title: Mutations in the N-terminal actin-binding domain of filamin C cause a distal myopathy.
abstract: Linkage analysis of the dominant distal myopathy we previously identified in a large Australian family demonstrated one significant linkage region located on chromosome 7 and encompassing 18.6 Mbp and 151 genes. The strongest candidate gene was FLNC because filamin C, the encoded protein, is muscle-specific and associated with myofibrillar myopathy. Sequencing of FLNC cDNA identified a c.752T>C (p.Met251Thr) mutation in the N-terminal actin-binding domain (ABD); this mutation segregated with the disease and was absent in 200 controls. We identified an Italian family with the same phenotype and found a c.577G>A (p.Ala193Thr) filamin C ABD mutation that segregated with the disease. Filamin C ABD mutations have not been described, although filamin A and filamin B ABD mutations cause multiple musculoskeletal disorders. The distal myopathy phenotype and muscle pathology in the two families differ from myofibrillar myopathies caused by filamin C rod and dimerization domain mutations because of the distinct involvement of hand muscles and lack of pathological protein aggregation. Thus, like the position of FLNA and B mutations, the position of the FLNC mutation determines disease phenotype. The two filamin C ABD mutations increase actin-binding affinity in a manner similar to filamin A and filamin B ABD mutations. Cell-culture expression of the c.752T>C (p.Met251)Thr mutant filamin C ABD demonstrated reduced nuclear localization as did mutant filamin A and filamin B ABDs. Expression of both filamin C ABD mutants as full-length proteins induced increased aggregation of filamin. We conclude filamin C ABD mutations cause a recognizable distal myopathy, most likely through increased actin affinity, similar to the pathological mechanism of filamin A and filamin B ABD mutations.
authors.affiliation: Centre for Medical Research, University of Western Australia and Western Australian Institute for Medical Research, Perth, Western Australia 6009, Australia; Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, Western Australia 6009, Australia.
authors.forename: Rachael M
authors.initials: RM
authors.lastname: Duff
authors.affiliation: Centre for Clinical Neurosciences and Neurological Research, St. Vincent's Hospital, Melbourne, Victoria 3065, Australia.
authors.forename: Valerie
authors.initials: V
authors.lastname: Tay
authors.affiliation: Folkhälsan Institute of Genetics, Department of Medical Genetics, Haartman Institute, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Peter
authors.initials: P
authors.lastname: Hackman
authors.affiliation: Centre for Medical Research, University of Western Australia and Western Australian Institute for Medical Research, Perth, Western Australia 6009, Australia.
authors.forename: Gianina
authors.initials: G
authors.lastname: Ravenscroft
authors.affiliation: State Neuropathology Service, Department of Pathology, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Catriona
authors.initials: C
authors.lastname: McLean
authors.affiliation: State Neuropathology Service, Department of Pathology, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Kennedy
authors.affiliation: Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, 53121 Bonn, Germany.
authors.forename: Alina
authors.initials: A
authors.lastname: Steinbach
authors.affiliation: Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, 53121 Bonn, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Schöffler
authors.affiliation: Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, 53121 Bonn, Germany.
authors.forename: Peter F M
authors.initials: PFM
authors.lastname: van der Ven
authors.affiliation: Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, 53121 Bonn, Germany.
authors.forename: Dieter O
authors.initials: DO
authors.lastname: Fürst
authors.affiliation: Department for Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria.
authors.forename: Jaeguen
authors.initials: J
authors.lastname: Song
authors.affiliation: Department for Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria; Department of Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana 1000, Slovenia.
authors.forename: Kristina
authors.initials: K
authors.lastname: Djinović-Carugo
authors.affiliation: Neuromuscular Research Unit, University of Tampere, Department of Neurology Tampere University Hospital, 33520 Tampere, Finland.
authors.forename: Sini
authors.initials: S
authors.lastname: Penttilä
authors.affiliation: Neuromuscular Research Unit, University of Tampere, Department of Neurology Tampere University Hospital, 33520 Tampere, Finland.
authors.forename: Olayinka
authors.initials: O
authors.lastname: Raheem
authors.affiliation: Centre for Clinical Neurosciences and Neurological Research, St. Vincent's Hospital, Melbourne, Victoria 3065, Australia.
authors.forename: Katrina
authors.initials: K
authors.lastname: Reardon
authors.affiliation: Department Neurological, Neurosurgical and Behavioural Sciences, Unit of Neurometabolic Diseases, University of Siena, 53100 Siena, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Malandrini
authors.affiliation: Department Neurological, Neurosurgical and Behavioural Sciences, Unit of Neurometabolic Diseases, University of Siena, 53100 Siena, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Gambelli
authors.affiliation: Casa di Cura Nigrisoli, 40125 Bologna, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Villanova
authors.affiliation: Centre for Medical Research, University of Western Australia and Western Australian Institute for Medical Research, Perth, Western Australia 6009, Australia.
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Nowak
authors.affiliation: Van Cleef Roet Centre for Nervous Disease, Monash University, Melbourne, Victoria 3800, Australia.
authors.forename: David R
authors.initials: DR
authors.lastname: Williams
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Landers
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
authors.affiliation: Folkhälsan Institute of Genetics, Department of Medical Genetics, Haartman Institute, University of Helsinki, 00014 Helsinki, Finland; Neuromuscular Research Unit, University of Tampere, Department of Neurology Tampere University Hospital, 33520 Tampere, Finland; Department of Neurology, Vasa Central Hospital, 65130 Vasa, Finland.
authors.forename: Bjarne
authors.initials: B
authors.lastname: Udd
authors.affiliation: Centre for Medical Research, University of Western Australia and Western Australian Institute for Medical Research, Perth, Western Australia 6009, Australia. Electronic address: nlaing@cyllene.uwa.edu.au.
authors.forename: Nigel G
authors.initials: NG
authors.lastname: Laing
mesh_terms: D000199:Actins / Q000378:metabolism; D000328:Adult; D000368:Aged; D001315:Australia; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D003285:Contractile Proteins / Q000235:genetics* / Q000378:metabolism; D049310:Distal Myopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D064448:Filamins; D006801:Humans; D007558:Italy; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D017434:Protein Structure, Tertiary / Q000235:genetics
chemical_list: D000199:Actins; D003285:Contractile Proteins; C578661:FLNC protein, human; D064448:Filamins; D008840:Microfilament Proteins