A missense mutation in human INSC causes peripheral neuropathy.

Yeh, Jui-YuJui-YuYehChao, Hua-ChuanHua-ChuanChaoHong, Cheng-LiCheng-LiHongHung, Yu-ChienYu-ChienHungTzou, Fei-YangFei-YangTzouHsiao, Cheng-TsungCheng-TsungHsiaoLi, Jeng-LinJeng-LinLiChen, Wen-JieWen-JieChenChou, Cheng-TaCheng-TaChouTsai, Yu-ShuenYu-ShuenTsaiLiao, Yi-ChuYi-ChuLiaoLin, Yu-ChunYu-ChunLinLin, SueweiSueweiLinHuang, Shu-YiShu-YiHuangKennerson, MarinaMarinaKennersonLee, Yi-ChungYi-ChungLeeCHIH-CHIANG CHAN2024-12-042024-12-042024-05https://scholars.lib.ntu.edu.tw/handle/123456789/723558PAR3/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 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 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.enInscuteableCharcot–Marie–Tooth Neuropathy Type 2Microtubule-Stabilizing AgentsNecrosisProprioceptionA missense mutation in human INSC causes peripheral neuropathy.journal article10.1038/s44321-024-00062-w38589651