Skip to main content

Advertisement

SpringerLink
Log in

The Alternative Heart: Impact of Alternative Splicing in Heart Disease

  • Published:
Journal of Cardiovascular Translational Research Aims and scope Submit manuscript

Abstract

Alternative splicing is the main driver of protein diversity and allows the production of different proteins from each gene in the genome. Changes in exon exclusion, intron retention or the use of alternative splice sites can alter protein structure, localisation, regulation and function. In the heart, alternative splicing of sarcomeric genes, ion channels and cell signalling proteins can lead to cardiomyopathies, arrhythmias and other pathologies. Also, a number of inherited conditions and heart-related diseases develop as a result of mutations affecting splicing. Here, we review the impact that changes in alternative splicing have on individual genes and on whole biological processes associated with heart disease. We also discuss promising therapeutic tools based on the manipulation of alternative splicing.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Lara-Pezzi, E., Dopazo, A., & Manzanares, M. (2012). Understanding cardiovascular disease: A journey through the genome (and what we found there). Disease Models & Mechanisms, 5, 434–443.

    CAS  Google Scholar 

  2. Wang, E. T., Sandberg, R., Luo, S., Khrebtukova, I., Zhang, L., Mayr, C., et al. (2008). Alternative isoform regulation in human tissue transcriptomes. Nature, 456, 470–476.

    PubMed  CAS  Google Scholar 

  3. Rodriguez, J. M., Maietta, P., Ezkurdia, I., Pietrelli, A., Wesselink, J.-J., Lopez, G., et al. (2013). APPRIS: Annotation of principal and alternative splice isoforms. Nuclear Acid Research, 41, D110–D117.

    CAS  Google Scholar 

  4. Wang, Z., & Burge, C. B. (2008). Splicing regulation: From a parts list of regulatory elements to an integrated splicing code. RNA, 14, 802–813.

    PubMed  CAS  Google Scholar 

  5. House, A. E., & Lynch, K. W. (2008). Regulation of alternative splicing: More than just the ABCs. Journal of Biological Chemistry, 283, 1217–1221.

    PubMed  CAS  Google Scholar 

  6. Wahl, M. C., Will, C. L., & Lührmann, R. (2009). The Spliceosome: design principles of a dynamic RNP machine. Cell, 136, 701–718.

    PubMed  CAS  Google Scholar 

  7. Pan, Q., Shai, O., Lee, L. J., Frey, B. J., & Blencowe, B. J. (2008). Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nature Genetics, 40, 1413–1415.

    PubMed  CAS  Google Scholar 

  8. Djebali, S., Davis, C. A., Merkel, A., Dobin, A., Lassmann, T., Mortazavi, A., et al. (2012). Landscape of transcription in human cells. Nature, 489, 101–108.

    PubMed  CAS  Google Scholar 

  9. Barbosa-Morais, N. L., Irimia, M., Pan, Q., Xiong, H. Y., Gueroussov, S., Lee, L. J., et al. (2012). The evolutionary landscape of alternative splicing in vertebrate species. Science, 338, 1587–1593.

    PubMed  CAS  Google Scholar 

  10. Merkin, J., Russell, C., Chen, P., & Burge, C. B. (2012). Evolutionary dynamics of gene and isoform regulation in mammalian tissues. Science, 338, 1593–1599.

    PubMed  CAS  Google Scholar 

  11. Licatalosi, D. D., & Darnell, R. B. (2010). RNA processing and its regulation: Global insights into biological networks. Nature Reviews Genetics, 11, 75–87.

    PubMed  CAS  Google Scholar 

  12. Sun, S., Zhang, Z., Fregoso, O., & Krainer, A. R. (2012). Mechanisms of activation and repression by the alternative splicing factors RBFOX1/2. RNA, 18, 274–283.

    PubMed  CAS  Google Scholar 

  13. Zhang, C., Frias, M. A., Mele, A., Ruggiu, M., Eom, T., Marney, C. B., et al. (2010). Integrative modeling defines the Nova splicing-regulatory network and its combinatorial controls. Science, 329, 439–443.

    PubMed  CAS  Google Scholar 

  14. Wang, E., Cody, N., Jog, S., Biancolella, M., Wang, T., Treacy, D., et al. (2012). Transcriptome-wide regulation of pre-mRNA splicing and mRNA localization by muscleblind proteins. Cell, 150, 710–724.

