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Acta Neuropathol. 2019 Jan 30. doi: 10.1007/s00401-019-01963-8. [Epub ahead of print]

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

Author information

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.

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

PMID:
30701273
DOI:
10.1007/s00401-019-01963-8

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