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A missense mutation in human INSC causes peripheral neuropathy.
- Source :
- EMBO Molecular Medicine; May2024, Vol. 16 Issue 5, p1091-1114, 24p
- Publication Year :
- 2024
-
Abstract
- 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<superscript>M70R</superscript> 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<superscript>M70R</superscript> 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. Synopsis: This study unveils the first discovery of an INSC gene missense mutation causing axonal Charcot-Marie-Tooth disease (CMT) and examines the microtubule-stabilizing role of PAR3/INSC/LGN in the adult peripheral nervous system (PNS). Microtubule-stabilizing agents effectively reverse proprioception defects and necrosis in INSC mutation individuals. Identification of INSC as a potential pathogenic gene in adult-onset peripheral neuropathy. Demonstration of PAR3/INSC/LGN dysfunction leading to proprioceptive defects resembling gait abnormalities in patients with CMT. Requirement of PAR3/INSC/LGN for microtubule stabilization in the adult PNS. Reversal of both morphological and functional defects in a disease model through the use of microtubule-stabilizing agents, presenting a potential therapeutic strategy for peripheral neuropathy. This study unveils the first discovery of an INSC gene missense mutation causing axonal Charcot-Marie-Tooth disease (CMT) and examines the microtubule-stabilizing role of PAR3/INSC/LGN in the adult peripheral nervous system (PNS). Microtubule-stabilizing agents effectively reverse proprioception defects and necrosis in INSC mutation individuals. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 17574676
- Volume :
- 16
- Issue :
- 5
- Database :
- Complementary Index
- Journal :
- EMBO Molecular Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 177322211
- Full Text :
- https://doi.org/10.1038/s44321-024-00062-w