Department of Human Genetics, McGill University, 1205 Avenue Docteur Penfield, N5/13, Montreal, Quebec H3A 1B1, Canada.
Department of Human Genetics, McGill University, 1205 Avenue Docteur Penfield, N5/13, Montreal, Quebec H3A 1B1, Canada; Department of Pediatrics, McGill University, Research Institute, Place Toulon, 4060 Ste. Catherine West PT 420, Montreal Children's Hospital, Montreal, Quebec H3Z 2Z3, Canada.
Mol Genet Metab. 2014 Jul;112(3):198-204. doi: 10.1016/j.ymgme.2014.05.002. Epub 2014 May 14.
Patients with mutations in MMACHC have the autosomal recessive disease of cobalamin metabolism known as cblC. These patients are unable to convert cobalamin into the two active forms, methylcobalamin and adenosylcobalamin and consequently have elevated homocysteine and methylmalonic acid in blood and urine. In addition, some cblC patients have structural abnormalities, including congenital heart defects. MMACHC is conserved in the mouse and shows tissue and stage-specific expression pattern in midgestation stage embryos. To create a mouse model of cblC we generated a line of mice with a gene-trap insertion in intron 1 of the Mmachc gene, (Mmachc(Gt(AZ0348)Wtsi)). Heterozygous mice show a 50% reduction of MMACHC protein, and have significantly higher levels of homocysteine and methylmalonic acid in their blood. The Mmachc(Gt) allele was inherited with a transmission ratio distortion in matings with heterozygous animals. Furthermore, homozygous Mmachc(Gt) embryos were not found after embryonic day 3.5 and these embryos were unable to generate giant cells in outgrowth assays. Our findings confirm that cblC is modeled in mice with reduced levels of Mmachc and suggest an early requirement for Mmachc in mouse development.
患有 MMACHC 基因突变的患者患有钴胺素代谢的常染色体隐性疾病，称为 cblC。这些患者无法将钴胺素转化为两种活性形式，即甲基钴胺素和腺苷钴胺素，因此血液和尿液中的同型半胱氨酸和甲基丙二酸水平升高。此外，一些 cblC 患者存在结构异常，包括先天性心脏病。MMACHC 在小鼠中保守，在中孕期胚胎中表现出组织和阶段特异性表达模式。为了创建 cblC 的小鼠模型，我们在 Mmachc 基因的内含子 1 中产生了一条基因捕获插入的小鼠品系（Mmachc(Gt(AZ0348)Wtsi))。杂合子小鼠的 MMACHC 蛋白减少 50%，血液中的同型半胱氨酸和甲基丙二酸水平显著升高。Mmachc(Gt)等位基因在与杂合子动物交配时存在遗传传递比失真。此外，在胚胎第 3.5 天之后没有发现纯合 Mmachc(Gt)胚胎，这些胚胎无法在体外培养实验中生成巨细胞。我们的研究结果证实，cblC 在 MMACHC 水平降低的小鼠中得到建模，并表明 Mmachc 在小鼠发育中早期存在需求。
