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Filamin C in cardiomyopathy: from physiological roles to DNA variants

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Abstract

Cardiomyopathy affects approximately 1 in 500 adults and is the leading cause of death. Familial cases are common, and mutations in many genes are involved in cardiomyopathy, especially those in genes encoding cytoskeletal, sarcomere, and nuclear envelope proteins. Filamin C is an actin-binding protein encoded by filamin C (FLNC) gene and participates in sarcomere stability maintenance. FLNC was first demonstrated to be a causal gene of myofibrillar myopathy; recently, it has been found that FLNC mutation plays a critical role in the pathogenesis of cardiomyopathy. In this review, we summarized the physiological roles of filamin C in cardiomyocytes and the genetic evidence for links between FLNC mutations and cardiomyopathies. Truncated FLNC is enriched in dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. Non-truncated FLNC is enriched in hypertrophic cardiomyopathy and restrictive cardiomyopathy. Two major pathomechanisms in FLNC-related cardiomyopathy have been described: protein aggregation resulting from non-truncating mutations and haploinsufficiency triggered by filamin C truncation. Therefore, it is important to understand the cellular biology and molecular regulation of FLNC to design new therapies to treat patients with FLNC-related cardiomyopathy.

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References

  1. Weintraub RG, Semsarian C, Macdonald P (2017) Dilated cardiomyopathy. Lancet 390:400–414

    Article  CAS  Google Scholar 

  2. Maron BJ, Maron MS (2013) Hypertrophic cardiomyopathy. Lancet 381:242–255

    Article  Google Scholar 

  3. Muchtar E, Blauwet LA, Gertz MA (2017) Restrictive cardiomyopathy: genetics pathogenesis clinical manifestations diagnosis and therapy. Circ Res 121:819–837. https://doi.org/10.1161/CIRCRESAHA.117.310982

    Article  CAS  PubMed  Google Scholar 

  4. Corrado D, Link MS, Calkins H (2017) Arrhythmogenic right ventricular cardiomyopathy. N Engl J Med 376:1489–1490. https://doi.org/10.1056/NEJMc1701400

    Article  PubMed  Google Scholar 

  5. Chakarova C, Wehnert MS, Uhl K, Sakthivel S, Vosberg HP, van der Ven PF et al (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 107:597–611. https://doi.org/10.1007/s004390000414

    Article  CAS  PubMed  Google Scholar 

  6. Xie Z, Xu W, Davie EW, Chung DW (1998) Molecular cloning of human ABPL an actin-binding protein homologue. Biochem Biophys Res Commun 251:914–919. https://doi.org/10.1006/bbrc.1998.9506

    Article  CAS  PubMed  Google Scholar 

  7. Maestrini E, Patrosso C, Mancini M, Rivella S, Rocchi M, Repetto M et al (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 2:761–766. https://doi.org/10.1093/hmg/2.6.761

    Article  CAS  PubMed  Google Scholar 

  8. Wang K, Ash JF, Singer SJ (1975) Filamin a new high-molecular-weight protein found in smooth muscle and non-muscle cells. Proc Natl Acad Sci USA 72:4483–4486. https://doi.org/10.1073/pnas.72.11.4483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhou J, Kang X, An H, Lv Y, Liu X (2021) The function and pathogenic mechanism of filamin A. Gene 784:145575. https://doi.org/10.1016/j.gene.2021.145575

    Article  CAS  PubMed  Google Scholar 

  10. Takafuta T, Wu G, Murphy GF, Shapiro SS (1998) Human beta-filamin is a new protein that interacts with the cytoplasmic tail of glycoprotein Ibalpha. J Biol Chem 273:17531–17538. https://doi.org/10.1074/jbc.273.28.17531

    Article  CAS  PubMed  Google Scholar 

  11. Gariboldi M, Maestrini E, Canzian F, Manenti G, De Gregorio L, Rivella S et al (1994) Comparative mapping of the actin-binding protein 280 genes in human and mouse. Genomics 21:428–430. https://doi.org/10.1006/geno.1994.1288

