2. Academic Validation
  3. Mutations in COMP cause familial carpal tunnel syndrome

Mutations in COMP cause familial carpal tunnel syndrome

  • Nat Commun. 2020 Jul 20;11(1):3642. doi: 10.1038/s41467-020-17378-z.
Chunyu Li # 1,  Ni Wang # 2,  Alejandro A Schäffer 3,  Xilin Liu 1,  Zhuo Zhao 1,  Gene Elliott 4,  Lisa Garrett 4,  Nga Ting Choi 2,  Yueshu Wang 1,  Yufa Wang 1,  Cheng Wang 2,  Jin Wang 2,  Danny Chan 2,  Peiqiang Su 5,  Shusen Cui 6,  Yingzi Yang 7 8,  Bo Gao 9 10
Affiliations

Affiliations

  • 1 Department of Hand Surgery, China-Japan Union Hospital of Jilin University, Changchun, China.
  • 2 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 3 National Center for Biotechnology Information and National Cancer Institute, National Institutes of Health, Bethesda, MD, US.
  • 4 National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, US.
  • 5 Department of Orthopaedic Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 6 Department of Hand Surgery, China-Japan Union Hospital of Jilin University, Changchun, China. [email protected].
  • 7 National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, US. [email protected].
  • 8 Department of Developmental Biology, Harvard School of Dental Medicine, Harvard Stem Cell Institute, Harvard University, Boston, MA, US. [email protected].
  • 9 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. [email protected].
  • 10 National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, US. [email protected].
  • # Contributed equally.
PMID: 32686688 DOI: 10.1038/s41467-020-17378-z
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.

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