Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition
Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition
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DOI：
10.1093/hmg/10.5.433
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发表时间：
2001-03-01
影响因子：
3.5
通讯作者：
Rozen, R
中科院分区：
文献类型：
--
作者：
Chen, ZT;Karaplis, AC;Rozen, R
高同型半胱氨酸血症是心血管疾病的危险因素，由同型半胱氨酸代谢的营养和/或遗传干扰引起。高同型半胱氨酸血症最常见的遗传原因是亚甲基四氢叶酸还原酶(MTHFR)基因的677C-->；T突变。这种突变，有轻微的酶缺乏，与神经管缺陷和妊娠并发症的风险增加，以及结肠癌和白血病的风险降低有关。尽管许多研究报道该变异也是血管疾病的危险因素，但这一领域的研究仍然存在争议。严重的MTHFR缺乏会导致同型半胱氨酸尿症，这是一种先天的代谢错误，伴有神经和血管并发症。为了研究MTHFR缺陷的体内致病机制，我们建立了MTHFR基因敲除的小鼠。杂合子和纯合子基因敲除小鼠的血浆总同型半胱氨酸水平分别是野生型同型半胱氨酸水平的1、6和10倍。杂合子和纯合子基因敲除都显著降低了S-腺苷蛋氨酸水平或显著升高了S-腺苷同型半胱氨酸水平，或两者兼而有之，并伴随着全球DNA低甲基化。杂合子基因敲除的小鼠看起来正常，而纯合子小鼠较小，并表现出发育迟缓的小脑病理。在年长的杂合子和纯合子的小鼠中，观察到了主动脉近端的异常脂肪沉积，这暗示了高同型半胱氨酸血症对动脉粥样硬化的影响。
Hyperhomocysteinemia, a risk factor for cardiovascular disease, is caused by nutritional and/or genetic disruptions in homocysteine metabolism. The most common genetic cause of hyperhomocysteinemia is the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene. This variant, with mild enzymatic deficiency, is associated with an increased risk for neural tube defects and pregnancy complications and with a decreased risk for colon cancer and leukemia. Although many studies have reported that this variant is also a risk factor for vascular disease, this area of investigation is still controversial. Severe MTHFR deficiency results in homocystinuria, an inborn error of metabolism with neurological and vascular complications. To investigate the in vivo pathogenetic mechanisms of MTHFR deficiency, we generated mice with a knockout of Mthfr. Plasma total homocysteine levels in heterozygous and homozygous knockout mice are 1.,6- and 10-fold higher than those in wild-type littermates, respectively. Both heterozygous and homozygous knockouts have either significantly decreased S-adenosylmethionine levels or significantly increased S-adenosylhomocysteine levels, or both, with global DNA hypomethylation. The heterozygous knockout mice appear normal, whereas the homozygotes are smaller and show developmental retardation with cerebellar pathology. Abnormal lipid deposition in the proximal portion of the aorta was observed in older heterozygotes and homozygotes, alluding to an atherogenic effect of hyperhomocysteinemia in these mice.