An Overview of Alternative Splicing Defects Implicated in Myotonic Dystrophy Type I
López-Martínez, Andrea (Instituto de Investigación Sanitaria Biocruces Bizkaia)
Soblechero-Martín, Patricia (Instituto de Investigación Sanitaria Biocruces Bizkaia)
de-la-Puente-Ovejero, Laura (Instituto de Investigación Sanitaria Biocruces Bizkaia)
Nogales, Gisela (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Arechavala-Gomeza, Virginia (Instituto de Investigación Sanitaria Biocruces Bizkaia)

Data:	2020
Resum:	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.
Ajuts:	Instituto de Salud Carlos III PI18/00114 Instituto de Salud Carlos III PI18/00713 Instituto de Salud Carlos III CM19/00104 Instituto de Salud Carlos III CPII17/00004 Ministerio de Economía y Competitividad CP14/00032
Drets:	Aquest 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.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Myotonic dystrophy ; Spliceopathy ; DMPK ; MBNL ; CELF1
Publicat a:	Genes, Vol. 11 (september 2020) , ISSN 2073-4425

DOI: 10.3390/genes11091109
PMID: 32971903

27 p, 1.8 MB

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