Research ArticleGenetic Medicine

Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease

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Science Translational Medicine  14 Jan 2015:
Vol. 7, Issue 270, pp. 270ra6
DOI: 10.1126/scitranslmed.3010134

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What Happens When Titins Are Trimmed?

The most common form of inherited heart failure, dilated cardiomyopathy, can be caused by mutations in a mammoth heart protein, appropriately called titin. Now, Roberts et al. sort out which titin mutations cause disease and why some people can carry certain titin mutations but remain perfectly healthy. In an exhaustive survey of more than 5200 people, with and without cardiomyopathy, the authors sequenced the titin gene and measured its corresponding RNA and protein levels. The alterations in titin were truncating mutations, which cause short nonfunctional versions of the RNA or protein. These defects produced cardiomyopathy when they occurred closer to the protein’s carboxyl terminus and in exons that were abundantly transcribed. The titin-truncating mutations that occur in the general population tended not to have these characteristics and were usually benign. This new detailed understanding of the molecular basis of dilated cardiomyopathy penetrance will promote better disease management and accelerate rational patient stratification.