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

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.

From Mice to Humans: An Overview of the Potentials and Limitations of Current Transgenic Mouse Models of Major Muscular Dystrophies and Congenital Myopathies

“…Atypical splicing of the insulin receptor (IR) may take part in the formation of insulin resistance. The genes mentioned above represent just a few examples of the more than 30 miss regulated splicing identified in DM patient’s tissue samples or of the more than 60 aberrant splicing described in mice tissues [ 102 ].…”

MBNL1 and RBFOX1 co-regulate alternative splicing events transcriptome-wide through a conserved buffering mechanism

“…These repeat RNAs serve as a sink for muscleblind-like (MBNL) proteins; a family of RBPs that regulate fetal to adult AS transitions critical for proper muscle, heart, and central nervous system (CNS) development 12,13 . Reduction of functional MBNL protein levels via this toxic RNA gain-of-function mechanism leads to global perturbations of AS established as causative of a number of DM disease symptoms [14][15][16] .…”

“…These repeat RNAs serve as a sink for muscleblind-like (MBNL) proteins; a family of RBPs that regulate fetal to adult AS transitions critical for proper muscle, heart, and central nervous system (CNS) development 12,13 . Reduction of functional MBNL protein levels via this toxic RNA gain-of-function mechanism leads to global perturbations of AS established as causative of a number of DM disease symptoms [14][15][16] .MBNL proteins have been shown to bind to YGCY cis-regulatory motifs to regulate AS outcomes of target pre-mRNAs in a positional-dependent manner whereby cassette exon inclusion is generally promoted through binding to downstream RNA motifs and repressed through use of upstream intronic elements 17 .Previous studies have indicated that MBNL-dependent AS responds to changes in MBNL concentrations across a broad, dynamic range of expression 18,19 . Using a titratable MBNL1 expression system to characterize the behavior of individual MBNL1-regulated AS events, it was previously reported that different amounts of MBNL are required to achieve half-maximal regulation with variable steepness of the dose-response curves 18 .While several studies have focused on the characterization of MBNL-dependent splicing regulation 13 , less work has been done to identify and characterize the role of other splicing factors that may coordinate with or antagonize MBNL splicing activity with the exception of CELF1 [20][21][22] .…”

The Biomarker Potential of miRNAs in Myotonic Dystrophy Type I

“…These foci can sequester muscleblind-like (MBNL) proteins, which subsequently lead to diminished activity and downstream deregulation of the alternative splicing of several genes [21,22]. In addition, the RNA foci cause hyper-phosphorylation and thus upregulation of the CUG-BP and ETR-3-like factors family member 1 (CELF1) via several signaling kinases [22,23]. CELF1 is also a splice factor, and its inappropriate phosphorylation results in deregulation of downstream target genes.…”