Unraveling obscurins in heart disease

  • Alyssa Grogan
  • Aikaterini Kontrogianni-KonstantopoulosEmail author
Invited Review


Obscurins, expressed from the single OBSCN gene, are a family of giant, modular, cytoskeletal proteins that play key structural and regulatory roles in striated muscles. They were first implicated in the development of heart disease in 2007 when two missense mutations were found in a patient diagnosed with hypertrophic cardiomyopathy (HCM). Since then, the discovery of over a dozen missense, frameshift, and splicing mutations that are linked to various forms of cardiomyopathy, including HCM, dilated cardiomyopathy (DCM), and left ventricular non-compaction (LVNC), has highlighted OBSCN as a potential disease-causing gene. At this time, the functional consequences of the identified mutations remain largely elusive, and much work has yet to be done to characterize the disease mechanisms of pathological OBSCN variants. Herein, we describe the OBSCN mutations known to date, discuss their potential impact on disease development, and provide future directions in order to better understand the involvement of obscurins in heart disease.


Obscurin Sarcomeric mutations Cardiomyopathy Heart failure 


Funding information

This work was supported by grants from the American Heart Association (16GRNT31290010 to AKK), Muscular Dystrophy Association (313579 to AKK), and NIH/MIAMS (T32AR7592 to AG).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Ackermann MA, Hu LY, Bowman AL, Bloch RJ, Kontrogianni-Konstantopoulos A (2009) Obscurin interacts with a novel isoform of MyBP-C slow at the periphery of the sarcomeric M-band and regulates thick filament assembly. Mol Biol Cell 20:2963–2978. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Ackermann MA, King B, Lieberman NAP, Bobbili PJ, Rudloff M, Berndsen CE, Wright NT, Hecker PA, Kontrogianni-Konstantopoulos A (2017) Novel obscurins mediate cardiomyocyte adhesion and size via the PI3K/AKT/mTOR signaling pathway. J Mol Cell Cardiol 111:27–39. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ackermann MA, Shriver M, Perry NA, Hu LY, Kontrogianni-Konstantopoulos A (2014) Obscurins: Goliaths and Davids take over non-muscle tissues. PLoS One 9:e88162. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Arbustini E, Favalli V, Narula N, Serio A, Grasso M (2016) Left ventricular noncompaction: a distinct genetic cardiomyopathy? J Am Coll Cardiol 68:949–966. CrossRefPubMedGoogle Scholar
  5. 5.
    Arimura T, Matsumoto Y, Okazaki O, Hayashi T, Takahashi M, Inagaki N, Hinohara K, Ashizawa N, Yano K, Kimura A (2007) Structural analysis of obscurin gene in hypertrophic cardiomyopathy. Biochem Biophys Res Commun 362:281–287. CrossRefPubMedGoogle Scholar
  6. 6.
    Bagnato P, Barone V, Giacomello E, Rossi D, Sorrentino V (2003) Binding of an ankyrin-1 isoform to obscurin suggests a molecular link between the sarcoplasmic reticulum and myofibrils in striated muscles. J Cell Biol 160:245–253. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Balakrishnan A, Bleeker FE, Lamba S, Rodolfo M, Daniotti M, Scarpa A, van Tilborg AA, Leenstra S, Zanon C, Bardelli A (2007) Novel somatic and germline mutations in cancer candidate genes in glioblastoma, melanoma, and pancreatic carcinoma. Cancer Res 67:3545–3550. CrossRefPubMedGoogle Scholar
  8. 8.
    Borisov AB, Kontrogianni-Konstantopoulos A, Bloch RJ, Westfall MV, Russell MW (2004) Dynamics of obscurin localization during differentiation and remodeling of cardiac myocytes: obscurin as an integrator of myofibrillar structure. J Histochem Cytochem 52:1117–1127. CrossRefPubMedGoogle Scholar
  9. 9.
