Yeh, J.Y., Chao, H.C., Hong, C.L., Hung, Y.C., Tzou, F.Y., Hsiao, C.T., Li, J.L., Chen, W.J., Chou, C.T., Tsai, Y.S., Liao, Y.C., Lin, Y.C., Lin, S., Huang, S.Y., Kennerson, M., Lee, Y.C., Chan, C.C. (2024). A missense mutation in human INSC causes peripheral neuropathy.  EMBO Mol. Med. 16(5): 1091--1114.

FBrf0259513

Research paper

PAR3/INSC/LGN form an evolutionarily conserved complex required for asymmetric cell division in the developing brain, but its post-developmental function and disease relevance in the peripheral nervous system (PNS) remains unknown. We mapped a new locus for axonal Charcot-Marie-Tooth disease (CMT2) and identified a missense mutation c.209 T > G (p.Met70Arg) in the INSC gene. Modeling the INSC[M70R] variant in Drosophila, we showed that it caused proprioceptive defects in adult flies, leading to gait defects resembling those in CMT2 patients. Cellularly, PAR3/INSC/LGN dysfunction caused tubulin aggregation and necrotic neurodegeneration, with microtubule-stabilizing agents rescuing both morphological and functional defects of the INSC[M70R] mutation in the PNS. Our findings underscore the critical role of the PAR3/INSC/LGN machinery in the adult PNS and highlight a potential therapeutic target for INSC-associated CMT2.

PMC11099080 (PMC) (EuropePMC)