    Article  CAS  PubMed  Google Scholar 

  12. Speer MC, Vance JM, Grubber JM, Lennon Graham F, Stajich JM, Viles KD et al (1999) Identification of a new autosomal dominant limb-girdle muscular dystrophy locus on chromosome 7. Am J Hum Genet 64:556–562. https://doi.org/10.1086/302252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Vorgerd M, van der Ven PF, Bruchertseifer V, Lowe T, Kley RA, Schroder R et al (2005) A mutation in the dimerization domain of filamin c causes a novel type of autosomal dominant myofibrillar myopathy. Am J Hum Genet 77:297–304. https://doi.org/10.1086/431959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kley RA, Hellenbroich Y, van der Ven PF, Furst DO, Huebner A, Bruchertseifer V et al (2007) Clinical and morphological phenotype of the filamin myopathy: a study of 31 German patients. Brain 130:3250–3264. https://doi.org/10.1093/brain/awm271

    Article  PubMed  Google Scholar 

  15. Valdes-Mas R, Gutierrez-Fernandez A, Gomez J, Coto E, Astudillo A, Puente DA et al (2014) Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy. Nat Commun 5:5326. https://doi.org/10.1038/ncomms6326

    Article  CAS  PubMed  Google Scholar 

  16. Thiene G, Corrado D, Basso C (2008) Revisiting definition and classification of cardiomyopathies in the era of molecular medicine. Eur Heart J 29:144–146. https://doi.org/10.1093/eurheartj/ehm585

    Article  PubMed  Google Scholar 

  17. Maron BJ, Doerer JJ, Haas TS, Tierney DM, Mueller FO (2009) Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States 1980–2006. Circulation 119:1085–1092. https://doi.org/10.1161/CIRCULATIONAHA.108.804617

    Article  PubMed  Google Scholar 

  18. Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, Kuhn HJ, Seidman CE et al (2003) American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. J Am Coll Cardiol 42:1687–1713. https://doi.org/10.1016/s0735-1097(03)00941-0

    Article  PubMed  Google Scholar 

  19. Ader F, De Groote P, Reant P, Rooryck-Thambo C, Dupin-Deguine D, Rambaud C et al (2019) FLNC pathogenic variants in patients with cardiomyopathies: Prevalence and genotype-phenotype correlations. Clin Genet 96:317–329. https://doi.org/10.1111/cge.13594

    Article  CAS  PubMed  Google Scholar 

  20. van der Ven PF, Obermann WM, Lemke B, Gautel M, Weber K, Furst DO (2000) Characterization of muscle filamin isoforms suggests a possible role of gamma-filamin/ABP-L in sarcomeric Z-disc formation. Cell Motil Cytoskeleton 45:149–162. https://doi.org/10.1002/(SICI)1097-0169(200002)45:2%3C149::AID-CM6%3E3.0.CO;2-G

    Article  PubMed  Google Scholar 

  21. 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 116:2169–2178. https://doi.org/10.1242/jcs.00425

    Article  CAS  PubMed  Google Scholar 

  22. 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 18:4731–4740. https://doi.org/10.1091/mbc.e07-06-0628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sparrow JC, Schock F (2009) The initial steps of myofibril assembly: integrins pave the way. Nat Rev Mol Cell Biol 10:293–298. https://doi.org/10.1038/nrm2634

    Article  CAS  PubMed  Google Scholar 

  24. Prill K, Dawson JF (2020) Assembly and maintenance of sarcomere thin filaments and associated diseases. Int J Mol Sci 21:542. https://doi.org/10.3390/ijms21020542

    Article  CAS  PubMed Central  Google Scholar 

  25. Duff RM, Tay V, Hackman P, Ravenscroft G, McLean C, Kennedy P et al (2011) Mutations in the N-terminal actin-binding domain of filamin C cause a distal myopathy. Am J Hum Genet 88:729–740. https://doi.org/10.1016/j.ajhg.2011.04.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang Z, Grange M, Wagner T, Kho AL, Gautel M, Raunser S (2021) The molecular basis for sarcomere organization in vertebrate skeletal muscle. Cell 184:2135–2150. https://doi.org/10.1016/j.cell.2021.02.047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mao Z, Nakamura F (2020) Structure and function of filamin C in the muscle Z-disc. Int J Mol Sci 21:2696. https://doi.org/10.3390/ijms21082696

    Article  CAS  PubMed Central  Google Scholar 

  28. Szikora S, Gajdos T, Novak T, Farkas D, Foldi I, Lenart P et al (2020) Nanoscopy reveals the layered organization of the sarcomeric H-zone and I-band complexes. J Cell Biol 219:e201907026. https://doi.org/10.1083/jcb.201907026

