Abstract
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.
Highlights
Myotonic dystrophies are a group of complex, dominantly inherited, disorders characterized by a multisystemic affection
In this review we focus on MBNL1 and CELF1 implication in alternative splicing to help misregulated due to MBNL1 sequestration and CELF1 upregulation [29,30]
In this review we focus on MBNL1 and CELF1 implication in alternative splicing to help understand
Summary
Myotonic dystrophies are a group of complex, dominantly inherited, disorders characterized by a multisystemic affection. There are two clinical and molecular forms of myotonic dystrophies described, both inherited in autosomal dominant pattern: myotonic dystrophy type I (DM1) or Steiner’s disease (OMIM 160900), with an incidence of approximately 1 in 8000 people [3,4], and myotonic dystrophy type II or DM2 (OMIM 602668), with an incidence of 1 in 20,000 people [5]
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