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Effective gene-based diagnosis is critical for the accurate clinical management of patients and their family members. However, the introduction of high-throughput DNA sequencing approaches for clinical diagnostics has vastly expanded the number of variants of uncertain significance, leading to many inconclusive results that limit the clinical utility of genetic testing. More recently, developments in RNA analysis have been improving diagnostic outcomes by identifying new variants that interfere with splicing. This review summarizes recent discoveries of RNA mis-splicing in HCM and provides an overview of research that aims to apply the concept of RNA therapeutics to HCM.<\/jats:p>","DOI":"10.3390\/ijms21041329","type":"journal-article","created":{"date-parts":[[2020,2,19]],"date-time":"2020-02-19T04:06:01Z","timestamp":1582085161000},"page":"1329","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["RNA Splicing Defects in Hypertrophic Cardiomyopathy: Implications for Diagnosis and Therapy"],"prefix":"10.3390","volume":"21","author":[{"given":"Marta","family":"Ribeiro","sequence":"first","affiliation":[{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Av Prof Egas Moniz, Edificio Egas Moniz, 1649-028 Lisboa, Portugal"},{"name":"Department of Bioengineering and iBB\u2013Institute for Bioengineering and Biosciences, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal"}]},{"given":"Marta","family":"Furtado","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Av Prof Egas Moniz, Edificio Egas Moniz, 1649-028 Lisboa, Portugal"}]},{"given":"Sandra","family":"Martins","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Av Prof Egas Moniz, Edificio Egas Moniz, 1649-028 Lisboa, Portugal"}]},{"given":"Teresa","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Av Prof Egas Moniz, Edificio Egas Moniz, 1649-028 Lisboa, Portugal"}]},{"given":"Maria","family":"Carmo-Fonseca","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Av Prof Egas Moniz, Edificio Egas Moniz, 1649-028 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1161\/01.CIR.92.4.785","article-title":"Prevalence of hypertrophic cardiomyopathy in a general population of young adults: Echocardiographic analysis of 4111 subjects in the CARDIA study","volume":"92","author":"Maron","year":"1995","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1016\/j.jacc.2015.01.019","article-title":"New perspectives on the prevalence of hypertrophic cardiomyopathy","volume":"65","author":"Semsarian","year":"2015","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1016\/j.amjcard.2013.02.040","article-title":"Risk of death in long-term follow-up of patients with apical hypertrophic cardiomyopathy","volume":"111","author":"Klarich","year":"2013","journal-title":"Am. J. Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.jacc.2014.05.003","article-title":"Hypertrophic cardiomyopathy: Present and future, with translation into contemporary cardiovascular medicine","volume":"64","author":"Maron","year":"2014","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1016\/j.jacc.2015.02.061","article-title":"Hypertrophic cardiomyopathy in adulthood associated with low cardiovascular mortality with contemporary management strategies","volume":"65","author":"Maron","year":"2015","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/nrcardio.2011.159","article-title":"Mechanisms of disease: Hypertrophic cardiomyopathy","volume":"9","author":"Frey","year":"2012","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1161\/CIRCRESAHA.117.311059","article-title":"Hypertrophic cardiomyopathy: Genetics, pathogenesis, clinical manifestations, diagnosis, and therapy","volume":"121","author":"Marian","year":"2017","journal-title":"Circ. Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Naidu, S.S. (2018). Novel medical therapeutics for hypertrophic cardiomyopathy. Hypertrophic Cardiomyopathy, Springer International Publishing.","DOI":"10.1007\/978-3-319-92423-6"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2733","DOI":"10.1093\/eurheartj\/ehu284","article-title":"2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy: The task force for the diagnosis and management of hypertrophic cardiomyopathy of the European Society of Cardiology (ESC)","volume":"35","author":"Elliott","year":"2014","journal-title":"Eur. Heart J."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Tejado, B.S.M., and Jou, C. (2018). Histopathology in HCM. Glob. Cardiol. Sci. Pract.","DOI":"10.21542\/gcsp.2018.20"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.jelectrocard.2016.03.005","article-title":"Differentiating hypertrophic cardiomyopathy from athlete\u2019s heart: An electrocardiographic and echocardiographic approach","volume":"49","author":"Grazioli","year":"2016","journal-title":"J. Electrocardiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1056\/NEJM199804303381802","article-title":"Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy","volume":"338","author":"Niimura","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1161\/hc0402.102990","article-title":"Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly","volume":"105","author":"Niimura","year":"2002","journal-title":"Circulation"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1161\/CIRCGENETICS.112.963363","article-title":"Toronto hypertrophic cardiomyopathy genotype score for prediction of a positive genotype in hypertrophic cardiomyopathy","volume":"6","author":"Gruner","year":"2013","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/gim.2016.90","article-title":"Reassessment of Mendelian gene pathogenicity using 7855 cardiomyopathy cases and 60,706 reference samples","volume":"19","author":"Walsh","year":"2017","journal-title":"Genet. