CAPN3 – Autosomal Recessive Limb-Girdle Muscular Dystrophy

CAPN3 encodes p94, a calcium-activated, skeletal muscle-specific protease. Pathogenic biallelic variants in CAPN3 cause autosomal recessive limb-girdle muscular dystrophy type 2A (LGMD2A; AR LGMDR1) characterized by progressive proximal muscle weakness and elevated serum creatine kinase (PMID:39973406).

Genetic Evidence

LGMD2A follows autosomal recessive inheritance with homozygous or compound heterozygous CAPN3 variants. A founder homozygous missense variant, c.367C>A (p.Gln123Lys), was identified in four unrelated Iraqi Jewish families presenting with childhood toe-walking and hyperCKemia (PMID:39973406). In a Dutch cohort of 244 patients, 68 (28%) carried two CAPN3 mutations, including missense, frameshift, splice-site, and nonsense alleles, confirming CAPN3 as the most common AR-LGMD locus in that population (PMID:30919934). Over 97 distinct pathogenic CAPN3 mutations (53 missense, 32 small indels, 8 splice-site, 4 nonsense) have been described, many private but with recurrent alleles in specific ancestries (PMID:10330340).

Segregation

Linkage analyses in 21 LGMD2A families demonstrated co-segregation of CAPN3 pathogenic variants with disease across multiple generations, supporting recessive inheritance and allelic heterogeneity (PMID:9150160).

Functional Evidence

Functional assays of recombinant p94 missense mutants showed loss or severe reduction of proteolytic activity against fodrin, whereas autolytic and titin-binding abilities were variably preserved, pinpointing protease inactivation as the key pathogenic mechanism (PMID:9642272). Transgenic mice overexpressing human CAPN3 isoforms demonstrated that full-length p94 is stable and its loss impairs muscle maturation without overt toxicity, confirming in vivo relevance (PMID:12084932). Proteomic profiling identified Myosin Light Chain 1 as a CAPN3 substrate, implicating calpain 3 in sarcomere remodeling (PMID:17051641).

Conflicting Evidence

A subset of LGMD2A muscle biopsies exhibit normal p94 proteolytic activity despite pathogenic CAPN3 variants, suggesting that non-proteolytic functions of calpain 3, such as sarcoplasmic reticulum Ca²⁺ handling, may also contribute to disease pathogenesis (PMID:21295580).

Integration & Clinical Utility

Extensive genetic and experimental data establish a definitive relationship between CAPN3 loss-of-function and AR LGMD2A. Genetic testing for CAPN3 variants should be prioritized in patients with early toe-walking, hyperCKemia, and proximal weakness. Functional assays remain valuable for variant classification and may guide future therapies targeting both proteolytic and non-proteolytic roles of p94.

Key take-home: CAPN3 variants are definitively causal for autosomal recessive LGMD2A; early molecular diagnosis facilitates genetic counseling and patient management.

References

• Journal of neuromuscular diseases • 2025 • A rare homozygous CAPN3 variant with distinct clinical features in unrelated families of Iraqi Jewish descent. PMID:39973406
• Clinical Genetics • 2019 • Autosomal recessive limb-girdle and Miyoshi muscular dystrophies in the Netherlands: The clinical and molecular spectrum of 244 patients. PMID:30919934
• American Journal of Human Genetics • 1997 • Multiple independent molecular etiology for limb-girdle muscular dystrophy type 2A patients from various geographical origins. PMID:9150160
• 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
• Proceedings of the National Academy of Sciences of the United States of America • 2002 • Stable expression of calpain 3 from a muscle transgene in vivo: immature muscle in transgenic mice suggests a role for calpain 3 in muscle maturation. PMID:12084932

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