biostudies-literatureYeh JYNational Health Research Institutes (NHRI)NYMU | Brain Research Center, National Yang-Ming University (NYMU-BRC)National Taiwan UniversityNational Taiwan University ()National Health Research InstitutesNYMU | Brain Research Center, National Yang-Ming UniversityNational Science and Technology CouncilNational Science and Technology Council (NSTC)1091-1114https://www.ebi.ac.uk/biostudies/studies/S-EPMC11099080biostudies-literatureUnknown16(5)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.EMBO molecular medicineA missense mutation in human INSC causes peripheral neuropathy.PMC11099080112-2628-B-007-004112-2314-B-075 -034 -MY3EX112-11228NIThe Featured Areas Research Center Program112-2314-B-002 -016112L895403112-2636-B-007-008111-2320-B-002-049-MY3109-2314-B-075-044-MY3Hong CLHung YCLin SHuang SYChao HCTzou FYChan CCYeh JYChou CTLiao YCLee YCKennerson MHsiao CTLin YCLi JLTsai YSChen WJfalseA missense mutation in human INSC causes peripheral neuropathy.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 CMT2.2024-01-01T00:00:00Z2024 May2026-06-01T17:29:25.392Z2026-04-08T14:17:21.491ZS-EPMC110990803858965110.1038/s44321-024-00062-w