A Homozygous ATP2A2 Variant Alters Sarcoendoplasmic Reticulum Ca 2+ -ATPase 2 Function in Skeletal Muscle and Causes a Novel Vacuolar Myopathy.

Aims: Sarcoendoplasmic reticulum Ca ²⁺ -ATPase 2 (SERCA2), encoded by ATP2A2, is a key protein involved in intracellular Ca ²⁺ homeostasis. The SERCA2a isoform is predominantly expressed in cardiomyocytes and type I myofibres. Variants in this gene are related to Darier disease, an autosomal dominant dermatologic disorder, but have never been linked to myopathy. We describe four patients suffering from a novel myopathy caused by a homozygous missense variant in ATP2A2.
Methods: We studied a family with four individuals suffering from an adult-onset skeletal myopathy. We evaluated the clinicopathological phenotype, muscle imaging, and genetic workup including whole genome sequencing and segregation analysis. SERCA2 expression in skeletal muscle was assessed. Functional studies to evaluate Ca ²⁺ handling in patient myotubes in response to electrical stimulation or caffeine exposure were performed.
Results: Four sisters developed slowly progressive proximal weakness in adulthood. Biopsy findings showed small vacuoles restricted to type I myofibres. Ultrastructural analysis showed sarcotubular dilation and autophagic vacuoles. Genome sequencing revealed a homozygous variant in ATP2A2 (c.1117G > A, p.(Glu373Lys)) which segregated with the disease. Immunohistochemistry suggested that there was SERCA2 mislocalisation in patient myofibres. Western blotting did not show changes in the amount of protein. In vitro functional studies revealed delayed sarcoendoplasmic reticulum Ca ²⁺ reuptake in patient myotubes, consistent with an altered pumping capacity of SERCA2 after cell stimulation.
Conclusions: We report a novel adult-onset vacuolar myopathy caused by a homozygous variant in ATP2A2. Biopsy findings and functional studies demonstrating an impaired function of SERCA2 and consequent Ca ²⁺ dysregulation in slow-twitch skeletal myofibres highly support the pathogenicity of the variant.
(© 2025 British Neuropathological Society.)