Effect of Triplet Repeat Expansion on Chromatin Structure and Expression of DMPK and Neighboring Genes, SIX5 and DMWD, in Myotonic Dystrophy

Frisch, Richard; Singleton, Kenneth R.; Moses, Priscilla A.; Gonzalez, Iris L.; Carango, Paul; Marks, Harold G.; Funanage, Vicky L.

doi:10.1006/mgme.2001.3229

Cited by 41 publications

(41 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The expansion in DMPK is located in a 3.5-kb CpG island [43] in the gene-rich DM1 locus and leads to epigenetic modifications both upstream and downstream of DMPK . This is important as the CTG-repeat also acts as the downstream promoter of another gene, SIX5 , and can also influence the transcription of yet another gene, DMWD [44]. …”

Section: Introductionmentioning

confidence: 99%

Elevated Global DNA Methylation Is Not Exclusive to Amyotrophic Lateral Sclerosis and Is Also Observed in Spinocerebellar Ataxia Types 1 and 2

et al. 2018

View full text Add to dashboard Cite

Adult-onset neurological disorders are caused and influenced by a multitude of different factors, including epigenetic modifications. Here, using an ELISA kit selected upon careful testing, we investigated global 5-methylcytosine (5-mC) levels in sporadic and familial amyotrophic lateral sclerosis (sALS and fALS), spinocerebellar ataxia types 1 and 2 (SCA1 and SCA2), Huntington’s disease, Friedreich’s ataxia, and myotonic dystrophy type 1. We report a significant elevation in global 5-mC levels of about 2–7% on average for sALS (p < 0.01 [F(1, 243) = 9.159, p = 0.0027]) and various forms of fALS along with SCA1 (p < 0.01 [F(1, 83) = 11.285], p = 0.0012) and SCA2 (p < 0.001 [F(1, 122) = 29.996, p = 0.0001]) when compared to age- and sex-matched healthy controls. C9orf72 expansion carrier ALS patients exhibit the highest global 5-mC levels along with C9orf72 promoter hypermethylation. We failed to measure global 5-hydroxymethylcytosine (5-hmC) levels in blood, probably due to the very low levels of 5-hmC and the limitations of the commercially available ELISA kits. Our results point towards a role for epigenetics modification in ALS, SCA1, and SCA2, and help conclude a dispute on the global 5-mC levels in sALS blood.

show abstract

Section: Introductionmentioning

confidence: 99%

Elevated Global DNA Methylation Is Not Exclusive to Amyotrophic Lateral Sclerosis and Is Also Observed in Spinocerebellar Ataxia Types 1 and 2

et al. 2018

View full text Add to dashboard Cite

show abstract

“…A mouse knockout of MBNL displays several of the characteristic phenotypes of DM1 (17). At the DNA level, CTG repeat expansions affect the transcription of the neighboring genes and this change may also play a role in DM1 pathogenesis (18). However, the primary pathogenic element in DM1 appears to be the long double-stranded r(CUG) repeats that sequester MBNL leading to inappropriate gene expression.…”

mentioning

confidence: 99%

The structural basis of myotonic dystrophy from the crystal structure of CUG repeats

Mooers

Logue

Berglund

2005

Proc. Natl. Acad. Sci. U.S.A.

165

172

View full text Add to dashboard Cite

Myotonic dystrophy (DM) type 1 is associated with an expansion of (>50) CTG repeats within the 3 untranslated region (UTR) of the dystrophin myotonin protein kinase gene (dmpk). In the corresponding mRNA transcript, the CUG repeats form an extended stem-loop structure. The double-stranded RNA of the stem sequesters RNA binding proteins away from their normal cellular targets resulting in aberrant transcription, alternative splicing patterns, or both, thereby leading to DM. To better understand the structural basis of DM type 1, we determined to 1.58-Å resolution the x-ray crystal structure of an 18-bp RNA containing six CUG repeats. The CUG repeats form antiparallel double-stranded helices that stack end-on-end in the crystal to form infinite, pseudocontinuous helices similar to the long CUG stem loops formed by the expanded CUG repeats in DM type 1. The CUG helix is very similar in structure to A-form RNA with the exception of the unique U-U mismatches. This structure provides a high-resolution view of a toxic, trinucleotide repeat RNA.toxic RNA ͉ U-U mismatches ͉ x-ray crystallography M yotonic dystrophy (DM) is the most common form of adult muscular dystrophy, affecting Ϸ1 in 8,000 individuals. There are two types of DM: type 1 (DM1) and type 2 (DM2). Both types are caused by a RNA gain-of-function mechanism (1, 2). DM1 is caused by a CTG repeat expansion within the 3Ј untranslated region (UTR) of the dystrophin myotonin protein kinase (dmpk) gene, whereas DM2 is caused by a CCTG repeat expansion within intron 1 of the Zn finger 9 (znf9) gene (3, 4). In both DM1 and DM2, normal individuals have Ͻ50 repeats, whereas individuals with DM1 and DM2 have hundreds or even thousands of repeats (5). Severity and age of onset of DM are correlated with repeat length. The clinical features of DM1 and DM2 are very similar and include muscle weakness, myotonia, cardiac arrhythmias, insulin resistance, cognitive impairment, and serological changes (6, 7). However, only DM1 has a severe congenital form.Dmpk and znf9 genes are on different chromosomes and encode very different proteins, yet both CUG and CCUG expansions cause DM, suggesting that the loss of function of DMPK and ZnF9 are not the primary causative agent of DM and that the repeat tracts themselves might be toxic. It is clear that the repeats cause DM because this difference is how affected individuals differ from normal individuals. In support of this model, the expression of an RNA containing Ϸ250 CUG repeats in mice causes characteristic features of DM1 (8). The CUG repeats form an extended stem-loop structure with U-U mismatches and G-C Watson-Crick base pairs (9, 10).The clinical features of DM appear to be caused by a ''toxic RNA gain-of-function'' mechanism in which the CUG repeat tracts bind and sequester specific RNA and DNA binding proteins. The CUG binding protein 1 appears to be up-regulated in the presence of extended CUG repeats and this increase might affect alternative splicing of genes relevant to the clinical features of . The muscleblind protein...

