Acta Neuropathologica

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

Filamin C-related myopathies: pathology and mechanisms

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


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.


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



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.


  1. 1.
    Arndt V, Dick N, Tawo R, Dreiseidler M, Wenzel D, Hesse M, Fürst DO, Saftig P, Saint R, Fleischmann BK, Hoch M, Höhfeld J (2010) Chaperone-assisted selective autophagy is essential for muscle maintenance. Curr Biol 20:143–148PubMedCrossRefGoogle Scholar
  2. 2.
    Avila-Smirnov D, Béhin A, Gueneau L, Claeys K, Beuvin M, Goudeau B, Richard P, Ben Yaou R, Romero NB, Mathis S, Voit T, Eymard B, Gil R, Fardeau M, Bonne G (2010) A novel missense FLNC mutation causes arrhythmia and late onset myofibrillar myopathy with particular histopathology features. Neuromuscul Disord 20:623–624CrossRefGoogle Scholar
  3. 3.
    Bicknell LS, Farrington-Rock C, Shafeghati Y, Rump P, Alanay Y, Alembik Y, Al-Madani N, Firth H, Karimi-Nejad MH, Kim CA, Leask K, Maisenbacher M, Moran E, Pappas JG, Prontera P, de Ravel T, Fryns JP, Sweeney E, Fryer A, Unger S, Wilson LC, Lachman RS, Rimoin DL, Cohn DH, Krakow D, Robertson SP (2007) A molecular and clinical study of Larsen syndrome caused by mutations in FLNB. J Med Genet 44:89–98PubMedCrossRefGoogle Scholar
  4. 4.
    Chakarova C, Wehnert MS, Uhl K, Sakthivel S, Vosberg HP, van der Ven PFM, Fürst DO (2000) Genomic structure and fine mapping of the two human filamin gene paralogues FLNB and FLNC and comparative analysis of the filamin gene family. Hum Genet 107:597–611PubMedCrossRefGoogle Scholar
  5. 5.
    Dalkilic I, Schienda J, Thompson TG, Kunkel LM (2006) Loss of FilaminC (FLNc) results in severe defects in myogenesis and myotube structure. Mol Cell Biol 26:6522–6534PubMedCrossRefGoogle Scholar
  6. 6.
    Duff RM, Tay V, Hackman P, Ravenscroft G, McLean C, Kennedy P, Steinbach A, Schöffler W, van der Ven PFM, Fürst DO, Song J, Djinović-Carugo K, Penttilä S, Raheem O, Reardon K, Malandrini A, Gambelli S, Villanova M, Nowak KJ, Williams DR, Landers JE, Brown RH Jr, Udd B, Laing NG (2011) Mutations in the N-terminal actin-binding domain of filamin C cause a distal myopathy. Am J Hum Genet 88:729–740PubMedCrossRefGoogle Scholar
  7. 7.
    Farrington-Rock C, Firestein MH, Bicknell LS, Superti-Furga A, Bacino CA, Cormier-Daire V, Le Merrer M, Baumann C, Roume J, Rump P, Verheij JB, Sweeney E, Rimoin DL, Lachman RS, Robertson SP, Cohn DH, Krakow D (2006) Mutations in two regions of FLNB result in atelosteogenesis I and III. Hum Mutat 27:705–710PubMedCrossRefGoogle Scholar
  8. 8.
    Faulkner G, Pallavicini A, Comelli A, Salamon M, Bortoletto G, Ievolella C, Trevisan S, Kojic S, Dalla VF, Laveder P, Valle G, Lanfranchi G (2000) FATZ: a filamin, actinin, and telethonin binding protein of the Z-disk of skeletal muscle. J Biol Chem 275:41234–41242PubMedCrossRefGoogle Scholar
  9. 9.
    Feng Y, Walsh CA (2004) The many faces of filamin: a versatile molecular scaffold for cell motility and signalling. Nat Cell Biol 6:1034–1038PubMedCrossRefGoogle Scholar
  10. 10.
    Fischer D, Kley RA, Strach K, Meyer C, Sommer T, Eger K, Rolfs A, Meyer W, Pou A, Pradas J, Heyer CM, Grossmann A, Huebner A, Kress W, Reimann J, Schröder R, Eymard B, Fardeau M, Udd B, Goldfarb L, Vorgerd M, Olivé M (2008) Distinct muscle imaging patterns in myofibrillar myopathies. Neurology 71:758–765PubMedCrossRefGoogle Scholar
  11. 11.