    Article  CAS  PubMed  Google Scholar 

  29. Burgoyne T, Morris EP, Luther PK (2015) Three-dimensional structure of vertebrate muscle Z-Bbnd: the small-square lattice z-band in rat cardiac muscle. J Mol Biol 427:3527–3537. https://doi.org/10.1016/j.jmb.2015.08.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Burgoyne T, Heumann JM, Morris EP, Knupp C, Liu J, Reedy MK et al (2019) Three-dimensional structure of the basketweave Z-band in midshipman fish sonic muscle. Proc Natl Acad Sci USA 116:15534–15539. https://doi.org/10.1073/pnas.1902235116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Esue O, Tseng Y, Wirtz D (2009) Alpha-actinin and filamin cooperatively enhance the stiffness of actin filament networks. PLoS ONE 4:e4411. https://doi.org/10.1371/journal.pone.0004411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. van der Ven PF, Ehler E, Vakeel P, Eulitz S, Schenk JA, Milting H et al (2006) Unusual splicing events result in distinct Xin isoforms that associate differentially with filamin C and Mena/VASP. Exp Cell Res 312:2154–2167. https://doi.org/10.1016/j.yexcr.2006.03.015

    Article  CAS  PubMed  Google Scholar 

  33. Liu L, Sun K, Zhang X, Tang Y, Xu D (2021) Advances in the role and mechanism of BAG3 in dilated cardiomyopathy. Heart Fail Rev 26:183–194. https://doi.org/10.1007/s10741-019-09899-7

    Article  PubMed  Google Scholar 

  34. Leber Y, Ruparelia AA, Kirfel G, van der Ven PF, Hoffmann B, Merkel R et al (2016) Filamin C is a highly dynamic protein associated with fast repair of myofibrillar microdamage. Hum Mol Genet 25:2776–2788. https://doi.org/10.1093/hmg/ddw135

    Article  CAS  PubMed  Google Scholar 

  35. Collier MP, Alderson TR, de Villiers CP, Nicholls D, Gastall HY, Allison TM et al (2019) HspB1 phosphorylation regulates its intramolecular dynamics and mechanosensitive molecular chaperone interaction with filamin C. Sci Adv 5:eaav8421. https://doi.org/10.1126/sciadv.aav8421

  36. Juo LY, Liao WC, Shih YL, Yang BY, Liu AB, Yan YT (2016) HSPB7 interacts with dimerized FLNC and its absence results in progressive myopathy in skeletal muscles. J Cell Sci 129:1661–1670. https://doi.org/10.1242/jcs.179887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Raynaud F, Jond-Necand C, Marcilhac A, Furst D, Benyamin Y (2006) Calpain 1-gamma filamin interaction in muscle cells: a possible in situ regulation by PKC-alpha. Int J Biochem Cell Biol 38:404–413. https://doi.org/10.1016/j.biocel.2005.09.020

    Article  CAS  PubMed  Google Scholar 

  38. Guyon JR, Kudryashova E, Potts A, Dalkilic I, Brosius MA, Thompson TG et al (2003) Calpain 3 cleaves filamin C and regulates its ability to interact with gamma- and delta-sarcoglycans. Muscle Nerve 28:472–483. https://doi.org/10.1002/mus.10465

    Article  CAS  PubMed  Google Scholar 

  39. Fielitz J, van Rooij E, Spencer JA, Shelton JM, Latif S, van der Nagel R et al (2007) Loss of muscle-specific RING-finger 3 predisposes the heart to cardiac rupture after myocardial infarction. Proc Natl Acad Sci USA 104:4377–4382. https://doi.org/10.1073/pnas.0611726104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Spaich S, Will RD, Just S, Spaich S, Kuhn C, Frank D et al (2012) F-box and leucine-rich repeat protein 22 is a cardiac-enriched F-box protein that regulates sarcomeric protein turnover and is essential for maintenance of contractile function in vivo. Circ Res 111:1504–1516. https://doi.org/10.1161/CIRCRESAHA.112.271007

    Article  CAS  PubMed  Google Scholar 

  41. Papizan JB, Garry GA, Brezprozvannaya S, McAnally JR, Bassel-Duby R, Liu N et al (2017) Deficiency in Kelch protein Klhl31 causes congenital myopathy in mice. J Clin Invest 127:3730–3740. https://doi.org/10.1172/JCI93445

