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）病是一种遗传性神经病，主要由周围髓磷脂蛋白（包括髓磷脂蛋白零（P0，MPZ））的基因突变引起。大的髓磷脂蛋白零（L-MPZ）是P0的一种亚型，它包含四足动物（包括人）的C末端通过翻译通读合成的延伸多肽。L-MPZ的生理作用以及外周髓磷脂中L-MPZ / P0比值改变的后果尚不清楚。为了澄清这一点，我们使用基因组编辑来生成产生L-MPZ而不是P0的小鼠品系（L-MPZ小鼠）。运动测试以及电生理，免疫组织学和电子显微镜分析表明，纯合L-MPZ小鼠表现出CMT样表型，包括稀薄和/或松散的髓鞘，小口径轴突增加以及轴突-胶质相互作用紊乱。杂合子小鼠表现出较温和的表型。这些结果突出了适当的L-MPZ / P0比例的重要性，并表明髓磷脂蛋白的异常通读引起神经病。