Titin Is a Major Human Disease Gene

Titin is a giant multi-functional sarcomeric filament that provides passive stiffness to cardiac myocytes. At its N terminus, titin is embedded in the Z-disk of the sarcomere. The rest of the molecule is divided between an elastic I-band region, a thick filament-binding A-band region, and the M-band region where the C terminus is embedded (Figure 1A, bottom).1 The extensible I-band region of titin functions as a molecular spring that develops passive force during diastole when sarcomeres are stretched.2 This force is important for centering the A-band in the sarcomere3 and, together with the extracellular matrix, for defining diastolic stiffness.2 Other regions of titin (Z-disk, A-band, and M-band) are involved in numerous cellular processes including force-dependent signaling.4 Here we discuss recently discovered post-transcriptional and post-translational modifications of titin and address their roles in acquired cardiac disease, including dilated cardiomyopathy (DCM) and heart failure with preserved ejection fraction (HFpEF, often termed diastolic heart failure; for the purposes of this study we restrict the term HFpEF to HF patients with left ventricular EF > 0.50 in the absence of hypertrophic cardiomyopathy or valvular, infiltrative, or pericardial disease). The review also focuses on recent work that reveals mutations in the titin gene as a major source of familial cardiomyopathies, including mutations in the spring region of titin linked to arrhythmogenic right ventricular dysplasia5 and mutations in the A-band region of titin responsible for ≈30% of DCM cases.6 These findings have given rise to the emerging view that titin gene is a major disease gene.Figure 1. Schematic of titin in the sarcomere ( A ) and mechanisms for modifying titin-based passive tension ( B and C ). A , Bottom: Single titin molecules (shown in blue and yellow) span from Z-disk (N terminus) to M-band (C terminus). Middle: Composition of extensible I-band …