    PubMed  CAS  Google Scholar 

  15. Cho, S., Hoang, A., Sinha, R., Zhong, X.-Y., Fu, X.-D., Krainer, A. R., et al. (2011). Interaction between the RNA binding domains of Ser-Arg splicing factor 1 and U1-70K snRNP protein determines early spliceosome assembly. Proc Natl Acad Sci USA, 108, 8233–8238.

    PubMed  CAS  Google Scholar 

  16. Braunschweig, U., Gueroussov, S., Plocik, A. M., Graveley, B. R., & Blencowe, B. J. (2013). Dynamic integration of splicing within gene regulatory pathways. Cell, 152, 1252–1269.

    PubMed  CAS  Google Scholar 

  17. Charlet-B, N., Logan, P., Singh, G., & Cooper, T. A. (2002). Dynamic antagonism between ETR-3 and PTB regulates cell type-specific alternative splicing. Molecular Cell, 9, 649–658.

    PubMed  CAS  Google Scholar 

  18. Chiou, N.-T., Shankarling, G., & Lynch, K. W. (2013). hnRNP L and hnRNP A1 induce extended U1 snRNA interactions with an exon to repress spliceosome assembly. Molecular Cell, 49, 972–982.

    PubMed  CAS  Google Scholar 

  19. Luco, R. F., Pan, Q., Tominaga, K., Blencowe, B. J., Pereira-Smith, O. M., & Misteli, T. (2010). Regulation of alternative splicing by histone modifications. Science, 327, 996–1000.

    PubMed  CAS  Google Scholar 

  20. Barash, Y., Calarco, J. A., Gao, W., Pan, Q., Wang, X., Shai, O., et al. (2010). Deciphering the splicing code. Nature, 465, 53–59.

    PubMed  CAS  Google Scholar 

  21. Kalsotra, A., Xiao, X., Ward, A. J., Castle, J. C., Johnson, J. M., Burge, C. B., et al. (2008). A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart. Proceedings of the National Academy of Sciences USA, 105, 20333–20338.

    CAS  Google Scholar 

  22. Kalsotra, A., Wang, K., Li, P.-F., & Cooper, T. A. (2010). MicroRNAs coordinate an alternative splicing network during mouse postnatal heart development. Genes & Development, 24, 653–658.

    CAS  Google Scholar 

  23. Park, J. Y., Li, W., Zheng, D., Zhai, P., Zhao, Y., Matsuda, T., et al. (2011). Comparative analysis of mRNA isoform expression in cardiac hypertrophy and development reveals multiple post-transcriptional regulatory modules. PLoS One, 6, e22391.

    PubMed  CAS  Google Scholar 

  24. Kong, S. W., Hu, Y. W., Ho, J. W. K., Ikeda, S., Polster, S., John, R., et al. (2010). Heart failure-associated changes in RNA splicing of sarcomere genes. Circulation. Cardiovascular Genetics, 3, 138–146.

    PubMed  CAS  Google Scholar 

  25. Felkin, L. E., Narita, T., Germack, R., Shintani, Y., Takahashi, K., Sarathchandra, P., et al. (2011). Calcineurin splicing variant CnAβ1 improves cardiac function after myocardial infarction without inducing hypertrophy. Circulation, 123, 2838–2847.

    PubMed  CAS  Google Scholar 

  26. Thierfelder, L., Watkins, H., Macrae, C., Lamas, R., Mckenna, W., Vosberg, H.-P., et al. (1994). α-Tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: A disease of the sarcomere. Cell, 77, 701–712.

    PubMed  Google Scholar 

  27. Watkins, H., Mckenna, W. J., Thierfelder, L., Suk, H. J., Anan, R., O'donoghue, A., et al. (1995). Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. The New England Journal of Medicine, 332, 1058–1065.

    PubMed  CAS  Google Scholar 

  28. Tardiff, J. C., Factor, S. M., Tompkins, B. D., Hewett, T. E., Palmer, B. M., Moore, R. L., et al. (1998). A truncated cardiac troponin T molecule in transgenic mice suggests multiple cellular mechanisms for familial hypertrophic cardiomyopathy. The Journal of Clinical Investigation, 101, 2800–2811.

    PubMed  CAS  Google Scholar 

  29. Ta, C., & Cp, O. (1984). A single troponin T gene regulated by different programs in cardiac and skeletal muscle development. Science, 226, 979–982.

