Unequal allelic expression of wild-type and mutated β-myosin in familial hypertrophic cardiomyopathyReportar como inadecuado

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Basic Research in Cardiology

, Volume 106, Issue 6, pp 1041–1055

First Online: 19 July 2011Received: 26 May 2011Revised: 29 June 2011Accepted: 07 July 2011


Familial hypertrophic cardiomyopathy FHC is an autosomal dominant disease, which in about 30% of the patients is caused by missense mutations in one allele of the β-myosin heavy chain β-MHC gene MYH7. To address potential molecular mechanisms underlying the family-specific prognosis, we determined the relative expression of mutant versus wild-type MYH7-mRNA. We found a hitherto unknown mutation-dependent unequal expression of mutant to wild-type MYH7-mRNA, which is paralleled by similar unequal expression of β-MHC at the protein level. Relative abundance of mutated versus wild-type MYH7-mRNA was determined by a specific restriction digest approach and by real-time PCR RT-qPCR. Fourteen samples from M. soleus and myocardium of 12 genotyped and clinically well-characterized FHC patients were analyzed. The fraction of mutated MYH7-mRNA in five patients with mutation R723G averaged to 66 and 68% of total MYH7-mRNA in soleus and myocardium, respectively. For mutations I736T, R719W and V606M, fractions of mutated MYH7-mRNA in M. soleus were 39, 57 and 29%, respectively. For all mutations, unequal abundance was similar at the protein level. Importantly, fractions of mutated transcripts were comparable among siblings, in younger relatives and unrelated carriers of the same mutation. Hence, the extent of unequal expression of mutated versus wild-type transcript and protein is characteristic for each mutation, implying cis-acting regulatory mechanisms. Bioinformatics suggest mRNA stability or splicing effectors to be affected by certain mutations. Intriguingly, we observed a correlation between disease expression and fraction of mutated mRNA and protein. This strongly suggests that mutation-specific allelic imbalance represents a new pathogenic factor for FHC.

KeywordsHypertrophic cardiomyopathy Allelic imbalance Cardiac β-myosin heavy chain Myosin missense mutation mRNA quantification Electronic supplementary materialThe online version of this article doi:10.1007-s00395-011-0205-9 contains supplementary material, which is available to authorized users.

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Autor: Snigdha Tripathi - Imke Schultz - Edgar Becker - Judith Montag - Bianca Borchert - Antonio Francino - Francisco Navarro-Lop

Fuente: https://link.springer.com/

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