer M, Blom H J
Department of Pediatrics, University Hospital Nijmegen, The Netherlands.
J Mol Med (Berl). 1996 Nov;74(11):691-4. doi: 10.1007/s001090050073.
Periconceptional folate intake reduces both the occurrence and recurrence risk of neural tube defects. Plasma homocysteine levels can be elevated in mothers of a child with a neural tube defect, suggesting a dysfunctional folate metabolism. Very recently we showed that a common 677C-->T mutation in the 5,10-methylene tetrahydrofolate reductase gene, causing thermolability of the enzyme, is a risk factor for spina bifida offspring. Restriction enzyme analysis of the genomic 5,10-methylene tetrahydrofolate reductase polymerase chain reaction fragment revealed a significantly higher prevalence of a +/+ genotype among spina bifida patients and their mothers. The risk for spina bifida offspring is the strongest if both the mother and her child have the mutation in the homozygous state. Enzymatic analysis showed that homozygosity for the 677C-->T mutation causes a decreased 5,10-methylene tetrahydrofolate reductase activity, resulting in elevated plasma homocysteine and red blood cell folate levels and lowered plasma folate and cysteine values. This extended study demonstrates that a nucleotide substitution in the coding region of 5,10-methylene tetrahydrofolate reductase, resulting in reduced activity and an impaired homocysteine and folate metabolism, is a genetic risk factor for spina bifida.
孕期叶酸摄入可降低神经管缺陷的发生和复发风险。神经管缺陷患儿母亲的血浆同型半胱氨酸水平可能升高，提示叶酸代谢功能异常。最近我们发现，5,10-亚甲基四氢叶酸还原酶基因常见的677C→T突变会导致该酶热不稳定性，是脊柱裂患儿的一个危险因素。对基因组5,10-亚甲基四氢叶酸还原酶聚合酶链反应片段进行限制性酶切分析发现，脊柱裂患者及其母亲中 +/+ 基因型的患病率显著更高。如果母亲及其孩子均为纯合状态的突变，则脊柱裂患儿的风险最强。酶分析表明，677C→T突变的纯合性会导致5,10-亚甲基四氢叶酸还原酶活性降低，导致血浆同型半胱氨酸和红细胞叶酸水平升高，血浆叶酸和半胱氨酸值降低。这项扩展研究表明，5,10-亚甲基四氢叶酸还原酶编码区的核苷酸替换导致活性降低以及同型半胱氨酸和叶酸代谢受损，是脊柱裂的一个遗传危险因素。
