Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Cardiac splicing as a diagnostic and therapeutic target

Nature Reviews Cardiology (2023)Cite this article

Subjects

Abstract

Despite advances in therapeutics for heart failure and arrhythmias, a substantial proportion of patients with cardiomyopathy do not respond to interventions, indicating a need to identify novel modifiable myocardial pathobiology. Human genetic variation associated with severe forms of cardiomyopathy and arrhythmias has highlighted the crucial role of alternative splicing in myocardial health and disease, given that it determines which mature RNA transcripts drive the mechanical, structural, signalling and metabolic properties of the heart. In this Review, we discuss how the analysis of cardiac isoform expression has been facilitated by technical advances in multiomics and long-read and single-cell sequencing technologies. The resulting insights into the regulation of alternative splicing — including the identification of cardiac splice regulators as therapeutic targets and the development of a translational pipeline to evaluate splice modulators in human engineered heart tissue, animal models and clinical trials — provide a basis for improved diagnosis and therapy. Finally, we consider how the medical and scientific communities can benefit from facilitated acquisition and interpretation of splicing data towards improved clinical decision-making and patient care.

Key points

  • Human genetic variation associated with severe forms of cardiomyopathy and arrhythmia has highlighted the crucial role of alternative splicing in myocardial health and disease.

  • Alternative splicing governs major adaptations in cardiac physiology and pathology, including the re-expression of fetal and perinatal isoforms in heart failure.

  • Up to 10% of mutations in cardiac disease-related genes affect splice sites.

  • Splicing factor mutations alter the global protein composition of cardiomyocytes, resulting in complex disease phenotypes.

  • Technical advances have enabled the global analysis of cardiac isoform expression through multiomics and single-cell approaches, with implications for improved clinical decision-making and patient care.

  • Cardiac splice regulators can be targeted therapeutically through small-molecule and antisense oligonucleotide approaches, whereas splice site mutations are now accessible to gene editing and trans-splicing.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Alternative splicing.
Fig. 2: Genotype and phenotype relationships in cardiac splicing disease.
Fig. 3: Analysis of splice networks.
Fig. 4: Splice diagnostics by mRNA sequencing of distinct splice defects.
Fig. 5: Translating basic research into improved splice therapeutics and clinical care.

References

  1. Pan, Q. et al. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat. Genet. 40, 1413–1415 (2008).

    Article  CAS  Google Scholar 

  2. Zhang, X. et al. Cell-type-specific alternative splicing governs cell fate in the developing cerebral cortex. Cell 166, 1147–1162.e15 (2016).

    Article  CAS  Google Scholar 

  3. Olivieri, J. E. et al. RNA splicing programs define tissue compartments and cell types at single-cell resolution. eLife 10, e70692 (2021).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Graveley, B. R. Sorting out the complexity of SR protein functions. RNA 6, 1197–1211 (2000).

    Article  CAS  Google Scholar 

  6. Geuens, T., Bouhy, D. & Timmerman, V. The hnRNP family: insights into their role in health and disease. Hum. Genet. 135, 851–867 (2016).

    Article  CAS  Google Scholar 

  7. Martí-Gómez, C. et al. Functional impact and regulation of alternative splicing in mouse heart development and disease. J. Cardiovasc. Transl. Res. 15, 1239–1255 (2022).

    Article  Google Scholar 

  8. Travers, J. G., Tharp, C. A., Rubino, M. & McKinsey, T. A. Therapeutic targets for cardiac fibrosis: from old school to next-gen. J. Clin. Invest. 132, e148554 (2022).

    Article  CAS  Google Scholar 

  9. Guo, W. et al. RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing. Nat. Med. 18, 766–773 (2012).

    Article  CAS  Google Scholar 

  10. Gittenberger-de Groot, A. C., Bartelings, M. M., Deruiter, M. C. & Poelmann, R. E. Basics of cardiac development for the understanding of congenital heart malformations. Pediatr. Res. 57, 169–176 (2005).

    Article  Google Scholar 

  11. Olson, E. N. Gene regulatory networks in the evolution and development of the heart. Science 313, 1922–1927 (2006).

    Article  CAS  Google Scholar 

  12. Opitz, C. A., Leake, M. C., Makarenko, I., Benes, V. & Linke, W. A. Developmentally regulated switching of titin size alters myofibrillar stiffness in the perinatal heart. Circ. Res. 94, 967–975 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Freiburg, A. et al. Series of exon-skipping events in the elastic spring region of titin as the structural basis for myofibrillar elastic diversity. Circ. Res. 86, 1114–1121 (2000).

