Mutations in the N-terminal actin-binding domain of filamin C cause a distal myopathy |
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| Authors: | 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 Djinović-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 |
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| Institution: | 1Centre for Medical Research, University of Western Australia and Western Australian Institute for Medical Research, Perth, Western Australia 6009, Australia;2Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, Western Australia 6009, Australia;3Centre for Clinical Neurosciences and Neurological Research, St. Vincent's Hospital, Melbourne, Victoria 3065, Australia;4Folkhälsan Institute of Genetics, Department of Medical Genetics, Haartman Institute, University of Helsinki, 00014 Helsinki, Finland;5State Neuropathology Service, Department of Pathology, University of Melbourne, Melbourne, Victoria 3010, Australia;6Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, 53121 Bonn, Germany;7Department for Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria;8Neuromuscular Research Unit, University of Tampere, Department of Neurology Tampere University Hospital, 33520 Tampere, Finland;9Department Neurological, Neurosurgical and Behavioural Sciences, Unit of Neurometabolic Diseases, University of Siena, 53100 Siena, Italy;10Casa di Cura Nigrisoli, 40125 Bologna, Italy;11Van Cleef Roet Centre for Nervous Disease, Monash University, Melbourne, Victoria 3800, Australia;12Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA;13Department of Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana 1000, Slovenia;14Department of Neurology, Vasa Central Hospital, 65130 Vasa, Finland |
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| 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. |
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