Recurrent CAPN3 p.Asp753Asn Variant Supports a Potential Dominant Calpainopathy with Variable Clinical Expressivity

Limb-Girdle Muscular Dystrophies (LGMDs) are genetically heterogeneous disorders primarily affecting proximal limb muscles. The most common form, LGMDR1, results from biallelic <i>CAPN3</i> mutations encoding calpain-3, a muscle-specific protease. Recently, growing evidence implicates heterozygous <i>CAPN3</i> variants in autosomal dominant disease (LGMDD4), with pathogenic mechanisms still incompletely understood. In a retrospective multicenter Italian study of patients harboring monoallelic <i>CAPN3</i> variants (ClinicalTrials.gov NCT05956132), the p.Asp753Asn substitution was the most frequent change, detected in eight unrelated individuals. These patients, aged 6-80 years, exhibited a spectrum of presentations ranging from asymptomatic hyperCKemia and exertional myalgia to mild proximal weakness. Muscle biopsies showed mild, nonspecific myopathic changes, while calpain-3 expression was variably reduced. Structural modeling suggested that Asp753 may stabilize the Ca²⁺-bound conformation, with substitution potentially disrupting inter-domain interactions. Literature review identified 31 additional reports worldwide, confirming recurrence while highlighting marked phenotypic heterogeneity and limited clinical annotation. The aggregated evidence supports a pathogenic role for p.Asp753Asn, though the precise mechanism, potentially involving a dominant-negative effect, remains to be validated. These findings emphasize diagnostic challenges posed by single <i>CAPN3</i> variants and underscore the need for integrated clinical, segregation, and functional studies to clarify pathogenic mechanisms, refine counseling, and guide patient-specific rehabilitation and therapeutic strategies.