    Article  CAS  Google Scholar 

  15. Agarkova, I., Auerbach, D., Ehler, E. & Perriard, J. C. A novel marker for vertebrate embryonic heart, the EH-myomesin isoform. J. Biol. Chem. 275, 10256–10264 (2000).

    Article  CAS  Google Scholar 

  16. Gomes, A. V., Guzman, G., Zhao, J. & Potter, J. D. Cardiac troponin T isoforms affect the Ca2+ sensitivity and inhibition of force development. Insights into the role of troponin T isoforms in the heart. J. Biol. Chem. 277, 35341–35349 (2002).

    Article  CAS  Google Scholar 

  17. Maytum, R., Bathe, F., Konrad, M. & Geeves, M. A. Tropomyosin exon 6b is troponin-specific and required for correct acto-myosin regulation. J. Biol. Chem. 279, 18203–18209 (2004).

    Article  CAS  Google Scholar 

  18. Hoshijima, M. Mechanical stress-strain sensors embedded in cardiac cytoskeleton: Z disk, titin, and associated structures. Am. J. Physiol. Heart Circ. Physiol. 290, H1313–H1325 (2006).

    Article  CAS  Google Scholar 

  19. Yamazaki, T. et al. Splice variants of enigma homolog, differentially expressed during heart development, promote or prevent hypertrophy. Cardiovasc. Res. 86, 374–382 (2010).

    Article  CAS  Google Scholar 

  20. Huang, C. et al. Characterization and in vivo functional analysis of splice variants of cypher. J. Biol. Chem. 278, 7360–7365 (2003).

    Article  CAS  Google Scholar 

  21. Weeland, C. J., van den Hoogenhof, M. M., Beqqali, A. & Creemers, E. E. Insights into alternative splicing of sarcomeric genes in the heart. J. Mol. Cell Cardiol. 81, 107–113 (2015).

    Article  CAS  Google Scholar 

  22. Guo, Y. & Pu, W. T. Cardiomyocyte maturation: new phase in development. Circ. Res. 126, 1086–1106 (2020).

    Article  CAS  Google Scholar 

  23. Link, S. et al. Diversity and developmental expression of L-type calcium channel β2 proteins and their influence on calcium current in murine heart. J. Biol. Chem. 284, 30129–30137 (2009).

    Article  CAS  Google Scholar 

  24. Bayer, K. U. & Schulman, H. Regulation of signal transduction by protein targeting: the case for CaMKII. Biochem. Biophys. Res. Commun. 289, 917–923 (2001).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  26. van den Hoogenhof, M. M. G. et al. RBM20 mutations induce an arrhythmogenic dilated cardiomyopathy related to disturbed calcium handling. Circulation 138, 1330–1342 (2018).

    Article  Google Scholar 

  27. Giudice, J. et al. Alternative splicing regulates vesicular trafficking genes in cardiomyocytes during postnatal heart development. Nat. Commun. 5, 3603 (2014).

    Article  CAS  Google Scholar 

  28. Wang, H. et al. Genome-wide analysis of alternative splicing during human heart development. Sci. Rep. 6, 35520 (2016).

    Article  CAS  Google Scholar 

  29. Liu, C.-X. & Chen, L.-L. Circular RNAs: characterization, cellular roles, and applications. Cell 185, 2016–2034 (2022).

    Article  CAS  Google Scholar 

  30. Mazin, P. V., Khaitovich, P., Cardoso-Moreira, M. & Kaessmann, H. Alternative splicing during mammalian organ development. Nat. Genet. 53, 925–934 (2021).

    Article  CAS  Google Scholar 

  31. Kalsotra, A. et al. A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart. Proc. Natl Acad. Sci. USA 105, 20333–20338 (2008).

    Article  CAS  Google Scholar 

  32. Riquelme, C. A. et al. Fatty acids identified in the burmese python promote beneficial cardiac growth. Science 334, 528–531 (2011).

    Article  CAS  Google Scholar 

  33. Secor, S. M. & Diamond, J. A vertebrate model of extreme physiological regulation. Nature 395, 659–662 (1998).

    Article  CAS  Google Scholar 

  34. Maillet, M., van Berlo, J. H. & Molkentin, J. D. Molecular basis of physiological heart growth: fundamental concepts and new players. Nat. Rev. Mol. Cell Biol. 14, 38–48 (2012).

