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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\n                      <jats:italic>missense<\/jats:italic>\n                      variant in\n                      <jats:italic>ATP2A2<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We studied a family with four individuals suffering from an adult\u2010onset 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\n                      <jats:sup>2+<\/jats:sup>\n                      handling in patient myotubes in response to electrical stimulation or caffeine exposure were performed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>ATP2A2<\/jats:italic>\n                      (c.1117G\u2009&gt;\u2009A, 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\u00a0vitro functional studies revealed delayed sarcoendoplasmic reticulum Ca\n                      <jats:sup>2+<\/jats:sup>\n                      reuptake in patient myotubes, consistent with an altered pumping capacity of SERCA2 after cell stimulation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      We report a novel adult\u2010onset vacuolar myopathy caused by a homozygous variant in\n                      <jats:italic>ATP2A2<\/jats:italic>\n                      . Biopsy findings and functional studies demonstrating an impaired function of SERCA2 and consequent Ca\n                      <jats:sup>2+<\/jats:sup>\n                      dysregulation in slow\u2010twitch skeletal myofibres highly support the pathogenicity of the variant.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/nan.70000","type":"journal-article","created":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T06:35:09Z","timestamp":1737009309000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A Homozygous\n                    <i>ATP2A2<\/i>\n                    Variant Alters Sarcoendoplasmic Reticulum Ca\n                    <sup>2+<\/sup>\n                    \u2010ATPase 2 Function in Skeletal Muscle and Causes a Novel Vacuolar Myopathy"],"prefix":"10.1111","volume":"51","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4950-7657","authenticated-orcid":false,"given":"Laura","family":"Llans\u00f3","sequence":"first","affiliation":[{"name":"Department of Neurology, Neuromuscular Diseases Unit Hospital de la Santa Creu i Sant Pau, Institut de Recerca Sant Pau (IR Sant Pau)  Barcelona Spain"},{"name":"Department of Medicine Universitat Aut\u00f2noma de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianina","family":"Ravenscroft","sequence":"additional","affiliation":[{"name":"Harry Perkins Institute of Medical Research, and Centre for Medical Research University of Western Australia  Perth Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Aceituno","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute Barcelona (IIBB\u2010CSIC) and Institut de Recerca Sant Pau (IR Sant Pau) Hospital de la Santa Creu 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