{
    "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 fiber type uniformity, core-like structures, and Z-band streaming, but normal levels of SERCA2 protein. Ca2+ imaging showed that SR/ER Ca2+ reuptake mediated by SERCA2 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 Ca\u00b2\u207a reuptake and causing cytosolic Ca\u00b2\u207a 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. Coinjection 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.",
    "authors": [
        {
            "affiliation": "Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada.\nDepartment of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.",
            "firstname": "Sivasankar",
            "initials": "S",
            "lastname": "Malaichamy"
        },
        {
            "affiliation": "Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada.",
            "firstname": "Romane",
            "initials": "R",
            "lastname": "Idoux"
        },
        {
            "affiliation": "Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada.",
            "firstname": "Kiran",
            "initials": "K",
            "lastname": "Polavarapu"
        },
        {
            "affiliation": "Department of Pediatrics, University Hospital Center Zagreb, Ki\u0161pati\u0107eva 12, 10 000, Zagreb, Croatia.",
            "firstname": "Katarina",
            "initials": "K",
            "lastname": "\u0160iki\u0107"
        },
        {
            "affiliation": "Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, Centre for Neuromuscular Disorders in Children, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.",
            "firstname": "Elisa",
            "initials": "E",
            "lastname": "Holla"
        },
        {
            "affiliation": "Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada.",
            "firstname": "Rachel",
            "initials": "R",
            "lastname": "Thompson"
        },
        {
            "affiliation": "Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada.",
            "firstname": "Sally",
            "initials": "S",
            "lastname": "Spendiff"
        },
        {
            "affiliation": "Institute of Neuropathology, Justus Liebig University Giessen, 35392 Giessen, Germany.",
            "firstname": "Anne",
            "initials": "A",
            "lastname": "Sch\u00e4nzer"
        },
        {
            "affiliation": "Department of Pathology, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.",
            "firstname": "Benno",
            "initials": "B",
            "lastname": "Kusters"
        },
        {
            "affiliation": "Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada.",
            "firstname": "Emily",
            "initials": "E",
            "lastname": "Freeman"
        },
        {
            "affiliation": "Leibniz Institut f\u00fcr Analytische Wissenschaften -ISAS- e.V., Dortmund 44227, Germany.",
            "firstname": "Andreas",
            "initials": "A",
            "lastname": "Hentschel"
        },
        {
            "affiliation": "Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada.",
            "firstname": "Daniel",
            "initials": "D",
            "lastname": "O'Neil"
        },
        {
            "affiliation": "Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada.",
            "firstname": "Ricardo",
            "initials": "R",
            "lastname": "Carmona-Martinez"
        },
        {
            "affiliation": "Department of Neurology, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich Heine University, D\u00fcsseldorf 40225, Germany.",
            "firstname": "Vera",
            "initials": "V",
            "lastname": "Dobelmann"
        },
        {
            "affiliation": "Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, Centre for Neuromuscular Disorders in Children, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.",
            "firstname": "Calvin",
            "initials": "C",
            "lastname": "Tucht"
        },
        {
            "affiliation": "Department of Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.",
            "firstname": "Meyke",
            "initials": "M",
            "lastname": "Schouten"
        },
        {
            "affiliation": "Department of Neurology, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich Heine University, D\u00fcsseldorf 40225, Germany.",
            "firstname": "Tobias",
            "initials": "T",
            "lastname": "Ruck"
        },
        {
            "affiliation": "Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, Centre for Neuromuscular Disorders in Children, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.",
            "firstname": "Ulrike",
            "initials": "U",
            "lastname": "Schara-Schmidt"
        },
        {
            "affiliation": "Department of Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.",
            "firstname": "Erik-Jan",
            "initials": "EJ",
            "lastname": "Kamsteeg"
        },
        {