    Article  Google Scholar 

  35. Song, H. K., Hong, S.-E., Kim, T. & Kim, D. H. Deep RNA sequencing reveals novel cardiac transcriptomic signatures for physiological and pathological hypertrophy. PLoS ONE 7, e35552 (2012).

    Article  CAS  Google Scholar 

  36. Beqqali, A. Alternative splicing in cardiomyopathy. Biophys. Rev. 10, 1061–1071 (2018).

    Article  CAS  Google Scholar 

  37. Neagoe, C. et al. Titin isoform switch in ischemic human heart disease. Circulation 106, 1333–1341 (2002).

    Article  Google Scholar 

  38. Nagueh, S. F. et al. Altered titin expression, myocardial stiffness, and left ventricular function in patients with dilated cardiomyopathy. Circulation 110, 155–162 (2004).

    Article  CAS  Google Scholar 

  39. Brauch, K. M. et al. Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy. J. Am. Coll. Cardiol. 54, 930–941 (2009).

    Article  CAS  Google Scholar 

  40. Parikh, V. N. et al. Regional variation in RBM20 causes a highly penetrant arrhythmogenic cardiomyopathy. Circ. Heart Fail. 12, e005371 (2019).

    Article  CAS  Google Scholar 

  41. Sedaghat-Hamedani, F. et al. Clinical genetics and outcome of left ventricular non-compaction cardiomyopathy. Eur. Heart J. 38, 3449–3460 (2017).

    Article  CAS  Google Scholar 

  42. Fenix, A. M. et al. Gain-of-function cardiomyopathic mutations in RBM20 rewire splicing regulation and re-distribute ribonucleoprotein granules within processing bodies. Nat. Commun. 12, 6324 (2021).

    Article  CAS  Google Scholar 

  43. Schneider, J. W. et al. Dysregulated ribonucleoprotein granules promote cardiomyopathy in RBM20 gene-edited pigs. Nat. Med. 26, 1788–1800 (2020).

    Article  CAS  Google Scholar 

  44. Methawasin, M. et al. Experimentally increasing titin compliance in a novel mouse model attenuates the Frank-Starling mechanism but has a beneficial effect on diastole. Circulation 129, 1924–1936 (2014).

    Article  CAS  Google Scholar 

  45. Hinze, F., Dieterich, C., Radke, M. H., Granzier, H. & Gotthardt, M. Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy. J. Mol. Med. 94, 1349–1358 (2016).

    Article  CAS  Google Scholar 

  46. Methawasin, M. et al. Experimentally increasing the compliance of titin through RNA binding motif-20 (RBM20) inhibition improves diastolic function in a mouse model of heart failure with preserved ejection fraction. Circulation 134, 1085–1099 (2016).

    Article  CAS  Google Scholar 

  47. Mazzarotto, F. et al. Reevaluating the genetic contribution of monogenic dilated cardiomyopathy. Circulation 141, 387–398 (2020).

    Article  CAS  Google Scholar 

  48. Sturm, A. C. & Hershberger, R. E. Genetic testing in cardiovascular medicine: current landscape and future horizons. Curr. Opin. Cardiol. 28, 317–325 (2013).

    Article  Google Scholar 

  49. Seeger, T. et al. A premature termination codon mutation in MYBPC3 causes hypertrophic cardiomyopathy via chronic activation of nonsense-mediated decay. Circulation 139, 799–811 (2019).

    Article  CAS  Google Scholar 

  50. Glazier, A. A. et al. HSC70 is a chaperone for wild-type and mutant cardiac myosin binding protein C. JCI Insight 3, 99319 (2018).

    Article  Google Scholar 

  51. Kumar, S. et al. Long-term arrhythmic and nonarrhythmic outcomes of lamin A/C mutation carriers. J. Am. Coll. Cardiol. 68, 2299–2307 (2016).

    Article  CAS  Google Scholar 

  52. Sen-Chowdhry, S. et al. Left-dominant arrhythmogenic cardiomyopathy: an under-recognized clinical entity. J. Am. Coll. Cardiol. 52, 2175–2187 (2008).

    Article  Google Scholar 

  53. Smith, E. D. et al. Desmoplakin cardiomyopathy, a fibrotic and inflammatory form of cardiomyopathy distinct from typical dilated or arrhythmogenic right ventricular cardiomyopathy. Circulation 141, 1872–1884 (2020).

