Mayo Clinic, Department of Neurology, Division of Peripheral Nerve Diseases, Rochester, Minnesota, USA.
Nat Genet. 2011 Jun;43(6):595-600. doi: 10.1038/ng.830. Epub 2011 May 1.
DNA methyltransferase 1 (DNMT1) is crucial for maintenance of methylation, gene regulation and chromatin stability. DNA mismatch repair, cell cycle regulation in post-mitotic neurons and neurogenesis are influenced by DNA methylation. Here we show that mutations in DNMT1 cause both central and peripheral neurodegeneration in one form of hereditary sensory and autonomic neuropathy with dementia and hearing loss. Exome sequencing led to the identification of DNMT1 mutation c.1484A>G (p.Tyr495Cys) in two American kindreds and one Japanese kindred and a triple nucleotide change, c.1470-1472TCC>ATA (p.Asp490Glu-Pro491Tyr), in one European kindred. All mutations are within the targeting-sequence domain of DNMT1. These mutations cause premature degradation of mutant proteins, reduced methyltransferase activity and impaired heterochromatin binding during the G2 cell cycle phase leading to global hypomethylation and site-specific hypermethylation. Our study shows that DNMT1 mutations cause the aberrant methylation implicated in complex pathogenesis. The discovered DNMT1 mutations provide a new framework for the study of neurodegenerative diseases.
DNA 甲基转移酶 1（DNMT1）对于维持甲基化、基因调控和染色质稳定性至关重要。DNA 错配修复、有丝分裂后神经元中的细胞周期调节和神经发生都受到 DNA 甲基化的影响。在这里，我们发现 DNMT1 中的突变会导致一种遗传性感觉和自主神经病变伴痴呆和听力损失的形式中出现中枢和周围神经退行性变。外显子组测序导致在两个美国家族和一个日本家族中发现了 DNMT1 突变 c.1484A>G（p.Tyr495Cys），在一个欧洲家族中发现了三核苷酸变化 c.1470-1472TCC>ATA（p.Asp490Glu-Pro491Tyr）。所有突变都位于 DNMT1 的靶向序列结构域内。这些突变导致突变蛋白的过早降解、甲基转移酶活性降低以及在 G2 细胞周期阶段异染色质结合受损，导致全基因组低甲基化和特定位点的高甲基化。我们的研究表明，DNMT1 突变导致了复杂发病机制中涉及的异常甲基化。发现的 DNMT1 突变为神经退行性疾病的研究提供了新的框架。
