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

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Science  04 Oct 2013:
Vol. 342, Issue 6154, pp. 111-114
DOI: 10.1126/science.1236921

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Silencing a Silent Killer

Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden death in young athletes. HCM is caused by dominant mutations in genes encoding constituents of the cardiac sarcomere, the contractile unit that keeps the heart pumping. Studying a mouse model that recapitulates a severe form of HCM caused by a mutation in a β myosin heavy chain gene, Jiang et al. (p. 111) investigated whether sarcomere dysfunction could be corrected by selectively silencing expression of the mutant allele. Mice treated shortly after birth with a viral vector encoding an appropriately designed RNA interference cassette did not develop cardiac hypertrophy or myocardial fibrosis—the pathologic manifestations of HCM—for at least 6 months.


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 MHC403/+ 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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