The effects of titin-truncating variants on metabolism and a possible target for intervention for dilated cardiomyopathy

Dilated cardiomyopathy (DCM) has a strong genetic basis, of which truncating variants in titin (TTNtv) are the most prevalent. However, a disease penetrance with reduced expression has been suggested. It seems that TTNtv carriers can cope with the molecular consequences of the variant and prevent full disease expression, until an additional trigger is introduced. Evidence is accumulating that the metabolic adaptation and observed mitochondrial dysfunction plays an important role in the TTNtv-associated pathogenesis, and potentially lead to disturbances in the post-translational modification of titin. Using patient derived iPSC cardiomyocytes we want to identify the mechanistic link between TTNtv and metabolic alteration as the cause a DCM phenotype. Better understanding of the molecular changes and consequences due to a TTNtv will provide insight in the coping mechanisms and associated pathogenesis towards full disease expression, eventually providing targets for intervention.