Dominant rhabdomyolysis linked to a recurrent ATP2A2 variant reducing SERCA2 function in muscle

Abstract Rhabdomyolysis is an acute failure of cellular homeostasis resulting in muscle breakdown, triggered by trauma, infection, drugs or strenuous exercise. Recurrent rhabdomyolysis is often associated with genetic and metabolic defects of skeletal muscle. The sarcoendoplasmic reticulum Ca2+-ATPase 2 (SERCA2), encoded by the ATP2A2 gene, is an intracellular pump located in the sarcoplasmic and endoplasmic reticulum that is essential for maintaining intracellular calcium (Ca2+) homeostasis and is highly expressed in slow-twitch muscle. Heterozygous loss-of-function variants in ATP2A2 have previously been associated with dominant skin diseases, but not with rhabdomyolysis. In this study, we report a rare novel heterozygous missense variant in the ATP2A2 gene (c.1583G>A, p.R528Q) identified in 14 affected individuals from three unrelated families with recurrent rhabdomyolysis. Muscle biopsy revealed mild myopathic changes with fibre type uniformity, core-like structures and Z-band streaming, but normal levels of SERCA2 protein. Ca2+ imaging showed that sarcoplasmic reticulum Ca2+ reuptake mediated by SERCA was significantly slower in myotubes derived from patient fibroblasts carrying the c.1583G > A variant. We hypothesize that the ATP2A2 variant impairs SERCA2a function in slow-twitch muscle, disrupting SR Ca2+ reuptake and causing cytosolic Ca2+ overload following a trigger, leading to recurrent rhabdomyolysis. Morphant zebrafish embryos with atp2a2a knockdown showed morphological and functional muscle abnormalities, with a reduction in body length and trunk muscle area associated with a reduction in locomotor activity in zebrafish larvae. Co-injection of wild-type human SERCA2a mRNA, but not variant SERCA2a mRNA, resulted in complete rescue of the phenotype. This study reveals a novel association between a heterozygous ATP2A2 variant and autosomal dominant recurrent rhabdomyolysis. Both in vitro and in vivo studies provide evidence that the variant alters SERCA2 function, causing abnormal intracellular Ca2+ homeostasis in skeletal muscle, resulting in rhabdomyolysis. The work not only increases understanding of autosomal dominant rhabdomyolysis but also provides a diagnostic conclusion for three generations of affected individuals across the three families.