CAPN3 – Autosomal Recessive Limb-Girdle Muscular Dystrophy Type 2A

Calpain-3, encoded by CAPN3 (HGNC:1480), is a muscle-specific calcium-activated protease whose loss of function causes autosomal recessive limb-girdle muscular dystrophy type 2A (LGMD2A, Disease). LGMD2A is characterized by progressive proximal muscle weakness, elevated serum creatine kinase, and onset typically in the first or second decade. Clinical diagnoses are confirmed by identification of biallelic CAPN3 variants and, in some cases, functional assays demonstrating deficient protease activity [PMID:8784805].

Genetic evidence for CAPN3 in LGMD2A is substantial: hundreds of probands have been reported with homozygous or compound heterozygous CAPN3 mutations across diverse populations. Founder and recurrent alleles, such as the c.550del deletion, account for a significant fraction of cases in Europe and elsewhere [PMID:14981715]. Multi-family segregation and consanguineous pedigrees demonstrate clear autosomal recessive inheritance ([PMID:9771675]).

Segregation analyses within inbred families reveal complete co-segregation of CAPN3 variants with LGMD2A phenotypes, including affected sib pairs and extended kindreds. Novel deep intronic and structural rearrangements have been uncovered by transcript- and genome-level studies, expanding the mutational spectrum and reinforcing the gene–disease link [PMID:31498126].

Functional studies establish that pathogenic CAPN3 missense and frameshift variants abolish or severely impair calpain-3 proteolytic activity against substrates such as fodrin and disrupt autolytic activation. Autolysis assays in muscle biopsies show loss of activity even when protein levels appear normal, highlighting the necessity of functional testing for diagnosis [PMID:9642272; PMID:14578192]. Animal and cellular models confirm a role for calpain-3 in sarcomere maintenance, calcium handling, and muscle maturation [PMID:12084932].

Some CAPN3 missense mutations retain proteolytic function yet cause disease through reduced titin binding or altered stability, indicating non-enzymatic roles for calpain-3 in muscle integrity. These findings underscore the importance of assessing both catalytic activity and protein interactions in variant interpretation [PMID:21624972].

Integration of genetic and experimental evidence yields a definitive gene-disease association: CAPN3 variants produce a loss-of-function mechanism consistent with haploinsufficiency in homozygous or compound heterozygous states. Diagnosis relies on NGS panels targeted to CAPN3, supplemented by functional assays to confirm pathogenicity. Early genetic confirmation enables reproductive counselling, prenatal diagnosis, and enrollment in emerging gene-therapy trials.

Key Take-home: Biallelic CAPN3 loss-of-function variants cause LGMD2A through impaired calpain-3 activity and disrupted sarcomeric homeostasis; precise molecular and functional analyses are essential for accurate diagnosis and counselling.

References

• Neuromuscular Disorders • 1996 • Prenatal diagnosis of limb-girdle muscular dystrophy type 2A PMID:8784805
• Muscle & Nerve • 1998 • Clinical, pathological, and genetic features of limb-girdle muscular dystrophy type 2A with new calpain 3 gene mutations in seven patients from three Japanese families PMID:9771675
• The Journal of Biological Chemistry • 1998 • Functional defects of a muscle-specific calpain, p94, caused by mutations associated with limb-girdle muscular dystrophy type 2A PMID:9642272
• The American Journal of Pathology • 2003 • Loss of calpain-3 autocatalytic activity in LGMD2A patients with normal protein expression PMID:14578192
• Journal of Clinical Neuromuscular Disease • 2015 • Limb-Girdle Muscular Dystrophy Type 2A Resulting From c.C479G and c.G1818A Mutations in the Calpain-3 Gene PMID:26583491
• Journal of Clinical Neuroscience • 2018 • A novel CAPN3 mutation in late-onset limb-girdle muscular dystrophy with early respiratory insufficiency PMID:29685414

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