title: The pathomechanism of filaminopathy: altered biochemical properties explain the cellular phenotype of a protein aggregation myopathy.
abstract: Myofibrillar myopathy (MFM) is a pathologically defined group of hereditary human muscle diseases, characterized by focal myofibrillar destruction and cytoplasmic aggregates that contain several Z-disc-related proteins. The previously reported MFM-associated mutation (8130G --> A; W2710X) in the filamin C gene (FLNC) leads to a partial disturbance of the secondary structure of the dimerization domain of filamin C, resulting in massive protein aggregation in skeletal muscle fibers of the patients. Here, we provide a thorough characterization of the biochemical, biophysical and cellular properties of the mutated filamin C polypeptide. Our experiments revealed that the mutant dimerization domain is less stable and more susceptible to proteolysis. As a consequence, it does not dimerize properly and forms aggregates in vitro. Furthermore, the expression of mutant filamin in cultured cells results in the formation of protein aggregates. The mutant filamin does not associate with wild type filamin. These findings are of great importance to explain the pathomechanism of this disease.
authors.affiliation: Department of Cell Biology, University of Potsdam, 14476 Potsdam-Golm, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Löwe
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: Kley
authors.forename: Peter F M
authors.initials: PF
authors.lastname: van der Ven
authors.forename: Mirko
authors.initials: M
authors.lastname: Himmel
authors.forename: Angela
authors.initials: A
authors.lastname: Huebner
authors.forename: Matthias
authors.initials: M
authors.lastname: Vorgerd
authors.forename: Dieter O
authors.initials: DO
authors.lastname: Fürst
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002478:Cells, Cultured; D002645:Chickens; D003285:Contractile Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D019281:Dimerization; D064448:Filamins; D006801:Humans; D008840:Microfilament Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009210:Myofibrils / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D048328:Potoroidae
chemical_list: D003285:Contractile Proteins; C578661:FLNC protein, human; D064448:Filamins; D008840:Microfilament Proteins