Department of Molecular Neurobiology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan.
Department of Anatomy, Division of Histology and Cell Biology, School of Medicine, Jichi Medical University, Shimotsuke, Japan.
Commun Biol. 2020 Mar 13;3(1):121. doi: 10.1038/s42003-020-0854-z.
Charcot-Marie-Tooth (CMT) disease is a hereditary neuropathy mainly caused by gene mutation of peripheral myelin proteins including myelin protein zero (P0, MPZ). Large myelin protein zero (L-MPZ) is an isoform of P0 that contains an extended polypeptide synthesized by translational readthrough at the C-terminus in tetrapods, including humans. The physiological role of L-MPZ and consequences of an altered L-MPZ/P0 ratio in peripheral myelin are not known. To clarify this, we used genome editing to generate a mouse line (L-MPZ mice) that produced L-MPZ instead of P0. Motor tests and electrophysiological, immunohistological, and electron microscopy analyses show that homozygous L-MPZ mice exhibit CMT-like phenotypes including thin and/or loose myelin, increased small-caliber axons, and disorganized axo-glial interactions. Heterozygous mice show a milder phenotype. These results highlight the importance of an appropriate L-MPZ/P0 ratio and show that aberrant readthrough of a myelin protein causes neuropathy.
Charcot-Marie-Tooth (CMT) 病是一种遗传性周围神经病，主要由外周髓鞘蛋白基因突变引起，包括髓鞘蛋白零（P0，MPZ）。大髓鞘蛋白零（L-MPZ）是 P0 的一种同工型，在包括人类在内的四足动物中，其 C 末端通过翻译通读合成了一个扩展的多肽。L-MPZ 在周围髓鞘中的生理作用以及改变的 L-MPZ/P0 比值的后果尚不清楚。为了阐明这一点，我们使用基因组编辑技术生成了一种产生 L-MPZ 而不是 P0 的小鼠品系（L-MPZ 小鼠）。运动测试和电生理学、免疫组织化学和电子显微镜分析表明，纯合 L-MPZ 小鼠表现出 CMT 样表型，包括薄而/或疏松的髓鞘、增加的小直径轴突和轴突-胶质相互作用紊乱。杂合子小鼠表现出较轻的表型。这些结果强调了适当的 L-MPZ/P0 比值的重要性，并表明髓鞘蛋白的异常通读会导致神经病。
