Autosomal-dominant distal myopathy associated with a recurrent missense mutation in the gene encoding the nuclear matrix protein, matrin 3.
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.
Institute of Cell Biology, ETH Zürich, 8093 Zürich, Switzerland. jan.senderek@cell.biol.ethz.ch
Jan
J
Senderek
Sean M
SM
Garvey
Michael
M
Krieger
Velina
V
Guergueltcheva
Andoni
A
Urtizberea
Andreas
A
Roos
Miriam
M
Elbracht
Claudia
C
Stendel
Ivailo
I
Tournev
Violeta
V
Mihailova
Howard
H
Feit
Jeff
J
Tramonte
Peter
P
Hedera
Kristy
K
Crooks
Carsten
C
Bergmann
Sabine
S
Rudnik-Schöneborn
Klaus
K
Zerres
Hanns
H
Lochmüller
Eric
E
Seboun
Joachim
J
Weis
Jacques S
JS
Beckmann
Michael A
MA
Hauser
Charles E
CE
Jackson
D000328:Adult; D017668:Age of Onset; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D002031:Bulgaria; D004247:DNA / Q000235:genetics; D003680:Deglutition Disorders / Q000235:genetics / Q000503:physiopathology; D049310:Distal Myopathies / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D055154:Dysphonia / Q000235:genetics / Q000503:physiopathology; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology; D020125:Mutation, Missense; D015530:Nuclear Matrix / Q000502:physiology; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics* / Q000502:physiology; D010375:Pedigree; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D013577:Syndrome
C518587:MATR3 protein, human; D034521:Nuclear Matrix-Associated Proteins; D016601:RNA-Binding Proteins; D004247:DNA