title: A mutation in the dimerization domain of filamin c causes a novel type of autosomal dominant myofibrillar myopathy.
abstract: 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.
authors.affiliation: Department of Neurology, Neuromuscular Center Ruhrgebiet, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Vorgerd
authors.forename: Peter F M
authors.initials: PF
authors.lastname: van der Ven
authors.forename: Vera
authors.initials: V
authors.lastname: Bruchertseifer
authors.forename: Thomas
authors.initials: T
authors.lastname: Löwe
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: Kley
authors.forename: Rolf
authors.initials: R
authors.lastname: Schröder
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.forename: Mirko
authors.initials: M
authors.lastname: Himmel
authors.forename: Katrin
authors.initials: K
authors.lastname: Koehler
authors.forename: Dieter O
authors.initials: DO
authors.lastname: Fürst
authors.forename: Angela
authors.initials: A
authors.lastname: Huebner
mesh_terms: 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
chemical_list: D018389:Codon, Nonsense; D003285:Contractile Proteins; C578661:FLNC protein, human; D064448:Filamins; D005819:Genetic Markers; D008840:Microfilament Proteins; D049031:Sarcoglycans