Gene Summary
RefSeq / NCBIThis gene encodes nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein. The encoded protein contains approximately 30-amino acid long modules that can be classified into 7 types and other repeated modules. Protein isoform sizes vary from 600 to 800 kD due to alternative splicing that is tissue-, species-,and developmental stage-specific. Of the 183 exons in the nebulin gene, at least 43 are alternatively spliced, although exons 143 and 144 are not found in the same transcript. Of the several thousand transcript variants predicted for nebulin, the RefSeq Project has decided to create three representative RefSeq records. Mutations in this gene are associated with recessive nemaline myopathy. [provided by RefSeq, Sep 2009]
Clinical Phenotype
Nemaline myopathy type 2: the most common nemaline myopathy gene. Ranges from severe neonatal hypotonia to mild adult-onset disease. Features: hypotonia, proximal weakness, facial weakness, high arched palate, and respiratory compromise.
Molecular Mechanism
Nebulin is an enormous protein (~800 kDa) spanning the thin filament of the sarcomere. It regulates actin filament length and thin filament function. Loss-of-function mutations shorten thin filaments, impairing force generation and leading to accumulation of nemaline rods (protein aggregates) on Gomori trichrome stain.
Clinical Hallmarks & Key Evidence
NEB is one of the largest human genes (183 exons) — pathogenic variants include missense, nonsense, splice-site, and a common Finnish founder deletion of exon 55.
Pelin K et al. Proc Natl Acad Sci USA. 1999;96(5):2305-10.
Nemaline rods (electron-dense Z-disc-derived aggregates) are the biopsy hallmark; they are best seen on Gomori modified trichrome stain as red-purple rods against a blue-green fiber background.
North KN et al. Neuromuscul Disord. 1997;7(6-7):375-82.
Cardiac involvement is uncommon in NEB-nemaline myopathy — in contrast to ACTA1, TPM2, and TPM3 nemaline myopathy, which more often have cardiomyopathy.
Sanoudou D, Beggs AH. Trends Cardiovasc Med. 2001;11(1):46-53.
External Resources
Gene data compiled from the Washington University Neuromuscular Disease Center, NCBI Gene, and OMIM. For clinical use, always refer to primary sources.