A missense mutation in human INSC causes peripheral neuropathy

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

doi:10.1038/s44321-024-00062-w

A missense mutation in human INSC causes peripheral neuropathy

EMBO Mol Med. 2024 May;16(5):1091-1114. doi: 10.1038/s44321-024-00062-w. Epub 2024 Apr 8.

Authors

Jui-Yu Yeh¹, Hua-Chuan Chao^{2

3

4}, Cheng-Li Hong¹, Yu-Chien Hung¹, Fei-Yang Tzou¹, Cheng-Tsung Hsiao^{2

5}, Jeng-Lin Li^{6

7}, Wen-Jie Chen^{8

9}, Cheng-Ta Chou¹⁰, Yu-Shuen Tsai¹¹, Yi-Chu Liao^{2

5

12}, Yu-Chun Lin^{13

14}, Suewei Lin⁸, Shu-Yi Huang¹⁵, Marina Kennerson^{16

17

18}, Yi-Chung Lee^{19

20

21}, Chih-Chiang Chan²²

Affiliations

¹ Graduate Institute of Physiology, National Taiwan University, Taipei, Taiwan.
² Department of Neurology, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan.
³ Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁴ Division of Neurology, Department of Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan.
⁵ Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.
⁶ Ph.D. Program in Translational Medicine, National Taiwan University and Academia Sinica, Taipei, Taiwan.
⁷ Department of Neurology, National Taiwan University Hospital Jinshan Branch, New Taipei City, Taiwan.
⁸ Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
⁹ Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Cheng Kung University and Academia Sinica, Tapiei, Taiwan.
¹⁰ Department of Neurology, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan.
¹¹ Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.
¹² Brain Research Center, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan.
¹³ Institute of Molecular Medicine, National Tsing Hua University, HsinChu, Taiwan.
¹⁴ Department of Medical Science, National Tsing Hua University, HsinChu, Taiwan.
¹⁵ Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
¹⁶ Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney Local Health District, Concord, NSW, Australia.
¹⁷ School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
¹⁸ Molecular Medicine Laboratory, Concord Hospital, Concord, NSW, Australia.
¹⁹ Department of Neurology, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan. ycli@vghtpe.gov.tw.
²⁰ Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan. ycli@vghtpe.gov.tw.
²¹ Brain Research Center, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan. ycli@vghtpe.gov.tw.
²² Graduate Institute of Physiology, National Taiwan University, Taipei, Taiwan. chancc1@ntu.edu.tw.

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^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.

Keywords: Inscuteable; Charcot–Marie–Tooth Neuropathy Type 2; Microtubule-Stabilizing Agents; Necrosis; Proprioception.

MeSH terms

Adaptor Proteins, Signal Transducing* / genetics
Adaptor Proteins, Signal Transducing* / metabolism
Animals
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Charcot-Marie-Tooth Disease* / genetics
Charcot-Marie-Tooth Disease* / pathology
Cytoskeletal Proteins* / genetics
Cytoskeletal Proteins* / metabolism
Disease Models, Animal
Drosophila / genetics
Drosophila Proteins / genetics
Drosophila Proteins / metabolism
Humans
Mutation, Missense*
Nuclear Proteins
Peripheral Nervous System Diseases / genetics
Peripheral Nervous System Diseases / pathology
Tubulin / genetics
Tubulin / metabolism

Substances

Adaptor Proteins, Signal Transducing
Cell Cycle Proteins
MAD2L1BP protein, human
Nuclear Proteins
Tubulin
insc protein, Drosophila
INSC protein, human
Cytoskeletal Proteins
Drosophila Proteins

Abstract

MeSH terms

Substances

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