The development of patient‐specific induced pluripotent stem cells (iPSCs) offered interesting insights in modeling the pathogenesis of Charcot‐Marie‐Tooth (CMT) disease and thus we decided to explore the phenotypes of iPSCs derived from a single CMT patient carrying a mutant ATP1A1 allele (p.Pro600Ala). iPSCs clones generated from CMT and control fibroblasts, were induced to differentiate into neural precursors and then into post‐mitotic neurons. Control iPSCs differentiated into neuronal precursors and then into post‐mitotic neurons within 6‐8 days. On the contrary, the differentiation of CMT iPSCs was clearly defective. Electrophysiological properties confirmed that post‐mitotic neurons were less mature compared to the normal counterpart. The impairment of in vitro differentiation of CMT iPSCs only concerned with the neuronal pathway, because they were able to differentiate into mesendodermal cells and other ectodermal derivatives. ATP1A1 was undetectable in the few neuronal cells derived from CMT iPSCs. ATP1A1 gene mutation (p.Pro600Ala), responsible for a form of axonal CMT disease, is associated in vitro with a dramatic alteration of the differentiation of patient‐derived iPSCs into post‐mitotic neurons. Thus, the defect in neuronal cell development might lead in vivo to a decreased number of mature neurons in ATP1A1‐CMT disease.

中文翻译：

---

使用患者特异性iPSC了解ATP1A1相关CMT疾病的发病机理。

患者特异性诱导多能干细胞（iPSC）的发展为模拟Charcot-Marie-Tooth（CMT）疾病的发病机理提供了有趣的见识，因此，我们决定探索源自一名携带突变ATP1A1的CMT患者的iPSC表型等位基因（p.Pro600Ala）。从CMT和对照成纤维细胞生成的iPSCs克隆被诱导分化为神经前体，然后分化为有丝分裂后神经元。对照iPSC在6-8天内分化为神经元前体，然后分化为有丝分裂后神经元。相反，CMT iPSC的区分显然存在缺陷。电生理特性证实，与正常对应物相比，有丝分裂后神经元不那么成熟。CMT iPSC体外分化的损害仅与神经元通路有关，因为它们能够分化为中胚层细胞和其他外胚层衍生物。在源自CMT iPSC的少数神经元细胞中未检测到ATP1A1。ATP1A1基因突变（p.Pro600Ala）是轴突CMT疾病的一种形式，在体外与患者衍生的iPSC向有丝分裂后神经元分化的显着改变有关。因此，神经元细胞发育的缺陷可能导致体内ATP1A1-CMT疾病中成熟神经元的数量减少。