THE ROLE OF NEBULIN IN NEMALINE MYOPATHY

The proper function of cardiac and skeletal striated muscle is dependent on the precise assembly and maintenance of numerous structural and regulatory proteins that form sarcomeres, the basic contractile units of myofibrils. Nebulin is a giant sarcomeric protein, which spans the entire length of thin filaments in skeletal muscle. In addition, its critical role in skeletal muscle function is demonstrated by human mutations in the nebulin gene resulting in nemaline myopathy, a neuromuscular disorder characterized by muscle weakness and the presence of rod-like "nemaline" bodies in the muscle fibers. Thus, a better understanding of nebulin's role in skeletal muscle is key to developing a potential therapy for nebulin based nemaline myopathy. We recently generated nebulin deficient mice, which revealed a critical role for nebulin in thin filament length regulation and in maintaining skeletal muscle structure during muscle contraction. In addition, our studies revealed an important role of nebulin in the Z-line, a multiprotein complex at the boundary between sarcomeres, which plays a pivotal role in skeletal muscle structure and function. Nebulin deficient mice developed progressive Z-line abnormalities and the presence of structures resembling nemaline rod bodies observed in nemaline myopathy patients. However, due to early lethality of the mice, we were unable to analyze the progression of the phenotype.