    Frey N, Olson EN (2002) Calsarcin-3, a novel skeletal muscle-specific member of the calsarcin family, interacts with multiple Z-disc proteins. J Biol Chem 277:13998–14004PubMedCrossRefGoogle Scholar
  12. 12.
    Fujita M, Mitsuhashi H, Isogai S, Nakata T, Kawakami A, Nonaka I, Noguchi S, Hayashi YK, Nishino I, Kudo A (2012) Filamin C plays an essential role in the maintenance of the structural integrity of cardiac and skeletal muscles, revealed by the medaka mutant zacro. Dev Biol 361:79–89PubMedCrossRefGoogle Scholar
  13. 13.
    Gariboldi M, Maestrini E, Canzian F, Manenti G, De Gregorio L, Rivella S, Chatterjee A, Herman GE, Archidiacono N, Antonacci R (1994) Comparative mapping of the actin-binding protein 280 genes in human and mouse. Genomics 21:428–430PubMedCrossRefGoogle Scholar
  14. 14.
    Gehmlich K, Hayeß K, Legler C, Haebel S, van der Ven PFM, Ehler E, Fürst DO (2010) Ponsin interacts with Nck adapter proteins: implications for a role in cytoskeletal remodelling during differentiation of skeletal muscle cells. Eur J Cell Biol 89:351–364PubMedCrossRefGoogle Scholar
  15. 15.
    Goebel HH (2003) Congenital myopathies at their molecular dawning. Muscle Nerve 27:527–548PubMedCrossRefGoogle Scholar
  16. 16.
    Goebel HH (2009) Protein aggregate myopathies. Introduction. Brain Pathol 19:480–482PubMedCrossRefGoogle Scholar
  17. 17.
    Gontier Y, Taivainen A, Fontao L, Sonnenberg A, van der Flier A, Carpén O, Faulkner G, Borradori L (2005) The Z-disc proteins myotilin and FATZ-1 interact with each other and are connected to the sarcolemma via muscle-specific filamins. J Cell Sci 118:3739–3749PubMedCrossRefGoogle Scholar
  18. 18.
    Guergueltcheva V, Peeters K, Baets J, Ceuterick-de Groote C, Martin JJ, Suls A, De Vriendt E, Mihaylova V, Chamova T, Almeida-Souza L, Ydens E, Tzekov C, Hadjidekov G, Gospodinova M, Storm K, Reyniers E, Bichev S, van der Ven PFM, Fürst DO, Mitev V, Lochmüller H, Timmerman V, Tournev I, De Jonghe P, Jordanova A (2011) Distal myopathy with upper limb predominance caused by filamin C haploinsufficiency. Neurology 77:2105–2114PubMedCrossRefGoogle Scholar
  19. 19.
    Harms MB, Sommerville RB, Allred P, Bell S, Ma D, Cooper P, Lopate G, Pestronk A, Weihl CC, Baloh RH (2012) Exome sequencing reveals DNAJB6 mutations in dominantly-inherited myopathy. Ann Neurol 71:407–416PubMedCrossRefGoogle Scholar
  20. 20.
    Himmel M, van der Ven PFM, Stöcklein W, Fürst DO (2003) The limits of promiscuity: isoform-specific dimerization of filamins. Biochemistry 42:430–439PubMedCrossRefGoogle Scholar
  21. 21.
    Holmes WB, Moncman CL (2008) Nebulette interacts with filamin C. Cell Motil Cytoskeleton 65:130–142PubMedCrossRefGoogle Scholar
  22. 22.
    Kley RA, Hellenbroich Y, van der Ven PFM, Fürst DO, Huebner A, Bruchertseifer V, Peters SA, Heyer CM, Kirschner J, Schröder R, Fischer D, Müller K, Tolksdorf K, Eger K, Germing A, Brodherr T, Reum C, Walter MC, Lochmüller H, Ketelsen UP, Vorgerd M (2007) Clinical and morphological phenotype of the filamin myopathy: a study of 31 German patients. Brain 130:3250–3264PubMedCrossRefGoogle Scholar
  23. 23.