    Article  CAS  Google Scholar 

  54. Patel, P. N. et al. Contribution of noncanonical splice variants to TTN truncating variant cardiomyopathy. Circ. Genom. Precis. Med. 14, e003389 (2021).

    Article  CAS  Google Scholar 

  55. Haggerty, C. M. et al. Genomics-first evaluation of heart disease associated with titin-truncating variants. Circulation 140, 42–54 (2019).

    Article  CAS  Google Scholar 

  56. Schafer, S. et al. Titin-truncating variants affect heart function in disease cohorts and the general population. Nat. Genet. 49, 46–53 (2017).

    Article  CAS  Google Scholar 

  57. Li, D. et al. Identification of novel mutations in RBM20 in patients with dilated cardiomyopathy. Clin. Transl. Sci. 3, 90–97 (2010).

    Article  CAS  Google Scholar 

  58. Lee, Y. & Rio, D. C. Mechanisms and regulation of alternative pre-mRNA splicing. Annu. Rev. Biochem. 84, 291–323 (2015).

    Article  CAS  Google Scholar 

  59. Koelemen, J., Gotthardt, M., Steinmetz, L. M. & Meder, B. RBM20-Related cardiomyopathy: current understanding and future options. J. Clin. Med. 10, 4101 (2021).

    Article  CAS  Google Scholar 

  60. Youn, J.-Y. et al. High-density proximity mapping reveals the subcellular organization of mRNA-associated granules and bodies. Mol. Cell 69, 517–532.e11 (2018).

    Article  CAS  Google Scholar 

  61. Maatz, H. et al. RNA-binding protein RBM20 represses splicing to orchestrate cardiac pre-mRNA processing. J. Clin. Invest. 124, 3419–3430 (2014).

    Article  Google Scholar 

  62. Rudolph, F. et al. Deconstructing sarcomeric structure-function relations in titin-BioID knock-in mice. Nat. Commun. 11, 3133 (2020).

    Article  CAS  Google Scholar 

  63. Vieira-Vieira, C. H., Dauksaite, V., Sporbert, A., Gotthardt, M. & Selbach, M. Proteome-wide quantitative RNA-interactome capture identifies phosphorylation sites with regulatory potential in RBM20. Mol. Cell 82, 2069–2083.e8 (2022).

    Article  CAS  Google Scholar 

  64. Ortiz-Sánchez, P. et al. Loss of SRSF3 in cardiomyocytes leads to decapping of contraction-related mRNAs and severe systolic dysfunction. Circ. Res. 125, 170–183 (2019).

    Article  Google Scholar 

  65. Larrasa-Alonso, J. et al. The SRSF4-GAS5-glucocorticoid receptor axis regulates ventricular hypertrophy. Circ. Res. 129, 669–683 (2021).

    Article  CAS  Google Scholar 

  66. Lee, J.-H. et al. Analysis of transcriptome complexity through RNA sequencing in normal and failing murine hearts. Circ. Res. 109, 1332–1341 (2011).

    Article  CAS  Google Scholar 

  67. Amarasinghe, S. L. et al. Opportunities and challenges in long-read sequencing data analysis. Genome Biol. 21, 30 (2020).

    Article  Google Scholar 

  68. Zhu, C. et al. Single-molecule, full-length transcript isoform sequencing reveals disease-associated RNA isoforms in cardiomyocytes. Nat. Commun. 12, 4203 (2021).

    Article  CAS  Google Scholar 

  69. Tabula Sapiens Consortium. The Tabula Sapiens: a multiple-organ, single-cell transcriptomic atlas of humans. Science 376, eabl4896 (2022).

    Article  Google Scholar 

  70. Picelli, S. et al. Smart-seq2 for sensitive full-length transcriptome profiling in single cells. Nat. Methods 10, 1096–1098 (2013).

    Article  CAS  Google Scholar 

  71. Yekelchyk, M., Guenther, S., Preussner, J. & Braun, T. Mono- and multi-nucleated ventricular cardiomyocytes constitute a transcriptionally homogenous cell population. Basic Res. Cardiol. 114, 36 (2019).

    Article  Google Scholar 

  72. Rosenberg, A. B. et al. Single-cell profiling of the developing mouse brain and spinal cord with split-pool barcoding. Science 360, 176–182 (2018).

