A mutation in the dimerization domain of filamin c causes a novel type of autosomal dominant myofibrillar myopathy.
Myofibrillar myopathy (MFM) is a human disease that is characterized by focal myofibrillar destruction and pathological cytoplasmic protein aggregations. In an extended German pedigree with a novel form of MFM characterized by clinical features of a limb-girdle myopathy and morphological features of MFM, we identified a co-segregating, heterozygous nonsense mutation (8130G-->A; W2710X) in the filamin c gene (FLNC) on chromosome 7q32.1. The mutation is the first found in FLNC and is localized in the dimerization domain of filamin c. Functional studies showed that, in the truncated mutant protein, this domain has a disturbed secondary structure that leads to the inability to dimerize properly. As a consequence of this malfunction, the muscle fibers of our patients display massive cytoplasmic aggregates containing filamin c and several Z-disk-associated and sarcolemmal proteins.
Vorgerd
Matthias
M
Department of Neurology, Neuromuscular Center Ruhrgebiet, Ruhr-University Bochum, Bochum, Germany.
van der Ven
Peter F M
PF
Bruchertseifer
Vera
V
Löwe
Thomas
T
Kley
Rudolf A
RA
Schröder
Rolf
R
Lochmüller
Hanns
H
Himmel
Mirko
M
Koehler
Katrin
K
Fürst
Dieter O
DO
Huebner
Angela
A
D001483:Base Sequence; D001706:Biopsy; D018389:Codon, Nonsense; D003285:Contractile Proteins / Q000737:chemistry* / Q000235:genetics; D003593:Cytoplasm / Q000378:metabolism; D019281:Dimerization; D064448:Filamins; D005819:Genetic Markers; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D008126:Lod Score; D008840:Microfilament Proteins / Q000737:chemistry* / Q000235:genetics; D046529:Microscopy, Electron, Transmission; D008957:Models, Genetic; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000166:cytology; D009135:Muscular Diseases / Q000473:pathology*; D009154:Mutation; D009210:Myofibrils / Q000378:metabolism*; D010375:Pedigree; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D049031:Sarcoglycans / Q000378:metabolism
D018389:Codon, Nonsense; D003285:Contractile Proteins; C578661:FLNC protein, human; D064448:Filamins; D005819:Genetic Markers; D008840:Microfilament Proteins; D049031:Sarcoglycans