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Mutations in COMP Cause Familial Carpal Tunnel Syndrome

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Mutations in COMP Cause Familial Carpal Tunnel Syndrome ARTICLE https://doi.org/10.1038/s41467-020-17378-z OPEN Mutations in COMP cause familial carpal tunnel syndrome Chunyu Li1,7, Ni Wang2,7, Alejandro A. Schäffer3, Xilin Liu1, Zhuo Zhao1, Gene Elliott4, Lisa Garrett4, Nga Ting Choi2, Yueshu Wang1, Yufa Wang1, Cheng Wang2, Jin Wang2, Danny Chan2, Peiqiang Su5, ✉ ✉ ✉ Shusen Cui 1,8 , Yingzi Yang 4,6,8 & Bo Gao 2,4,8 Carpal tunnel syndrome (CTS) is the most common peripheral nerve entrapment syndrome, 1234567890():,; 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/liga- ments. The extracellular matrix (ECM) organization is also altered. Our studies uncover a previously unrecognized mechanism in CTS pathogenesis. 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 Developmental Biology, Harvard School of Dental Medicine, Harvard Stem Cell Institute, Harvard University, Boston, MA, US. 7These authors contributed equally: Chunyu Li, Ni Wang. 8These authors jointly supervised ✉ this work: Shusen Cui, Yingzi Yang and Bo Gao. email: [email protected]; [email protected]; [email protected] NATURE COMMUNICATIONS | (2020) 11:3642 | https://doi.org/10.1038/s41467-020-17378-z | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-17378-z TS, characterized by paresthesia, pain, and numbness in carpal tunnels, similar to, but more severe than what has been the hands due to excessive pressure on the median nerve, found in other sporadic CTS patients. The affected family C 1,2 is a common disorder treated by hand surgeons . CTS is members’ transverse carpal ligaments (TCLs) and flexor tendons often caused by swelling and thickening of soft connective tissues were severely enlarged, restricting the space within the carpal surrounding the median nerve within the carpal tunnel, rather tunnel, leading to median nerve compression (Supplementary than a problem with the nerve itself3–9. Enlarged and fibrotic soft Fig. 2a). connective tissues can result in compression or traction on the We also reviewed hospital records of (supposedly) sporadic median nerve at the carpal tunnel. CTS affects 1–5% of the CTS patients who underwent carpal tunnel release surgeries. Two general population, and is a leading cause of work disability10,11. sister patients drew our attention (III-5 and III-7 of Family 2 in In the United States, CTS causes $1–2 billion in annual direct Fig. 1a). Genealogical investigation revealed that their family costs12; the number of CTS surgeries is continually increasing13. included 11 living CTS patients. Compared with Family 1, the Without appropriate treatment, CTS can lead to nerve damage, CTS symptoms of Family 2 are less severe. The age of onset is permanent muscle atrophy, or loss of hand function. However, between 30 and 50 s (Supplementary Table 1). Family 2 patients despite its prevalence and considerable psychological and eco- had previously complained of joint pains and were further nomic impact, the molecular and pathogenic bases of CTS remain examined by orthopedists. The orthopedists suspected that largely unknown. Family 2 patients have MED, which is characterized by epiphyseal While CTS is mostly sporadic and idiopathic, familial occur- deformity with joint pain and stiffness. However, no joint or rence of CTS in 17–39% of cases suggests a genetic growth-plate defects were observed in CTS patients in Family 1. predisposition14,15. CTS is also a symptom in two syndromic Some affected members from each family, as well as familial diseases, transthyretin-related amyloidosis and Charcot– and nonfamilial controls, were examined by magnetic resonance Marie–Tooth (CMT) disease, in which CTS is one of many imaging (MRI), which revealed swelling of flexor tendons and manifestations of neuropathy caused by either defects in the smaller median nerves in patients’ carpal tunnels (Fig. 1b). nerve itself or amyloid deposits16,17. TTR and SH3TC2 mutations Like we observed in the carpal tunnel release surgery, MRI have been identified in amyloidosis and CMT patients with CTS, showed that the patients’ TCLs were