2. Academic Validation
  3. ACTN2 mutations cause "Multiple structured Core Disease" (MsCD)

ACTN2 mutations cause "Multiple structured Core Disease" (MsCD)

  • Acta Neuropathol. 2019 Mar;137(3):501-519. doi: 10.1007/s00401-019-01963-8.
Xavière Lornage 1 2 3 4,  Norma B Romero 5 6 7,  Claire A Grosgogeat 8,  Edoardo Malfatti 6 7 9,  Sandra Donkervoort 10,  Michael M Marchetti 8,  Sarah B Neuhaus 10,  A Reghan Foley 10,  Clémence Labasse 6 7,  Raphaël Schneider 1 2 3 4,  Robert Y Carlier 11 12,  Katherine R Chao 13,  Livija Medne 14,  Jean-François Deleuze 15,  David Orlikowski 16,  Carsten G Bönnemann 10,  Vandana A Gupta 8,  Michel Fardeau 5 6 7,  Johann Böhm 1 2 3 4,  Jocelyn Laporte 17 18 19 20
Affiliations

Affiliations

  • 1 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404, Illkirch, France.
  • 2 INSERM U1258, 67404, Illkirch, France.
  • 3 CNRS, UMR7104, 67404, Illkirch, France.
  • 4 Université de Strasbourg, 67404, Illkirch, France.
  • 5 Université Sorbonne, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, GH Pitié-Salpêtrière, 47 Boulevard de l'hôpital, 75013, Paris, France.
  • 6 Centre de référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 75013, Paris, France.
  • 7 Neuromuscular Morphology Unit, Myology Institute, GHU Pitié-Salpêtrière, 75013, Paris, France.
  • 8 Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
  • 9 Neurology Department, Raymond-Poincaré teaching hospital, Centre de référence des maladies neuromusculaires Nord/Est/Ile-de-France, AP-HP, 92380, Garches, France.
  • 10 Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA.
  • 11 Neurolocomotor Division, Department of Radiology, Raymond Poincare Hospital, University Hospitals Paris-Ile-de-France West, Public Hospital Network of Paris, 92380, Garches, France.
  • 12 Versailles Saint-Quentin-en-Yvelines University, 78000, Versailles, France.
  • 13 Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Boston, MA, 02115, USA.
  • 14 Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
  • 15 Centre National de Recherche en Génomique Humaine (CNRGH), Institut de biologie François Jacob, CEA, 91000, Evry, France.
  • 16 CIC 1429, INSERM, AP-HP, Hôpital Raymond Poincaré, 92380, Garches, France.
  • 17 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404, Illkirch, France. jocelyn@igbmc.fr.
  • 18 INSERM U1258, 67404, Illkirch, France. jocelyn@igbmc.fr.
  • 19 CNRS, UMR7104, 67404, Illkirch, France. jocelyn@igbmc.fr.
  • 20 Université de Strasbourg, 67404, Illkirch, France. jocelyn@igbmc.fr.
PMID: 30701273 DOI: 10.1007/s00401-019-01963-8
Abstract

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.

Keywords

ACTN2; Alpha-actinin-2; Congenital myopathy; Core myopathy; Nemaline myopathy; Z-line.

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