    Article  CAS  Google Scholar 

  73. Rebboah, E. et al. Mapping and modeling the genomic basis of differential RNA isoform expression at single-cell resolution with LR-Split-seq. Genome Biol. 22, 286 (2021).

    Article  CAS  Google Scholar 

  74. Reichart, D. et al. Pathogenic variants damage cell composition and single cell transcription in cardiomyopathies. Science 377, eabo1984 (2022).

    Article  CAS  Google Scholar 

  75. Rudolph, F. et al. Resolving titin’s lifecycle and the spatial organization of protein turnover in mouse cardiomyocytes. Proc. Natl Acad. Sci. USA 116, 25126–25136 (2019).

    Article  CAS  Google Scholar 

  76. Liss, M. et al. Drug discovery with an RBM20 dependent titin splice reporter identifies cardenolides as lead structures to improve cardiac filling. PLoS ONE 13, e0198492 (2018).

    Article  Google Scholar 

  77. König, J. et al. iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution. Nat. Struct. Mol. Biol. 17, 909–915 (2010).

    Article  Google Scholar 

  78. Cooper, T. A. & Mattox, W. The regulation of splice-site selection, and its role in human disease. Am. J. Hum. Genet. 61, 259–266 (1997).

    Article  CAS  Google Scholar 

  79. Goodall, G. J. & Wickramasinghe, V. O. RNA in cancer. Nat. Rev. Cancer 21, 22–36 (2021).

    Article  CAS  Google Scholar 

  80. Parikh, V. N. & Ashley, E. A. Next-generation sequencing in cardiovascular disease: present clinical applications and the horizon of precision medicine. Circulation 135, 406–409 (2017).

    Article  Google Scholar 

  81. Hershberger, R. E. et al. Genetic evaluation of cardiomyopathy: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet. Med. 20, 899–909 (2018).

    Article  Google Scholar 

  82. Baralle, D. & Baralle, M. Splicing in action: assessing disease causing sequence changes. J. Med. Genet. 42, 737–748 (2005).

    Article  CAS  Google Scholar 

  83. Manning, K. S. & Cooper, T. A. The roles of RNA processing in translating genotype to phenotype. Nat. Rev. Mol. Cell Biol. 18, 102–114 (2016).

    Article  Google Scholar 

  84. Chang, Y.-F., Imam, J. S. & Wilkinson, M. F. The nonsense-mediated decay RNA surveillance pathway. Annu. Rev. Biochem. 76, 51–74 (2007).

    Article  CAS  Google Scholar 

  85. Ito, K. et al. Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing. Proc. Natl Acad. Sci. USA 114, 7689–7694 (2017).

    Article  CAS  Google Scholar 

  86. Holliday, M. et al. Transcriptome sequencing of patients with hypertrophic cardiomyopathy reveals novel splice-altering variants in MYBPC3. Circ. Genom. Precis. Med. 14, e003202 (2021).

    Article  CAS  Google Scholar 

  87. Moolman, J. A. et al. A newly created splice donor site in exon 25 of the MyBP-C gene is responsible for inherited hypertrophic cardiomyopathy with incomplete disease penetrance. Circulation 101, 1396–1402 (2000).

    Article  CAS  Google Scholar 

  88. Brodehl, A. et al. The desmin mutation DES-c.735G>C causes severe restrictive cardiomyopathy by inducing in-frame skipping of exon-3. Biomedicines 9, 1400 (2021).

    Article  CAS  Google Scholar 

  89. Singer, E. S., Ingles, J., Semsarian, C. & Bagnall, R. D. Key value of RNA analysis of MYBPC3 splice-site variants in hypertrophic cardiomyopathy. Circ. Genom. Precis. Med. 12, e002368 (2019).

    Article  CAS  Google Scholar 

  90. Abramowicz, A. & Gos, M. Splicing mutations in human genetic disorders: examples, detection, and confirmation. J. Appl. Genet. 59, 253–268 (2018).

    Article  Google Scholar 

  91. Helms, A. S. et al. Sarcomere mutation-specific expression patterns in human hypertrophic cardiomyopathy. Circ. Cardiovasc. Genet. 7, 434–443 (2014).

    Article  CAS  Google Scholar 

  92. Karakikes, I., Ameen, M., Termglinchan, V. & Wu, J. C. Human induced pluripotent stem cell-derived cardiomyocytes: insights into molecular, cellular, and functional phenotypes. Circ. Res. 117, 80–88 (2015).