    Article  PubMed  PubMed Central  Google Scholar 

  42. Arndt V, Dick N, Tawo R, Dreiseidler M, Wenzel D, Hesse M et al (2010) Chaperone-assisted selective autophagy is essential for muscle maintenance. Curr Biol 20:143–148. https://doi.org/10.1016/j.cub.2009.11.022

    Article  CAS  PubMed  Google Scholar 

  43. Paranavitane V, Coadwell WJ, Eguinoa A, Hawkins PT, Stephens L (2003) LL5beta is a phosphatidylinositol (3,4,5)-trisphosphate sensor that can bind the cytoskeletal adaptor, gamma-filamin. J Biol Chem 278:1328–1335. https://doi.org/10.1074/jbc.M208352200

    Article  CAS  PubMed  Google Scholar 

  44. Molt S, Buhrdel JB, Yakovlev S, Schein P, Orfanos Z, Kirfel G et al (2014) Aciculin interacts with filamin C and Xin and is essential for myofibril assembly, remodeling and maintenance. J Cell Sci 127:3578–3592. https://doi.org/10.1242/jcs.152157

    Article  CAS  PubMed  Google Scholar 

  45. Chang YW, Chang YT, Wang Q, Lin JJ, Chen YJ, Chen CC (2013) Quantitative phosphoproteomic study of pressure-overloaded mouse heart reveals dynamin-related protein 1 as a modulator of cardiac hypertrophy. Mol Cell Proteomics 12:3094–3107. https://doi.org/10.1074/mcp.M113.027649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Reimann L, Wiese H, Leber Y, Schwable AN, Fricke AL, Rohland A et al (2017) Myofibrillar Z-discs are a protein phosphorylation hot spot with protein kinase C (PKCalpha) modulating protein dynamics. Mol Cell Proteomics 16:346–367. https://doi.org/10.1074/mcp.M116.065425

    Article  CAS  PubMed  Google Scholar 

  47. Waardenberg AJ, Bernardo BC, Ng DCH, Shepherd PR, Cemerlang N, Sbroggio M et al (2011) Phosphoinositide 3-kinase (PI3K(p110alpha)) directly regulates key components of the Z-disc and cardiac structure. J Biol Chem 286:30837–30846. https://doi.org/10.1074/jbc.M111.271684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Murray JT, Campbell DG, Peggie M, Mora A, Cohen P (2004) Identification of filamin C as a new physiological substrate of PKBalpha using KESTREL. Biochem J 384:489–494. https://doi.org/10.1042/BJ20041058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Chiang W, Greaser ML (2000) Binding of filamin isoforms to myofibrils. J Muscle Res Cell Motil 21:321–333. https://doi.org/10.1023/a:1005650706464

    Article  CAS  PubMed  Google Scholar 

  50. Reimann L, Schwable AN, Fricke AL, Muhlhauser WWD, Leber Y, Lohanadan K et al (2020) Phosphoproteomics identifies dual-site phosphorylation in an extended basophilic motif regulating FILIP1-mediated degradation of filamin-C. Commun Biol 3:253. https://doi.org/10.1038/s42003-020-0982-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Pathak P, Blech-Hermoni Y, Subedi K, Mpamugo J, Obeng-Nyarko C, Ohman R et al (2021) Myopathy associated LDB3 mutation causes Z-disc disassembly and protein aggregation through PKCalpha and TSC2-mTOR downregulation. Commun Biol 4:355. https://doi.org/10.1038/s42003-021-01864-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Dyson JM, O’Malley CJ, Becanovic J, Munday AD, Berndt MC, Coghill ID et al (2001) The SH2-containing inositol polyphosphate 5-phosphatase, SHIP-2, binds filamin and regulates submembraneous actin. J Cell Biol 155:1065–1079. https://doi.org/10.1083/jcb.200104005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Nakagawa K, Sugahara M, Yamasaki T, Kajiho H, Takahashi S, Hirayama J et al (2010) Filamin associates with stress signalling kinases MKK7 and MKK4 and regulates JNK activation. Biochem J 427:237–245. https://doi.org/10.1042/BJ20091011

    Article  CAS  PubMed  Google Scholar 

  54. Ortiz-Genga MF, Cuenca S, Dal Ferro M, Zorio E, Salgado-Aranda R, Climent V et al (2016) Truncating FLNC mutations are associated with high-risk dilated and arrhythmogenic cardiomyopathies. J Am Coll Cardiol 68:2440–2451. https://doi.org/10.1016/j.jacc.2016.09.927

