Exploring Genetic Mechanisms in Nebulin-Based Nemaline Myopathy and Rhabdomyolysis

Skeletal muscle is a highly organized tissue housing components of contraction, metabolic, and regulatory machinery. These elements function coordinately to facilitate efficient energy production and maintain cellular homeostasis, thereby generating stability and power for all body movements. Any perturbations (e.g., genetic or environmental) to this coordination, result in loss of muscle health and function. Skeletal muscle diseases are genetically and clinically heterogenous which makes both accurate diagnosis and treatment challenging. Understanding molecular mechanism of these diseases is important, both for disease management and for the development of therapeutic strategies. This study has focused on studying molecular mechanisms in two types of skeletal muscle disease, nebulin-based nemaline myopathy and rhabdomyolysis. Nebulin, encoded by NEB gene, is a giant ~800 KDa filamentous protein and a crucial component of the thin filament in skeletal muscle, which play a critical role in various important processes in skeletal muscle such as maintaining Z-disk structure, myofibril alignment and crossbridge cycling and thin filament length measurement. The mutations in NEB gene lead to NEB-based nemaline myopathy (NEM2), a rare, clinically and genetically heterogeneous disorder, characterized by hypotonia and muscle weakness which does not have any curative treatment. The mutations causing NEM2 are of different types including splice site, truncation, frameshift, deletion or duplication. Splice site mutations are the most prevalent type of mutation within the NEB gene. Although characterization of some type of NEB mutations has partly revealed the disease mechanism in NEM2 such as shorter thin filament, structurally altered thin filament or altered cross-bridge cycling which explains force deficit, however, they cannot explain disease mechanism by all NEB mutations. In this study we characterized NEB mutations in 10 NEM2 patients with different type of mutations at