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HKUMed reveals the pathogenic gene of carpal tunnel syndrome, providing new directions for prevention and treatment

27 July 2020

The LKS Faculty of Medicine of The University of Hong Kong (HKUMed), in collaboration with China-Japan Union Hospital of Jilin University, Mainland China, Harvard University and National Institutes of Health (NIH), U.S., have discovered that genetic mutation is one of the key risk factors of carpal tunnel syndrome (CTS). The study revealed a previously unrecognised mechanism in CTS pathogenesis and provided new insight into the development of new preventive and therapeutic strategies. The findings are now published in the leading multidisciplinary science journal Nature Communications [link to the publication].

Background

CTS, sometimes also known as “mouse hand”, is a fairly common condition in people, who have repeated and forceful movements of the hand and the wrist in their work and daily life, such as I.T. professionals, construction workers, cleaners and housewives. CTS is characterised by pain, numbness, tingling and weakness in the hand and the wrist due to excessive pressure on the median nerve within the carpal tunnel, which is often caused by swelling and thickening of soft connective tissues surrounding the median nerve. 

CTS is a progressive disorder that can worsen without appropriate treatment, leading to nerve damage, permanent muscle atrophy, or loss of hand function. It is estimated to affect 1-5% of the general population¹ and is a leading cause of work disability. It is more common in people older than 40, and women are more likely to develop the condition than men; and more than one-half of cases will experience bilateral symptoms. According to the 0.1-0.3% incidence of CTS in U.S., the number of new cases in Hong Kong is estimated to be at least 7,000 per year². 

In the past, most people believed that environmental factors, such as repetitive use of hands and wrists, were the main causes of CTS. However, familial occurrence of CTS in 17–39% of cases^3,4, a number of CTS families reported over the world and a large twin study that found an approximate 46% genetic contribution⁵, suggest that genetic factors significantly influence CTS susceptibility. Nevertheless, so far, no causal genes were identified.

Research findings

It is challenging to study the pathogenesis of complex human diseases due to their multifactorial and polygenic nature, but Mendelian forms of common diseases have proven invaluable in identifying disease genes and elucidating pathogenic mechanisms. In this study, the research team analyzed two large pedigrees of CTS (nearly 100 cases) by using clinical, genetic, histological and biochemical methods. They discovered that mutations in a gene called COMP caused CTS in these two families. 

COMP is highly expressed in the soft connective tissues surrounding the median nerve. The mutant COMP induced cellular stress response, leading to an accumulation of fibrotic and adipogenic cells. Eventually, fibrotic connective tissues in the human carpal tunnel become thickened and swollen, thus compressing the median nerve in causing CTS. Scientists further generated a CTS animal model, which recapitulated the progressive phenotype of human patients, and found that injury could significantly accelerate CTS onset.

“Our findings provide solid evidence that genetic mutations can cause CTS, and COMP is the first identified causative gene. We also revealed cellular stress response as a novel mechanism underlying the pathogenesis of CTS, which lays the foundation for the future development of new treatments by inhibiting such response,” said Dr Gao Bo, Assistant Professor of the School of Biomedical Sciences, HKUMed, who led the research. 

The onset time and symptoms of familial patients are usually earlier and stronger than sporadic patients because the major risk factor is intrinsic (e.g. genetic) rather than extrinsic (e.g. life style, occupation). But sporadic CTS more likely result from combined effects of genetic susceptibility and environmental factors. “When consulting a doctor, the patient should inform whether there are other affected members in his/her family, which will assist in diagnosis. I would also suggest, when introducing CTS to the public, the Hospital Authority should include genetic predisposition as one of the important risk factors of CTS,” Dr Gao said.

About the Research Team

In collaboration with multiple institutions, the research was led by Dr Gao Bo, Assistant Professor of the School of Biomedical Sciences, HKUMed. Dr Li Chun-yu, China-Japan Union Hospital of Jilin University, Mainland China and Dr Wang Ni, Research Associate, School of Biomedical Sciences, HKUMed are co-first authors. Key international collaborators include Professor Yang Ying-zi, Harvard University, U.S.; Professor Cui Shu-sen, China-Japan Union Hospital of Jilin University, Mainland China and Dr Alejandro Schaffer, National Institutes of Health, U.S.. Other HKU scientists contributing to the research include Professor Danny Chan, S Y and H Y Cheng Professorship in Stem Cell Biology and Regenerative Medicine, Interim Director of School of Biomedical Sciences, HKUMed and Assistant Dean (Research postgraduate studies), HKUMed; Dr Wang Jin, Post-doctoral Fellow, School of Biomedical Sciences, HKUMed; Dr Wang Cheng, former Post-doctoral Fellow, School of Biomedical Sciences, HKUMed; and Ms Vanessa Choi Nga-ting, Technician, School of Biomedical Sciences, HKUMed.

The work was supported in part by Health and Medical Research Fund (Project #05160946) in Hong Kong.

1. Atroshi, I. et al. Prevalence of carpal tunnel syndrome in a general population. JAMA 282, 153–158 (1999).
2. Bickel, K.D. Carpal tunnel syndrome. J Hand Surg Am 35, 147-52 (2010).
3. Radecki, P. The familial occurrence of carpal tunnel syndrome. Muscle Nerve 17, 325–330 (1994).
4. Puchalski, P. et al. Familial occurrence of carpal tunnel syndrome. Neurol. Neurochir. Pol. 53, 43–46 (2019).
5. Hakim, A. J. et al. The genetic contribution to carpal tunnel syndrome in women: a twin study. Arthritis Rheum. 47, 275–279 (2002).