    Borisov AB, Raeker MO, Kontrogianni-Konstantopoulos A, Yang K, Kurnit DM, Bloch RJ, Russell MW (2003) Rapid response of cardiac obscurin gene cluster to aortic stenosis: differential activation of rho-GEF and MLCK and involvement in hypertrophic growth. Biochem Biophys Res Commun 310:910–918CrossRefPubMedGoogle Scholar
  10. 10.
    Borisov AB, Sutter SB, Kontrogianni-Konstantopoulos A, Bloch RJ, Westfall MV, Russell MW (2006) Essential role of obscurin in cardiac myofibrillogenesis and hypertrophic response: evidence from small interfering RNA-mediated gene silencing. Histochem Cell Biol 125:227–238. CrossRefPubMedGoogle Scholar
  11. 11.
    Bowman A, Catino D, Strong J, Randall W, Kontrogianni-Konstantopoulos A, Bloch R (2008) The rho-guanine nucleotide exchange factor domain of obscurin regulates assembly of titin at the Z-disk through interactions with Ran binding protein 9. Mol Biol Cell 19:3782–3792CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Braunwald E (2017) Cardiomyopathies: an overview. Circ Res 121:711–721. CrossRefPubMedGoogle Scholar
  13. 13.
    Burke MA, Cook SA, Seidman JG, Seidman CE (2016) Clinical and mechanistic insights into the genetics of cardiomyopathy. J Am Coll Cardiol 68:2871–2886. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Catalano J, Paynton B, Kaniper S, Gerhard G, Alvarez R (2018) Identification of a novel obscurin protein variant in nonischemic cardiomyopathy. J Am Coll Cardiol 71:A743CrossRefGoogle Scholar
  15. 15.
    Connolly H, Attenhofer-Jost C Isolated left ventricular noncompaction. UpToDate. Accessed May 2018
  16. 16.
    Elliott P, Andersson B, Arbustini E, Bilinska Z, Cecchi F, Charron P, Dubourg O, Kühl U, Maisch B, McKenna WJ, Monserrat L, Pankuweit S, Rapezzi C, Seferovic P, Tavazzi L, Keren A (2008) Classification of the cardiomyopathies: a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 29:270–276. CrossRefPubMedGoogle Scholar
  17. 17.
    Ford-Speelman DL, Roche JA, Bowman AL, Bloch RJ (2009) The rho-guanine nucleotide exchange factor domain of obscurin activates rhoA signaling in skeletal muscle. Mol Biol Cell 20:3905–3917. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Garfinkel AC, Seidman JG, Seidman CE (2018) Genetic pathogenesis of hypertrophic and dilated cardiomyopathy. Heart Fail Clin 14:139–146. CrossRefPubMedGoogle Scholar
  19. 19.
    Gautel M (2011) Cytoskeletal protein kinases: titin and its relations in mechanosensing. Pflugers Arch 462:119–134. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Magid D, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER, Moy CS, Mussolino ME, Nichol G, Paynter NP, Schreiner PJ, Sorlie PD, Stein J, Turan TN, Virani SS, Wong ND, Woo D, Turner MB, Subcommittee AHASCaSS (2013) Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation 127:e6–e245. CrossRefPubMedGoogle Scholar
  21. 21.
    Granzier H, Labeit S (2002) Cardiac titin: an adjustable multi-functional spring. J Physiol 541:335–342CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Granzier HL, Labeit S (2004) The giant protein titin: a major player in myocardial mechanics, signaling, and disease. Circ Res 94:284–295. CrossRefPubMedGoogle Scholar
  23. 23.
    Granzier HL, Labeit S (2006) The giant muscle protein titin is an adjustable molecular spring. Exerc Sport Sci Rev 34:50–53CrossRefPubMedGoogle Scholar
  24. 24.
    Guo H, Isserlin R, Emili A, Burniston JG (2017) Exercise-responsive phosphoproteins in the heart. J Mol Cell Cardiol 111:61–68. CrossRefPubMedGoogle Scholar
  25. 25.
    Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR, McDonough B, Sparks E, Teodorescu DL, Cirino AL, Banner NR, Pennell DJ, Graw S, Merlo M, Di Lenarda A, Sinagra G, Bos JM, Ackerman MJ, Mitchell RN, Murry CE, Lakdawala NK, Ho CY, Barton PJ, Cook SA, Mestroni L, Seidman JG, Seidman CE (2012) Truncations of titin causing dilated cardiomyopathy. N Engl J Med 366:619–628. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Hershberger RE, Hedges DJ, Morales A (2013) Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat Rev Cardiol 10:531–547. CrossRefPubMedGoogle Scholar
  27. 27.
    Hu L-YR, Ackermann MA, Hecker PA, Prosser BL, King B, O'Connell KA, Grogan A, Meyer LC, Berndsen CE, Wright NT, Lederer WJ, Kontrogianni-Konstantopoulos A (2017) Deregulated Ca2+ cycling underlies the development of arrhythmia due to mutant obscurin. Sci Adv 3:e1603081.
  28. 28.
    Hu LY, Kontrogianni-Konstantopoulos A (2013) The kinase domains of obscurin interact with intercellular adhesion proteins. Faseb J 27:2001–2012. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Ichida F, Tsubata S, Bowles KR, Haneda N, Uese K, Miyawaki T, Dreyer WJ, Messina J, Li H, Bowles NE, Towbin JA (2001) Novel gene mutations in patients with left ventricular noncompaction or Barth syndrome. Circulation 103:1256–1263CrossRefPubMedGoogle Scholar
  30. 30.
    Kiando SR, Barlassina C, Cusi D, Galan P, Lathrop M, Plouin PF, Jeunemaitre X, Bouatia-Naji N (2015) Exome sequencing in seven families and gene-based association studies indicate genetic heterogeneity and suggest possible candidates for fibromuscular dysplasia. J Hypertens 33:1802–1810; discussion 1810. CrossRefPubMedGoogle Scholar
  31. 31.
    Kim JH, Park BL, Pasaje CF, Kim Y, Bae JS, Park JS, Uh ST, Kim YH, Kim MK, Choi IS, Cho SH, Choi BW, Koh I, Park CS, Shin HD (2010) Contribution of the OBSCN nonsynonymous variants to aspirin exacerbated respiratory disease susceptibility in Korean population. DNA Cell Biol 31:1001–1009. CrossRefGoogle Scholar
  32. 32.
    Kirk JA, Holewinski RJ, Kooij V, Agnetti G, Tunin RS, Witayavanitkul N, de Tombe PP, Gao WD, Van Eyk J, Kass DA (2014) Cardiac resynchronization sensitizes the sarcomere to calcium by reactivating GSK-3β. J Clin Invest 124:129–138. CrossRefPubMedGoogle Scholar
  33. 33.
    Kontrogianni-Konstantopoulos A, Ackermann MA, Bowman AL, Yap SV, Bloch RJ (2009) Muscle giants: molecular scaffolds in sarcomerogenesis. Physiol Rev 89:1217–1267. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Kontrogianni-Konstantopoulos A, Catino DH, Strong JC, Randall WR, Bloch RJ (2004) Obscurin regulates the organization of myosin into A bands. American journal of physiology Cell physiology 287:C209–C217. CrossRefPubMedGoogle Scholar
  35. 35.
    Kontrogianni-Konstantopoulos A, Catino DH, Strong JC, Sutter S, Borisov AB, Pumplin DW, Russell MW, Bloch RJ (2006) Obscurin modulates the assembly and organization of sarcomeres and the sarcoplasmic reticulum. FASEB J 20:2102–2111. CrossRefPubMedGoogle Scholar
  36. 36.
