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

Acta Neuropathol. 2019 Mar;137(3):501-519. doi: 10.1007/s00401-019-01963-8. Epub 2019 Jan 30.


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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actinin / genetics*
  • Animals
  • Female
  • Humans
  • Male
  • Mice
  • Muscle, Skeletal / pathology*
  • Mutation
  • Myotonia Congenita / genetics*
  • Myotonia Congenita / pathology*
  • Zebrafish


  • ACTN2 protein, human
  • Actinin