A missense mutation in human INSC causes peripheral neuropathy
EMBO Mol Med. 2024 Apr 8. doi: 10.1038/s44321-024-00062-w. Online ahead of print.ABSTRACTPAR3/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 INSCM70R 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 INSCM70R 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.PMID:38589651 | DOI:10.1038/s44321-024-00062-w
Source: Molecular Medicine - Category: Molecular Biology Authors: Jui-Yu Yeh Hua-Chuan Chao Cheng-Li Hong Yu-Chien Hung Fei-Yang Tzou Cheng-Tsung Hsiao Jeng-Lin Li Wen-Jie Chen Cheng-Ta Chou Yu-Shuen Tsai Yi-Chu Liao Yu-Chun Lin Suewei Lin Shu-Yi Huang Marina Kennerson Yi-Chung Lee Chih-Chiang Chan Source Type: research
More News: Brain | Charcot-Marie-Tooth Disease | Genetics | Molecular Biology | Neurology | Peripheral Neuropathy