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1038\/ng.259","article-title":"Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing","volume":"40","author":"Pan","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1038\/nature07509","article-title":"Alternative isoform regulation in human tissue transcriptomes","volume":"456","author":"Wang","year":"2008","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.ceb.2012.03.005","article-title":"Alternative splicing: Decoding an expansive regulatory layer","volume":"24","author":"Irimia","year":"2012","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/nrm.2017.27","article-title":"Alternative splicing as a regulator of development and tissue identity","volume":"18","author":"Baralle","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.yjmcc.2015.02.008","article-title":"Insights into alternative splicing of sarcomeric genes in the heart","volume":"81","author":"Weeland","year":"2015","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1016\/j.cell.2009.02.009","article-title":"The spliceosome: Design principles of a dynamic RNP machine","volume":"136","author":"Wahl","year":"2009","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Yan, C., Wan, R., and Shi, Y. (2019). Molecular mechanisms of pre-mRNA splicing through structural biology of the spliceosome. Cold Spring Harb. Perspect. Biol., 11.","DOI":"10.1101\/cshperspect.a032409"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Kastner, B., Will, C.L., Stark, H., and L\u00fchrmann, R. (2019). Structural insights into nuclear pre-mRNA splicing in higher eukaryotes. Cold Spring Harb. Perspect. Biol., 11.","DOI":"10.1101\/cshperspect.a032417"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1038\/nrm1259","article-title":"Splicing double: Insights from the second spliceosome","volume":"4","author":"Patel","year":"2003","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.semcdb.2017.09.036","article-title":"Minor spliceosome and disease","volume":"79","author":"Verma","year":"2018","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/S0968-0004(00)01549-8","article-title":"Exonic splicing enhancers: Mechanism of action, diversity and role in human genetic diseases","volume":"25","author":"Blencowe","year":"2000","journal-title":"Trends Biochem. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.molcel.2006.05.018","article-title":"General and specific functions of exonic splicing silencers in splicing control","volume":"23","author":"Wang","year":"2006","journal-title":"Mol. Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/nature08909","article-title":"Expansion of the eukaryotic proteome by alternative splicing","volume":"463","author":"Nilsen","year":"2010","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1126\/science.1184208","article-title":"Regulation of alternative splicing by histone modifications","volume":"327","author":"Luco","year":"2010","journal-title":"Science"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.molcel.2017.01.011","article-title":"Multilayered control of alternative splicing regulatory networks by transcription factors","volume":"65","author":"Han","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4823","DOI":"10.1093\/nar\/gkn463","article-title":"Tissue-specific splicing factor gene expression signatures","volume":"36","author":"Grosso","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1101\/gad.1048803","article-title":"Pre-mRNA splicing and human disease","volume":"17","author":"Faustino","year":"2003","journal-title":"Genes Dev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1007\/s13353-018-0444-7","article-title":"Splicing mutations in human genetic disorders: Examples, detection, and confirmation","volume":"59","author":"Abramowicz","year":"2018","journal-title":"J. Appl. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/nrg.2015.3","article-title":"RNA mis-splicing in disease","volume":"17","author":"Scotti","year":"2016","journal-title":"Nat. Rev. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1126\/science.1261877","article-title":"Effect of predicted protein-truncating genetic variants on the human transcriptome","volume":"348","author":"Rivas","year":"2015","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nature19057","article-title":"Analysis of protein-coding genetic variation in 60,706 humans","volume":"536","author":"Lek","year":"2016","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1101\/gr.231902.117","article-title":"Base-specific mutational intolerance near splice sites clarifies the role of nonessential splice nucleotides","volume":"28","author":"Zhang","year":"2018","journal-title":"Genome Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1146\/annurev.biochem.76.050106.093909","article-title":"The nonsense-mediated decay RNA surveillance pathway","volume":"76","author":"Chang","year":"2007","journal-title":"Annu. Rev. Biochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.cell.2004.11.010","article-title":"Systematic identification and analysis of exonic splicing silencers","volume":"119","author":"Wang","year":"2004","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1261\/rna.876308","article-title":"Splicing regulation: From a parts list of regulatory elements to an integrated splicing code","volume":"14","author":"Wang","year":"2008","journal-title":"RNA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nrg775","article-title":"Listening to silence and understanding nonsense: Exonic mutations that affect splicing","volume":"3","author":"Cartegni","year":"2002","journal-title":"Nat. Rev. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1007\/s00439-017-1809-4","article-title":"Deep intronic mutations and human disease","volume":"136","year":"2017","journal-title":"Hum. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/S1097-2765(01)00305-7","article-title":"A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19q13.4 (RP11)","volume":"8","author":"Vithana","year":"2001","journal-title":"Mol. Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1093\/hmg\/11.1.87","article-title":"Mutations in HPRP3, a third member of pre-mRNA splicing factor genes, implicated in autosomal dominant retinitis pigmentosa","volume":"11","author":"Chakarova","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1093\/hmg\/10.15.1555","article-title":"Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominant retinitis pigmentosa (RP13)","volume":"10","author":"McKie","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/S0955-0674(02)00332-0","article-title":"The SMN complex, an assemblyosome of ribonucleoproteins","volume":"14","author":"Paushkin","year":"2002","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1136\/hrt.58.3.259","article-title":"Inheritance of hypertrophic cardiomyopathy: A cross sectional and M mode echocardiographic study of 50 families","volume":"58","author":"Greaves","year":"1987","journal-title":"Heart"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1056\/NEJMra0902923","article-title":"Inherited cardiomyopathies","volume":"364","author":"Watkins","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1097\/HCO.0b013e3283375698","article-title":"Genetics of hypertrophic cardiomyopathy","volume":"25","author":"Konno","year":"2010","journal-title":"Curr. Opin. Cardiol."},{"key":"ref_50","first-page":"3461","article-title":"Defining the genetic architecture of hypertrophic cardiomyopathy: Re-evaluating the role of non-sarcomeric genes","volume":"38","author":"Walsh","year":"2017","journal-title":"Eur. Heart J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1161\/01.RES.86.7.737","article-title":"Single-molecule mechanics of R403Q cardiac myosin isolated from the mouse model of familial hypertrophic cardiomyopathy","volume":"86","author":"Tyska","year":"2000","journal-title":"Circ. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1161\/CIRCRESAHA.109.202440","article-title":"Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency","volume":"105","author":"Marston","year":"2009","journal-title":"Circ. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1161\/CIRCULATIONAHA.108.838672","article-title":"Cardiac myosin-binding protein C mutations and hypertrophic cardiomyopathy: Haploinsufficiency, deranged phosphorylation, and cardiomyocyte dysfunction","volume":"119","author":"Dooijes","year":"2009","journal-title":"Circulation"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/nature09000","article-title":"Deciphering the splicing code","volume":"465","author":"Barash","year":"2010","journal-title":"Nature"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1002\/humu.22428","article-title":"Functional analysis of a large set of brca2 exon 7 variants highlights the predictive value of hexamer scores in detecting alterations of exonic splicing regulatory elements","volume":"34","author":"Gaildrat","year":"2013","journal-title":"Hum. Mutat."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"10681","DOI":"10.1093\/nar\/gku736","article-title":"Genomic HEXploring allows landscaping of novel potential splicing regulatory elements","volume":"42","author":"Erkelenz","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1016\/j.cell.2015.09.054","article-title":"Learning the sequence determinants of alternative splicing from millions of random sequences","volume":"163","author":"Rosenberg","year":"2015","journal-title":"Cell"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1254806","DOI":"10.1126\/science.1254806","article-title":"The human splicing code reveals new insights into the genetic determinants of disease","volume":"347","author":"Xiong","year":"2015","journal-title":"Science"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","article-title":"Predicting splicing from primary sequence with deep learning","volume":"176","author":"Jaganathan","year":"2019","journal-title":"Cell"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"7689","DOI":"10.1073\/pnas.1707741114","article-title":"Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing","volume":"114","author":"Ito","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1161\/CIRCGENETICS.113.000448","article-title":"Sarcomere mutation-specific expression patterns in human hypertrophic cardiomyopathy","volume":"7","author":"Helms","year":"2014","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.jacc.2018.04.078","article-title":"Whole Genome Sequencing Improves Outcomes of Genetic Testing in Patients With Hypertrophic Cardiomyopathy","volume":"72","author":"Bagnall","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e002368","DOI":"10.1161\/CIRCGEN.118.002368","article-title":"Key value of RNA analysis of MYBPC3 splice-site variants in hypertrophic cardiomyopathy","volume":"12","author":"Singer","year":"2019","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.stem.2012.10.010","article-title":"Abnormal calcium handling properties underlie familial hypertrophic cardiomyopathy pathology in patient-specific induced pluripotent stem cells","volume":"12","author":"Lan","year":"2013","journal-title":"Cell