            "affiliation": "Department of Pediatrics, University Hospital Center Zagreb, Ki\u0161pati\u0107eva 12, 10 000, Zagreb, Croatia.\nUniversity of Zagreb, School of Medicine, \u0160alata 3, 10 000 Zagreb, Croatia.",
            "firstname": "Danijela Petkovi\u0107",
            "initials": "DP",
            "lastname": "Ramad\u017ea"
        },
        {
            "affiliation": "University of Zagreb, School of Medicine, \u0160alata 3, 10 000 Zagreb, Croatia.\nDepartment of Pathology, University Hospital Center Zagreb, Ki\u0161pati\u0107eva 12, 10 000 Zagreb, Croatia.",
            "firstname": "Antonia",
            "initials": "A",
            "lastname": "Jakov\u010devi\u0107"
        },
        {
            "affiliation": "Department of Pediatrics, University Hospital Center Zagreb, Ki\u0161pati\u0107eva 12, 10 000, Zagreb, Croatia.\nUniversity of Zagreb, School of Medicine, \u0160alata 3, 10 000 Zagreb, Croatia.",
            "firstname": "Tamara",
            "initials": "T",
            "lastname": "Zigman"
        },
        {
            "affiliation": "University of Zagreb, School of Medicine, \u0160alata 3, 10 000 Zagreb, Croatia.\nDepartment of Diagnostic and Interventional Radiology, University Hospital Center Zagreb, 10 000 Zagreb, Croatia.",
            "firstname": "Mislav",
            "initials": "M",
            "lastname": "\u010cavka"
        },
        {
            "affiliation": "Istenhegyi Genetic Diagnostic Centre, Molecular Genetic Laboratory, 1125 Budapest, Hungary.",
            "firstname": "Veronika",
            "initials": "V",
            "lastname": "Karcagi"
        },
        {
            "affiliation": "Semmelweis University Pediatric Center, T\u0171zolt\u00f3 Street Unit, 1083 Budapest, Hungary.",
            "firstname": "Agnes",
            "initials": "A",
            "lastname": "Herczegfalvi"
        },
        {
            "affiliation": "Centro Nacional de An\u00e1lisis Gen\u00f3mico (CNAG), Baldiri Reixac 4, 08028 Barcelona, Spain.\nUniversitat de Barcelona (UB), 08007, Barcelona, Spain.",
            "firstname": "Steven",
            "initials": "S",
            "lastname": "Laurie"
        },
        {
            "affiliation": "Centro Nacional de An\u00e1lisis Gen\u00f3mico (CNAG), Baldiri Reixac 4, 08028 Barcelona, Spain.\nUniversitat de Barcelona (UB), 08007, Barcelona, Spain.",
            "firstname": "Leslie",
            "initials": "L",
            "lastname": "Matalonga"
        },
        {
            "affiliation": "Centro Nacional de An\u00e1lisis Gen\u00f3mico (CNAG), Baldiri Reixac 4, 08028 Barcelona, Spain.\nDepartament de Gen\u00e8tica, Microbiologia i Estadistica, Facultat de Biologia, Universitat de Barcelona (UB), 08028 Barcelona.",
            "firstname": "Sergi",
            "initials": "S",
            "lastname": "Beltran"
        },
        {
            "affiliation": "Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0SP, UK.",
            "firstname": "Rita",
            "initials": "R",
            "lastname": "Horvath"
        },
        {
            "affiliation": "Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.",
            "firstname": "Nicol",
            "initials": "N",
            "lastname": "Voermans"
        },
        {
            "affiliation": "Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, Centre for Neuromuscular Disorders in Children, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.",
            "firstname": "Andreas",
            "initials": "A",
            "lastname": "Roos"
        },
        {
            "affiliation": "Department of Pediatrics, University Hospital Center Zagreb, Ki\u0161pati\u0107eva 12, 10 000, Zagreb, Croatia.\nUniversity of Zagreb, School of Medicine, \u0160alata 3, 10 000 Zagreb, Croatia.",
            "firstname": "Ivo",
            "initials": "I",
            "lastname": "Bari\u0107"
        },
        {
            "affiliation": "Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada.\nCentro Nacional de An\u00e1lisis Gen\u00f3mico (CNAG), Baldiri Reixac 4, 08028 Barcelona, Spain.\nDivision of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, ON K1H 8M5, Canada.\nBrain and Mind Research Institute, University of Ottawa, Ottawa, ON K1H 8M5, Canada.\nDepartment of Neuropediatrics and Muscle Disorders, Medical Center - University of Freiburg, Faculty of Medicine, 79110 Freiburg, Germany.",
            "firstname": "Hanns",
            "initials": "H",
            "lastname": "Lochm\u00fcller"
        }
    ],
    "conclusions": null,
    "copyrights": "\u00a9 The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site\u2014for further information please contact journals.permissions@oup.com.",
    "doi": "10.1093/brain/awaf067",
    "journal": "Brain : a journal of neurology",
    "keywords": [
        "ATP2A2",
        "Ca2+ homeostasis",
        "autosomal dominant",
        "functional studies",
        "next generation sequencing",
        "rhabdomyolysis"
    ],
    "methods": null,
    "publication_date": "2025-02-19",
    "pubmed_id": "39970126",
    "results": null,
    "title": "Dominant rhabdomyolysis linked to a recurrent ATP2A2 variant reducing SERCA2 function in muscle.",
    "xml": "<Element 'PubmedArticle' at 0x7885040e71f0>"
}