Journal
GENES
Volume 11, Issue 9, Pages -Publisher
MDPI
DOI: 10.3390/genes11091109
Keywords
myotonic dystrophy; spliceopathy; DMPK; MBNL; CELF1
Categories
Funding
- Health Institute Carlos III (ISCIII, Spain)
- European Regional Development Fund (ERDF/FEDER, 'A way of making Europe') [PI18/00114, PI18/00713]
- Basque Government [2019111010]
- Ikerbasque [RP/2018/001STARTUP]
- Biocruces Bizkaia Health Research Institute [BC/I/DIV/19/001]
- ISCIII [CM19/00104]
- ISCIII - ERDF/FEDER [CPII17/00004, CP14/00032, CP19/00021]
- Ikerbasque (Basque Foundation for Science)
Ask authors/readers for more resources
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 decreasedDMPKtranslation 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) andMBNL2. 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available