Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy

• DOI: 10.1073/pnas.96.5.2305
• Publication Date: 2002-07-26T14:42:40Z
• Authors: Katarina Pelin; Pirta Hilpelä; Kati Donner; Caroline Sewry; Patrick A. Akkari; Stephen D. Wilton; Duangrurdee Watta...; Marie-Louise Bang; Thomas Centner; Folker Hanefeld; Sylvie Odent; Michel Fardeau; J. Andoni Urtizberea; Francesco Muntoni; Victor Dubowitz; Alan H. Beggs; Nigel G. Laing; Siegfried Labeit; Albert de la Chap...; Carina Wallgren-P...
• Keywords: Genetic Markers; Male; 0301 basic medicine; 0303 health sciences; Base Sequence; Reverse Transcriptase Polymerase Chain Reaction; Molecular Sequence Data; Muscle Fibers, Skeletal; Australia; Chromosome Mapping; Genetic Variation; Muscle Proteins; Myopathies, Nemaline; Nuclear Family; Pedigree; 3. Good health; 03 medical and health sciences; Chromosomes, Human, Pair 2; 616; Codon, Terminator; Humans; Point Mutation; Female; Frameshift Mutation; Muscle, Skeletal

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.