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Open AccessReview

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

1
Neuromuscular Disorders Group, Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain
2
Neuromuscular and Neuropediatric Research Group, Germans Trias i Pujol Research Institute, Campus Can Ruti, Universitat Autònoma de Barcelona, 08916 Badalona, Spain
3
Ikerbasque, Basque Foundation for Science, 48009 Bilbao, Spain
*
Author to whom correspondence should be addressed.
Genes 2020, 11(9), 1109; https://doi.org/10.3390/genes11091109
Received: 11 August 2020 / Revised: 14 September 2020 / Accepted: 17 September 2020 / Published: 22 September 2020
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. View Full-Text
Keywords: myotonic dystrophy; spliceopathy; DMPK; MBNL; CELF1 myotonic dystrophy; spliceopathy; DMPK; MBNL; CELF1
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López-Martínez, A.; Soblechero-Martín, P.; de-la-Puente-Ovejero, L.; Nogales-Gadea, G.; Arechavala-Gomeza, V. An Overview of Alternative Splicing Defects Implicated in Myotonic Dystrophy Type I. Genes 2020, 11, 1109.

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