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Updated: Mar 19, 2026
Functional Characterization of Endogenously Expressed Human RYR1 Variants
Published on: June 9, 2021
CAV3 mutations causing exercise intolerance, myalgia and rhabdomyolysis: Expanding the phenotypic spectrum of
Renata Siciliani Scalco1, Alice R Gardiner2, Robert D S Pitceathly3
1MRC Centre for Neuromuscular Diseases and Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; CAPES Foundation, Ministry of Education of Brazil, Brasilia DF, Brazil.
Abstract:
Rhabdomyolysis is often due to a combination of environmental trigger(s) and genetic predisposition; however, the underlying genetic cause remains elusive in many cases. Mutations in CAV3 lead to various neuromuscular phenotypes with partial overlap, including limb girdle muscular dystrophy type 1C (LGMD1C), rippling muscle disease, distal myopathy and isolated hyperCKemia. Here we present a series of eight patients from seven families presenting with exercise intolerance and rhabdomyolysis caused by mutations in CAV3 diagnosed by next generation sequencing (NGS) (n = 6). Symptoms included myalgia (n = 7), exercise intolerance (n = 7) and episodes of rhabdomyolysis (n = 2). Percussion-induced rapid muscle contractions (PIRCs) were seen in five out of six patients examined. A previously reported heterozygous mutation in CAV3 (p.T78M) and three novel variants (p.V14I, p.F41S, p.F54V) were identified. Caveolin-3 immunolabeling in muscle was normal in 3/4 patients; however, immunoblotting showed more than 50% reduction of caveolin-3 in five patients compared with controls. This case series demonstrates that exercise intolerance, myalgia and rhabdomyolysis may be caused by CAV3 mutations and broadens the phenotypic spectrum of caveolinopathies. In our series, immunoblotting was a more sensitive method to detect reduced caveolin-3 levels than immunohistochemistry in skeletal muscle. Patients presenting with muscle pain, exercise intolerance and rhabdomyolysis should be routinely tested for PIRCs as this may be an important clinical clue for caveolinopathies, even in the absence of other "typical" features. The use of NGS may expand current knowledge concerning inherited diseases, and unexpected/atypical phenotypes may be attributed to well-known human disease genes.
Insights
Genetic mutations in CAV3 can cause rhabdomyolysis and exercise intolerance. This study identified new and known CAV3 variants in patients, highlighting immunoblotting as a sensitive diagnostic tool for caveolinopathies.
Area of Science:
- Genetics
- Neuromuscular Disorders
- Molecular Biology
Background:
- Rhabdomyolysis often results from environmental triggers and genetic factors, but the genetic cause is frequently unknown.
- Mutations in the CAV3 gene are linked to various neuromuscular conditions, including limb girdle muscular dystrophy type 1C, rippling muscle disease, distal myopathy, and isolated hyperCKemia.
Purpose of the Study:
- To investigate the genetic basis of exercise intolerance and rhabdomyolysis in patients with suspected inherited muscle disorders.
- To identify mutations in the CAV3 gene as a cause for these symptoms and expand the known phenotypic spectrum of caveolinopathies.
Main Methods:
- Next-generation sequencing (NGS) was employed to diagnose mutations in CAV3 in eight patients from seven families.
- Clinical data, including symptoms like myalgia and exercise intolerance, and physical examination findings such as percussion-induced rapid muscle contractions (PIRCs), were collected.
- Muscle tissue analysis included caveolin-3 immunolabeling and immunoblotting to assess protein levels.
Main Results:
- NGS identified CAV3 mutations in six patients, including a known mutation (p.T78M) and three novel variants (p.V14I, p.F41S, p.F54V).
- Common symptoms were myalgia (7/8), exercise intolerance (7/8), and rhabdomyolysis episodes (2/8). PIRCs were observed in five of six examined patients.
- Immunoblotting revealed a significant reduction (>50%) in caveolin-3 levels in five patients, while immunolabeling was normal in most cases, indicating immunoblotting's higher sensitivity.
Conclusions:
- Mutations in CAV3 are a significant cause of exercise intolerance, myalgia, and rhabdomyolysis, broadening the spectrum of caveolinopathies.
- Immunoblotting is a more sensitive diagnostic method than immunohistochemistry for detecting reduced caveolin-3 levels in skeletal muscle.
- PIRCs serve as a crucial clinical indicator for caveolinopathies, even in the absence of typical symptoms, warranting routine testing in patients with unexplained muscle pain and exercise intolerance.
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