C1orf194 deficiency leads to incomplete early embryonic lethality and dominant intermediate Charcot-Marie-Tooth disease in a knockout mouse model
C1orf194 deficiency leads to incomplete early embryonic lethality and dominant intermediate Charcot-Marie-Tooth disease in a knockout mouse model
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DOI：
10.1093/hmg/ddaa129
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发表时间：
2020-08-01
影响因子：
3.5
通讯作者：
Xiong, Fu
中科院分区：
文献类型：
--
作者：
Huang, Cheng;Shen, Zong Rui;Xiong, Fu
腓骨肌萎缩症（CMT）是最常见的遗传性周围神经病，并显示临床和遗传异质性。C1 orf 194编码神经元和雪旺氏细胞中的Ca 2+调节因子，我们以前曾报道过C1 orf 194突变会导致CMT疾病。本研究通过建立C1 orf 194基因敲除（KO）小鼠模型，进一步研究了C1 orf 194的功能和致病机制。C1 orf 194小鼠的纯合子突变体表现出不完全的胚胎致死性，其特征在于分化异常和死胎的胚胎天7.5-15.5。杂合子和存活的纯合子C1 orf 194 KO小鼠在4月龄时出现运动和感觉缺陷。电生理记录显示，C1 orf 194缺陷小鼠坐骨神经的复合肌肉动作电位和运动神经传导速度下降，这是显性中间型CMT的病理特征。透射电子显微镜分析显示脱髓鞘和轴突萎缩的坐骨神经，以及肿胀和线粒体基质的损失和其他异常的轴突和雪旺细胞。组织病理学检查显示脊髓前角运动神经元丢失和肌肉萎缩。在受影响动物的坐骨神经中检测到Ranvier和Schmidt-Lanterman切口节点之间的节间长度较短。这些结果表明，C1 orf 194 KO小鼠可以作为一种具有严重显性中间CMT表型的CMT动物模型，可用于研究疾病的分子机制和评估治疗策略的疗效。
Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy and shows clinical and genetic heterogeneity. Mutations in C1orf194 encoding a Ca2+ regulator in neurons and Schwann cells have been reported previously by us to cause CMT disease. In here, we further investigated the function and pathogenic mechanism of C1or194 by generating C1orf194 knockout (KO) mice. Homozygous mutants of C1orf194 mice exhibited incomplete embryonic lethality, characterized by differentiation abnormalities and stillbirth on embryonic days 7.5-15.5. Heterozygous and surviving homozygous C1orf194 KO mice developed motor and sensory defects at the age of 4 months. Electrophysiologic recordings showed decreased compound muscle action potential and motor nerve conduction velocity in the sciatic nerve of C1orf194-deficient mice as a pathologic feature of dominant intermediate-type CMT. Transmission electron microscopy analysis revealed demyelination and axonal atrophy in the sciatic nerve as well as swelling and loss of mitochondrial matrix and other abnormalities in axons and Schwann cells. A histopathologic examination showed a loss of motor neurons in the anterior horn of the spinal cord and muscle atrophy. Shorter internodal length between nodes of Ranvier and Schmidt-Lanterman incisures was detected in the sciatic nerve of affected animals. These results indicate that C1orf194 KO mice can serve as an animal model of CMT with a severe dominant intermediate CMT phenotype that can be used to investigate the molecular mechanisms of the disease and evaluate the efficacy of therapeutic strategies.