1. Autosomal-dominant distal myopathy associated with a recurrent missense mutation in the gene encoding the nuclear matrix protein, matrin 3.
- Author
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Senderek J, Garvey SM, Krieger M, Guergueltcheva V, Urtizberea A, Roos A, Elbracht M, Stendel C, Tournev I, Mihailova V, Feit H, Tramonte J, Hedera P, Crooks K, Bergmann C, Rudnik-Schöneborn S, Zerres K, Lochmüller H, Seboun E, Weis J, Beckmann JS, Hauser MA, and Jackson CE
- Subjects
- Adult, Age of Onset, Amino Acid Sequence, Amino Acid Substitution, Base Sequence, Bulgaria, DNA genetics, Deglutition Disorders genetics, Deglutition Disorders physiopathology, Distal Myopathies pathology, Distal Myopathies physiopathology, Dysphonia genetics, Dysphonia physiopathology, Female, Genes, Dominant, Humans, Male, Middle Aged, Molecular Sequence Data, Muscle, Skeletal pathology, Muscle, Skeletal physiopathology, Nuclear Matrix physiology, Nuclear Matrix-Associated Proteins physiology, Pedigree, RNA-Binding Proteins physiology, Sequence Homology, Amino Acid, Syndrome, Distal Myopathies genetics, Mutation, Missense, Nuclear Matrix-Associated Proteins genetics, RNA-Binding Proteins genetics
- Abstract
Distal myopathies represent a heterogeneous group of inherited skeletal muscle disorders. One type of adult-onset, progressive autosomal-dominant distal myopathy, frequently associated with dysphagia and dysphonia (vocal cord and pharyngeal weakness with distal myopathy [VCPDM]), has been mapped to chromosome 5q31 in a North American pedigree. Here, we report the identification of a second large VCPDM family of Bulgarian descent and fine mapping of the critical interval. Sequencing of positional candidate genes revealed precisely the same nonconservative S85C missense mutation affecting an interspecies conserved residue in the MATR3 gene in both families. MATR3 is expressed in skeletal muscle and encodes matrin 3, a component of the nuclear matrix, which is a proteinaceous network that extends throughout the nucleus. Different disease related haplotype signatures in the two families provided evidence that two independent mutational events at the same position in MATR3 cause VCPDM. Our data establish proof of principle that the nuclear matrix is crucial for normal skeletal muscle structure and function and put VCPDM on the growing list of monogenic disorders associated with the nuclear proteome.
- Published
- 2009
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