Genes, Vol. 11, Pages 1109: An Overview of Alternative Splicing Defects Implicated in Myotonic Dystrophy Type I

Genes, Vol. 11, Pages 1109: An Overview of Alternative Splicing Defects Implicated in Myotonic Dystrophy Type I Genes doi: 10.3390/genes11091109 Authors: Andrea López-Martínez Patricia Soblechero-Martín Laura de-la-Puente-Ovejero Gisela Nogales-Gadea Virginia Arechavala-Gomeza 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 trans...
Source: Genes - Category: Genetics & Stem Cells Authors: Tags: Review Source Type: research