ACTN2 mutations cause “Multiple structured Core Disease” (MsCD)
The identification of genes implicated in myopathies is essential for diagnosis and for revealing novel therapeutic targets. Here we characterize a novel subclass of congenital myopathy at the morphological, molecular, and functional level. Through exome sequencing, we identified de novo ACTN2 mutations, a missense and a deletion, in two unrelated patients presenting with progressive early-onset muscle weakness and respiratory involvement. Morphological and ultrastructural analyses of muscle biopsies revealed a distinctive pattern with the presence of muscle fibers containing small structured cores and jagged Z-lines. Deeper analysis of the missense mutation revealed mutant alpha-actinin-2 properly localized to the Z-line in differentiating myotubes and its level was not altered in muscle biopsy. Modelling of the disease in zebrafish and mice by exogenous expression of mutated alpha-actinin-2 recapitulated the abnormal muscle function and structure seen in the patients. Motor deficits were noted in zebrafish, and muscle force was impaired in isolated muscles from AAV-transduced mice. In both models, sarcomeric disorganization was evident, while expression of wild-type alpha-actinin-2 did not result in muscle anomalies. The murine muscles injected with mutant ACTN2 displayed cores and Z-line defects. Dominant ACTN2 mutations were previously associated with cardiomyopathies, and our data demonstrate that specific mutations in the well-known Z-line regulator alpha-actinin-2 can cause a skeletal muscle disorder.
KeywordsACTN2 Alpha-actinin-2 Congenital myopathy Core myopathy Z-line Nemaline myopathy
We thank the families for their participation in the study. We also thank Valentina Lionello, Loïc Talide, Suzie Buono, Coralie Spiegelhalter, Bruno Weber and Pascale Koebel for technical assistance, Jahannaz Dastgir, Katherine Meilleur, Neal Busis, Lauren Elman, Xilma Ortiz-Gonzalez, and Henry Wessel for their help with patient care, and Susana Quijano-Roy, Christopher Mendoza and Gilberto Averion for their help in clinic. We also would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://exac.broadinstitute.org/about.
NBR, CB, JB, JL conceived and designed the study. XL, CAG, SD, MMM, SN, ARF, CL, KRC, LM, JFD performed the experiments. XL, NBR, EM, SD, SN, ARF, RS, RYC, CB, VAG, MF analyzed the data. XL, NBR, MF, JB, JL wrote the manuscript with input from the other coauthors.
This work was funded by the Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), University of Strasbourg, GIS IBiSA maladies rares, the France Génomique National infrastructure funded as part of the Investissements d’Avenir program managed by the Agence Nationale pour la Recherche (ANR-10-INBS-09) and by Fondation Maladies Rares within the frame of the “Myocapture” sequencing project, the Fondation pour la Recherche Médicale, and the Association Française contre les Myopathies. The work performed at the NIH was supported by intramural funds from the NIH National Institute of Neurological Disorders and Stroke. Sequencing analysis was provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics and was funded by the National Human Genome Research Institute, the National Eye Institute and the National Heart, Lung and Blood Institute grant UM1 HG008900 to Daniel MacArthur and Heidi Rehm.
Compliance with ethical standards
Conflict of interest
None of the authors reports conflicts of interest.
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