CAPN3 – Limb-Girdle Muscular Dystrophy

CAPN3 (calpain-3), encoded on chromosome 15q15.1, is a muscle-specific calcium-activated protease. Biallelic variants in CAPN3 cause autosomal recessive limb-girdle muscular dystrophy type 2A (LGMD2A), the most common recessive LGMD subtype. This association was first mapped by linkage in 21 independent pedigrees with segregation and mutation screening established pathogenicity across diverse populations (PMID:9150160). Early studies reported 16 unique mutations and identified 19 novel alleles, defining the broad heterogeneity of calpainopathy. Subsequent case series have expanded the variant spectrum and documented founder alleles in specific ethnic groups. The accumulated genetic and functional data firmly classify CAPN3 as a definitive LGMD gene. The disease is catalogued as Limb-Girdle Muscular Dystrophy.

LGMD2A is inherited in an autosomal recessive pattern, requiring biallelic CAPN3 loss-of-function variants. Segregation analyses confirm cosegregation in affected sibships and consanguineous families, with at least 19 additional affected relatives reported across studies (PMID:21172462). Large cohort screens (>530 subjects) identified 82 distinct CAPN3 mutations—missense, nonsense, frameshift, splice-site, and in-frame deletions—confirming allelic heterogeneity (PMID:16141003). A prototypical pathogenic variant is c.2338G>C (p.Asp780His), detected homozygously in an Indian patient and shown to cosegregate with disease (PMID:21386772). Founder and recurrent alleles such as c.550delA (p.Thr184ArgfsTer36) in Roma and Central European cohorts underscore mutational hotspots (PMID:31612648). Carrier frequency estimates range from 1:103 to 1:123,000 in different populations (PMID:16141003).

Clinically, LGMD2A presents with progressive symmetric proximal muscle weakness affecting the shoulder and pelvic girdles, often manifesting in the first two decades of life (PMID:34355366). Gower’s sign is common, and 55.8% of patients lose ambulation within years of onset (PMID:38298311). Serum creatine kinase is elevated and muscle biopsy shows dystrophic changes, including lobulated fibers and variable calpain-3 deficiency (PMID:11525884). Phenotypic variability correlates poorly with mutation class but may be influenced by modifier genes and ethnic background (PMID:12461690).

Functional studies demonstrate that LGMD2A arises from loss of calpain-3 proteolytic function. Nine disease-associated missense mutants (e.g., p.Val354Gly, p.Arg490Trp) abolish fodrin cleavage activity while sometimes preserving autolysis or titin binding, pinpointing substrate proteolysis as the pathogenic mechanism (PMID:9642272). Autolytic decay is modulated by unique insertion sequences and the titin N2A fragment, which stabilizes p94 and regulates its activation (PMID:16627476). Knock-in mice expressing protease-inactive CAPN3 (C129S) recapitulate mild dystrophic changes and reveal non-enzymatic roles in sarcoplasmic reticulum calcium handling (PMID:21295580). Gene expression profiling in CAPN3-null mice implicates dysregulation of cytoskeletal proteases and ubiquitin ligases, linking CAPN3 to sarcomere maintenance pathways (PMID:22820870). These data support a loss-of-function mechanism across diverse variant classes.

Diagnostic yield for CAPN3 variants is enhanced by targeted next-generation sequencing panels: up to 28.4% of Italian LGMD cases and 19.6% of Saudi families are attributable to CAPN3 (PMID:17994539, PMID:34355366). Combined sequence and copy-number assays achieve 76% sensitivity in consanguineous cohorts, with CAPN3 variants accounting for 5.4% of diagnoses (PMID:27671536). For unresolved cases, transcript analysis and autolytic assays can uncover splice-site and deep-intronic mutations, highlighting the value of mRNA-based diagnostics (PMID:17979987, PMID:16971480). Genetic counseling in affected families informs recurrence risk, carrier screening, and prenatal testing strategies.

In summary, the CAPN3–LGMD2A association is definitive, supported by robust genetic segregation, extensive variant cataloging, concordant functional impairment assays, and animal models. CAPN3 loss-of-function underlies sarcomeric instability and impaired proteolysis in skeletal muscle. Molecular confirmation of CAPN3 variants is critical for accurate diagnosis, prognosis, and personalized care. Key Take-home: Biallelic CAPN3 mutations cause LGMD2A, a clinically variable yet genetically definitive dystrophy where precise molecular diagnosis guides management.

References

• American journal of human genetics • 1997 • Multiple independent molecular etiology for limb-girdle muscular dystrophy type 2A patients from various geographical origins. PMID:9150160
• Journal of clinical neuromuscular disease • 2010 • Limb-girdle muscular dystrophy type 2A resulting from homozygous G2338C transversion mutation in the calpain-3 gene. PMID:21386772
• European journal of medical genetics • 2011 • SNP-array based whole genome homozygosity mapping: a quick and powerful tool to achieve an accurate diagnosis in LGMD2 patients. PMID:21172462
• Journal of medical genetics • 2005 • Extensive scanning of the calpain-3 gene broadens the spectrum of LGMD2A phenotypes. PMID:16141003
• 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
• European review for medical and pharmacological sciences • 2021 • Clinical and genetic features of Calpainopathies in Saudi Arabia - a descriptive cross-sectional study. PMID:34355366
• Cureus • 2024 • Management of a 25-Year-Old Female Patient With Limb-Girdle Muscular Dystrophy With Physiotherapy: A Case Report. PMID:38298311
• Human mutation • 2008 • Clinical, molecular, and protein correlations in a large sample of genetically diagnosed Italian limb girdle muscular dystrophy patients. PMID:17994539

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