Allele-specific Silencing of Mutant Myh6 Transcripts in Mice Suppresses Hypertrophic Cardiomyopathy

Overview

Journal Science

Specialty Science

Date 2013 Oct 5

PMID 24092743

Citations 100

Authors

Jianming Jiang

Hiroko Wakimoto

J G Seidman

Christine E Seidman

Affiliations

Soon will be listed here.

Abstract

Dominant mutations in sarcomere proteins such as the myosin heavy chains (MHC) are the leading genetic causes of human hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy. We found that expression of the HCM-causing cardiac MHC gene (Myh6) R403Q mutation in mice can be selectively silenced by an RNA interference (RNAi) cassette delivered by an adeno-associated virus vector. RNAi-transduced MHC(403/+) mice developed neither hypertrophy nor myocardial fibrosis, the pathologic manifestations of HCM, for at least 6 months. Because inhibition of HCM was achieved by only a 25% reduction in the levels of the mutant transcripts, we suggest that the variable clinical phenotype in HCM patients reflects allele-specific expression and that partial silencing of mutant transcripts may have therapeutic benefit.

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References

Rodriguez-Lebron E, Paulson H . Allele-specific RNA interference for neurological disease. Gene Ther. 2005; 13(6):576-81. DOI: 10.1038/sj.gt.3302702. View

Tyska M, Hayes E, Giewat M, Seidman C, Seidman J, Warshaw D . Single-molecule mechanics of R403Q cardiac myosin isolated from the mouse model of familial hypertrophic cardiomyopathy. Circ Res. 2000; 86(7):737-44. DOI: 10.1161/01.res.86.7.737. View

Fatkin D, McConnell B, Mudd J, Semsarian C, Moskowitz I, Schoen F . An abnormal Ca(2+) response in mutant sarcomere protein-mediated familial hypertrophic cardiomyopathy. J Clin Invest. 2000; 106(11):1351-9. PMC: 381468. DOI: 10.1172/JCI11093. View

Prasad K, Xu Y, Yang Z, Acton S, French B . Robust cardiomyocyte-specific gene expression following systemic injection of AAV: in vivo gene delivery follows a Poisson distribution. Gene Ther. 2010; 18(1):43-52. PMC: 2988989. DOI: 10.1038/gt.2010.105. View

Maron B, Maron M . Hypertrophic cardiomyopathy. Lancet. 2012; 381(9862):242-55. DOI: 10.1016/S0140-6736(12)60397-3. View

Ho C . Hypertrophic cardiomyopathy in 2012. Circulation. 2012; 125(11):1432-8. PMC: 3328186. DOI: 10.1161/CIRCULATIONAHA.110.017277. View

Teekakirikul P, Eminaga S, Toka O, Alcalai R, Wang L, Wakimoto H . Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β. J Clin Invest. 2010; 120(10):3520-9. PMC: 2947222. DOI: 10.1172/JCI42028. View

Kass S, Tanigawa G, Vosberg H, McKenna W, Seidman C, Seidman J . A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell. 1990; 62(5):999-1006. DOI: 10.1016/0092-8674(90)90274-i. View

Kim J, Porreca G, Song L, Greenway S, Gorham J, Church G . Polony multiplex analysis of gene expression (PMAGE) in mouse hypertrophic cardiomyopathy. Science. 2007; 316(5830):1481-4. DOI: 10.1126/science.1137325. View

10.

Gao G, Vandenberghe L, Wilson J . New recombinant serotypes of AAV vectors. Curr Gene Ther. 2005; 5(3):285-97. DOI: 10.2174/1566523054065057. View

11.

Semsarian C, Ahmad I, Giewat M, Georgakopoulos D, Schmitt J, McConnell B . The L-type calcium channel inhibitor diltiazem prevents cardiomyopathy in a mouse model. J Clin Invest. 2002; 109(8):1013-20. PMC: 150949. DOI: 10.1172/JCI14677. View

12.

Spirito P, Seidman C, McKenna W, Maron B . The management of hypertrophic cardiomyopathy. N Engl J Med. 1997; 336(11):775-85. DOI: 10.1056/NEJM199703133361107. View

13.

Jones W, GRUPP I, Doetschman T, GRUPP G, Osinska H, Hewett T . Ablation of the murine alpha myosin heavy chain gene leads to dosage effects and functional deficits in the heart. J Clin Invest. 1996; 98(8):1906-17. PMC: 507631. DOI: 10.1172/JCI118992. View

14.

Ho C, Sweitzer N, McDonough B, Maron B, Casey S, Seidman J . Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation. 2002; 105(25):2992-7. DOI: 10.1161/01.cir.0000019070.70491.6d. View

15.

Tripathi S, Schultz I, Becker E, Montag J, Borchert B, Francino A . Unequal allelic expression of wild-type and mutated β-myosin in familial hypertrophic cardiomyopathy. Basic Res Cardiol. 2011; 106(6):1041-55. PMC: 3228959. DOI: 10.1007/s00395-011-0205-9. View

16.

Bish L, Morine K, Sleeper M, Sanmiguel J, Wu D, Gao G . Adeno-associated virus (AAV) serotype 9 provides global cardiac gene transfer superior to AAV1, AAV6, AAV7, and AAV8 in the mouse and rat. Hum Gene Ther. 2008; 19(12):1359-68. PMC: 2940566. DOI: 10.1089/hum.2008.123. View

17.

Yu D, Pendergraff H, Liu J, Kordasiewicz H, Cleveland D, Swayze E . Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression. Cell. 2012; 150(5):895-908. PMC: 3444165. DOI: 10.1016/j.cell.2012.08.002. View

18.

Maron B, Doerer J, Haas T, Tierney D, Mueller F . Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980-2006. Circulation. 2009; 119(8):1085-92. DOI: 10.1161/CIRCULATIONAHA.108.804617. View

19.

Lang R, Bierig M, Devereux R, Flachskampf F, Foster E, Pellikka P . Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of.... J Am Soc Echocardiogr. 2005; 18(12):1440-63. DOI: 10.1016/j.echo.2005.10.005. View

20.

Teekakirikul P, Padera R, Seidman J, Seidman C . Hypertrophic cardiomyopathy: translating cellular cross talk into therapeutics. J Cell Biol. 2012; 199(3):417-21. PMC: 3483129. DOI: 10.1083/jcb.201207033. View