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The complexity of titin splicing pattern in human adult skeletal muscles

BACKGROUND: Mutations in the titin gene (TTN) cause a large spectrum of diseases affecting skeletal and/or cardiac muscle. TTN includes 363 coding exons, a repeated region with a high degree of complexity, isoform-specific elements, and metatranscript-only exons thought to be expressed only during f...

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Autores principales: Savarese, Marco, Jonson, Per Harald, Huovinen, Sanna, Paulin, Lars, Auvinen, Petri, Udd, Bjarne, Hackman, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874998/
https://www.ncbi.nlm.nih.gov/pubmed/29598826
http://dx.doi.org/10.1186/s13395-018-0156-z
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author Savarese, Marco
Jonson, Per Harald
Huovinen, Sanna
Paulin, Lars
Auvinen, Petri
Udd, Bjarne
Hackman, Peter
author_facet Savarese, Marco
Jonson, Per Harald
Huovinen, Sanna
Paulin, Lars
Auvinen, Petri
Udd, Bjarne
Hackman, Peter
author_sort Savarese, Marco
collection PubMed
description BACKGROUND: Mutations in the titin gene (TTN) cause a large spectrum of diseases affecting skeletal and/or cardiac muscle. TTN includes 363 coding exons, a repeated region with a high degree of complexity, isoform-specific elements, and metatranscript-only exons thought to be expressed only during fetal development. Although three main classes of isoforms have been described so far, alternative splicing events (ASEs) in different tissues or in different developmental and physiological states have been reported. METHODS: To achieve a comprehensive view of titin ASEs in adult human skeletal muscles, we performed a RNA-Sequencing experiment on 42 human biopsies collected from 12 anatomically different skeletal muscles of 11 individuals without any skeletal-muscle disorders. RESULTS: We confirmed that the skeletal muscle N2A isoforms are highly prevalent, but we found an elevated number of alternative splicing events, some at a very high level. These include previously unknown exon skipping events and alternative 5′ and 3′ splice sites. Our data suggests the partial inclusion in the TTN transcript of some metatranscript-only exons and the partial exclusion of canonical N2A exons. CONCLUSIONS: This study provides an extensive picture of the complex TTN splicing pattern in human adult skeletal muscle, which is crucial for a proper clinical interpretation of TTN variants. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13395-018-0156-z) contains supplementary material, which is available to authorized users.
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spelling pubmed-58749982018-04-02 The complexity of titin splicing pattern in human adult skeletal muscles Savarese, Marco Jonson, Per Harald Huovinen, Sanna Paulin, Lars Auvinen, Petri Udd, Bjarne Hackman, Peter Skelet Muscle Research BACKGROUND: Mutations in the titin gene (TTN) cause a large spectrum of diseases affecting skeletal and/or cardiac muscle. TTN includes 363 coding exons, a repeated region with a high degree of complexity, isoform-specific elements, and metatranscript-only exons thought to be expressed only during fetal development. Although three main classes of isoforms have been described so far, alternative splicing events (ASEs) in different tissues or in different developmental and physiological states have been reported. METHODS: To achieve a comprehensive view of titin ASEs in adult human skeletal muscles, we performed a RNA-Sequencing experiment on 42 human biopsies collected from 12 anatomically different skeletal muscles of 11 individuals without any skeletal-muscle disorders. RESULTS: We confirmed that the skeletal muscle N2A isoforms are highly prevalent, but we found an elevated number of alternative splicing events, some at a very high level. These include previously unknown exon skipping events and alternative 5′ and 3′ splice sites. Our data suggests the partial inclusion in the TTN transcript of some metatranscript-only exons and the partial exclusion of canonical N2A exons. CONCLUSIONS: This study provides an extensive picture of the complex TTN splicing pattern in human adult skeletal muscle, which is crucial for a proper clinical interpretation of TTN variants. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13395-018-0156-z) contains supplementary material, which is available to authorized users. BioMed Central 2018-03-29 /pmc/articles/PMC5874998/ /pubmed/29598826 http://dx.doi.org/10.1186/s13395-018-0156-z Text en © The Author(s). 2018 Open AccessThis 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. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Savarese, Marco
Jonson, Per Harald
Huovinen, Sanna
Paulin, Lars
Auvinen, Petri
Udd, Bjarne
Hackman, Peter
The complexity of titin splicing pattern in human adult skeletal muscles
title The complexity of titin splicing pattern in human adult skeletal muscles
title_full The complexity of titin splicing pattern in human adult skeletal muscles
title_fullStr The complexity of titin splicing pattern in human adult skeletal muscles
title_full_unstemmed The complexity of titin splicing pattern in human adult skeletal muscles
title_short The complexity of titin splicing pattern in human adult skeletal muscles
title_sort complexity of titin splicing pattern in human adult skeletal muscles
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874998/
https://www.ncbi.nlm.nih.gov/pubmed/29598826
http://dx.doi.org/10.1186/s13395-018-0156-z
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