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A Review of the Giant Protein Titin in Clinical Molecular Diagnostics of Cardiomyopathies

Titin (TTN) is known as the largest sarcomeric protein that resides within the heart muscle. Due to alternative splicing of TTN, the heart expresses two major isoforms (N2B and N2BA) that incorporate four distinct regions termed the Z-line, I-band, A-band, and M-line. Next-generation sequencing allo...

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Autores principales: Gigli, Marta, Begay, Rene L., Morea, Gaetano, Graw, Sharon L., Sinagra, Gianfranco, Taylor, Matthew R. G., Granzier, Henk, Mestroni, Luisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4954824/
https://www.ncbi.nlm.nih.gov/pubmed/27493940
http://dx.doi.org/10.3389/fcvm.2016.00021
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author Gigli, Marta
Begay, Rene L.
Morea, Gaetano
Graw, Sharon L.
Sinagra, Gianfranco
Taylor, Matthew R. G.
Granzier, Henk
Mestroni, Luisa
author_facet Gigli, Marta
Begay, Rene L.
Morea, Gaetano
Graw, Sharon L.
Sinagra, Gianfranco
Taylor, Matthew R. G.
Granzier, Henk
Mestroni, Luisa
author_sort Gigli, Marta
collection PubMed
description Titin (TTN) is known as the largest sarcomeric protein that resides within the heart muscle. Due to alternative splicing of TTN, the heart expresses two major isoforms (N2B and N2BA) that incorporate four distinct regions termed the Z-line, I-band, A-band, and M-line. Next-generation sequencing allows a large number of genes to be sequenced simultaneously and provides the opportunity to easily analyze giant genes such as TTN. Mutations in the TTN gene can cause cardiomyopathies, in particular dilated cardiomyopathy (DCM). DCM is the most common form of cardiomyopathy, and it is characterized by systolic dysfunction and dilation of the left ventricle. TTN truncating variants have been described as the most common cause of DCM, while the real impact of TTN missense variants in the pathogenesis of DCM is still unclear. In a recent population screening study, rare missense variants potentially pathogenic based on bioinformatic filtering represented only 12.6% of the several hundred rare TTN missense variants found, suggesting that missense variants are very common in TTN and are frequently benign. The aim of this review is to understand the clinical role of TTN mutations in DCM and in other cardiomyopathies. Whereas TTN truncations are common in DCM, there is evidence that TTN truncations are rare in the hypertrophic cardiomyopathy (HCM) phenotype. Furthermore, TTN mutations can also cause arrhythmogenic right ventricular cardiomyopathy (ARVC) with distinct clinical features and outcomes. Finally, the identification of a rare TTN missense variant cosegregating with the restrictive cardiomyopathy (RCM) phenotype suggests that TTN is a novel disease-causing gene in this disease. Clinical diagnostic testing is currently able to analyze over 100 cardiomyopathy genes, including TTN; however, the size and presence of extensive genetic variation in TTN presents clinical challenges in determining significant disease-causing mutations. This review discusses the current knowledge of TTN genetic variations in cardiomyopathies and the impact of the diagnosis of TTN pathogenic mutations in the clinical setting.
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spelling pubmed-49548242016-08-04 A Review of the Giant Protein Titin in Clinical Molecular Diagnostics of Cardiomyopathies Gigli, Marta Begay, Rene L. Morea, Gaetano Graw, Sharon L. Sinagra, Gianfranco Taylor, Matthew R. G. Granzier, Henk Mestroni, Luisa Front Cardiovasc Med Cardiovascular Medicine Titin (TTN) is known as the largest sarcomeric protein that resides within the heart muscle. Due to alternative splicing of TTN, the heart expresses two major isoforms (N2B and N2BA) that incorporate four distinct regions termed the Z-line, I-band, A-band, and M-line. Next-generation sequencing allows a large number of genes to be sequenced simultaneously and provides the opportunity to easily analyze giant genes such as TTN. Mutations in the TTN gene can cause cardiomyopathies, in particular dilated cardiomyopathy (DCM). DCM is the most common form of cardiomyopathy, and it is characterized by systolic dysfunction and dilation of the left ventricle. TTN truncating variants have been described as the most common cause of DCM, while the real impact of TTN missense variants in the pathogenesis of DCM is still unclear. In a recent population screening study, rare missense variants potentially pathogenic based on bioinformatic filtering represented only 12.6% of the several hundred rare TTN missense variants found, suggesting that missense variants are very common in TTN and are frequently benign. The aim of this review is to understand the clinical role of TTN mutations in DCM and in other cardiomyopathies. Whereas TTN truncations are common in DCM, there is evidence that TTN truncations are rare in the hypertrophic cardiomyopathy (HCM) phenotype. Furthermore, TTN mutations can also cause arrhythmogenic right ventricular cardiomyopathy (ARVC) with distinct clinical features and outcomes. Finally, the identification of a rare TTN missense variant cosegregating with the restrictive cardiomyopathy (RCM) phenotype suggests that TTN is a novel disease-causing gene in this disease. Clinical diagnostic testing is currently able to analyze over 100 cardiomyopathy genes, including TTN; however, the size and presence of extensive genetic variation in TTN presents clinical challenges in determining significant disease-causing mutations. This review discusses the current knowledge of TTN genetic variations in cardiomyopathies and the impact of the diagnosis of TTN pathogenic mutations in the clinical setting. Frontiers Media S.A. 2016-07-21 /pmc/articles/PMC4954824/ /pubmed/27493940 http://dx.doi.org/10.3389/fcvm.2016.00021 Text en Copyright © 2016 Gigli, Begay, Morea, Graw, Sinagra, Taylor, Granzier and Mestroni. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cardiovascular Medicine
Gigli, Marta
Begay, Rene L.
Morea, Gaetano
Graw, Sharon L.
Sinagra, Gianfranco
Taylor, Matthew R. G.
Granzier, Henk
Mestroni, Luisa
A Review of the Giant Protein Titin in Clinical Molecular Diagnostics of Cardiomyopathies
title A Review of the Giant Protein Titin in Clinical Molecular Diagnostics of Cardiomyopathies
title_full A Review of the Giant Protein Titin in Clinical Molecular Diagnostics of Cardiomyopathies
title_fullStr A Review of the Giant Protein Titin in Clinical Molecular Diagnostics of Cardiomyopathies
title_full_unstemmed A Review of the Giant Protein Titin in Clinical Molecular Diagnostics of Cardiomyopathies
title_short A Review of the Giant Protein Titin in Clinical Molecular Diagnostics of Cardiomyopathies
title_sort review of the giant protein titin in clinical molecular diagnostics of cardiomyopathies
topic Cardiovascular Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4954824/
https://www.ncbi.nlm.nih.gov/pubmed/27493940
http://dx.doi.org/10.3389/fcvm.2016.00021
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