Stem Cell"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.scr.2017.02.016","article-title":"Peripheral blood derived induced pluripotent stem cells (iPSCs) from a female with familial hypertrophic cardiomyopathy","volume":"20","author":"Ross","year":"2017","journal-title":"Stem Cell Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2666","DOI":"10.1161\/CIRCULATIONAHA.117.032273","article-title":"Determining the pathogenicity of a genomic variant of uncertain significance using CRISPR\/Cas9 and human-induced pluripotent stem cells","volume":"138","author":"Ma","year":"2018","journal-title":"Circulation"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e2135","DOI":"10.1212\/WNL.0000000000005680","article-title":"Eteplirsen treatment for Duchenne muscular dystrophy","volume":"90","author":"Charleston","year":"2018","journal-title":"Neurology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1212\/WNL.0000000000006502","article-title":"Evidence in focus: Nusinersen use in spinal muscular atrophy report of the guideline development, dissemination, and implementation subcommittee of the American academy of neurology","volume":"91","author":"Michelson","year":"2018","journal-title":"Neurology"},{"key":"ref_69","first-page":"1060","article-title":"Rescue of cardiomyopathy through U7snRNA-mediated exon skipping in Mybpc3-targeted knock-in mice","volume":"5","author":"Reischmann","year":"2013","journal-title":"EMBO Mol. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/s41573-019-0017-4","article-title":"The current state and future directions of RNAi-based therapeutics","volume":"18","author":"Setten","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1038\/35888","article-title":"Potent and specific genetic interference by double-stranded RNA in caenorhabditis elegans","volume":"391","author":"Fire","year":"1998","journal-title":"Nature"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"15502","DOI":"10.1073\/pnas.95.26.15502","article-title":"RNA as a target of double-stranded RNA-mediated genetic interference in Caenorhabditis elegans","volume":"95","author":"Montgomery","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1038\/35078107","article-title":"Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells","volume":"411","author":"Elbashir","year":"2001","journal-title":"Nature"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1080\/17512433.2019.1567326","article-title":"Patisiran for the treatment of hereditary transthyretin-mediated amyloidosis","volume":"12","author":"Yang","year":"2019","journal-title":"Expert Rev. Clin. Pharmacol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1038\/nbt.4297","article-title":"RNAi modulation of placental sFLT1 for the treatment of preeclampsia","volume":"36","author":"Turanov","year":"2018","journal-title":"Nat. Biotechnol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1126\/science.1236921","article-title":"Allele-specific silencing of mutant Myh6 transcripts in mice suppresses hypertrophic cardiomyopathy","volume":"342","author":"Jiang","year":"2013","journal-title":"Science"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1002\/wrna.1347","article-title":"mRNA trans-splicing in gene therapy for genetic diseases","volume":"7","author":"Berger","year":"2016","journal-title":"Wiley Interdiscip. Rev. RNA"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e102","DOI":"10.1038\/mtna.2013.31","article-title":"Repair of Mybpc3 mRNA by 5\u2032-trans-splicing in a mouse model of hypertrophic cardiomyopathy","volume":"2","author":"Mearini","year":"2013","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.omtn.2017.05.008","article-title":"Evaluation of MYBPC3 trans-splicing and gene replacement as therapeutic options in human ipsc-derived cardiomyocytes","volume":"7","author":"Prondzynski","year":"2017","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1161\/01.RES.0000257913.42552.23","article-title":"MicroRNAs play an essential role in the development of cardiac hypertrophy","volume":"100","author":"Sayed","year":"2007","journal-title":"Circ. Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1016\/j.jacc.2013.09.041","article-title":"Circulating miR-29a, among other up-regulated microRNAs, is the only biomarker for both hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy","volume":"63","author":"Roncarati","year":"2014","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2266","DOI":"10.1111\/jcmm.12380","article-title":"MiR-451 is decreased in hypertrophic cardiomyopathy and regulates autophagy by targeting TSC1","volume":"18","author":"Song","year":"2014","journal-title":"J. Cell. Mol. Med."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Su, M., Wang, S., Qiu, W., Li, J., Hui, R., Song, L., Jia, M., Wang, H., and Wang, J. (2018). MIR-139-5p inhibits isoproterenol-induced cardiac hypertrophy by targetting c-Jun. Biosci. Rep., 38.","DOI":"10.1042\/BSR20171430"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"18255","DOI":"10.1073\/pnas.0608791103","article-title":"A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure","volume":"103","author":"Sutherland","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/4\/1329\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T08:58:17Z","timestamp":1760173097000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/4\/1329"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,16]]},"references-count":84,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["ijms21041329"],"URL":"https:\/\/doi.org\/10.3390\/ijms21041329","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,16]]}}}