ACTN2 mutations cause "Multiple structured Core Disease" (MsCD).
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.
['Lornage|Xavière|X|', 'Romero|Norma B|NB|', 'Grosgogeat|Claire A|CA|', 'Malfatti|Edoardo|E|', 'Donkervoort|Sandra|S|', 'Marchetti|Michael M|MM|', 'Neuhaus|Sarah B|SB|', 'Foley|A Reghan|AR|', 'Labasse|Clémence|C|', 'Schneider|Raphaël|R|', 'Carlier|Robert Y|RY|', 'Chao|Katherine R|KR|', 'Medne|Livija|L|', 'Deleuze|Jean-François|JF|', 'Orlikowski|David|D|', 'Bönnemann|Carsten G|CG|', 'Gupta|Vandana A|VA|', 'Fardeau|Michel|M|', 'Böhm|Johann|J|', 'Laporte|Jocelyn|J|0000-0001-7370-3469']
D000185:Actinin D000818:Animals D005260:Female D006801:Humans D008297:Male D051379:Mice D018482:Muscle, Skeletal D009154:Mutation D009224:Myotonia Congenita D015027:Zebrafish
ACTN2 Congenital myopathy Z-line Alpha-actinin-2 Core myopathy Nemaline myopathy