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Acta Neuropathologica

, Volume 137, Issue 3, pp 501–519 | Cite as

ACTN2 mutations cause “Multiple structured Core Disease” (MsCD)

  • Xavière Lornage
  • Norma B. Romero
  • Claire A. Grosgogeat
  • Edoardo Malfatti
  • Sandra Donkervoort
  • Michael M. Marchetti
  • Sarah B. Neuhaus
  • A. Reghan Foley
  • Clémence Labasse
  • Raphaël Schneider
  • Robert Y. Carlier
  • Katherine R. Chao
  • Livija Medne
  • Jean-François Deleuze
  • David Orlikowski
  • Carsten G. Bönnemann
  • Vandana A. Gupta
  • Michel Fardeau
  • Johann Böhm
  • Jocelyn LaporteEmail author
Original Paper

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 Z-line Nemaline myopathy 

Notes

Acknowledgements

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.

Author contributions

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.

Funding

This study was supported by the grant ANR-10-LABX-0030-INRT, a French State fund managed by the Agence Nationale de la Recherche under the frame program Investissements d’Avenir ANR-10-IDEX-0002-02. 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.

Supplementary material

401_2019_1963_MOESM1_ESM.pdf (733 kb)
Supplementary material 1 (PDF 733 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • 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
    • 1
    • 2
    • 3
    • 4
    Email author
  1. 1.Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)IllkirchFrance
  2. 2.INSERM U1258IllkirchFrance
  3. 3.CNRS, UMR7104IllkirchFrance
  4. 4.Université de StrasbourgIllkirchFrance
  5. 5.Université Sorbonne, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, GH Pitié-SalpêtrièreParisFrance
  6. 6.Centre de référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de ParisParisFrance
  7. 7.Neuromuscular Morphology Unit, Myology InstituteGHU Pitié-SalpêtrièreParisFrance
  8. 8.Division of GeneticsBrigham and Women’s Hospital, Harvard Medical SchoolBostonUSA
  9. 9.Neurology Department, Raymond-Poincaré teaching hospital, Centre de référence des maladies neuromusculaires Nord/Est/Ile-de-France, AP-HPGarchesFrance
  10. 10.Neuromuscular and Neurogenetic Disorders of Childhood SectionNational Institute of Neurological Disorders and Stroke, National Institutes of HealthBethesdaUSA
  11. 11.Neurolocomotor Division, Department of Radiology, Raymond Poincare HospitalUniversity Hospitals Paris–Ile-de-France West, Public Hospital Network of ParisGarchesFrance
  12. 12.Versailles Saint-Quentin-en-Yvelines UniversityVersaillesFrance
  13. 13.Center for Mendelian Genomics, Program in Medical and Population GeneticsBroad Institute of MIT and HarvardBostonUSA
  14. 14.Division of Human GeneticsThe Children’s Hospital of PhiladelphiaPhiladelphiaUSA
  15. 15.Centre National de Recherche en Génomique Humaine (CNRGH), Institut de biologie François Jacob, CEAEvryFrance
  16. 16.CIC 1429, INSERM, AP-HP, Hôpital Raymond PoincaréGarchesFrance

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