Mutations in COMP cause familial carpal tunnel syndrome

Chunyu Li, Ni Wang, Alejandro A. Schäffer, Xilin Liu, Zhuo Zhao, Gene Elliott, Lisa Garrett, Nga Ting Choi, Yueshu Wang, Yufa Wang, Cheng Wang, Jin Wang, Danny Chan, Peiqiang Su, Shusen Cui (), Yingzi Yang () and Bo Gao ()
Additional contact information
Chunyu Li: China-Japan Union Hospital of Jilin University
Ni Wang: The University of Hong Kong
Alejandro A. Schäffer: National Center for Biotechnology Information and National Cancer Institute, National Institutes of Health
Xilin Liu: China-Japan Union Hospital of Jilin University
Zhuo Zhao: China-Japan Union Hospital of Jilin University
Gene Elliott: National Human Genome Research Institute, National Institutes of Health
Lisa Garrett: National Human Genome Research Institute, National Institutes of Health
Nga Ting Choi: The University of Hong Kong
Yueshu Wang: China-Japan Union Hospital of Jilin University
Yufa Wang: China-Japan Union Hospital of Jilin University
Cheng Wang: The University of Hong Kong
Jin Wang: The University of Hong Kong
Danny Chan: The University of Hong Kong
Peiqiang Su: First Affiliated Hospital of Sun Yat-sen University
Shusen Cui: China-Japan Union Hospital of Jilin University
Yingzi Yang: National Human Genome Research Institute, National Institutes of Health
Bo Gao: The University of Hong Kong

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Carpal tunnel syndrome (CTS) is the most common peripheral nerve entrapment syndrome, affecting a large proportion of the general population. Genetic susceptibility has been implicated in CTS, but the causative genes remain elusive. Here, we report the identification of two mutations in cartilage oligomeric matrix protein (COMP) that segregate with CTS in two large families with or without multiple epiphyseal dysplasia (MED). Both mutations impair the secretion of COMP by tenocytes, but the mutation associated with MED also perturbs its secretion in chondrocytes. Further functional characterization of the CTS-specific mutation reveals similar histological and molecular changes of tendons/ligaments in patients’ biopsies and the mouse models. The mutant COMP fails to oligomerize properly and is trapped in the ER, resulting in ER stress-induced unfolded protein response and cell death, leading to inflammation, progressive fibrosis and cell composition change in tendons/ligaments. The extracellular matrix (ECM) organization is also altered. Our studies uncover a previously unrecognized mechanism in CTS pathogenesis.

Date: 2020
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DOI: 10.1038/s41467-020-17378-z

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