    Article  CAS  Google Scholar 

  93. Tilgner, H. et al. Comprehensive transcriptome analysis using synthetic long-read sequencing reveals molecular co-association of distant splicing events. Nat. Biotechnol. 33, 736–742 (2015).

    Article  CAS  Google Scholar 

  94. Jaganathan, K. et al. Predicting splicing from primary sequence with deep learning. Cell 176, 535–548.e24 (2019).

    Article  CAS  Google Scholar 

  95. Lopes, L. R. et al. Cryptic splice-altering variants in MYBPC3 are a prevalent cause of hypertrophic cardiomyopathy. Circ. Genom. Precis. Med. 13, e002905 (2020).

    Article  CAS  Google Scholar 

  96. Dauksaite, V. & Gotthardt, M. Molecular basis of titin exon exclusion by RBM20 and the novel titin splice regulator PTB4. Nucleic Acids Res. 46, 5227–5238 (2018).

    Article  CAS  Google Scholar 

  97. Gao, G. et al. Enhanced risk profiling of implanted defibrillator shocks with circulating SCN5A mRNA splicing variants: a pilot trial. J. Am. Coll. Cardiol. 63, 2261–2269 (2014).

    Article  CAS  Google Scholar 

  98. Liu, N. & Olson, E. N. CRISPR modeling and correction of cardiovascular disease. Circ. Res. 130, 1827–1850 (2022).

    Article  CAS  Google Scholar 

  99. Briganti, F. et al. iPSC modeling of RBM20-deficient DCM identifies upregulation of RBM20 as a therapeutic strategy. Cell Rep. 32, 108117 (2020).

    Article  CAS  Google Scholar 

  100. Meyer, S. M. et al. Small molecule recognition of disease-relevant RNA structures. Chem. Soc. Rev. 49, 7167–7199 (2020).

    Article  CAS  Google Scholar 

  101. Salton, M. & Misteli, T. Small molecule modulators of pre-mRNA splicing in cancer therapy. Trends Mol. Med. 22, 28–37 (2016).

    Article  CAS  Google Scholar 

  102. Singh, R. N., Ottesen, E. W. & Singh, N. N. The first orally deliverable small molecule for the treatment of spinal muscular atrophy. Neurosci. Insights 15, 2633105520973985 (2020).

    Article  Google Scholar 

  103. Palacino, J. et al. SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice. Nat. Chem. Biol. 11, 511–517 (2015).

    Article  CAS  Google Scholar 

  104. Keller, C. G. et al. An orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion. Nat. Commun. 13, 1150 (2022).

    Article  CAS  Google Scholar 

  105. Bull, M. et al. Alternative splicing of titin restores diastolic function in an HFpEF-like genetic murine model (TtnΔIAjxn). Circ. Res. 119, 764–772 (2016).

    Article  CAS  Google Scholar 

  106. Radke, M. H. et al. Therapeutic inhibition of RBM20 improves diastolic function in a murine heart failure model and human engineered heart tissue. Sci. Transl. Med. 13, eabe8952 (2021).

    Article  CAS  Google Scholar 

  107. Musunuru, K. et al. Genetic testing for inherited cardiovascular diseases: a scientific statement from the American Heart Association. Circ. Genom. Precis. Med. 13, e000067 (2020).

    Article  Google Scholar 

  108. Minoche, A. E. et al. Genome sequencing as a first-line genetic test in familial dilated cardiomyopathy. Genet. Med. 21, 650–662 (2019).

    Article  CAS  Google Scholar 

  109. Riepe, T. V., Khan, M., Roosing, S., Cremers, F. P. M. & ’t Hoen, P. A. C. Benchmarking deep learning splice prediction tools using functional splice assays. Hum. Mutat. 42, 799–810 (2021).

    Article  CAS  Google Scholar 

  110. Marasco, L. E. & Kornblihtt, A. R. The physiology of alternative splicing. Nat. Rev. Mol. Cell Biol. https://doi.org/10.1038/s41580-022-00545-z (2022).

    Article  Google Scholar 

  111. Kornblihtt, A. R. et al. Alternative splicing: a pivotal step between eukaryotic transcription and translation. Nat. Rev. Mol. Cell Biol. 14, 153–165 (2013).

    Article  CAS  Google Scholar 

  112. Filippello, A., Lorenzi, P., Bergamo, E. & Romanelli, M. G. Identification of nuclear retention domains in the RBM20 protein. FEBS Lett. 587, 2989–2995 (2013).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was funded by Leducq TAN CASTT grant 21CVD02. Jacobo Lopez Carballo (Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Germany) supported the data analysis and generation of the supplementary tables.

