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

TitleACTN2 mutations cause "Multiple structured Core Disease" (MsCD).
Publication TypeJournal Article
Year of Publication2019
AuthorsLornage, X, Romero, NB, Grosgogeat, CA, Malfatti, E, Donkervoort, S, Marchetti, MM, Neuhaus, SB, A Foley, R, Labasse, C, Schneider, R, Carlier, RY, Chao, KR, Medne, L, Deleuze, J-F, Orlikowski, D, Bönnemann, CG, Gupta, VA, Fardeau, M, Böhm, J, Laporte, J
JournalActa Neuropathol
Date Published2019 Mar

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.

Alternate JournalActa Neuropathol.
PubMed ID30701273
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States
ANR-10-INBS-09 / / Agence Nationale pour la Recherche /
UM1 HG008900 / / National Heart, Lung, and Blood Institute /