Mutations in COMP cause familial carpal tunnel syndrome.
Animals
Carpal Tunnel Syndrome
/ etiology
Cartilage Oligomeric Matrix Protein
/ genetics
Chondrocytes
/ pathology
Endoplasmic Reticulum Stress
/ physiology
Extracellular Matrix
/ pathology
Humans
Inflammation
Ligaments
/ cytology
Mutation
Osteochondrodysplasias
/ genetics
Tendons
/ cytology
Tenocytes
/ pathology
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
20 07 2020
20 07 2020
Historique:
received:
17
10
2019
accepted:
21
06
2020
entrez:
21
7
2020
pubmed:
21
7
2020
medline:
29
8
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32686688
doi: 10.1038/s41467-020-17378-z
pii: 10.1038/s41467-020-17378-z
pmc: PMC7371736
doi:
Substances chimiques
Cartilage Oligomeric Matrix Protein
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3642Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR070877
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA222571
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE025866
Pays : United States
Commentaires et corrections
Type : ErratumIn
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