    Kontrogianni-Konstantopoulos A, Jones EM, Van Rossum DB, Bloch RJ (2003) Obscurin is a ligand for small ankyrin 1 in skeletal muscle. Mol Biol Cell 14:1138–1148. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Landstrom AP, Ackerman MJ (2012) Beyond the cardiac myofilament: hypertrophic cardiomyopathy-associated mutations in genes that encode calcium-handling proteins. Curr Mol Med 12:507–518CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Lange S, Ouyang K, Meyer G, Cui L, Cheng H, Lieber RL, Chen J (2009) Obscurin determines the architecture of the longitudinal sarcoplasmic reticulum. J Cell Sci 122:2640–2650. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Lin BL, Song T, Sadayappan S (2017) Myofilaments: movers and rulers of the sarcomere. Compr Physiol 7:675–692. CrossRefPubMedGoogle Scholar
  40. 40.
    Linke W (2017) Titin gene and protein functions in passive and active muscle. Annu Rev Physiol 80:389–411.
  41. 41.
    Makarenko I, Opitz CA, Leake MC, Neagoe C, Kulke M, Gwathmey JK, del Monte F, Hajjar RJ, Linke WA (2004) Passive stiffness changes caused by upregulation of compliant titin isoforms in human dilated cardiomyopathy hearts. Circ Res 95:708–716. CrossRefPubMedGoogle Scholar
  42. 42.
    Manrai AK, Funke BH, Rehm HL, Olesen MS, Maron BA, Szolovits P, Margulies DM, Loscalzo J, Kohane IS (2016) Genetic misdiagnoses and the potential for health disparities. N Engl J Med 375:655–665. CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Manring HR, Dorn LE, Ex-Willey A, Accornero F, Ackermann MA (2018) At the heart of inter- and intracellular signaling: the intercalated disc. Biophys Rev 10:961–971.
  44. 44.
    Marian AJ, van Rooij E, Roberts R (2016) Genetics and genomics of single-gene cardiovascular diseases: common hereditary cardiomyopathies as prototypes of single-gene disorders. J Am Coll Cardiol 68:2831–2849. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, Moss AJ, Seidman CE, Young JB, Association AH, Council on Clinical Cardiology HaFaTC, Groups QoCaORaFGaTBIW, Prevention CoEa (2006) Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation 113:1807–1816. CrossRefPubMedGoogle Scholar
  46. 46.
    Marston S (2017) Obscurin variants and inherited cardiomyopathies. Biophys Rev 9:239–243CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Marston S, Montgiraud C, Munster AB, Copeland O, Choi O, Dos Remedios C, Messer AE, Ehler E, Knöll R (2015) OBSCN mutations associated with dilated cardiomyopathy and haploinsufficiency. PLoS One 10:e0138568. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Masarone D, Kaski JP, Pacileo G, Elliott PM, Bossone E, Day SM, Limongelli G (2018) Epidemiology and clinical aspects of genetic cardiomyopathies. Heart Fail Clin 14:119–128. CrossRefPubMedGoogle Scholar
  49. 49.
    Olin JW, Froehlich J, Gu X, Bacharach JM, Eagle K, Gray BH, Jaff MR, Kim ES, Mace P, Matsumoto AH, McBane RD, Kline-Rogers E, White CJ, Gornik HL (2012) The United States registry for fibromuscular dysplasia: results in the first 447 patients. Circulation 125:3182–3190. CrossRefPubMedGoogle Scholar
  50. 50.
    Online Mendelian Inheritance in Man, OMIM. McKusick-Nathans Institute of Genetic Medicine. Johns Hopkins University, BaltimoreGoogle Scholar
  51. 51.
