Centronuclear myopathies are a group of childhood onset muscle diseases defined by shared muscle biopsy features and characterized by muscle weakness and severe motor disability. Currently there are 5 known genetic causes for CNM, and recent studies on these gene products have identified abnormal excitation- contraction coupling as a key aspect of disease pathogenesis. Despite these advancements, no treatments current exist for CNMs and much remains to be understood about these clinically severe conditions. Approximately 40% of cases of CNM are genetic unresolved. Determination of additional genetic causes is critical to advance the knowledge of and to develop treatments for this disease. We have used linkage analysis and whole exome sequencing to identify a novel gene mutation in the CCDC78 gene in a family with autosomal dominant CNM. CCDC78 encodes a previously uncharacterized gene product, and the gene mutation is predicted to result in production of a protein with an internal deletion. Our hypotheses are that (a) wild type CCDC78 is required for muscle development and in particular for stabilizing the excitation-contraction coupling machinery and that (b) mutant CCDC78 functions in a dominant negative manner to sequester ECC proteins and thereby impair motor function. These hypotheses will be tested in two aims.
Aim 1 will examine the function(s) of wild type CCDC78 and Aim 2 will test the impact of the CCDC78 mutation on muscle development and function.
Both aims will utilize a combinatorial approach that includes in vitro studies, biochemical and proteomic techniques, and in vivo experimentation in the zebrafish. In particular, the project will take advantage of the power in the zebrafish for manipulation of gene expression, used to create both loss of function and dominant negative models, and live image analysis, used to dynamically examine specific properties of muscle function. In all, this proposal will determine the function of CCDC78 in muscle development as well as the pathogenic mechanisms underlying its mutation in CNM. These data will be placed in the context of the existing knowledge of CNM, allowing for critical advancements in the understanding of muscle function and the pathogenesis of this devastating disease.
Centronuclear myopathies are a common childhood muscle disease, associated with significant morbidity and early mortality, for which no treatments currently exist. While recent studies have advanced the knowledge of this condition, much remains to be understood before therapies can be developed. The goal of this proposal is to provide this advancement in understanding of centronuclear myopathy by determining the function of CCDC78, mutations in which we have newly identified as one cause of this disorder.
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