    Kley RA, Serdaroglu-Oflazer P, Leber Y, Odgerel Z, van der Ven PFM, Olivé M, Ferrer I, Onipe A, Mihaylov M, Bilbao JM, Lee HS, Höhfeld J, Djinović-Carugo K, Kong K, Tegenthoff M, Peters SA, Stenzel W, Vorgerd M, Goldfarb LG, Fürst DO (2012) Pathophysiology of protein aggregation and extended phenotyping in filaminopathy. Brain 135:2642–2660Google Scholar
  24. 24.
    Kono S, Nishio T, Takahashi Y, Goto-Inoue N, Kinoshita M, Zaima N, Suzuki H, Fukutoku-Otsuji A, Setou M, Miyajima H (2010) Dominant-negative effects of a novel mutation in the filamin myopathy. Neurology 75:547–554PubMedCrossRefGoogle Scholar
  25. 25.
    Linnemann A, van der Ven PFM, Vakeel P, Albinus B, Simonis D, Bendas G, Schenk JA, Micheel B, Kley RA, Fürst DO (2010) The sarcomeric Z-disc component myopodin is a multiadapter protein that interacts with filamin and alpha-actinin. Eur J Cell Biol 89:681–692PubMedCrossRefGoogle Scholar
  26. 26.
    Löwe T, Kley RA, van der Ven PFM, Himmel M, Huebner A, Vorgerd M, Fürst DO (2007) The pathomechanism of filaminopathy: altered biochemical properties explain the cellular phenotype of a protein aggregation myopathy. Hum Mol Genet 16:1351–1358PubMedCrossRefGoogle Scholar
  27. 27.
    Lu S, Carroll SL, Herrera AH, Ozanne B, Horowits R (2003) New N-RAP-binding partners alpha-actinin, filamin and Krp1 detected by yeast two-hybrid screening: implications for myofibril assembly. J Cell Sci 116:2169–2178PubMedCrossRefGoogle Scholar
  28. 28.
    Luan X, Hong D, Zhang W, Wang Z, Yuan Y (2010) A novel heterozygous deletion-insertion mutation (2695–2712 del/GTTTGT ins) in exon 18 of the filamin C gene causes filaminopathy in a large Chinese family. Neuromuscul Disord 20:390–396PubMedCrossRefGoogle Scholar
  29. 29.
    Maestrini E, Patrosso C, Mancini M, Rivella S, Rocchi M, Repetto M, Villa A, Frattini A, Zoppe M, Vezzoni P (1993) Mapping of two genes encoding isoforms of the actin binding protein ABP- 280, a dystrophin like protein, to Xq28 and to chromosome 7. Hum Mol Genet 2:761–766PubMedCrossRefGoogle Scholar
  30. 30.
    Nakano S, Engel AG, Waclawik AJ, Emslie-Smith AM, Busis NA (1996) Myofibrillar myopathy with abnormal foci of desmin positivity. I. Light and electron microscopy analysis of 10 cases. J Neuropathol Exp Neurol 55:549–562PubMedCrossRefGoogle Scholar
  31. 31.
    Odgerel Z, van der Ven PFM, Fürst DO, Goldfarb LG (2010) DNA sequencing errors in molecular diagnostics of filamin myopathy. Clin Chem Lab Med 48:1409–1414PubMedCrossRefGoogle Scholar
  32. 32.
    Ohlsson M, Hedberg C, Bradvik B, Lindberg C, Tajsharghi H, Danielsson O, Melberg A, Udd B, Martinsson T, Oldfors A (2012) Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin. Brain 135:1682–1694PubMedCrossRefGoogle Scholar
  33. 33.
    Olivé M, Odgerel Z, Martinez A, Poza JJ, Bragado FG, Zabalza RJ, Jerico I, Gonzalez-Mera L, Shatunov A, Lee HS, Armstrong J, Maravi E, Arroyo MR, Pascual-Calvet J, Navarro C, Paradas C, Huerta M, Marquez F, Rivas EG, Pou A, Ferrer I, Goldfarb LG (2011) Clinical and myopathological evaluation of early- and late-onset subtypes of myofibrillar myopathy. Neuromuscul Disord 21:533–542PubMedCrossRefGoogle Scholar
  34. 34.
