Mutations in COMP cause familial carpal tunnel syndrome

• Published in: Nature communications Vol. 11; no. 1; p. 3642
• Main Authors: Li, Chunyu, Wang, Ni, Schäffer, Alejandro A., Liu, Xilin, Zhao, Zhuo, Elliott, Gene, Garrett, Lisa, Choi, Nga Ting, Wang, Yueshu, Wang, Yufa, Wang, Cheng, Wang, Jin, Chan, Danny, Su, Peiqiang, Cui, Shusen, Yang, Yingzi, Gao, Bo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.07.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/109; 13/51; 14/19; 14/28; 38/22; 38/23; 38/70; 45/29; 59; 631/208/2489/144; 631/208/737; 631/80/304; 64; 64/110; 64/60; 692/308/2056; 692/420/2489/144; 82/83; 96/2; Animal models; Animals; Carpal tunnel syndrome; Carpal Tunnel Syndrome - etiology; Carpal Tunnel Syndrome - genetics; Carpal Tunnel Syndrome - metabolism; Carpal Tunnel Syndrome - pathology; Cartilage; Cartilage oligomeric matrix protein; Cartilage Oligomeric Matrix Protein - genetics; Cartilage Oligomeric Matrix Protein - metabolism; Cell death; Chondrocytes; Chondrocytes - pathology; Dysplasia; Endoplasmic Reticulum Stress - physiology; Entrapment; Extracellular matrix; Extracellular Matrix - pathology; Fibrosis; Genes; Humanities and Social Sciences; Humans; Inflammation; Ligaments; Ligaments - cytology; Ligaments - pathology; Matrix protein; multidisciplinary; Mutation; Oligomerization; Osteochondrodysplasias - genetics; Osteochondrodysplasias - pathology; Overuse injuries; Pathogenesis; Peripheral nerves; Population genetics; Protein folding; Proteins; Science; Science (multidisciplinary); Secretion; Tendons; Tendons - cytology; Tendons - pathology; Tenocytes - pathology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-17378-z

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. Familial carpal tunnel syndrome (CTS) is common, but causal genes are not characterized. Here the authors report two CTS-related mutations in two large families that impair secretion of COMP in tenocytes, leading to ER stress-induced unfolded protein response, inflammation and fibrosis in patients and mouse models.