P9.17 Function of CCDC78 in muscle development and muscle disease

Abstract

Congenital myopathies are a heterogeneous group of diseases that typically present in childhood with hypotonia and weakness and are commonly defined by characteristic changes observed on muscle biopsy. Currently, no treatments or disease-modifying therapies have been identified. Therapy development is hindered because approximately 40% of congenital myopathies are genetically unresolved. An overarching goal of our laboratory is to identify and characterize new causes of congenital myopathy. To this end, using whole exome sequencing we recently identified a splice-acceptor variant in the coiled-coil domain containing 78 gene (CCDC78) in a family with autosomal dominant core myopathy. CCDC78 is a previously uncharacterized gene with no known function that is highly enriched in skeletal muscle and localized to the perinuclear compartment and to the excitation contraction coupling apparatus. The specific goals of this study are to determine how mutation in CCDC78 results in muscle disease, establish the relationship between CCDC78 and other congenital myopathies, and to elucidate the normal function of CCDC78. To accomplish these goals we have created both morpholino based and stable genetic models of CCDC78 mutation in the zebrafish, including characterization of a newly developed loss of function CCDC78 mutant (sa3254). We have combined analysis of these zebrafish models with cell culture studies and examination of a range of human muscle biopsies. Current data suggests that CCDC78 participates in both the regulation of excitation-contraction coupling and in the regulation of autophagy. Additional ongoing experimentation will examine expression of CCDC78 in other congenital muscle diseases, will determine interacting partners for CCDC78, and will establish the normal function for CCDC78 in skeletal muscle development and homeostasis. In all, we present the first extensive characterization of this newly identified congenital myopathy gene.