Transgenic mouse models for myotonic dystrophy type 1 (DM1)

Dg, Wansink; Wieringa, Bé

doi:10.1159/000072859

Cited by 32 publications

(23 citation statements)

References 129 publications

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“…The myotonic dystrophies (DM1 and DM2) are characterized by nuclear RNA aggregates formed by CUG or CCUG repeat expansions in the 3′ UTR of DMPK and 5′UTR of SIX5 (DM1) and in the first intron of ZNF9 (DM2) (Wansink and Wieringa 2003). CUG-binding protein and muscleblind-like protein 1 can bind these RNA repeats and are involved in alternative splice site selection.…”

Section: Discussionmentioning

confidence: 99%

FRG1P-mediated aggregation of proteins involved in pre-mRNA processing

et al. 2006

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FRG1 is considered a candidate gene for facioscapulohumeral muscular dystrophy (FSHD) based on its location at chromosome 4qter and its upregulation in FSHD muscle. The FRG1 protein (FRG1P) localizes to nucleoli, Cajal bodies (and speckles), and has been suggested to be a component of the human spliceosome but its exact function is unknown. Recently, transgenic mice overexpressing high levels of FRG1P in skeletal muscle were described to present with muscular dystrophy. Moreover, upregulation of FRG1P was demonstrated to correlate with missplicing of specific pre-mRNAs. In this study, we have combined colocalization studies with yeast two-hybrid screens to identify proteins that associate with FRG1P. We demonstrate that artificially induced nucleolar aggregates of VSV-FRG1P specifically sequester proteins involved in pre-mRNA processing. In addition, we have identified SMN, PABPN1, and FAM71B, a novel speckle and Cajal body protein, as binding partners of FRG1P. All these proteins are, or seem to be, involved in RNA biogenesis. Our data confirm the presence of FRG1P in protein complexes containing human spliceosomes and support a potential role of FRG1P in either splicing or another step in nuclear RNA biogenesis. Intriguingly, among FRG1P-associated proteins are SMN and PABPN1, both being involved in neuromuscular disorders, possibly through RNA biogenesis-related processes.

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Section: Discussionmentioning

confidence: 99%

FRG1P-mediated aggregation of proteins involved in pre-mRNA processing

et al. 2006

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“…This would place DM1 into the large category of alternative splicing disorders (reviewed in references 13 and 38). Previously, already strong evidence was provided that a different mechanism, involving titration of RNA processing factors by the abnormal long expanded (CUG) n repeats in the 3Ј-UTR of DMPK mRNA, has transeffects on the processing of other transcripts, like that of the chloride channel, tau protein, and insulin receptor in patients with DM1 (53).…”

Section: Discussionmentioning

confidence: 99%

“…Various studies have shown that expansion of the (CTG) n repeat results in reduced appearance of DMPK in the cytoplasm (53). Studies in knockout mouse and myocyte cell models indicated that lack of DMPK protein may be associated with typical DM1 symptoms like myopathy and heart conduction defects, perhaps via effects on Ca 2ϩ or Na ϩ ion homeostasis (5,6,25,35,42).…”

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confidence: 99%

Alternative Splicing Controls Myotonic Dystrophy Protein Kinase Structure, Enzymatic Activity, and Subcellular Localization

