Trinucleotide expansion in disease: why is there a length threshold?

Lee, Do-Yup; McMurray, Cynthia T.

doi:10.1016/j.gde.2014.07.003

Cited by 54 publications

(49 citation statements)

References 64 publications

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“…Trinucleotide repeat disorders are caused by the pathogenic expansion of usually stable polymorphic tandem repeats, with larger pathological repeats generally leading to an earlier age of onset [25]. Often named repeat expansions, they can occur in coding or noncoding regions and are thought to arise from errors in DNA replication, recombination, and mismatch repair mechanisms.…”

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

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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.

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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

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“…Disease-causing repeats can occur in the coding or non-coding regions of RNA transcripts 2 . Intriguingly, in all of the nucleotide repeat expansion disorders identified to date, disease only manifests beyond a critical number of repeats 2,4–6 .…”

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confidence: 99%

RNA phase transitions in repeat expansion disorders

Jain

Vale

2017

Nature

727

846

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Expansions of short nucleotide repeats produce several neurological and neuromuscular disorders including Huntington’s disease, muscular dystrophy and amyotrophic lateral sclerosis. A common pathological feature of these diseases is the accumulation of the repeat containing transcripts into aberrant foci in the nucleus. RNA foci, as well as the disease symptoms, only manifest above a critical number of nucleotide repeats, but the molecular mechanism governing foci formation above this characteristic threshold remains unresolved. Here, we show that repeat expansions create templates for multivalent base-pairing, which causes purified RNA to undergo a sol-gel transition at a similar critical repeat number as observed in the diseases. In cells, RNA foci form by phase separation of the repeat-containing RNA and can be dissolved by agents that disrupt RNA gelation in vitro. Analogous to protein aggregation disorders, our results suggest that the sequence-specific gelation of RNAs could be a contributing factor to neurological disease.

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“…The molecular mechanisms governing CAG repeat instability revolve around the ability of these sequences to fold into non-B-DNA structures when exposed as single-stranded DNA789. These unusual structures are mistaken for damaged DNA whether or not they contain lesions.…”

mentioning

confidence: 99%

Contracting CAG/CTG repeats using the CRISPR-Cas9 nickase

et al. 2016

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CAG/CTG repeat expansions cause over 13 neurological diseases that remain without a cure. Because longer tracts cause more severe phenotypes, contracting them may provide a therapeutic avenue. No currently known agent can specifically generate contractions. Using a GFP-based chromosomal reporter that monitors expansions and contractions in the same cell population, here we find that inducing double-strand breaks within the repeat tract causes instability in both directions. In contrast, the CRISPR-Cas9 D10A nickase induces mainly contractions independently of single-strand break repair. Nickase-induced contractions depend on the DNA damage response kinase ATM, whereas ATR inhibition increases both expansions and contractions in a MSH2- and XPA-dependent manner. We propose that DNA gaps lead to contractions and that the type of DNA damage present within the repeat tract dictates the levels and the direction of CAG repeat instability. Our study paves the way towards deliberate induction of CAG/CTG repeat contractions in vivo.

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Trinucleotide expansion in disease: why is there a length threshold?

Cited by 54 publications

References 64 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

RNA phase transitions in repeat expansion disorders

Contracting CAG/CTG repeats using the CRISPR-Cas9 nickase

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