Upregulation of large myelin protein zero leads to Charcot-Marie-Tooth disease-like neuropathy in mice

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. Otani et al. show that upregulation of large myelin protein zero (L-MPZ), an isoform of myelin protein zero (P0) which contains an extended polypeptide synthesized by translational readthrough, can cause neuropathy, using mice that produce L-MPZ instead of P0. This study suggests the importance of keeping L-MPZ low for the proper functioning of myelin.