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

  • Am J Hum Genet. 2011 Jun 10;88(6):729-740. doi: 10.1016/j.ajhg.2011.04.021.
Rachael M Duff  1 ,  Valerie Tay  2 ,  Peter Hackman  3 ,  Gianina Ravenscroft  4 ,  Catriona McLean  5 ,  Paul Kennedy  5 ,  Alina Steinbach  6 ,  Wiebke Schöffler  6 ,  Peter F M van der Ven  6 ,  Dieter O Fürst  6 ,  Jaeguen Song  7 ,  Kristina Djinović-Carugo  8 ,  Sini Penttilä  9 ,  Olayinka Raheem  9 ,  Katrina Reardon  2 ,  Alessandro Malandrini  10 ,  Simona Gambelli  10 ,  Marcello Villanova  11 ,  Kristen J Nowak  4 ,  David R Williams  12 ,  John E Landers  13 ,  Robert H Brown Jr  13 ,  Bjarne Udd  14 ,  Nigel G Laing  15
Affiliations
  • 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: [email protected].
PMID: 21620354 DOI: 10.1016/j.ajhg.2011.04.021
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.