    Google Scholar 

  30. Warf, M. B., Diegel, J. V., Von Hippel, P. H., & Berglund, J. A. (2009). The protein factors MBNL1 and U2AF65 bind alternative RNA structures to regulate splicing. Proceedings of the National Academy of Sciences USA, 106, 9203–9208.

    CAS  Google Scholar 

  31. Goo, Y.-H., & Cooper, T. A. (2009). CUGBP2 directly interacts with U2 17S snRNP components and promotes U2 snRNA binding to cardiac troponin T pre-mRNA. Nuclear Acid Research, 37, 4275–4286.

    CAS  Google Scholar 

  32. Xu, X., et al. (2005). ASF/SF2-regulated CaMKIIdelta alternative splicing temporally reprograms excitation–contraction coupling in cardiac muscle. Cell, 120, 59–72.

    PubMed  CAS  Google Scholar 

  33. Gunning, P. W., Schevzov, G., Kee, A. J., & Hardeman, E. C. (2005). Tropomyosin isoforms: Divining rods for actin cytoskeleton function. Trends in Cell Biology, 15, 333–341.

    PubMed  CAS  Google Scholar 

  34. Rajan, S., Jagatheesan, G., Karam, C. N., Alves, M. L., Bodi, I., Schwartz, A., et al. (2010). Molecular and functional characterization of a novel cardiac-specific human tropomyosin isoform. Circulation, 121, 410–418.

    PubMed  CAS  Google Scholar 

  35. Bonne, G., Carrier, L., Bercovici, J., Cruaud, C., Richard, P., Hainque, B., et al. (1995). Cardiac myosin binding protein-C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy. Nature Genetics, 11, 438–440.

    PubMed  CAS  Google Scholar 

  36. Watkins, H., Conner, D., Thierfelder, L., Jarcho, J. A., Macrae, C., Mckenna, W. J., et al. (1995). Mutations in the cardiac myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy. Nature Genetics, 11, 434–437.

    PubMed  CAS  Google Scholar 

  37. Marston, S., Copeland, O. N., Jacques, A., Livesey, K., Tsang, V., Mckenna, W. J., et al. (2009). Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency. Circulation Research, 105, 219–222.

    PubMed  CAS  Google Scholar 

  38. Schoenauer, R., Emmert, M., Felley, A., Ehler, E., Brokopp, C., Weber, B., et al. (2011). EH-myomesin splice isoform is a novel marker for dilated cardiomyopathy. Basic Research in Cardiology, 106, 233–247.

    PubMed  CAS  Google Scholar 

  39. Lahmers, S., Wu, Y., Call, D. R., Labeit, S., & Granzier, H. (2004). Developmental control of titin isoform expression and passive stiffness in fetal and neonatal myocardium. Circulation Research, 94, 505–513.

    PubMed  CAS  Google Scholar 

  40. Makarenko, I., Opitz, C. A., Leake, M. C., Neagoe, C., Kulke, M., Gwathmey, J. K., et al. (2004). Passive stiffness changes caused by upregulation of compliant titin isoforms in human dilated cardiomyopathy hearts. Circulation Research, 95, 708–716.

    PubMed  CAS  Google Scholar 

  41. Herman, D. S., Lam, L., Taylor, M. R. G., Wang, L., Teekakirikul, P., Christodoulou, D., et al. (2012). Truncations of titin causing dilated cardiomyopathy. The New England Journal of Medicine, 366, 619–628.

    PubMed  CAS  Google Scholar 

  42. Guo, W., Schafer, S., Greaser, M. L., Radke, M. H., Liss, M., Govindarajan, T., et al. (2012). RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing. Nature Medicine, 18, 766–773.

    PubMed  CAS  Google Scholar 

  43. Brauch, K. M., Karst, M. L., Herron, K. J., De Andrade, M., Pellikka, P. A., Rodeheffer, R. J., et al. (2009). Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy. Journal of the American College of Cardiology, 54, 930–941.

    PubMed  CAS  Google Scholar 

  44. Arimura, T., Inagaki, N., Hayashi, T., Shichi, D., Sato, A., Hinohara, K., et al. (2009). Impaired binding of ZASP/Cypher with phosphoglucomutase 1 is associated with dilated cardiomyopathy. Cardiovascular Research, 83, 80–88.

    PubMed  CAS  Google Scholar 

  45. Yamazaki, T., Wälchli, S., Fujita, T., Ryser, S., Hoshijima, M., Schlegel, W., et al. (2010). Splice variants of enigma homolog, differentially expressed during heart development, promote or prevent hypertrophy. Cardiovascular Research, 86, 374–382.

