Elucidating Effects of RYR1 in a Zebrafish and a Novel Recessive Mouse Model

Congenital myopathies are a genetically heterogeneous group of neuromuscular disorders that typically present in childhood and are associated with an estimated prevalence of one in 26,000 live births. These myopathies present with significant morbidities, including wheelchair and ventilator dependence. RYR1-related myopathies are defined by mutations in Ryanodine Receptor 1 or RYR1, the gene for the protein RyR1, an intracellular Ca2+ channel required for muscle contraction. Despite the severity of this disorder, there are no treatment options available for RYR1-related myopathy patients. To address this, I screened an ryr1a-/-; ryr1b-/- zebrafish mutant against 2,000 well-characterized compounds, none of which restored mutant levels to wild type. As a secondary aim, I performed a phenotypic analysis of a recessive mouse model that recapitulates several characteristics of these myopathies that will one day serve as a useful model for therapeutic development. This work herein explores the complicated spectrum of RYR1-related myopathies and expands our current understanding.M.Sc.2020-01-26 00:00:0