    Pfeffer G, Elliott HR, Griffin H, Barresi R, Miller J, Marsh J, Evila A, Vihola A, Hackman P, Straub V, Dick DJ, Horvath R, Santibanez-Koref M, Udd B, Chinnery PF (2012) Titin mutation segregates with hereditary myopathy with early respiratory failure. Brain 135:1695–1713PubMedCrossRefGoogle Scholar
  35. 35.
    Popowicz GM, Schleicher M, Noegel AA, Holak TA (2006) Filamins: promiscuous organizers of the cytoskeleton. Trends Biochem Sci 31:411–419PubMedCrossRefGoogle Scholar
  36. 36.
    Pudas R, Kiema TR, Butler PJ, Stewart M, Ylänne J (2005) Structural basis for vertebrate filamin dimerization. Structure (Camb) 13:111–119CrossRefGoogle Scholar
  37. 37.
    Robertson SP, Twigg SR, Sutherland-Smith AJ, Biancalana V, Gorlin RJ, Horn D, Kenwrick SJ, Kim CA, Morava E, Newbury-Ecob R, Orstavik KH, Quarrell OW, Schwartz CE, Shears DJ, Suri M, Kendrick-Jones J, Wilkie AO (2003) Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet 33:487–491PubMedCrossRefGoogle Scholar
  38. 38.
    Sarparanta J, Jonson PH, Golzio C, Sandell S, Luque H, Screen M, McDonald K, Stajich JM, Mahjneh I, Vihola A, Raheem O, Penttilä S, Lehtinen S, Huovinen S, Palmio J, Tasca G, Ricci E, Hackman P, Hauser M, Katsanis N, Udd B (2012) Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy. Nat Genet 44:450–452PubMedCrossRefGoogle Scholar
  39. 39.
    Schröder R, Schoser B (2009) Myofibrillar myopathies: a clinical and myopathological guide. Brain Pathol 19:483–492PubMedCrossRefGoogle Scholar
  40. 40.
    Selcen D (2008) Myofibrillar myopathies. Curr Opin Neurol 21:585–589PubMedCrossRefGoogle Scholar
  41. 41.
    Selcen D (2011) Myofibrillar myopathies. Neuromuscul Disord 21:161–171PubMedCrossRefGoogle Scholar
  42. 42.
    Selcen D, Bromberg MB, Chin SS, Engel AG (2011) Reducing bodies and myofibrillar myopathy features in FHL1 muscular dystrophy. Neurology 77:1951–1959PubMedCrossRefGoogle Scholar
  43. 43.
    Selcen D, Muntoni F, Burton BK, Pegoraro E, Sewry C, Bite AV, Engel AG (2009) Mutation in BAG3 causes severe dominant childhood muscular dystrophy. Ann Neurol 65:83–89PubMedCrossRefGoogle Scholar
  44. 44.
    Shatunov A, Olivé M, Odgerel Z, Stadelmann-Nessler C, Irlbacher K, van Landeghem F, Bayarsaikhan M, Lee HS, Goudeau B, Chinnery PF, Straub V, Hilton-Jones D, Damian MS, Kaminska A, Vicart P, Bushby K, Dalakas MC, Sambuughin N, Ferrer I, Goebel HH, Goldfarb LG (2009) In-frame deletion in the seventh immunoglobulin-like repeat of filamin C in a family with myofibrillar myopathy. Eur J Hum Genet 17:656–663PubMedCrossRefGoogle Scholar
  45. 45.
    Sjekloca L, Pudas R, Sjöblom B, Konarev P, Carugo O, Rybin V, Kiema TR, Svergun D, Ylänne J, Djinović-Carugo K (2007) Crystal structure of human filamin C domain 23 and small angle scattering model for filamin C 23–24 dimer. J Mol Biol 368:1011–1023PubMedCrossRefGoogle Scholar
  46. 46.
    Stossel TP, Condeelis J, Cooley L, Hartwig JH, Noegel A, Schleicher M, Shapiro SS (2001) Filamins as integrators of cell mechanics and signalling. Nat Rev Mol Cell Biol 2:138–145PubMedCrossRefGoogle Scholar
  47. 47.
    Takada F, Vander Woude DL, Tong HQ, Thompson TG, Watkins SC, Beggs AH, Kunkel LM (2001) Myozenin: an α-actinin- and γ-filamin-binding protein of skeletal muscle Z lines. Proc Natl Acad Sci USA 98:1595–1600PubMedGoogle Scholar
  48. 48.