    Article  CAS  PubMed  Google Scholar 

  55. Augusto JB, Eiros R, Nakou E, Moura-Ferreira S, Treibel TA, Captur G et al (2020) Dilated cardiomyopathy and arrhythmogenic left ventricular cardiomyopathy: a comprehensive genotype-imaging phenotype study. Eur Heart J Cardiovasc Imaging 21:326–336. https://doi.org/10.1093/ehjci/jez188

    Article  PubMed  Google Scholar 

  56. Hall CL, Akhtar MM, Sabater-Molina M, Futema M, Asimaki A, Protonotarios A et al (2020) Filamin C variants are associated with a distinctive clinical and immunohistochemical arrhythmogenic cardiomyopathy phenotype. Int J Cardiol 307:101–108. https://doi.org/10.1016/j.ijcard.2019.09.048

    Article  PubMed  Google Scholar 

  57. Gomez J, Lorca R, Reguero JR, Moris C, Martin M, Tranche S et al (2017) Screening of the filamin C gene in a large cohort of hypertrophic cardiomyopathy patients. Circ Cardiovasc Genet 10:e001584. https://doi.org/10.1161/CIRCGENETICS.116.001584

    Article  CAS  PubMed  Google Scholar 

  58. Cui H, Wang J, Zhang C, Wu G, Zhu C, Tang B et al (2018) Mutation profile of FLNC gene and its prognostic relevance in patients with hypertrophic cardiomyopathy. Mol Genet Genomic Med 6:1104–1113. https://doi.org/10.1002/mgg3.488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hernandez SG, Ortiz-Genga M, Ramos KA, Ochoa JP, Monserrat L (2020) Novel filamin C missense mutation associated with severe restrictive cardiomyopathy overlapping with left ventricular non-compaction. Eur Heart J 41.

  60. Lorca R, Martin M, Pascual I, Astudillo A, Diaz Molina B, Cigarran H et al (2020) Characterization of left ventricular non-compaction cardiomyopathy. J Clin Med 9:2524. https://doi.org/10.3390/jcm9082524

    Article  PubMed Central  Google Scholar 

  61. Esslinger U, Garnier S, Korniat A, Proust C, Kararigas G, Muller-Nurasyid M et al (2017) Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy. PLoS ONE 12:e0172995. https://doi.org/10.1371/journal.pone.0172995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Sveinbjornsson G, Olafsdottir EF, Thorolfsdottir RB, Davidsson OB, Helgadottir A, Jonasdottir A et al (2018) Variants in NKX2-5 and FLNC cause dilated cardiomyopathy and sudden cardiac death. Circ Genom Precis Med 11:e002151. https://doi.org/10.1161/CIRCGEN.117.002151

    Article  CAS  PubMed  Google Scholar 

  63. Pirruccello JP, Bick A, Wang M, Chaffin M, Friedman S, Yao J et al (2020) Analysis of cardiac magnetic resonance imaging in 36,000 individuals yields genetic insights into dilated cardiomyopathy. Nat Commun 11:2254. https://doi.org/10.1038/s41467-020-15823-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ruparelia AA, Zhao M, Currie PD, Bryson-Richardson RJ (2012) Characterization and investigation of zebrafish models of filamin-related myofibrillar myopathy. Hum Mol Genet 21:4073–4083. https://doi.org/10.1093/hmg/dds231

    Article  CAS  PubMed  Google Scholar 

  65. Begay RL, Tharp CA, Martin A, Graw SL, Sinagra G, Miani D et al (2016) FLNC gene splice mutations cause dilated cardiomyopathy. JACC Basic Transl Sci 1:344–359. https://doi.org/10.1016/j.jacbts.2016.05.004

    Article  PubMed  PubMed Central  Google Scholar 

  66. Ruparelia AA, Oorschot V, Ramm G, Bryson-Richardson RJ (2016) FLNC myofibrillar myopathy results from impaired autophagy and protein insufficiency. Hum Mol Genet 25:2131–2142. https://doi.org/10.1093/hmg/ddw080

