Genetic epidemiology of titin-truncating variants in the etiology of dilated cardiomyopathy

Abstract

Heart failure (HF) is a complex clinical syndrome defined by the inability of the heart to pump enough blood to meet the body’s metabolic demands. Major causes of HF are cardiomyopathies (diseases of the myocardium associated with mechanical and/or electrical dysfunction), among which the most common form is dilated cardiomyopathy (DCM). DCM is defined by ventricular chamber enlargement and systolic dysfunction with normal left ventricular wall thickness, which leads to progressive HF. Over 60 genes are linked to the etiology of DCM. Titin (TTN) is the largest known protein in biology, spanning half the cardiac sarcomere and, as such, is a basic structural and functional unit of striated muscles. It is essential for heart development as well as mechanical and regulatory functions of the sarcomere. Next-generation sequencing (NGS) in clinical DCM cohorts implicated truncating variants in titin (TTNtv) as major disease alleles, accounting for more than 25% of familial DCM cases, but these variants have also been identified in 2–3% of the general population, where these TTNtv blur diagnostic and clinical utility. Taking into account the published TTNtv and their association to DCM, it becomes clear that TTNtv harm the heart with position-dependent occurrence, being more harmful when present in the A-band TTN, presumably with dominant negative/gain-of-function mechanisms. However, these insights are challenged by the depiction of position-independent toxicity of TTNtv acting via haploinsufficient alleles, which are sufficient to induce cardiac pathology upon stress. In the current review, we provide an overview of TTN and discuss studies investigating various TTN mutations. We also present an overview of different mechanisms postulated or experimentally validated in the pathogenicity of TTNtv. DCM-causing genes are also discussed with respect to non-truncating mutations in the etiology of DCM. One way of understanding pathogenic variants is probably to understand the context in which they may or may not affect protein–protein interactions, changes in cell signaling, and substrate specificity. In this regard, we also provide a brief overview of TTN interactions in situ. Quantitative models in the risk assessment of TTNtv are also discussed. In summary, we highlight the importance of gene–environment interactions in the etiology of DCM and further mechanistic studies used to delineate the pathways which could be targeted in the management of DCM.

Takotsubo as Initial Manifestation of Non-Myopathic Cardiomyopathy Due to the Titin Variant c.1489G > T

“…Heart failure is a major health burden and affects approximately 40 million people worldwide [ 2 ]. One of the major causes of heart failure is dCMP [ 2 ], which is defined by ventricular chamber enlargement and systolic dysfunction without left ventricular wall thickness, leading to progressive heart failure [ 3 ]. dCMP occurs with a prevalence of 1:2500 and is responsible for half of the cases with heart failure [ 4 ].…”

“…About one third of the dCMPs are due to genetic causes [ 2 ]. Mutations in >60 genes have been identified so far, which are made responsible for dCMP [ 3 ].…”

“…One of the dCMP genes is the titin gene, located on chromosome 2q31. The titin gene encodes titin, the largest known protein in biology, spanning half the cardiac and muscle sarcomere and, as such a basic structural and functional unit of striated muscles [ 3 ]. Titin is built up of 38,000 aminoacids from 364 exons [ 5 ].…”

Modifications of Titin Contribute to the Progression of Cardiomyopathy and Represent a Therapeutic Target for Treatment of Heart Failure

“…Metabolic stress is generated by abnormal mRNA transcripts from the truncation variant leading to increased non-sense mRNA decay (NMD). This leads to long term compensatory changes and development of a common DCM phenotype that is independent of TTN mutation location [ 31 , 32 , 33 ] ( Figure 3 ). Rat models with A-band and I-band TTNtv do not alter the amount of TTN expressed, but there is increased NMD and a shift in cardiac metabolism to preference branched chain amino acids and glycolytic intermediates instead of fatty acids that are typically utilized in healthy cardiomyocytes [ 34 , 35 ].…”

A common polymorphism in the SCN5A gene is associated with dilated cardiomyopathy

“…To date, about 100 genes have been associated with DCM, 12 most of which are autosomal and encode such structural components of the heart muscle such as the sarcomeric and cardiac Z-disk genes. 10 , 12 , 14 , 15 Mutations in TTN , MYH7 , LMNA and SCN5A genes, which appear to be pathogenic, are present in variable percentage, with Titin ( TTN ) being the most prevalent one. 1 , 11 , 15 , 16 On the contrary, there is evidence that the natural history of DCM is different depending on the various causes.…”