Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland.
Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland.
Brain. 2017 Aug 1;140(8):2093-2103. doi: 10.1093/brain/awx138.
Defects in mRNA export from the nucleus have been linked to various neurodegenerative disorders. We report mutations in the gene MCM3AP, encoding the germinal center associated nuclear protein (GANP), in nine affected individuals from five unrelated families. The variants were associated with severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot-Marie-Tooth neuropathy. Mild to moderate intellectual disability was present in seven of nine affected individuals. The affected individuals were either compound heterozygous or homozygous for different MCM3AP variants, which were predicted to cause depletion of GANP or affect conserved amino acids with likely importance for its function. Accordingly, fibroblasts of affected individuals from one family demonstrated severe depletion of GANP. GANP has been described to function as an mRNA export factor, and to suppress TDP-43-mediated motor neuron degeneration in flies. Thus our results suggest defective mRNA export from nucleus as a potential pathogenic mechanism of axonal degeneration in these patients. The identification of MCM3AP variants in affected individuals from multiple centres establishes it as a disease gene for childhood-onset recessively inherited Charcot-Marie-Tooth neuropathy with intellectual disability.
mRNA 从细胞核输出的缺陷与各种神经退行性疾病有关。我们报告了五个无关家庭的九名受影响个体中，编码生殖中心相关核蛋白（GANP）的基因 MCM3AP 发生突变。这些变体与严重的儿童发病的主要轴突（四个家庭）或脱髓鞘（一个家庭）夏科-马里-图病神经病有关。九名受影响个体中的七名存在轻度至中度智力障碍。受影响的个体要么是不同 MCM3AP 变体的复合杂合子或纯合子，这些变体预计会导致 GANP 耗竭或影响其功能的保守氨基酸。因此，一个家庭的受影响个体的成纤维细胞显示出 GANP 的严重耗竭。已经描述 GANP 作为一种 mRNA 输出因子，并且在果蝇中抑制 TDP-43 介导的运动神经元退化。因此，我们的结果表明，核内 mRNA 输出缺陷可能是这些患者轴突退化的潜在致病机制。多个中心受影响个体中 MCM3AP 变体的鉴定确立了它作为一种具有智力障碍的儿童发病隐性遗传夏科-马里-图病神经病的疾病基因。
