Cargando…

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

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 commo...

Descripción completa

Detalles Bibliográficos
Autores principales: Tabish, Ali M., Azzimato, Valerio, Alexiadis, Aris, Buyandelger, Byambajav, Knöll, Ralph
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498329/
https://www.ncbi.nlm.nih.gov/pubmed/28510119
http://dx.doi.org/10.1007/s12551-017-0265-7
_version_ 1783248277311848448
author Tabish, Ali M.
Azzimato, Valerio
Alexiadis, Aris
Buyandelger, Byambajav
Knöll, Ralph
author_facet Tabish, Ali M.
Azzimato, Valerio
Alexiadis, Aris
Buyandelger, Byambajav
Knöll, Ralph
author_sort Tabish, Ali M.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-5498329
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Springer Berlin Heidelberg
record_format MEDLINE/PubMed
spelling pubmed-54983292017-07-20 Genetic epidemiology of titin-truncating variants in the etiology of dilated cardiomyopathy Tabish, Ali M. Azzimato, Valerio Alexiadis, Aris Buyandelger, Byambajav Knöll, Ralph Biophys Rev Review 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. Springer Berlin Heidelberg 2017-05-05 /pmc/articles/PMC5498329/ /pubmed/28510119 http://dx.doi.org/10.1007/s12551-017-0265-7 Text en © The Author(s) 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Review
Tabish, Ali M.
Azzimato, Valerio
Alexiadis, Aris
Buyandelger, Byambajav
Knöll, Ralph
Genetic epidemiology of titin-truncating variants in the etiology of dilated cardiomyopathy
title Genetic epidemiology of titin-truncating variants in the etiology of dilated cardiomyopathy
title_full Genetic epidemiology of titin-truncating variants in the etiology of dilated cardiomyopathy
title_fullStr Genetic epidemiology of titin-truncating variants in the etiology of dilated cardiomyopathy
title_full_unstemmed Genetic epidemiology of titin-truncating variants in the etiology of dilated cardiomyopathy
title_short Genetic epidemiology of titin-truncating variants in the etiology of dilated cardiomyopathy
title_sort genetic epidemiology of titin-truncating variants in the etiology of dilated cardiomyopathy
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498329/
https://www.ncbi.nlm.nih.gov/pubmed/28510119
http://dx.doi.org/10.1007/s12551-017-0265-7
work_keys_str_mv AT tabishalim geneticepidemiologyoftitintruncatingvariantsintheetiologyofdilatedcardiomyopathy
AT azzimatovalerio geneticepidemiologyoftitintruncatingvariantsintheetiologyofdilatedcardiomyopathy
AT alexiadisaris geneticepidemiologyoftitintruncatingvariantsintheetiologyofdilatedcardiomyopathy
AT buyandelgerbyambajav geneticepidemiologyoftitintruncatingvariantsintheetiologyofdilatedcardiomyopathy
AT knollralph geneticepidemiologyoftitintruncatingvariantsintheetiologyofdilatedcardiomyopathy