    Article  CAS  PubMed  Google Scholar 

  67. Ruparelia A, Oorschot V, Ramm G, Bryson-Richardson R (2015) Investigating the pathobiology of myofibrillar myopathies and potential therapies using zebrafish. Neuromuscul Disord 25:S256–S257. https://doi.org/10.1016/j.nmd.2015.06.259

    Article  Google Scholar 

  68. Kiselev A, Vaz R, Knyazeva A, Khudiakov A, Tarnovskaya S, Liu J et al (2018) De novo mutations in FLNC leading to early-onset restrictive cardiomyopathy and congenital myopathy. Hum Mutat 39:1161–1172. https://doi.org/10.1002/humu.23559

    Article  CAS  PubMed  Google Scholar 

  69. Brodehl A, Ferrier RA, Hamilton SJ, Greenway SC, Brundler MA, Yu W et al (2016) Mutations in FLNC are associated with familial restrictive cardiomyopathy. Hum Mutat 37:269–279. https://doi.org/10.1002/humu.22942

    Article  CAS  PubMed  Google Scholar 

  70. Lowe T, Kley RA, van der Ven PF, Himmel M, Huebner A, Vorgerd M et al (2007) The pathomechanism of filaminopathy: altered biochemical properties explain the cellular phenotype of a protein aggregation myopathy. Hum Mol Genet 16:1351–1358. https://doi.org/10.1093/hmg/ddm085

    Article  CAS  PubMed  Google Scholar 

  71. Kley RA, Serdaroglu-Oflazer P, Leber Y, Odgerel Z, van der Ven PF, Olive M et al (2012) Pathophysiology of protein aggregation and extended phenotyping in filaminopathy. Brain 135:2642–2660. https://doi.org/10.1093/brain/aws200

    Article  PubMed  PubMed Central  Google Scholar 

  72. 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 26:6522–6534. https://doi.org/10.1128/MCB.00243-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Zhou Y, Chen Z, Zhang L, Zhu M, Tan C, Zhou X et al (2020) Loss of filamin C is catastrophic for heart function. Circulation 141:869–871. https://doi.org/10.1161/CIRCULATIONAHA.119.044061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Schuld J, Orfanos Z, Chevessier F, Eggers B, Heil L, Uszkoreit J et al (2020) Homozygous expression of the myofibrillar myopathy-associated p.W2710X filamin C variant reveals major pathomechanisms of sarcomeric lesion formation. Acta Neuropathol Commun 8:154. https://doi.org/10.1186/s40478-020-01001-9

  75. Chevessier F, Schuld J, Orfanos Z, Plank AC, Wolf L, Maerkens A et al (2015) Myofibrillar instability exacerbated by acute exercise in filaminopathy. Hum Mol Genet 24:7207–7220. https://doi.org/10.1093/hmg/ddv421

    Article  CAS  PubMed  Google Scholar 

  76. Powers JD, Liu C, Fang X, Omens JH, Chen J, McCulloch AD (2020) Cardiac-specific deletion of filamin C decouples myocyte contractility and calcium handling in adult mice. FASEB J 34:1–1. https://doi.org/10.1096/fasebj.2020.34.s1.04277

    Article  Google Scholar 

  77. Tucker NR, McLellan MA, Hu D, Ye J, Parsons VA, Mills RW et al (2017) Novel mutation in FLNC (filamin C) causes familial restrictive cardiomyopathy. Circ Cardiovasc Genet 10:e001780. https://doi.org/10.1161/CIRCGENETICS.117.001780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Gabbin B (2020) Modeling of a novel filamin-C mutation in restrictive cardiomyopathy using hiPSC-derived cardiomyocytes. University of Applied Sciences Technikum Wien, Vienna

    Google Scholar 

  79. Zou J, Mali P, Huang X, Dowey SN, Cheng L (2011) Site-specific gene correction of a point mutation in human iPS cells derived from an adult patient with sickle cell disease. Blood 118:4599–4608. https://doi.org/10.1182/blood-2011-02-335554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Maiweilidan Y, Klauza I, Kordeli E (2011) Novel interactions of ankyrins-G at the costameres: the muscle-specific Obscurin/Titin-Binding-related Domain (OTBD) binds plectin and filamin C. Exp Cell Res 317:724–736. https://doi.org/10.1016/j.yexcr.2011.01.002

