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

摘要: The identification of genes implicated in myopathies is essential for diagnosis and revealing novel therapeutic targets. Here we characterize a subclass congenital myopathy at the morphological, molecular, functional level. Through exome sequencing, identified de novo ACTN2 mutations, missense deletion, two unrelated patients presenting with progressive early-onset muscle weakness respiratory involvement. Morphological ultrastructural analyses biopsies revealed distinctive pattern presence fibers containing small structured cores jagged Z-lines. Deeper analysis mutation mutant alpha-actinin-2 properly localized to Z-line differentiating myotubes its level was not altered biopsy. Modelling disease zebrafish mice by exogenous expression mutated recapitulated abnormal function structure seen patients. Motor deficits were noted zebrafish, force impaired isolated muscles from AAV-transduced mice. In both models, sarcomeric disorganization evident, while wild-type did result anomalies. murine injected displayed defects. Dominant mutations previously associated cardiomyopathies, our data demonstrate that specific well-known regulator can cause skeletal disorder.