Mutations in COMP cause familial carpal tunnel syndrome

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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Bo Gao, Yingzi Yang and Shusen Cui Jun 5, 2020 No software was used for data collection.
The following software tools are publicly available and used as described in METHODS: • Linkage analysis: Superlink-SNP 1.1, FASTLINK 4.1P • Sequence data analysis tools: MPG (Most Probable Genotype) and Varsifter (https://research.nhgri.nih.gov/software/VarSifter/) • MRI was performed on a 3.0T MRI scanner (Siemens Skyra VE11) and analyzed by 3D MPR (Multiplanar reconstruction) • MR scanner platform software (SIEMENS-VE11) and RadiAnt DICOM Viewer (SIEMENS-VE40B) • Mouse X-Ray was performed in a Varian linear accelerator 6 MV X-ray machine • TEM sections were scanned by a Philips CM100 transmission electron microscope • TEM firbils distribution was plotted by Prism 6.0 • Images were acquired by a Nikon fluorescent microscope or a Zeiss LSM710 confocal microscope • Quantification of images was performed by ImageJ software (version:2.0.0-rc-43/1.50e) • Prism version 6 was used for statistical analysis nature research | reporting summary

October 2018
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All studies must disclose on these points even when the disclosure is negative. Sample size was as large as possible with at least three independent replicates in critical experiments and the number is sufficient to support the statistical analyses performed in this manuscripts. Only few experiments which are not critical were conducted twice. For mouse studies, we achieved !3 mice per genotype per experiment and/or condition. This was based on Mendelian segregation and not any imposed cutoffs.
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