Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy

TLDR

Congenital nemaline myopathies are rare hereditary muscle disorders marked by nemaline bodies in fibers, with autosomal dominant forms linked to TPM3 mutations and the typical recessive form mapped to chromosome 2q21.2‑q22, where the giant nebulin protein of thin filaments and its diverse isoforms contribute to Z‑disc structure. This study demonstrates that mutations in the nebulin gene within this locus are associated with autosomal recessive nemaline myopathy. The authors analyzed the 3′ end of the 20.8‑kb nebulin cDNA encoding the Z‑disc region and identified six disease‑associated mutations in patients from five ethnically diverse families. Patients carried homozygous or compound heterozygous nebulin mutations, and immunofluorescence revealed that these mutations likely truncate the protein, potentially causing loss of fiber‑type diversity and contributing to disease pathogenesis.

Abstract

The congenital nemaline myopathies are rare hereditary muscle disorders characterized by the presence in the muscle fibers of nemaline bodies consisting of proteins derived from the Z disc and thin filament. In a single large Australian family with an autosomal dominant form of nemaline myopathy, the disease is caused by a mutation in the α-tropomyosin gene TPM3 . The typical form of nemaline myopathy is inherited as an autosomal recessive trait, the locus of which we previously assigned to chromosome 2q21.2-q22. We show here that mutations in the nebulin gene located within this region are associated with the disease. The nebulin protein is a giant protein found in the thin filaments of striated muscle. A variety of nebulin isoforms are thought to contribute to the molecular diversity of Z discs. We have studied the 3′ end of the 20.8-kb cDNA encoding the Z disc part of the 800-kDa protein and describe six disease-associated mutations in patients from five families of different ethnic origins. In two families with consanguineous parents, the patients were homozygous for point mutations. In one family with nonconsanguineous parents, the affected siblings were compound heterozygotes for two different mutations, and in two further families with one detected mutation each, haplotypes are compatible with compound heterozygosity. Immunofluorescence studies with antibodies specific to the C-terminal region of nebulin indicate that the mutations may cause protein truncation possibly associated with loss of fiber-type diversity, which may be relevant to disease pathogenesis.