G.P.3 Modeling congenital muscle diseases in zebrafish

Abstract

Primary inherited disorders of muscle include both dystrophies and non-dystrophic congenital myopathies. These disorders, characterized by muscle weakness and impaired locomotion, form a heterogeneous group of hereditary diseases affecting both children and adults. Their complexity is highlighted by occasional involvement of associated symptoms in brain, eyes, heart or respiratory system. Owing to disease heterogeneity, variable penetrance, and mortality, genetic studies to determine the basis for these conditions in humans are often problematic. The zebrafish, Danio rerio, is a powerful developmental and genetic model system for dissection of skeletal muscle disorders and diseases. Several features of zebrafish, such as high degrees of synteny and sequence homology, conserved structure of skeletal muscles, transparency at embryonic stages, and rapid ex vivo development, make them ideal for skeletal muscle biology research. To identify novel genes causing muscular disorders, we conducted an ENU mutagenesis screen in zebrafish that led to the identification of 12 unique neuromuscular mutants. One of these represents a model of the dystroglycanopathies (dag1) and another, of congenital muscular dystrophy (lama2). Another mutant identified in this screen, osoi, displays impaired motility behavior and skeletal muscle myotonia. These mutant fish show skeletal muscle hypotrophy with extensive central nucleation. Ultrastructural studies revealed sarcomeric disorganization in osoi fish. Genetic mapping of the osoi locus has identified a loss of function mutation in a novel RNA binding protein implicated in RNA splicing. Preliminary studies point towards a role for this gene in the disease pathogenesis of myotonic dystrophy. Through an understanding of the abnormal skeletal muscle molecular pathways in osoi fish, we can better understand human neuromuscular diseases and begin to develop corrective therapies.