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Am J Hum Genet. 2011 Jun 10;88(6):729-740. doi: 10.1016/j.ajhg.2011.04.021. Epub 2011 May 27.

Mutations in the N-terminal actin-binding domain of filamin C cause a distal myopathy.

Author information

1
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.
2
Centre for Clinical Neurosciences and Neurological Research, St. Vincent's Hospital, Melbourne, Victoria 3065, Australia.
3
Folkhälsan Institute of Genetics, Department of Medical Genetics, Haartman Institute, University of Helsinki, 00014 Helsinki, Finland.
4
Centre for Medical Research, University of Western Australia and Western Australian Institute for Medical Research, Perth, Western Australia 6009, Australia.
5
State Neuropathology Service, Department of Pathology, University of Melbourne, Melbourne, Victoria 3010, Australia.
6
Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, 53121 Bonn, Germany.
7
Department for Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria.
8
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.
9
Neuromuscular Research Unit, University of Tampere, Department of Neurology Tampere University Hospital, 33520 Tampere, Finland.
10
Department Neurological, Neurosurgical and Behavioural Sciences, Unit of Neurometabolic Diseases, University of Siena, 53100 Siena, Italy.
11
Casa di Cura Nigrisoli, 40125 Bologna, Italy.
12
Van Cleef Roet Centre for Nervous Disease, Monash University, Melbourne, Victoria 3800, Australia.
13
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
14
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.
15
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.

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.

PMID:
21620354
PMCID:
PMC3113346
DOI:
10.1016/j.ajhg.2011.04.021
[Indexed for MEDLINE]
Free PMC Article

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