Genetic screening and therapies for nemaline myopathies

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PROJECT SUMMARY/ABSTRACT The long-term goals of this project are to complete our understanding of the genetic basis for the nemaline myopathies (NMs) with the aim of developing rapid genetic diagnostic tests suitable for newborn screening programs, and to develop effective and innovative therapies for one of the common causes of NM that would be identified through such screening. The nemaline myopathies are a genetically heterogeneous group of closely related congenital myopathies, defined on the basis of congenital presentation of moderate to profound skeletal muscle weakness and muscle biopsy revealing nemaline rods in myofibers of affected children. The unifying molecular feature of these conditions is that fact that six of the seven known genes encode components of the actin thin filament, making this a disease of the sarcomere. Despite extensive genetic investigations utilizing mapping and candidate gene analysis, the genetic basis for many cases remains unknown. However, the advent of next generation DNA sequencing, and availability of whole exome and genome sequencing makes comprehensive genetic studies feasible in a rapid and cost-effective manner. Whole exome sequencing will be utilized to complete the genetic analysis of a large and well- characterized cohort of NM patients, and on the basis of these results, a specific DNA capture chip will be designed to facilitate rapid analysis of all the genes for NM and related congenital myopathies for use in screening hypotonic and weak newborns. Effective therapies for NM are lacking, and a major hurdle to their development is absence of model systems suitable for screening potential therapeutic compounds. To address this problem, zebrafish models of skeletal actin (ACTA1 gene) related NM (NEM3) will be developed and characterized, and utilized in high throughput drug screens to identify lead compounds with therapeutic potential for NM and related disorders in patients with primary skeletal myopathies and muscular dystrophies. Development of this efficient and sensitive newborn DNA-based screening protocol will allow for rapid and accurate diagnosis, eliminating the need for more invasive and risky procedures such as muscle biopsy, and will allow for early prognostic determinations, carrier testing in at risk relatives to prevent births of future affected children, and will allow for optimal early medical management. Identification of new therapeutic compounds and approaches will set the stage for preclinical testing of new therapies that may one day be used to treat children with these devastating neuromuscular diseases. These advances will also increase our knowledge of basic muscle biology with implications for our understanding of other neuromuscular diseases.