NRAP reduction rescues sarcomere defects in nebulin-related nemaline myopathy.

Nemaline myopathy is a rare neuromuscular disorder associated with congenital or childhood-onset of skeletal muscle weakness and hypotonia that results in limited motor function. Nemaline myopathy is a genetic disorder and mutations in 12 genes are known to contribute to autosomal dominant or recessive forms of the disease. Recessive mutations in nebulin (NEB) are the most common cause of nemaline myopathy affecting about 50% of patients. Due to the large size of the NEB gene and lack of mutational hot spots, developing therapies that can benefit a wide group of patients is challenging. Although there are several promising therapies under investigation, there is no cure for nemaline myopathy. Therefore, targeting disease modifiers that can stabilize or improve skeletal muscle function may represent alternative therapeutic strategies. Our studies have identified Nrap upregulation in nebulin deficiency that contributes to structural and functional deficits in nemaline myopathy. We show that genetic ablation of nrap in nebulin deficiency restored sarcomeric disorganization, reduced protein aggregates and improved skeletal muscle function in zebrafish. Our findings suggest that Nrap is a disease modifier that affects skeletal muscle structure and function in nemaline myopathy, thus therapeutic targeting of Nrap in nebulin related nemaline myopathy and related diseases may be beneficial for patients.