    Tasca G, Odgerel Z, Monforte M, Aurino S, Clarke NF, Waddell LB, Udd B, Ricci E, Goldfarb LG (2012) Novel FLNC mutation in a patient with myofibrillar myopathy in combination with late-onset cerebellar ataxia. Muscle Nerve 46:275–282PubMedCrossRefGoogle Scholar
  49. 49.
    Thompson TG, Chan YM, Hack AA, Brosius M, Rajala M, Lidov HG, McNally EM, Watkins S, Kunkel LM (2000) Filamin 2 (FLN2). A muscle-specific sarcoglycan interacting protein. J Cell Biol 148:115–126PubMedCrossRefGoogle Scholar
  50. 50.
    Udd B (2011) Distal muscular dystrophies. Handb Clin Neurol 101:239–262PubMedCrossRefGoogle Scholar
  51. 51.
    Uhlén M, Oksvold P, Fagerberg L, Lundberg E, Jonasson K, Forsberg M, Zwahlen M, Kampf C, Wester K, Hober S, Wernerus H, Björling L, Ponten F (2010) Towards a knowledge-based Human Protein Atlas. Nat Biotechnol 28:1248–1250PubMedCrossRefGoogle Scholar
  52. 52.
    van der Flier A, Sonnenberg A (2001) Structural and functional aspects of filamins. Biochim Biophys Acta 1538:99–117PubMedCrossRefGoogle Scholar
  53. 53.
    van der Ven PFM, Ehler E, Vakeel P, Eulitz S, Schenk JA, Milting H, Micheel B, Fürst DO (2006) Unusual splicing events result in distinct Xin isoforms that associate differentially with filamin C and Mena/VASP. Exp Cell Res 312:2154–2167PubMedCrossRefGoogle Scholar
  54. 54.
    van der Ven PFM, Obermann WMJ, Lemke B, Gautel M, Weber K, Fürst DO (2000) Characterization of muscle filamin isoforms suggests a possible role of γ-filamin/ABP-L in sarcomeric Z-disc formation. Cell Motil Cytoskeleton 45:149–162PubMedCrossRefGoogle Scholar
  55. 55.
    van der Ven PFM, Odgerel Z, Fürst DO, Goldfarb LG, Kono S, Miyajima H (2010) Dominant-negative effects of a novel mutation in the filamin myopathy. Neurology 75:2137–2138PubMedCrossRefGoogle Scholar
  56. 56.
    van der Ven PFM, Wiesner S, Salmikangas P, Auerbach D, Himmel M, Kempa S, Hayeß K, Pacholsky D, Taivainen A, Schröder R, Carpén O, Fürst DO (2000) Indications for a novel muscular dystrophy pathway. γ-filamin, the muscle-specific filamin isoform, interacts with myotilin. J Cell Biol 151:235–248PubMedCrossRefGoogle Scholar
  57. 57.
    Vorgerd M, van der Ven PFM, Bruchertseifer V, Löwe T, Kley RA, Schröder R, Lochmüller H, Himmel M, Koehler K, Fürst DO, Huebner A (2005) A mutation in the dimerization domain of filamin c causes a novel type of autosomal-dominant myofibrillar myopathy. Am J Hum Genet 7:297–304CrossRefGoogle Scholar
  58. 58.
    Williams DR, Reardon K, Roberts L, Dennet X, Duff R, Laing NG, Byrne E (2005) A new dominant distal myopathy affecting posterior leg and anterior upper limb muscles. Neurology 64:1245–1254PubMedCrossRefGoogle Scholar
  59. 59.
    Willis MS, Schisler JC, Portbury AL, Patterson C (2009) Build it up-Tear it down: protein quality control in the cardiac sarcomere. Cardiovasc Res 81:439–448PubMedCrossRefGoogle Scholar
  60. 60.
    Xie Z, Xu W, Davie EW, Chung DW (1998) Molecular cloning of human ABPL, an actin-binding protein homologue. Biochem Biophys Res Commun 251:914–919PubMedCrossRefGoogle Scholar
  61. 61.
    Zhang M, Liu J, Cheng A, Deyoung SM, Saltiel AR (2007) Identification of CAP as a costameric protein that interacts with filamin C. Mol Biol Cell 18:4731–4740PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Dieter O. Fürst
    • 1
    Email author
  • 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

Personalised recommendations