    PubMed  CAS  Google Scholar 

  46. Hede, M. S., Salimova, E., Piszczek, A., Perlas, E., Winn, N., Nastasi, T., et al. (2012). E-peptides control bioavailability of IGF-1. PLoS One, 7, e51152.

    PubMed  CAS  Google Scholar 

  47. Santini, M. P., Tsao, L., Monassier, L., Theodoropoulos, C., Carter, J., Lara-Pezzi, E., et al. (2007). Enhanced regeneration of the mammalian heart. Circulation Research, 100, 1732–1740.

    PubMed  CAS  Google Scholar 

  48. Santini, M. P., Lexow, J., Borsellino, G., Slonimski, E., Zarrinpashneh, E., Poggioli, T., et al. (2011). IGF-1Ea induces vessel formation after injury and mediates bone marrow and heart cross-talk through the expression of specific cytokines. Biochemical and Biophysical Research Communications, 410, 201–207.

    PubMed  CAS  Google Scholar 

  49. Vinciguerra, M., Santini, M. P., Martinez, C., Pazienza, V., Claycomb, W. C., Giuliani, A., et al. (2012). mIGF-1/JNK1/SirT1 signaling confers protection against oxidative stress in the heart. Aging Cell, 11, 139–149.

    PubMed  CAS  Google Scholar 

  50. Touvron, M., Escoubet, B., Mericskay, M., Angelini, A., Lamotte, L., Santini, M. P., et al. (2012). Locally expressed IGF1 propeptide improves mouse heart function in induced dilated cardiomyopathy by blocking myocardial fibrosis and SRF-dependent CTGF induction. Disease Models & Mechanisms, 5, 481–491.

    CAS  Google Scholar 

  51. Musarò, A., Mccullagh, K., Paul, A., Houghton, L., Dobrowolny, G., Molinaro, M., et al. (2001). Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nature Genetics, 27, 195–200.

    PubMed  Google Scholar 

  52. Lara-Pezzi, E., Winn, N., Paul, A., Mccullagh, K., Slominsky, E., Santini, M. P., et al. (2007). A naturally occurring calcineurin variant inhibits FoxO activity and enhances skeletal muscle regeneration. The Journal of Cell Biology, 179, 1205–1218.

    PubMed  CAS  Google Scholar 

  53. Molkentin, J. D., Lu, J. R., Antos, C. L., Markham, B., Richardson, J., Robbins, J., et al. (1998). A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell, 93, 215–228.

    PubMed  CAS  Google Scholar 

  54. Woolard, J., Bevan, H. S., Harper, S. J., & Bates, D. O. (2009). Molecular diversity of VEGF-A as a regulator of its biological activity. Microcirculation, 16, 572–592.

    PubMed  CAS  Google Scholar 

  55. Carmeliet, P., Ng, Y.-S., Nuyens, D., Theilmeier, G., Brusselmans, K., Cornelissen, I., et al. (1999). Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Nature Medicine, 5, 495–502.

    PubMed  CAS  Google Scholar 

  56. Zeng, L., Xiao, Q., Chen, M., Margariti, A., Martin, D., Ivetic, A., et al. (2013). Vascular endothelial cell growth-activated XBP1 splicing in endothelial cells is crucial for angiogenesis. Circulation, 127, 1712–1722.

    PubMed  CAS  Google Scholar 

  57. Thuerauf, D. J., Marcinko, M., Gude, N., Rubio, M., Sussman, M. A., & Glembotski, C. C. (2006). Activation of the unfolded protein response in infarcted mouse heart and hypoxic cultured cardiac myocytes. Circulation Research, 99, 275–282.

    PubMed  CAS  Google Scholar 

  58. Hetz, C., & Glimcher, L. (2009). Fine-tuning of the unfolded protein response: Assembling the IRE1α interactome. Molecular Cell, 35, 551–561.

    PubMed  CAS  Google Scholar 

  59. Sawada, T., Minamino, T., Fu, H., Asai, M., Okuda, K., Isomura, T., et al. (2010). X-box binding protein 1 regulates brain natriuretic peptide through a novel AP1/CRE-like element in cardiomyocytes. Journal of Molecular and Cellular Cardiology, 48, 1280–1289.

