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

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.

Authors

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 Laporte

Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404, Illkirch, France.