The giant muscle filament protein titin is encoded by a single gene consisting of 364 exons. In the past, because of its enormous size and complexity, only few titin mutations were discovered causing different cardiac and skeletal muscle conditions; however, the overall role for heritable diseases, in particular dilated cardiomyopathy (DCM), has been significantly underestimated. Recently performed systematic studies using next-generation sequencing (NGS) recognized TTN as the major human disease gene for DCM, but at the same time those data sets revealed that unique genetic variations are also more common in the general population than previously expected. Truncating variants in TTN have been reported in about 25% of patients with DCM and in 2%-3% of controls; however, most of the disease-associated truncation variants were found in constitutively expressed exons across the gene and in A-band titin, which is abundant in both major cardiac isoforms N2B and N2BA. Titin isoform composition and switch is an important factor for determination and modulation of titin-based stiffness in health and heart disease. Moreover, other factors, including post-translational modification resulting from phosphorylation and oxidative modifications of titin spring elements contribute at the cellular level to titin’s stiffness. A better understanding of titin’s role in cardiac (patho)physiology will achieve further insights into the molecular mechanisms leading to heart failure and arrhythmias in patients with DCM caused by titin truncation mutations and may provide potential targets for future therapeutic interventions.
Copyright © 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.