Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA
Hum Mol Genet. 2013 May 1;22(9):1755-70. doi: 10.1093/hmg/ddt022. Epub 2013 Jan 28.
Charcot-Marie-Tooth disease type 1C (CMT1C) is a dominantly inherited motor and sensory neuropathy. Despite human genetic evidence linking missense mutations in SIMPLE to CMT1C, the in vivo role of CMT1C-linked SIMPLE mutations remains undetermined. To investigate the molecular mechanism underlying CMT1C pathogenesis, we generated transgenic mice expressing either wild-type or CMT1C-linked W116G human SIMPLE. Mice expressing mutant, but not wild type, SIMPLE develop a late-onset motor and sensory neuropathy that recapitulates key clinical features of CMT1C disease. SIMPLE mutant mice exhibit motor and sensory behavioral impairments accompanied by decreased motor and sensory nerve conduction velocity and reduced compound muscle action potential amplitude. This neuropathy phenotype is associated with focally infolded myelin loops that protrude into the axons at paranodal regions and near Schmidt-Lanterman incisures of peripheral nerves. We find that myelin infolding is often linked to constricted axons with signs of impaired axonal transport and to paranodal defects and abnormal organization of the node of Ranvier. Our findings support that SIMPLE mutation disrupts myelin homeostasis and causes peripheral neuropathy via a combination of toxic gain-of-function and dominant-negative mechanisms. The results from this study suggest that myelin infolding and paranodal damage may represent pathogenic precursors preceding demyelination and axonal degeneration in CMT1C patients.
腓骨肌萎缩症 1C 型（CMT1C）是一种显性遗传性运动感觉神经病。尽管人类遗传证据表明 SIMPLE 中的错义突变与 CMT1C 相关，但与 CMT1C 相关的 SIMPLE 突变的体内作用仍未确定。为了研究 CMT1C 发病机制的分子机制，我们生成了表达野生型或 CMT1C 相关 W116G 人 SIMPLE 的转基因小鼠。表达突变型而非野生型 SIMPLE 的小鼠会发展出迟发性运动和感觉神经病，该疾病可重现 CMT1C 疾病的关键临床特征。SIMPLE 突变型小鼠表现出运动和感觉行为障碍，伴有运动和感觉神经传导速度降低以及复合肌肉动作电位幅度减小。这种神经病表型与局灶性内折的髓鞘环有关，这些髓鞘环在神经节旁区和周围神经的施密特-兰伯特切迹处突入轴突。我们发现髓鞘内折通常与轴突受限有关，伴有轴突运输受损的迹象，以及神经节旁缺陷和Ranvier 结的异常结构。我们的研究结果支持 SIMPLE 突变通过毒性获得功能和显性负性机制破坏髓鞘稳态并导致周围神经病。本研究结果表明，髓鞘内折和神经节旁损伤可能代表 CMT1C 患者脱髓鞘和轴突变性之前的致病前体。
