Truncated titin protein in dilated cardiomyopathy

Truncating variations in the gene coding for titin (TTNtv) have long been known to cause dilated cardiomyopathy (DCM), but efforts to detect direct evidence of either haploinsufficiency or dominant negative mechanisms have left the mechanism open to controversy, with the default assumption being that TTNtv proteins are absent in the myocardium. By analyzing a collection of 184 post-transplant human hearts, 22 of which bear TTNtv’s, we show evidence supporting both dominant-negative gain of toxic function due to truncated titin protein associated with the sarcomeric fraction of the myocardium, as well as haploinsufficiency due to lack of sufficient full length titin.