significantly thickened respectively18,19. A few nonsyndromic CTS pedigrees with (Fig. 1c). Flexor pollicis longus tendons and Achilles tendons of autosomal-dominant inheritance have been reported, but no Family 1 patients also tended to be bigger (Supplementary Fig. 2b, causal genes or loci were identified16,17,20–25. Variants in some c), suggesting a systemic change in patients’ tendons/ligaments. genes, including BGN, ACAN, COL5A1, and IL6R, have been Because MED patients may exhibit ligamentous laxity, we further associated with the risk of sporadic CTS26–28. Since environ- assessed the mobility of their thumbs, little fingers, wrists, and mental factors, such as repetitive hand use, contribute to CTS by ankles. While no joint hypermobility was observed in Family 2 preferentially affecting the dominant hand, the high percentage of patients, joint hypomobility was prominent in Family 1 patients bilateral CTS (about 60%)29,30 and twin studies (estimated 46% (Supplementary Fig. 3). heritability)31 suggests that genetic factors significantly influence CTS susceptibility. A recent genome-wide association study Histological analysis of patients’ biopsies. To understand the (GWAS) of CTS identified a couple of CTS-associated variants mechanism underlying soft connective tissues’ swelling and within genes implicated in growth and ECM architecture, thickening, we performed histological analysis on TCL tissues although the causative link has not been established32. from Family 1 patients and unrelated controls. Consistent with Here, we report identification of two causative mutations in MRI findings, the patients’ TCLs were markedly thicker than COMP gene in two large families with a dominant inheritance controls (Fig. 2a). In patients’ samples, we identified collagen pattern of bilateral CTS. Patients in Family 1 exhibit severe CTS fragmentation, edema (asterisk in Fig. 2a), neovascular structure symptoms only, but patients in Family 2 have both CTS and (arrows in Fig. 2a), and lipomatosis (Fig. 2b), with mild amy- multiple epiphyseal dysplasia (MED). Functional studies in the loidosis and few skeletal muscles (Supplementary Fig. 4a). We CTS-specific patients’ tissues and in genetically modified animal also found a large amount of alpha-smooth muscle actin (α- models reveal the molecular and pathogenic mechanism of the SMA)-positive cells (Fig. 2c). As α-SMA also labels blood vessels, COMP mutation. Our studies reveal critical roles of ECM pro- its co-staining with CD34, an endothelial cell marker, was used to teins and cellular stress response in the pathogenesis of CTS. + − count α-SMA CD34 myofibroblasts. This revealed an increased number of myofibroblasts and thickening of the vascular walls in ’ Results CTS patients TCLs (Supplementary Fig. 4b). The upregulation of type III collagen and FSP1 in CTS patients also indicates strong Patients and clinical examination. We previously described a fibrosis in TCLs (Fig. 2d and Supplementary Fig. 4c). These pedigree with isolated bilateral CTS and autosomal-dominant histological features in the familial CTS patients resembled fea- inheritance33. Further genealogical investigations identified a – tures reported in sporadic, idiopathic CTS patients35 39. Trans- larger multiplex family (Family 1 in Fig. 1a and Supplementary mission electron microscopy (TEM) identified ectopic small Fig. 1). Initial CTS symptoms in most affected family members fibrils and contrast difference in ECM of patients’ TCLs (Fig. 2e), occurred at 20–30 years of age, earlier than the typical onset of suggesting a change in ECM composition and organization. CTS between 45 and 6434. Median nerve entrapment in affected Immuno-TEM showed that these ectopic small fibrils contained family members caused pain, paranesthesia, and numbness in the several main components of ECM, such as type I collagen, type III thumb, middle, and index fingers that are innervated by the collagen, and COMP. Type III collagen appeared more abundant median nerve. Symptoms were exacerbated at night, by overuse in the ectopic small fibrils than in the normal fibrils (Supple- or by exercise. Patients had typical CTS symptoms and positive mentary
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