Wansink

Herpen

Coerwinkel-Driessen

et al. 2003

Molecular and Cellular Biology

103

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Transcripts of the myotonic dystrophy protein kinase (DMPK) gene, a member of the Rho kinase family, are subject to cell-type specific alternative splicing. An imbalance in the splice isoform profile of DMPK may play a role in the pathogenesis of DM1, a severe multisystemic disorder. Here, we report how structural subdomains determine biochemical properties and subcellular distribution of DMPK isoforms. A newly developed kinase assay revealed that DMPK is a Lys/Arg-directed kinase. Individual DMPK isoforms displayed comparable transphosphorylation activity and sequence preference for peptide substrates. However, DMPK autophosphorylation and phosphorylation of MYPT1 (as putative in vivo target of DMPK), were dependent on presence of an alternatively spliced VSGGG motif and the nature of the C terminus. In-gel effects of the VSGGG motif on the migration behavior of full-length kinase provide evidence for a model in which this motif mediates 3-D-conformational changes in DMPK isoforms. Finally, different C termini endow DMPK with the ability to bind to either endoplasmic reticulum or mitochondria or to adopt a cytosolic location. Our results suggest that DMPK isoforms have cell-type and location dependent substrate specificities with a role in organellar and cytoarchitectural dynamics.Myotonic dystrophy (DM1) is the most common form of muscular dystrophy in adults (23), caused by amplification of an unstable (CTG) n repeat in the 3Ј untranslated region (3Ј-UTR) of the DM1 protein kinase (DMPK) gene (10,20,29). The severity of the disease is correlated to the length of this repeat expansion, whereas there is an inverse correlation to the age of onset. The favored explanation for the DM1 phenotype is a gain-of-function at the RNA level (reviewed in references 41 and 53), whereby long (CUG) n repeat tracts in DMPK transcripts cause a global perturbation of RNA processing events in the nucleus. Reports of cis-effects on the accumulation of (CUG) n repeat containing DMPK transcripts in the nucleus and trans-effects on alternative splicing of transcripts encoding other muscle or brain proteins support this hypothesis (15,16,30,40,43,45).It is widely accepted, nonetheless, that the highly variable and complex DM1 phenotype is not caused solely by detrimental effects of (CUG) n expansion at the RNA level, but that also direct effects on DMPK gene products and local gene effects are involved in specific disease features. Various studies have shown that expansion of the (CTG) n repeat results in reduced appearance of DMPK in the cytoplasm (53). Studies in knockout mouse and myocyte cell models indicated that lack of DMPK protein may be associated with typical DM1 symptoms like myopathy and heart conduction defects, perhaps via effects on Ca 2ϩ or Na ϩ ion homeostasis (5,6,25,35,42).DMPK is a member of the AGC group of serine/threonine kinases (31) and is most homologous to the p21-activated kinases MRCK (28) and ROCK/rho-kinase/ROK (4). Other mammalian homologues are NDR1 (32), warts/lats (26, 55), and citron kinase (17). DM...

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“…3 In myotonic dystrophy, CUG-containing RNA transcripts are improperly spliced and exported out of the nucleus, affecting the function of both the DM1 gene and other RNA transcripts dependent on CUG-interacting proteins for proper splicing and translation. 7,8 The mechanism of trinucleotide repeat expansion is of considerable interest not only for a general understanding of genome stability but also because the timing and degree of expansion influences disease pathology and timing of disease onset. The repeats can expand during passage from one generation to the next as well as in somatic cells.…”

Section: Abbreviationsmentioning

confidence: 99%

“…9,10 In addition, somatic instability is observed in the affected tissues of the various diseases, for example striatal neurons in HD and muscle cells of DM, and is recapitulated in mouse models. 8,11,12 Somatic instability may be a contributing factor in determining the timing of disease onset.…”

Section: Abbreviationsmentioning

confidence: 99%

Structure-Forming CAG/CTG Repeat Sequences are Sensitive to Breakage in the Absence of Mrc1 Checkpoint Function and S-Phase Checkpoint Signaling: Implications for Trinucleotide Repeat Expansion Diseases

Freudenreich

Lahiri²

2004

Cell Cycle

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Expansion of trinucleotide repeat sequences is the cause of multiple inherited human genetic diseases including Huntington's disease and myotonic dystrophy. CTG and CAG repeats have been shown to form stable secondary structures that can impair Okazaki fragment processing and may impede replication fork progression. We recently showed that mutation of DNA damage checkpoint proteins results in increased chromosome breaks at expanded CAG/CTG repeats and in increased repeat instability (expansions and contractions). 1 Here we report that long CAG~155 tracts are especially sensitive to the absence of Mrc1 (Claspin) checkpoint function, implicating the S-phase checkpoint in maintenance of trinucleotide repeats and other secondary-structure forming sequences. Based on all of our results, we propose a model for the detection of different types of structures by different checkpoint signaling pathways.

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Transgenic mouse models for myotonic dystrophy type 1 (DM1)

Cited by 32 publications

References 129 publications

FRG1P-mediated aggregation of proteins involved in pre-mRNA processing

FRG1P-mediated aggregation of proteins involved in pre-mRNA processing

Alternative Splicing Controls Myotonic Dystrophy Protein Kinase Structure, Enzymatic Activity, and Subcellular Localization

Structure-Forming CAG/CTG Repeat Sequences are Sensitive to Breakage in the Absence of Mrc1 Checkpoint Function and S-Phase Checkpoint Signaling: Implications for Trinucleotide Repeat Expansion Diseases

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