show abstract

“…In DM1 patients with large repeats, it has been demonstrated that DMWD expression was lowered, with (CTG) n expansion size being correlated inversely with DMWD expression levels (Hamshere et al, 1997;Alwazzan et al, 1999;Eriksson et al, 1999; but see also Frisch et al, 2001). It is now of utmost importance to define the repeat expansion thresholds that could be involved, and to develop animal models to study the pathogenic effects that a decreased Dmwd level could have.…”

Section: Dm1 Locus Transcripts and Proteinsmentioning

confidence: 99%

“…After the discovery of the (CTG) n repeat in the early nineties, the mere observation that DMPK was central in the DM1 locus and (CTG) n repeat expansion resulted in an alteredaccording to most researchers, decreased -cytoplasmic DMPK level in patients triggered the speculation that the DM1 phenotype was caused by DMPK (haplo)insufficiency (Carango et al, 1993;Fu et al, 1993;Hofmann-Radvanyi et al, 1993;Novelli et al, 1993;Krahe et al, 1995;Hamshere et al, 1997;Eriksson et al, 1999;Eriksson et al, 2001;Frisch et al, 2001; but see also Sabouri et al, 1993;Inukai et al, 2000;Narang et al, 2000). As was discussed above (section (i) DMPK), any decrease in cytoplasmic DMPK level in DM1 patients is presumably due to nuclear retention of DMPK transcripts bearing long (CUG) n repeats.…”

Section: Dmpk Knock-out Micementioning

confidence: 99%

“…Apart from affecting the DMPK transcript level, (CTG) n repeat expansion also lowers expression of the adjacent gene SIX5 (Klesert et al, 1997;Thornton et al, 1997;Korade-Mirnics et al, 1999;Inukai et al, 2000;Frisch et al, 2001; but see also Hamshere et al, 1997;Eriksson et al, 1999). Since the (CTG) n repeat is located outside the SIX5 gene, yet is positioned very close to its enhancer/promoter region and the DNaseI-hypersensitive site, the underlying mechanism for loss of SIX5 transcripts is probably not a transeffect (posttranscriptional), like for DMPK mRNA, but a repression effect in cis.…”

Section: Six5 Knock-out Micementioning

confidence: 99%

See 1 more Smart Citation

Transgenic mouse models for myotonic dystrophy type 1 (DM1)

Dg¹,

Wieringa²

2003

Cytogenet Genome Res

View full text Add to dashboard Cite

The study of animal models for myotonic dystrophy type 1 (DM1) has helped us to ‘de- and reconstruct’ our ideas on how the highly variable multisystemic constellation of disease features can be caused by only one type of event, i.e., the expansion of a perfect (CTG)_n repeat in the DM1 locus on 19q. Evidence is now accumulating that cell type, cell state and species dependent activities of the DNA replication/repair/recombination machinery contribute to the intergenerational and somatic behavior of the (CTG)_n repeat at the DNA level. At the RNA level, a gain-of-function mechanism, with dominant toxic effects of (CUG)_n repeat containing transcripts, probably has a central role in DM1 pathology. Parallel study of DM2, a closely related form of myotonic dystrophy, has revealed a similar mechanism, but also made clear that part of the attention should remain focused on a possible role for candidate loss-of-function genes from the DM1 locus itself (like DMWD, DMPK and SIX5) or elsewhere in the genome, to find explanations for clinical aspects that are unique to DM1. This review will focus on new insight regarding structure-function features of candidate genes involved in DM1 pathobiology, and on the mechanisms of expansion and disease pathology that have now partly been disclosed with the help of transgenic animal models.

show abstract

Effect of Triplet Repeat Expansion on Chromatin Structure and Expression of DMPK and Neighboring Genes, SIX5 and DMWD, in Myotonic Dystrophy

Cited by 41 publications

References 45 publications

Elevated Global DNA Methylation Is Not Exclusive to Amyotrophic Lateral Sclerosis and Is Also Observed in Spinocerebellar Ataxia Types 1 and 2

Elevated Global DNA Methylation Is Not Exclusive to Amyotrophic Lateral Sclerosis and Is Also Observed in Spinocerebellar Ataxia Types 1 and 2

The structural basis of myotonic dystrophy from the crystal structure of CUG repeats

Transgenic mouse models for myotonic dystrophy type 1 (DM1)

Contact Info

Product

Resources

About