    PubMed  CAS  Google Scholar 

  60. Pan, S., Chen, H. H., Dickey, D. M., Boerrigter, G., Lee, C., Kleppe, L. S., et al. (2009). Biodesign of a renal-protective peptide based on alternative splicing of B-type natriuretic peptide. Proceedings of the National Academy of Sciences USA, 106, 11282–11287.

    CAS  Google Scholar 

  61. Zeng, L., Zampetaki, A., Margariti, A., Pepe, A., Alam, S., Martin, D., et al. (2009). Sustained activation of XBP1 splicing leads to endothelial apoptosis and atherosclerosis development in response to disturbed flow. Proceedings of the National Academy of Sciences USA, 106, 8326–8331.

    CAS  Google Scholar 

  62. Davis, F. J., Gupta, M., Pogwizd, S. M., Bacha, E., Jeevanandam, V., & Gupta, M. P. (2002). Increased expression of alternatively spliced dominant-negative isoform of SRF in human failing hearts. American Journal of Physiology - Heart and Circulatory Physiology, 282, H1521–H1533.

    PubMed  CAS  Google Scholar 

  63. Creemers, E. E., Sutherland, L. B., Oh, J., Barbosa, A. C., & Olson, E. N. (2006). Coactivation of MEF2 by the SAP domain proteins myocardin and MASTR. Molecular Cell, 23, 83–96.

    PubMed  CAS  Google Scholar 

  64. Zhu, B., Ramachandran, B., & Gulick, T. (2005). Alternative pre-mRNA splicing governs expression of a conserved acidic transactivation domain in myocyte enhancer factor 2 factors of striated muscle and brain. Journal of Biological Chemistry, 280, 28749–28760.

    PubMed  CAS  Google Scholar 

  65. Debenedittis, P., & Jiao, K. (2011). Alternative splicing of T-box transcription factor genes. Biochemical and Biophysical Research Communications, 412, 513–517.

    PubMed  CAS  Google Scholar 

  66. Georges, R., Nemer, G., Morin, M., Lefebvre, C., & Nemer, M. (2008). Distinct expression and function of alternatively spliced Tbx5 isoforms in cell growth and differentiation. Molecular and Cellular Biology, 28, 4052–4067.

    PubMed  CAS  Google Scholar 

  67. Fan, C., Chen, Q., & Wang, Q. K. (2009). Functional role of transcriptional factor TBX5 in pre-mRNA splicing and Holt-Oram syndrome via association with SC35. Journal of Biological Chemistry, 284, 25653–25663.

    PubMed  CAS  Google Scholar 

  68. Liao, P., Yong, T. F., Liang, M. C., Yue, D. T., & Soong, T. W. (2005). Splicing for alternative structures of Cav1.2 Ca2+ channels in cardiac and smooth muscles. Cardiovascular Research, 68, 197–203.

    PubMed  CAS  Google Scholar 

  69. Welling, A., Ludwig, A., Zimmer, S., Klugbauer, N., Flockerzi, V., & Hofmann, F. (1997). Alternatively spliced IS6 segments of the alpha 1C gene determine the tissue-specific dihydropyridine sensitivity of cardiac and vascular smooth muscle L-type Ca2+ channels. Circulation Research, 81, 526–532.

    PubMed  CAS  Google Scholar 

  70. Splawski, I., Timothy, K. W., Decher, N., Kumar, P., Sachse, F. B., Beggs, A. H., et al. (2005). Severe arrhythmia disorder caused by cardiac l-type calcium channel mutations. Proceedings of the National Academy of Sciences USA, 102, 8089–8096.

    CAS  Google Scholar 

  71. Tang, Z. Z., Sharma, S., Zheng, S., Chawla, G., Nikolic, J., & Black, D. L. (2011). Regulation of the mutually exclusive exons 8a and 8 in the CaV1.2 calcium channel transcript by polypyrimidine tract-binding protein. Journal of Biological Chemistry, 286, 10007–10016.

    PubMed  CAS  Google Scholar 

  72. George, C. H., Rogers, S. A., Bertrand, B. M., Tunwell, R. E., Thomas, N. L., Steele, D. S., et al. (2007). Alternative splicing of ryanodine receptors modulates cardiomyocyte Ca2+ signaling and susceptibility to apoptosis. Circulation Research, 100, 874–883.

    PubMed  CAS  Google Scholar 

  73. Hein, S., Arnon, E., Kostin, S., Schönburg, M., Elsässer, A., Polyakova, V., et al. (2003). Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: Structural deterioration and compensatory mechanisms. Circulation, 107, 984–991.

    PubMed  Google Scholar 

  74. Ding, J. H., Xu, X., Yang, D., Chu, P. H., Dalton, N. D., Ye, Z., et al. (2004). Dilated cardiomyopathy caused by tissue-specific ablation of SC35 in the heart. The EMBO Journal, 23, 885–896.

    PubMed  CAS  Google Scholar 

  75. Feng, Y., Valley, M. T., Lazar, J., Yang, A. L., Bronson, R. T., Firestein, S., et al. (2009). SRp38 regulates alternative splicing and is required for Ca2+ handling in the embryonic heart. Developmental Cell, 16, 528–538.

    PubMed  CAS  Google Scholar 

  76. Ver Heyen, M., Heymans, S., Antoons, G., Reed, T., Periasamy, M., Awede, B., et al. (2001). Replacement of the muscle-specific sarcoplasmic reticulum Ca(2+)-ATPase isoform SERCA2a by the nonmuscle SERCA2b homologue causes mild concentric hypertrophy and impairs contraction-relaxation of the heart. Circulation Research, 89, 838–846.

    PubMed  CAS  Google Scholar 

  77. Shang, L. L., Pfahnl, A. E., Sanyal, S., Jiao, Z., Allen, J., Banach, K., et al. (2007). Human heart failure is associated with abnormal C-terminal splicing variants in the cardiac sodium channel. Circulation Research, 101, 1146–1154.

    PubMed  CAS  Google Scholar 

  78. Gao, G., Xie, A., Huang, S.-C., Zhou, A., Zhang, J., Herman, A. M., et al. (2011). Role of RBM25/LUC7L3 in abnormal cardiac sodium channel splicing regulation in human heart failure. Circulation, 124, 1124–1131.

    PubMed  CAS  Google Scholar 

  79. Chen, Q., Kirsch, G. E., Zhang, D., Brugada, R., Brugada, J., Brugada, P., et al. (1998). Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature, 392, 293–296.

    PubMed  CAS  Google Scholar 

  80. Zhang, L., Vincent, G. M., Baralle, M., Baralle, F. E., Anson, B. D., Benson, D. W., et al. (2004). An intronic mutation causes long QT syndrome. Journal of the American College of Cardiology, 44, 1283–1291.

    PubMed  CAS  Google Scholar 

  81. Murray, A., Donger, C., Fenske, C., Spillman, I., Richard, P., Dong, Y. B., et al. (1999). Splicing mutations in KCNQ1: A mutation hot spot at codon 344 that produces in frame transcripts. Circulation, 100, 1077–1084.

    PubMed  CAS  Google Scholar 

  82. Deschênes, I., Disilvestre, D., Juang, G. J., Wu, R. C., An, W. F., & Tomaselli, G. F. (2002). Regulation of Kv4.3 current by KChIP2 splice variants: A component of native cardiac I(to)? Circulation, 106, 423–429.

    PubMed  Google Scholar 

  83. Singh, R. K., & Cooper, T. A. (2012). Pre-mRNA splicing in disease and therapeutics. Trends in Molecular Medicine, 18, 472–482.

    PubMed  CAS  Google Scholar 

  84. Philips, A. V., Timchenko, L. T., & Cooper, T. A. (1998). Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science, 280, 737–741.

    PubMed  CAS  Google Scholar 

  85. Liquori, C. L., Ricker, K., Moseley, M. L., Jacobsen, J. F., Kress, W., Naylor, S. L., et al. (2001). Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science, 293, 864–867.

    PubMed  CAS  Google Scholar 

  86. Kanadia, R. N., Johnstone, K. A., Mankodi, A., Lungu, C., Thornton, C. A., Esson, D., et al. (2003). A muscleblind knockout model for myotonic dystrophy. Science, 302, 1978–1980.

    PubMed  CAS  Google Scholar 

  87. Ho, T. H., Bundman, D., Armstrong, D. L., & Cooper, T. A. (2005). Transgenic mice expressing CUG-BP1 reproduce splicing mis-regulation observed in myotonic dystrophy. Human Molecular Genetics, 14, 1539–1547.

    PubMed  CAS  Google Scholar 

  88. Wang, G. S., Kearney, D. L., Biasi, M. D., Taffet, G., & Cooper, T. A. (2007). Elevation of RNA-binding protein CUGBP1 is an early event in an inducible heart-specific mouse model of myotonic dystrophy. The Journal of Clinical Investigation, 117, 2802–2811.