    Perry NA, Shriver M, Mameza MG, Grabias B, Balzer E, Kontrogianni-Konstantopoulos A (2012) Loss of giant obscurins promotes breast epithelial cell survival through apoptotic resistance. FASEB J 26:2764–2775. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Perry NA, Vitolo MI, Martin SS, Kontrogianni-Konstantopoulos A (2014) Loss of the obscurin-RhoGEF downregulates RhoA signaling and increases microtentacle formation and attachment of breast epithelial cells. Oncotarget 5:8558–8568. PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Potts GK, McNally RM, Blanco R, You JS, Hebert AS, Westphall MS, Coon JJ, Hornberger TA (2017) A map of the phosphoproteomic alterations that occur after a bout of maximal-intensity contractions. J Physiol 595:5209–5226. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Raeker M, Russell MW (2011) Obscurin depletion impairs organization of skeletal muscle in developing zebrafish embryos. J Biomed Biotechnol 2011:479135–479115. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Raeker MO, Bieniek AN, Ryan AS, Tsai HJ, Zahn KM, Russell MW (2010) Targeted deletion of the zebrafish obscurin a RhoGEF domain affects heart, skeletal muscle and brain development. Dev Biol 337:432–443. CrossRefPubMedGoogle Scholar
  56. 56.
    Raeker MO, Su F, Geisler SB, Borisov AB, Kontrogianni-Konstantopoulos A, Lyons SE, Russell MW (2006) Obscurin is required for the lateral alignment of striated myofibrils in zebrafish. Dev Dyn 235:2018–2029. CrossRefPubMedGoogle Scholar
  57. 57.
    Rajendran BK, Deng CX (2017) Characterization of potential driver mutations involved in human breast cancer by computational approaches. Oncotarget 8:50252–50272. PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Randazzo D, Blaauw B, Paolini C, Pierantozzi E, Spinozzi S, Lange S, Chen J, Protasi F, Reggiani C, Sorrentino V (2017) Exercise-induced alterations and loss of sarcomeric M-line organization in the diaphragm muscle of obscurin knockout mice. Am J Physiol Cell Physiol 312:C16–C28. CrossRefPubMedGoogle Scholar
  59. 59.
    Randazzo D, Giacomello E, Lorenzini S, Rossi D, Pierantozzi E, Blaauw B, Reggiani C, Lange S, Peter AK, Chen J, Sorrentino V (2013) Obscurin is required for ankyrinB-dependent dystrophin localization and sarcolemma integrity. J Cell Biol 200:523–536. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Randazzo D, Pierantozzi E, Rossi D, Sorrentino V (2017) The potential of obscurin as a therapeutic target in muscle disorders. Expert Opin Ther Targets 21:897–910CrossRefPubMedGoogle Scholar
  61. 61.
    Roberts AM, Ware JS, Herman DS, Schafer S, Baksi J, Bick AG, Buchan RJ, Walsh R, John S, Wilkinson S, Mazzarotto F, Felkin LE, Gong S, MacArthur JA, Cunningham F, Flannick J, Gabriel SB, Altshuler DM, Macdonald PS, Heinig M, Keogh AM, Hayward CS, Banner NR, Pennell DJ, O'Regan DP, San TR, de Marvao A, Dawes TJ, Gulati A, Birks EJ, Yacoub MH, Radke M, Gotthardt M, Wilson JG, O'Donnell CJ, Prasad SK, Barton PJ, Fatkin D, Hubner N, Seidman JG, Seidman CE, Cook SA (2015) Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med 7:270ra276. CrossRefGoogle Scholar
  62. 62.
    Rossi D, Palmio J, Evilä A, Galli L, Barone V, Caldwell TA, Policke RA, Aldkheil E, Berndsen CE, Wright NT, Malfatti E, Brochier G, Pierantozzi E, Jordanova A, Guergueltcheva V, Romero NB, Hackman P, Eymard B, Udd B, Sorrentino V (2017) A novel FLNC frameshift and an OBSCN variant in a family with distal muscular dystrophy. PLoS One 12:e0186642. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Rowland T, Graw S, Sweet M, Gigli M, Taylor M, Mestroni L (2016) Obscurin variants in patients with left ventricular noncompaction. J Am Coll Cardiol 68:2237–2238CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Russell MW, Raeker MO, Korytkowski KA, Sonneman KJ (2002) Identification, tissue expression and chromosomal localization of human Obscurin-MLCK, a member of the titin and Dbl families of myosin light chain kinases. Gene 282:237–246CrossRefPubMedGoogle Scholar
  65. 65.