Author information

Authors and Affiliations

  1. Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany

    Michael Gotthardt & Victor Badillo-Lisakowski

  2. DZHK (German Center for Cardiovascular Research Partner Site Berlin), Berlin, Germany

    Michael Gotthardt & Victor Badillo-Lisakowski

  3. Department of Cardiology, Charité – Universitätsmedizin Berlin, Berlin, Germany

    Michael Gotthardt

  4. Stanford Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Palo Alto, CA, USA

    Victoria Nicole Parikh & Euan Ashley

  5. Stanford Genome Technology Center, Stanford University, Palo Alto, CA, USA

    Euan Ashley & Lars Steinmetz

  6. Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA

    Euan Ashley & Lars Steinmetz

  7. Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal

    Marta Furtado & Maria Carmo-Fonseca

  8. Institute for Cardiomyopathies, Department of Medicine III, University of Heidelberg, Heidelberg, Germany

    Sarah Schudy & Benjamin Meder

  9. DZHK (German Center for Cardiovascular Research Partner Site Heidelberg-Mannheim), Heidelberg, Germany

    Benjamin Meder

  10. European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany

    Markus Grosch & Lars Steinmetz

  11. Department of Molecular, Cellular, and Developmental Biology and BioFrontiers Institute, University of Colorado, Boulder, CO, USA

    Claudia Crocini & Leslie Leinwand

Authors
  1. Michael Gotthardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Victor Badillo-Lisakowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Victoria Nicole Parikh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Euan Ashley
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marta Furtado
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maria Carmo-Fonseca
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sarah Schudy
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Benjamin Meder
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Markus Grosch
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lars Steinmetz
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Claudia Crocini
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Leslie Leinwand
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M. Gotthardt, V.B.-L., V.N.P., M.F., S.S., M. Grosch, C.C. and L.L. researched data for the article. M. Gotthardt, V.B.-L., V.N.P., E.A., M.C.-F., B.M., M. Grosch, L.S. and L.L. discussed the content of the article. All the authors wrote the manuscript. M. Gotthardt and L.L. reviewed/edited the manuscript before submission.

Corresponding author

Correspondence to Michael Gotthardt.

Ethics declarations

Competing interests

M. Gotthardt has a consultancy agreement with River BioMedics and has received speaker honoraria from Bayer. V.N.P. reports a sponsored research agreement with BioMarin and consulting relationships with Constantiam and viz.ai. E.A. reports sponsored research from Bristol Myers Squibb, has ownership interest in DeepCell, Nuevocor and Personalis, and is a board member of AstraZeneca. M.C.-F. is a cofounder and scientific adviser of GenoMed, a molecular diagnosis company. B.M. holds stocks in biotech and pharma, has received speaker honoraria from Bayer, Bristol Myers Squibb, Daiichi Sankyo, Novartis and Pfizer, and is on the Scientific Advisory Boards of Bristol Myers Squibb/Myokardia and Fleischhacker. L.S. is a co-founder of SOPHiA Genetics, as well as co-founder and board member of LevitasBio and Recombia Biosciences, and receives research support from GlaxoSmithKline. L.L. has sponsored research agreements from Bristol Myers Squibb and Edgewise Therapeutics, and is on the scientific advisory boards of Bristol Meyers Squibb/MyoKardia and Edgewise Therapeutics. The other authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Cardiology thanks Samuel Dudley and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

Alamut software: https://www.sophiagenetics.com/platform/alamut-visual-plus/

AltAnalyze: http://www.altanalyze.org/

ClinVar database: https://www.ncbi.nlm.nih.gov/clinvar/

Cytoscape: https://cytoscape.org/

Gene Ontology: https://www.ebi.ac.uk/QuickGO/

GTEx: https://gtexportal.org/home/

Human Protein Atlas: https://www.proteinatlas.org/

Oxford Nanopore Technology: https://nanoporetech.com

Pacific Biosciences: https://www.pacb.com

VALERIE: https://cran.r-project.org/package=VALERIE

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Gotthardt, M., Badillo-Lisakowski, V., Parikh, V.N. et al. Cardiac splicing as a diagnostic and therapeutic target. Nat Rev Cardiol (2023). https://doi.org/10.1038/s41569-022-00828-0

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41569-022-00828-0

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research