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Mutations in the N-terminal actin-binding domain of filamin C cause a distal myopathy.
Duff, Rachael M; Tay, Valerie; Hackman, Peter; Ravenscroft, Gianina; McLean, Catriona; Kennedy, Paul; Steinbach, Alina; Schöffler, Wiebke; van der Ven, Peter F M; Fürst, Dieter O; Song, Jaeguen; Djinovic-Carugo, Kristina; Penttilä, Sini; Raheem, Olayinka; Reardon, Katrina; Malandrini, Alessandro; Gambelli, Simona; Villanova, Marcello; Nowak, Kristen J; Williams, David R; Landers, John E; Brown, Robert H; Udd, Bjarne; Laing, Nigel G.
Afiliación
  • Duff RM; 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.
  • Tay V; Centre for Clinical Neurosciences and Neurological Research, St. Vincent's Hospital, Melbourne, Victoria 3065, Australia.
  • Hackman P; Folkhälsan Institute of Genetics, Department of Medical Genetics, Haartman Institute, University of Helsinki, 00014 Helsinki, Finland.
  • Ravenscroft G; Centre for Medical Research, University of Western Australia and Western Australian Institute for Medical Research, Perth, Western Australia 6009, Australia.
  • McLean C; State Neuropathology Service, Department of Pathology, University of Melbourne, Melbourne, Victoria 3010, Australia.
  • Kennedy P; State Neuropathology Service, Department of Pathology, University of Melbourne, Melbourne, Victoria 3010, Australia.
  • Steinbach A; Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, 53121 Bonn, Germany.
  • Schöffler W; Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, 53121 Bonn, Germany.
  • van der Ven PFM; Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, 53121 Bonn, Germany.
  • Fürst DO; Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, 53121 Bonn, Germany.
  • Song J; Department for Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria.
  • Djinovic-Carugo K; 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.
  • Penttilä S; Neuromuscular Research Unit, University of Tampere, Department of Neurology Tampere University Hospital, 33520 Tampere, Finland.
  • Raheem O; Neuromuscular Research Unit, University of Tampere, Department of Neurology Tampere University Hospital, 33520 Tampere, Finland.
  • Reardon K; Centre for Clinical Neurosciences and Neurological Research, St. Vincent's Hospital, Melbourne, Victoria 3065, Australia.
  • Malandrini A; Department Neurological, Neurosurgical and Behavioural Sciences, Unit of Neurometabolic Diseases, University of Siena, 53100 Siena, Italy.
  • Gambelli S; Department Neurological, Neurosurgical and Behavioural Sciences, Unit of Neurometabolic Diseases, University of Siena, 53100 Siena, Italy.
  • Villanova M; Casa di Cura Nigrisoli, 40125 Bologna, Italy.
  • Nowak KJ; Centre for Medical Research, University of Western Australia and Western Australian Institute for Medical Research, Perth, Western Australia 6009, Australia.
  • Williams DR; Van Cleef Roet Centre for Nervous Disease, Monash University, Melbourne, Victoria 3800, Australia.
  • Landers JE; Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • Brown RH; Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • Udd B; 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 Centra
  • Laing NG; 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.
Am J Hum Genet ; 88(6): 729-740, 2011 Jun 10.
Article en En | MEDLINE | ID: mdl-21620354
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Contráctiles / Miopatías Distales / Proteínas de Microfilamentos Límite: Adult / Aged / Female / Humans / Male / Middle aged País/Región como asunto: Europa / Oceania Idioma: En Revista: Am J Hum Genet Año: 2011 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Contráctiles / Miopatías Distales / Proteínas de Microfilamentos Límite: Adult / Aged / Female / Humans / Male / Middle aged País/Región como asunto: Europa / Oceania Idioma: En Revista: Am J Hum Genet Año: 2011 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos