Mutations in COMP cause familial carpal tunnel syndrome

Nat Commun. 2020 Jul 20;11(1):3642. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carpal Tunnel Syndrome* / etiology
  • Carpal Tunnel Syndrome* / genetics
  • Carpal Tunnel Syndrome* / metabolism
  • Carpal Tunnel Syndrome* / pathology
  • Cartilage Oligomeric Matrix Protein* / genetics
  • Cartilage Oligomeric Matrix Protein* / metabolism
  • Chondrocytes / pathology
  • Endoplasmic Reticulum Stress / physiology
  • Extracellular Matrix / pathology
  • Humans
  • Inflammation
  • Ligaments / cytology
  • Ligaments / pathology
  • Mutation
  • Osteochondrodysplasias / genetics
  • Osteochondrodysplasias / pathology
  • Tendons / cytology
  • Tendons / pathology
  • Tenocytes / pathology


  • Cartilage Oligomeric Matrix Protein