    PubMed  CAS  Google Scholar 

  89. Kuyumcu-Martinez, N. M., Wang, G.-S., & Cooper, T. A. (2007). Increased steady-state levels of CUGBP1 in myotonic dystrophy 1 are due to PKC-mediated hyperphosphorylation. Molecular Cell, 28, 68–78.

    PubMed  CAS  Google Scholar 

  90. Wang, G.-S., Kuyumcu-Martinez, M. N., Sarma, S., Mathur, N., Wehrens, X. H. T., & Cooper, T. A. (2009). PKC inhibition ameliorates the cardiac phenotype in a mouse model of myotonic dystrophy type 1. The Journal of Clinical Investigation, 119, 3797–3806.

    PubMed  CAS  Google Scholar 

  91. Savkur, R. S., Philips, A. V., & Cooper, T. A. (2001). Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nature Genetics, 29, 40–47.

    PubMed  CAS  Google Scholar 

  92. Mankodi, A., Takahashi, M. P., Jiang, H., Beck, C. L., Bowers, W. J., Moxley, R. T., et al. (2002). Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Molecular Cell, 10, 35–44.

    PubMed  CAS  Google Scholar 

  93. Charlet-B, N., Savkur, R. S., Singh, G., Philips, A. V., Grice, E. A., & Cooper, T. A. (2002). Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. Molecular Cell, 10, 45–53.

    PubMed  CAS  Google Scholar 

  94. Yadava, R. S., Frenzel-Mccardell, C. D., Yu, Q., Srinivasan, V., Tucker, A. L., Puymirat, J., et al. (2008). RNA toxicity in myotonic muscular dystrophy induces NKX2-5 expression. Nature Genetics, 40, 61–68.

    PubMed  CAS  Google Scholar 

  95. Eriksson, M., Brown, W. T., Gordon, L. B., Glynn, M. W., Singer, J., Scott, L., et al. (2003). Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature, 423, 293–298.

    PubMed  CAS  Google Scholar 

  96. Pendas, A. M., Zhou, Z., Cadinanos, J., Freije, J. M. P., Wang, J., Hultenby, K., et al. (2002). Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice. Nature Genetics, 31, 94–99.

    PubMed  CAS  Google Scholar 

  97. Lopez-Mejia, I. C., Vautrot, V., De Toledo, M., Behm-Ansmant, I., Bourgeois, C. F., Navarro, C. L., et al. (2011). A conserved splicing mechanism of the LMNA gene controls premature aging. Human Molecular Genetics, 20, 4540–4555.

    PubMed  CAS  Google Scholar 

  98. Scaffidi, P., & Misteli, T. (2006). Lamin A-dependent nuclear defects in human aging. Science, 312, 1059–1063.

    PubMed  CAS  Google Scholar 

  99. Cao, K., Blair, C. D., Faddah, D. A., Kieckhaefer, J. E., Olive, M., Erdos, M. R., et al. (2011). Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts. The Journal of Clinical Investigation, 121, 2833–2844.

    PubMed  CAS  Google Scholar 

  100. Osorio, F. G., Navarro, C. L., Cadiñanos, J., López-Mejía, I. C., Quirós, P. M., Bartoli, C., et al. (2011). Splicing-directed therapy in a new mouse model of human accelerated aging. Science Translational Medicine, 3, 106–107.

    Google Scholar 

  101. Aartsma-Rus, A. (2012). Overview on AON design. Methods in Molecular Biology, 867, 117–129.

    PubMed  CAS  Google Scholar 

  102. Wheeler, T. M., Sobczak, K., Lueck, J. D., Osborne, R. J., Lin, X., Dirksen, R. T., et al. (2009). Reversal of RNA dominance by displacement of protein sequestered on triplet repeat RNA. Science, 325, 336–339.

    PubMed  CAS  Google Scholar 

  103. Wheeler, T. M., Leger, A. J., Pandey, S. K., Macleod, A. R., Nakamori, M., Cheng, S. H., et al. (2012). Targeting nuclear RNA for in vivo correction of myotonic dystrophy. Nature, 488, 111–115.

    PubMed  CAS  Google Scholar 

  104. Qi-Long Lu, T. Y., Takeda, S.'i., Garcia, L., Muntoni, F., & Partridge, T. (2011). The status of exon skipping as a therapeutic approach to Duchenne muscular dystrophy. Molecular Therapy, 19, 9–15.

