An Overview of Alternative Splicing Defects Implicated in Myotonic Dystrophy Type I

Myotonic dystrophy type I (DM1) is the most common form of adult muscular dystrophy, caused by expansion of a CTG triplet repeat in the 3' untranslated region (3'UTR) of the myotonic dystrophy protein kinase (DMPK) gene. The pathological CTG repeats result in protein trapping by expanded t...

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Autores: López-Martínez, Andrea|||0000-0003-4711-7495, Soblechero-Martín, Patricia, de-la-Puente-Ovejero, Laura|||0000-0002-0835-7069, Nogales, Gisela|||0000-0002-7414-212X, Arechavala-Gomeza, Virginia|||0000-0001-7703-3255
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:252934
Acceso en línea:https://ddd.uab.cat/record/252934
https://dx.doi.org/urn:doi:10.3390/genes11091109
Access Level:acceso abierto
Palabra clave:Myotonic dystrophy
Spliceopathy
DMPK
MBNL
CELF1
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spelling An Overview of Alternative Splicing Defects Implicated in Myotonic Dystrophy Type ILópez-Martínez, Andrea|||0000-0003-4711-7495Soblechero-Martín, Patriciade-la-Puente-Ovejero, Laura|||0000-0002-0835-7069Nogales, Gisela|||0000-0002-7414-212XArechavala-Gomeza, Virginia|||0000-0001-7703-3255Myotonic dystrophySpliceopathyDMPKMBNLCELF1Myotonic dystrophy type I (DM1) is the most common form of adult muscular dystrophy, caused by expansion of a CTG triplet repeat in the 3' untranslated region (3'UTR) of the myotonic dystrophy protein kinase (DMPK) gene. The pathological CTG repeats result in protein trapping by expanded transcripts, a decreased DMPK translation and the disruption of the chromatin structure, affecting neighboring genes expression. The muscleblind-like (MBNL) and CUG-BP and ETR-3-like factors (CELF) are two families of tissue-specific regulators of developmentally programmed alternative splicing that act as antagonist regulators of several pre-mRNA targets, including troponin 2 (TNNT2), insulin receptor (INSR), chloride channel 1 (CLCN1) and MBNL2. Sequestration of MBNL proteins and up-regulation of CELF1 are key to DM1 pathology, inducing a spliceopathy that leads to a developmental remodelling of the transcriptome due to an adult-to-foetal splicing switch, which results in the loss of cell function and viability. Moreover, recent studies indicate that additional pathogenic mechanisms may also contribute to disease pathology, including a misregulation of cellular mRNA translation, localization and stability. This review focuses on the cause and effects of MBNL and CELF1 deregulation in DM1, describing the molecular mechanisms underlying alternative splicing misregulation for a deeper understanding of DM1 complexity. To contribute to this analysis, we have prepared a comprehensive list of transcript alterations involved in DM1 pathogenesis, as well as other deregulated mRNA processing pathways implications. 22020-01-0120202020-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/252934https://dx.doi.org/urn:doi:10.3390/genes11091109reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengInstituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI18/00114Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI18/00713Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 CM19/00104Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 CPII17/00004Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 CP14/00032open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2529342026-06-06T12:50:31Z
dc.title.none.fl_str_mv An Overview of Alternative Splicing Defects Implicated in Myotonic Dystrophy Type I
title An Overview of Alternative Splicing Defects Implicated in Myotonic Dystrophy Type I
spellingShingle An Overview of Alternative Splicing Defects Implicated in Myotonic Dystrophy Type I
López-Martínez, Andrea|||0000-0003-4711-7495
Myotonic dystrophy
Spliceopathy
DMPK
MBNL
CELF1
title_short An Overview of Alternative Splicing Defects Implicated in Myotonic Dystrophy Type I
title_full An Overview of Alternative Splicing Defects Implicated in Myotonic Dystrophy Type I
title_fullStr An Overview of Alternative Splicing Defects Implicated in Myotonic Dystrophy Type I
title_full_unstemmed An Overview of Alternative Splicing Defects Implicated in Myotonic Dystrophy Type I
title_sort An Overview of Alternative Splicing Defects Implicated in Myotonic Dystrophy Type I
dc.creator.none.fl_str_mv López-Martínez, Andrea|||0000-0003-4711-7495
Soblechero-Martín, Patricia
de-la-Puente-Ovejero, Laura|||0000-0002-0835-7069
Nogales, Gisela|||0000-0002-7414-212X
Arechavala-Gomeza, Virginia|||0000-0001-7703-3255
author López-Martínez, Andrea|||0000-0003-4711-7495
author_facet López-Martínez, Andrea|||0000-0003-4711-7495
Soblechero-Martín, Patricia
de-la-Puente-Ovejero, Laura|||0000-0002-0835-7069
Nogales, Gisela|||0000-0002-7414-212X
Arechavala-Gomeza, Virginia|||0000-0001-7703-3255
author_role author
author2 Soblechero-Martín, Patricia
de-la-Puente-Ovejero, Laura|||0000-0002-0835-7069
Nogales, Gisela|||0000-0002-7414-212X
Arechavala-Gomeza, Virginia|||0000-0001-7703-3255
author2_role author
author
author
author
dc.subject.none.fl_str_mv Myotonic dystrophy
Spliceopathy
DMPK
MBNL
CELF1
topic Myotonic dystrophy
Spliceopathy
DMPK
MBNL
CELF1
description Myotonic dystrophy type I (DM1) is the most common form of adult muscular dystrophy, caused by expansion of a CTG triplet repeat in the 3' untranslated region (3'UTR) of the myotonic dystrophy protein kinase (DMPK) gene. The pathological CTG repeats result in protein trapping by expanded transcripts, a decreased DMPK translation and the disruption of the chromatin structure, affecting neighboring genes expression. The muscleblind-like (MBNL) and CUG-BP and ETR-3-like factors (CELF) are two families of tissue-specific regulators of developmentally programmed alternative splicing that act as antagonist regulators of several pre-mRNA targets, including troponin 2 (TNNT2), insulin receptor (INSR), chloride channel 1 (CLCN1) and MBNL2. Sequestration of MBNL proteins and up-regulation of CELF1 are key to DM1 pathology, inducing a spliceopathy that leads to a developmental remodelling of the transcriptome due to an adult-to-foetal splicing switch, which results in the loss of cell function and viability. Moreover, recent studies indicate that additional pathogenic mechanisms may also contribute to disease pathology, including a misregulation of cellular mRNA translation, localization and stability. This review focuses on the cause and effects of MBNL and CELF1 deregulation in DM1, describing the molecular mechanisms underlying alternative splicing misregulation for a deeper understanding of DM1 complexity. To contribute to this analysis, we have prepared a comprehensive list of transcript alterations involved in DM1 pathogenesis, as well as other deregulated mRNA processing pathways implications.
publishDate 2020
dc.date.none.fl_str_mv 2
2020-01-01
2020
2020-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/252934
https://dx.doi.org/urn:doi:10.3390/genes11091109
url https://ddd.uab.cat/record/252934
https://dx.doi.org/urn:doi:10.3390/genes11091109
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI18/00114
Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI18/00713
Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 CM19/00104
Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 CPII17/00004
Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 CP14/00032
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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