Mutations in COMP cause familial carpal tunnel syndrome

Chunyu Li,Chunyu Li,Ni Wang,Yingzi Yang,Yingzi Yang,Yingzi Yang,Yingzi Yang,Zhuo Zhao,Zhuo Zhao,Shusen Cui,Shusen Cui,Yueshu Wang,Yueshu Wang,Xilin Liu,Danny Chan,Peiqiang Su,Peiqiang Su,Lisa Garrett,Lisa Garrett,Jin Wang,Gene Elliott,Gene Elliott,Cheng Wang,Alejandro A Schäffer,Alejandro A Schäffer,Nga Ting Choi,Bo Gao,Bo Gao,Bo Gao,Yufa Wang,Yufa Wang

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.

Highlights

Carpal tunnel syndrome (CTS) is the most common peripheral nerve entrapment syndrome, affecting a large proportion of the general population
We previously described a pedigree with isolated bilateral CTS and autosomal-dominant inheritance[33]
We identified two missense mutations in cartilage oligomeric matrix protein (COMP) as the basis of familial CTS, a progressive, painful condition caused by nerve compression in the wrist

Summary

Introduction

Carpal tunnel syndrome (CTS) is the most common peripheral nerve entrapment syndrome, affecting a large proportion of the general population. 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). Variants in some genes, including BGN, ACAN, COL5A1, and IL6R, have been associated with the risk of sporadic CTS26–28 Since environmental factors, such as repetitive hand use, contribute to CTS by preferentially affecting the dominant hand, the high percentage of bilateral CTS (about 60%)[29,30] and twin studies (estimated 46% heritability)[31] suggests that genetic factors significantly influence CTS susceptibility. We report identification of two causative mutations in COMP gene in two large families with a dominant inheritance pattern of bilateral CTS. Functional studies in the CTS-specific patients’ tissues and in genetically modified animal models reveal the molecular and pathogenic mechanism of the COMP mutation.

Methods

Results

Conclusion