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Acta Neuropathologica

, Volume 125, Issue 1, pp 33–46 | Cite as

Filamin C-related myopathies: pathology and mechanisms

  • Dieter O. Fürst
  • Lev G. Goldfarb
  • Rudolf A. Kley
  • Matthias Vorgerd
  • Montse Olivé
  • Peter F. M. van der Ven
Review

Abstract

The term filaminopathy was introduced after a truncating mutation in the dimerization domain of filamin C (FLNc) was shown to be responsible for a devastating muscle disease. Subsequently, the same mutation was found in patients from diverse ethnical origins, indicating that this specific alteration is a mutational hot spot. Patients initially present with proximal muscle weakness, while distal and respiratory muscles become affected with disease progression. Muscle biopsies of these patients show typical signs of myofibrillar myopathy, including disintegration of myofibrils and aggregation of several proteins into distinct intracellular deposits. Highly similar phenotypes were observed in patients with other mutations in Ig-like domains of FLNc that result in expression of a noxious protein. Biochemical and biophysical studies showed that the mutated domains acquire an abnormal structure causing decreased stability and eventually becoming a seed for abnormal aggregation with other proteins. The disease usually presents only after the fourth decade of life possibly as a result of ageing-related impairments in the machinery that is responsible for disposal of damaged proteins. This is confirmed by mutations in components of this machinery that cause a highly similar phenotype. Transfection studies of cultured muscle cells reflect the events observed in patient muscles and, therefore, may provide a helpful model for testing future dedicated therapeutic strategies. More recently, FLNC mutations were also found in families with a distal myopathy phenotype, caused either by mutations in the actin-binding domain of FLNc that result in increased actin-binding and non-specific myopathic abnormalities without myofibrillar myopathy pathology, or a nonsense mutation in the rod domain that leads to RNA instability, haploinsufficiency with decreased expression levels of FLNc in the muscle fibers and myofibrillar abnormalities, but not to the formation of desmin-positive protein aggregates required for the diagnosis of myofibrillar myopathy.

Keywords

Filamin C Filaminopathy Myofibrillar myopathy Distal myopathy Limb-girdle muscular dystrophy Pathomechanism 

Notes

Acknowledgments

This research was supported in part by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, NIH [L.G.G], the German Research foundation [KL 2487/1-1 to R.A.K., FOR1228 to M.V., D.O.F., FOR1352 to D.O.F.], the German Ministry of Education and Research [01GM0887 to R.A.K., P.F.M.v.d.V., M.V., D.O.F.], the Ruhr-University Bochum [FoRUM K042-09 to R.A.K.], and the Spanish Instituto de Salud Carlos III [PI08-574 to M.O.].

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Dieter O. Fürst
    • 1
  • Lev G. Goldfarb
    • 2
  • Rudolf A. Kley
    • 3
  • Matthias Vorgerd
    • 3
  • Montse Olivé
    • 4
  • Peter F. M. van der Ven
    • 1
  1. 1.Institute for Cell BiologyUniversity of BonnBonnGermany
  2. 2.Clinical NeurogeneticsNational Institutes of HealthBethesdaUSA
  3. 3.Department of Neurology, Neuromuscular Center Ruhrgebiet, University Hospital BergmannsheilRuhr-University BochumBochumGermany
  4. 4.Institute of Neuropathology, Department of Pathology, and Neuromuscular Unit, Department of NeurologyIDIBELL-Hospital Universitari de BellvitgeBarcelonaSpain

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