Abstract
Truncating variants in the gene for titin (TTNtvs) strongly associate with dilated cardiomyopathy (DCM) and peripartum cardiomyopathy (PPCM). How TTNtvs lead to cardiomyopathy is unclear. Both haploinsufficient and dominant negative mechanisms have been proposed. To begin to address this question, we have obtained left ventricular myocardium from explanted hearts from patients with DCM or PPCM undergoing cardiac transplantation, as well as myocardium from non-failing donor hearts. Targeted exome sequencing identified 8 hearts bearing TTNtvs in isoforms expressed in adult heart. Modified gel electrophoresis of extracts from these samples revealed no apparent band at the expected (truncated) molecular weight predicted for each TTNtv, indicating that truncated titin protein is likely absent. In addition, the total amount of titin protein appeared preserved in TTNtv extracts, arguing against haploinsufficiency in these hearts. RNAseq of TTNtv-positive hearts revealed balanced representation of all identified heterozygous variants, i.e. preserved allelic balance, indicating that the alleles encoding TTNtvs are appropriately transcribed, and do not undergo nonsense mediated decay. Together these data support neither haploinsufficiency nor dominant negative mechanisms, and leave open the question of how TTNtvs contribute to the development of DCM and PPCM.
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