    Shriver M, Marimuthu S, Paul C, Geist J, Seale T, Konstantopoulos K, Kontrogianni-Konstantopoulos A (2016) Giant obscurins regulate the PI3K cascade in breast epithelial cells via direct binding to the PI3K/p85 regulatory subunit. Oncotarget 7:45414–45428. CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Shriver M, Stroka KM, Vitolo MI, Martin S, Huso DL, Konstantopoulos K, Kontrogianni-Konstantopoulos A (2015) Loss of giant obscurins from breast epithelium promotes epithelial-to-mesenchymal transition, tumorigenicity and metastasis. Oncogene 34:4248–4259. CrossRefPubMedGoogle Scholar
  67. 67.
    Sjöblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE (2006) The consensus coding sequences of human breast and colorectal cancers. Science 314:268–274. CrossRefPubMedGoogle Scholar
  68. 68.
    Tardiff JC (2011) Thin filament mutations: developing an integrative approach to a complex disorder. Circ Res 108:765–782. CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Tardiff JC, Carrier L, Bers DM, Poggesi C, Ferrantini C, Coppini R, Maier LS, Ashrafian H, Huke S, van der Velden J (2015) Targets for therapy in sarcomeric cardiomyopathies. Cardiovasc Res 105:457–470. CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Towbin JA, Lorts A, Jefferies JL (2015) Left ventricular non-compaction cardiomyopathy. Lancet 386:813–825. CrossRefPubMedGoogle Scholar
  71. 71.
    van der Velden J, Ho CY, Tardiff JC, Olivotto I, Knollmann BC, Carrier L (2015) Research priorities in sarcomeric cardiomyopathies. Cardiovasc Res 105:449–456. CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Vernon EG, Malik K, Reynolds P, Powlesland R, Dallosso AR, Jackson S, Henthorn K, Green ED, Brown KW (2003) The parathyroid hormone-responsive B1 gene is interrupted by a t(1;7)(q42;p15) breakpoint associated with Wilms' tumour. Oncogene 22:1371–1380. CrossRefPubMedGoogle Scholar
  73. 73.
    Wang L, Geist J, Grogan A, Hu LR, Kontrogianni-Konstantopoulos A (2018) Thick filament protein network, functions, and disease association. Compr Physiol 8(2):631–709.
  74. 74.
    Wang L, Geist J, Grogan A, Hu LR, Kontrogianni-Konstantopoulos A (2018) Thick filament protein network, functions, and disease association. Compr Physiol 8:631–709. CrossRefPubMedGoogle Scholar
  75. 75.
    Wexler RK, Elton T, Pleister A, Feldman D (2009) Cardiomyopathy: an overview. Am Fam Physician 79:778–784PubMedPubMedCentralGoogle Scholar
  76. 76.
    Wu Y, Bell SP, Trombitas K, Witt CC, Labeit S, LeWinter MM, Granzier H (2002) Changes in titin isoform expression in pacing-induced cardiac failure give rise to increased passive muscle stiffness. Circulation 106:1384–1389CrossRefPubMedGoogle Scholar
  77. 77.
    Xu J, Li Z, Ren X, Dong M, Li J, Shi X, Zhang Y, Xie W, Sun Z, Liu X, Dai Q (2015) Investigation of pathogenic genes in Chinese sporadic hypertrophic cardiomyopathy patients by whole exome sequencing. Sci Rep 5:16609CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Young P, Ehler E, Gautel M (2001) Obscurin, a giant sarcomeric rho guanine nucleotide exchange factor protein involved in sarcomere assembly. J Cell Biol 154:123–136CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular BiologyUniversity of Maryland School of MedicineBaltimoreUSA

Personalised recommendations