    PubMed  Google Scholar 

  105. Betts, C., Saleh, A. F., Arzumanov, A. A., Hammond, S. M., Godfrey, C., Coursindel, T., et al. (2012). Pip6-PMO, A new generation of peptide-oligonucleotide conjugates with improved cardiac exon skipping activity for DMD treatment. Molecular Therapy—Nucleic Acids, 1, e38.

    PubMed  Google Scholar 

  106. Goemans, N. M., Tulinius, M., Van Den Akker, J. T., Burm, B. E., Ekhart, P. F., Heuvelmans, N., et al. (2011). Systemic administration of PRO051 in Duchenne's muscular dystrophy. The New England Journal of Medicine, 364, 1513–1522.

    PubMed  CAS  Google Scholar 

  107. Goyenvalle, A., Vulin, A., Fougerousse, F., Leturcq, F., Kaplan, J.-C., Garcia, L., et al. (2004). Rescue of dystrophic muscle through U7 snRNA-mediated exon skipping. Science, 306, 1796–1799.

    PubMed  CAS  Google Scholar 

  108. Scaffidi, P. M. T. (2005). Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome. Nature Medicine, 11, 440–445.

    PubMed  CAS  Google Scholar 

  109. Hua, Y., Sahashi, K., Rigo, F., Hung, G., Horev, G., Bennett, C. F., et al. (2011). Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature, 478, 123–126.

    PubMed  CAS  Google Scholar 

  110. Spitali, P., & Aartsma-Rus, A. (2012). Splice modulating therapies for human disease. Cell, 148, 1085–1088.

    PubMed  CAS  Google Scholar 

  111. Wang, Z., Jeon, H. Y., Rigo, F., Bennett, C. F., & Krainer, A. R. (2012). Manipulation of PK-M mutually exclusive alternative splicing by antisense oligonucleotides. Open Biol 2.

  112. Zammarchi, F., De Stanchina, E., Bournazou, E., Supakorndej, T., Martires, K., Riedel, E., et al. (2011). Antitumorigenic potential of STAT3 alternative splicing modulation. Proc Natl Acad Sci USA, 108, 17779–17784.

    PubMed  CAS  Google Scholar 

  113. Sahashi, K., Hua, Y., Ling, K. K. Y., Hung, G., Rigo, F., Horev, G., et al. (2012). TSUNAMI: An antisense method to phenocopy splicing-associated diseases in animals. Genes & Development, 26, 1874–1884.

    CAS  Google Scholar 

Download references

Acknowledgements

E.L-P. is supported by grants from the European Union’s FP7 (“CardioNeT” ITN-289600), the Spanish Ministry of Economy (SAF2012-31451) and from the Madrid Regional Government (“Fibroteam”, S2010/BMD-2321). P.G-P. and E.L-P. are supported by the Instituto de Salud Carlos III (Red Enfermedades Cardiovasculares RD12/0042/0002).

Clinical Statement

Alternative splicing is the main mechanism driving protein diversity and allows expression of different proteins from each gene. We are slowly beginning to unveil the complexity of post-transcriptional regulation in the diseased heart. Alternative splicing can change protein structure, localisation, regulation and function, leading to cardiomyopathies, arrhythmias and other pathologies. Identifying a protein that is differentially expressed in a pathological condition is not sufficient; it is essential to identify the version (isoform) of such protein, which may have particular features. It is also important to understand how alternative splicing is regulated in a global manner, so that potential therapeutic targets can be unveiled. Alternative splicing modulation using antisense oligonucleotides has recently emerged as a therapeutic option for different conditions in which splicing is altered.

Author information

Authors and Affiliations

  1. Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares, Melchor Fernández Almagro 3, 28029, Madrid, Spain

    Enrique Lara-Pezzi, Jesús Gómez-Salinero & Alberto Gatto

  2. Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain

    Pablo García-Pavía

Authors
  1. Enrique Lara-Pezzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jesús Gómez-Salinero
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alberto Gatto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pablo García-Pavía
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Enrique Lara-Pezzi.

Additional information

Associate Editor: Lorrie Kirshenbaum

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lara-Pezzi, E., Gómez-Salinero, J., Gatto, A. et al. The Alternative Heart: Impact of Alternative Splicing in Heart Disease. J. of Cardiovasc. Trans. Res. 6, 945–955 (2013). https://doi.org/10.1007/s12265-013-9482-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12265-013-9482-z

Keywords

Search

Navigation