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Molecular Effects of the CTG Repeats in Mutant Dystrophia Myotonica Protein Kinase Gene.

ABSTRACT: Myotonic Dystrophy type 1 (DM1) is a multi-system disorder characterized by muscle wasting, myotonia, cardiac conduction defects, cataracts, and neuropsychological dysfunction. DM1 is caused by expansion of a CTG repeat in the 3 untranslated region (UTR) of the Dystrophia Myotonica Protein Kinase (DMPK) gene. A body of work demonstrates that DMPK mRNAs containing abnormally expanded CUG repeats are toxic to several cell types. A core mechanism underlying symptoms of DM1 is that mutant DMPK RNA interferes with the developmentally regulated alternative splicing of defined pre-mRNAs. Expanded CUG repeats fold into ds(CUG) hairpins that sequester nuclear proteins including human Muscleblind-like (MBNL) and hnRNP H alternative splicing factors. DM1 cells activate CELF family member CUG-BP1 protein through hyperphosphorylation and stabilization in the cell nucleus. CUG-BP1 and MBNL1 proteins act antagonistically in exon selection in several pre-mRNA transcripts, thus MBNL1 sequestration and increase in nuclear activity of CUG-BP1 both act synergistically to missplice defined transcripts. Mutant DMPK-mediated effect on subcellular localization, and defective phosphorylation of cytoplasmic CUG-BP1, have additionally been linked to defective translation of p21 and MEF2A in DM1, possibly explaining delayed differentiation of DM1 muscle cells. Mutant DMPK transcripts bind and sequester transcription factors such as Specificity protein 1 leading to reduced transcription of selected genes. Recently, transcripts containing long hairpin structures of CUG repeats have been shown to be a Dicer ribonuclease target and Dicer-induced downregulation of the mutant DMPK transcripts triggers silencing effects on RNAs containing long complementary repeats. In summary, mutant DMPK transcripts alter gene transcription, alternative splicing, and translation of specific gene transcripts, and have the ability to trigger gene-specific silencing effects in DM1 cells. Therapies aimed at reversing these gene expression alterations should prove effective ways to treat DM1.

SUBMITTER: Llamusi B

PROVIDER: S-EPMC2694559 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Molecular Effects of the CTG Repeats in Mutant Dystrophia Myotonica Protein Kinase Gene.

Llamusí Beatriz B Artero Ruben R

Current genomics 20081201 8

Myotonic Dystrophy type 1 (DM1) is a multi-system disorder characterized by muscle wasting, myotonia, cardiac conduction defects, cataracts, and neuropsychological dysfunction. DM1 is caused by expansion of a CTG repeat in the 3 untranslated region (UTR) of the Dystrophia Myotonica Protein Kinase (DMPK) gene. A body of work demonstrates that DMPK mRNAs containing abnormally expanded CUG repeats are toxic to several cell types. A core mechanism underlying symptoms of DM1 is that mutant DMPK RNA i ...[more]

PMID: 19516957

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Project description:Myotonic dystrophy type 1 (DM1) is caused by an unstable CTG repeat expansion in the 3'UTR of the DM protein kinase (DMPK) gene. DMPK transcripts carrying CUG expansions form nuclear foci and affect splicing regulation of various RNA transcripts. Furthermore, bidirectional transcription over the DMPK gene and non-conventional RNA translation of repeated transcripts have been described in DM1. It is clear now that this disease may involve multiple pathogenic pathways including changes in gene expression, RNA stability and splicing regulation, protein translation, and micro-RNA metabolism. We previously generated transgenic mice with 45-kb of the DM1 locus and >300 CTG repeats (DM300 mice). After successive breeding and a high level of CTG repeat instability, we obtained transgenic mice carrying >1,000 CTG (DMSXL mice). Here we described for the first time the expression pattern of the DMPK sense transcripts in DMSXL and human tissues. Interestingly, we also demonstrate that DMPK antisense transcripts are expressed in various DMSXL and human tissues, and that both sense and antisense transcripts accumulate in independent nuclear foci that do not co-localize together. Molecular features of DM1-associated RNA toxicity in DMSXL mice (such as foci accumulation and mild missplicing), were associated with high mortality, growth retardation, and muscle defects (abnormal histopathology, reduced muscle strength, and lower motor performances). We have found that lower levels of IGFBP-3 may contribute to DMSXL growth retardation, while increased proteasome activity may affect muscle function. These data demonstrate that the human DM1 locus carrying very large expansions induced a variety of molecular and physiological defects in transgenic mice, reflecting DM1 to a certain extent. As a result, DMSXL mice provide an animal tool to decipher various aspects of the disease mechanisms. In addition, these mice can be used to test the preclinical impact of systemic therapeutic strategies on molecular and physiological phenotypes.

Dataset Information

Molecular Effects of the CTG Repeats in Mutant Dystrophia Myotonica Protein Kinase Gene.

Publications

Molecular Effects of the CTG Repeats in Mutant Dystrophia Myotonica Protein Kinase Gene.

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