    Article  CAS  PubMed  Google Scholar 

  81. Labeit S, Lahmers S, Burkart C, Fong C, McNabb M, Witt S et al (2006) Expression of distinct classes of titin isoforms in striated and smooth muscles by alternative splicing and their conserved interaction with filamins. J Mol Biol 362:664–681. https://doi.org/10.1016/j.jmb.2006.07.077

    Article  CAS  PubMed  Google Scholar 

  82. Holmes WB, Moncman CL (2008) Nebulette interacts with filamin C. Cell Motil Cytoskeleton 65:130–142. https://doi.org/10.1002/cm.20249

    Article  CAS  PubMed  Google Scholar 

  83. van der Ven PF, Wiesner S, Salmikangas P, Auerbach D, Himmel M, Kempa S et al (2000) Indications for a novel muscular dystrophy pathway. gamma-filamin, the muscle-specific filamin isoform, interacts with myotilin. J Cell Biol 151:235–248. https://doi.org/10.1083/jcb.151.2.235

    Article  PubMed  PubMed Central  Google Scholar 

  84. Faulkner G, Pallavicini A, Comelli A, Salamon M, Bortoletto G, Ievolella C et al (2000) FATZ, a filamin-, actinin-, and telethonin-binding protein of the Z-disc of skeletal muscle. J Biol Chem 275:41234–41242. https://doi.org/10.1074/jbc.M007493200

    Article  CAS  PubMed  Google Scholar 

  85. Baker J, Riley G, Romero MR, Haynes AR, Hilton H, Simon M et al (2010) Identification of a Z-band associated protein complex involving KY, FLNC and IGFN1. Exp Cell Res 316:1856–1870. https://doi.org/10.1016/j.yexcr.2010.02.027

    Article  CAS  PubMed  Google Scholar 

  86. Beatham J, Romero R, Townsend SK, Hacker T, van der Ven PF, Blanco G (2004) Filamin C interacts with the muscular dystrophy KY protein and is abnormally distributed in mouse KY deficient muscle fibres. Hum Mol Genet 13:2863–2874. https://doi.org/10.1093/hmg/ddh308

    Article  CAS  PubMed  Google Scholar 

  87. Gontier Y, Taivainen A, Fontao L, Sonnenberg A, van der Flier A, Carpen O et al (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 118:3739–3749. https://doi.org/10.1242/jcs.02484

    Article  CAS  PubMed  Google Scholar 

  88. Thompson TG, Chan YM, Hack AA, Brosius M, Rajala M, Lidov HG et al (2000) Filamin 2 (FLN2): A muscle-specific sarcoglycan interacting protein. J Cell Biol 148:115–126. https://doi.org/10.1083/jcb.148.1.115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. McNamara E, Ravenscroft G, Duff R, Daniel P, Robertson S, Laing N et al (2014) AP 10: Investigating a novel knock-in mouse model with a mutation (E247K) in the skeletal muscle-specific filamin C gene. Neuromuscul Disord 24:833

    Article  Google Scholar 

  90. Deo RC, Musso G, Tasan M, Tang P, Poon A, Yuan C et al (2014) Prioritizing causal disease genes using unbiased genomic features. Genome Biol 15:534. https://doi.org/10.1186/s13059-014-0534-8

    Article  PubMed  Google Scholar 

  91. Alnefaie RM (2019) Characterization of zebrafish models of filamin C related cardiomyopathy. Colorado State University, Fort Collins

    Google Scholar 

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Acknowledgements

We thank Dr. Haobin Jiang for his aid in figure drawing and Zhuyun Qin for her help in English language editing.

Funding

This work was supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS, 2016-I2M-1–015), the National Key Research and Development Project of China (2016YFC1300900 and 2019YFA0801500), and the National Natural Science Foundation of China (81900343 and 31801068).

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  1. State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China

    Shen Song, Anteng Shi, Hong Lian, Shengshou Hu & Yu Nie

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  1. Shen Song
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  2. Anteng Shi
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  3. Hong Lian
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Shengshou Hu and Yu Nie had the idea for the article. Shen Song and Anteng Shi performed the literature search and data analysis and drafted the article. Hong Lian revised the manuscript. All authors approved the final version of the manuscript.

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Shen Song and Anteng Shi are co-first author.

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Song, S., Shi, A., Lian, H. et al. Filamin C in cardiomyopathy: from physiological roles to DNA variants. Heart Fail Rev 27, 1373–1385 (2022). https://doi.org/10.1007/s10741-021-10172-z

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