Nebulin: Structure, Function, and Disease in Striated Muscle

Nebulin is a giant myofibri1lar protein (600-900 kDa) and forms the fourth filament system in striated sarcomeres. Single nebulin molecules span the entire length of the thin filament from the Z-disc to the thin filament pointed ends. Nebulin consists of an acidic domain, 35-residue modular repeats, a linker domain, and a Src homologous (SH3) domain. The major function of nebulin is to act as a unique regulator of thin filament length, a vital modulator of actomyosin sliding, and a biomolecular sensor of signal transduction. Mutation in the nebulin gene is a disease-causing factor of nemaline myopathies, and this case report presents a specific loss of the nebulin's SH3 domain in the Z-disc. Based on pathological similarities, it seems that the nebulin decline exists in some skeletal muscle diseases, such as disuse atrophy, Duchenne muscular dystrophy (DMD), exercise-induced muscle damage, and myopathies of excessive alcohol consumption. In addition to nebulette and the nebulin-related anchoring protein (N-RAP), there are numerous data supporting that cardiac nebulin is expressed in vertebrate hearts. Taken together, this article aims to summarize recent studies in the hopes of improving the knowledge base of various aspects of nebulin.