Mechanisms of trinucleotide repeat instability during human development

McMurray, Cynthia T.

doi:10.1038/nrg2828

Cited by 433 publications

(516 citation statements)

References 122 publications

(168 reference statements)

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“…This may lead to abnormal expression levels and/or impair protein function. 8 In other cases, however, the expanded repeat is found in non-coding regions of the mRNA, suggesting that translation into homopolymeric stretches of amino acids may not be required for the pathology. Furthermore, the expanded repeat sequence can be inserted into the non-coding portion of a heterologous transcript and still induce corresponding pathological changes in animal models of FXTAS 9 and spinocerebellar ataxia type 3.…”

Section: Introductionmentioning

confidence: 99%

Drosophila Pur-α binds to trinucleotide-repeat containing cellular RNAs and translocates to the early oocyte

et al. 2012

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Section: Introductionmentioning

confidence: 99%

Drosophila Pur-α binds to trinucleotide-repeat containing cellular RNAs and translocates to the early oocyte

et al. 2012

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“…Somatic instability has been linked to disease onset and progression in both human14 and mouse HD studies,15 and decreasing somatic expansion in HD model mice delays phenotype progression 16. Many of the principles of somatic instability in HD extend to SCAs 1, 10. Somatic instability12, 17, 18 has been attributed to the actions of DNA repair proteins, and as well as the individually associated variants, the GeM‐HD GWAS found significant association between age at motor onset and several DNA repair pathways 6.…”

mentioning

confidence: 99%

DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

Bettencourt

Hensman-Moss

Flower

et al. 2016

Annals of Neurology

197

186

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ObjectiveThe polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome‐wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases.MethodsWe assembled an independent cohort of 1,462 subjects with HD and polyglutamine SCAs, and genotyped single‐nucleotide polymorphisms (SNPs) selected from the most significant hits in the HD study.ResultsIn the analysis of DNA repair genes as a group, we found the most significant association with age at onset when grouping all polyglutamine diseases (HD+SCAs; p = 1.43 × 10–5). In individual SNP analysis, we found significant associations for rs3512 in FAN1 with HD+SCAs (p = 1.52 × 10–5) and all SCAs (p = 2.22 × 10–4) and rs1805323 in PMS2 with HD+SCAs (p = 3.14 × 10–5), all in the same direction as in the HD GWAS.InterpretationWe show that DNA repair genes significantly modify age at onset in HD and SCAs, suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats that can be modulated by genetic manipulation of DNA repair in disease models. This offers novel therapeutic opportunities in multiple diseases. Ann Neurol 2016;79:983–990

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“…While the mechanism that gives rise to CGG repeat expansion in FMR1 is not understood, evidence suggests repair of single-strand breaks in the meiotically arrested oocytes form loops, which may be incorporated into the DNA through mismatch repair resulting in an expansion (4).…”

Section: Introductionmentioning

confidence: 99%

Distribution of AGG interruption patterns within nine world populations

Yrigollen

Sweha

Durbin‐Johnson

et al. 2014

IRDR

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The CGG trinucleotide repeat within the FMR1 gene is associated with multiple clinical disorders, including fragile X-associated tremor/ataxia syndrome, fragile X-associated primary ovarian insufficiency, and fragile X syndrome. Differences in the distribution and prevalence of CGG repeat length and of AGG interruption patterns have been reported among different populations and ethnicities. In this study we characterized the AGG interruption patterns within 3,065 normal CGG repeat alleles from nine world populations including Australia, Chile, United Arab Emirates, Guatemala, Indonesia, Italy, Mexico, Spain, and United States. Additionally, we compared these populations with those previously reported, and summarized the similarities and differences. We observed significant differences in AGG interruption patterns. Frequencies of longer alleles, longer uninterrupted CGG repeat segments and alleles with greater than 2 AGG interruptions varied between cohorts. The prevalence of fragile X syndrome and FMR1 associated disorders in various populations is thought to be affected by the total length of the CGG repeat and may also be influenced by the AGG distribution pattern. Thus, the results of this study may be important in considering the risk of fragile X-related conditions in various populations

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Mechanisms of trinucleotide repeat instability during human development

Cited by 433 publications

References 122 publications

Drosophila Pur-α binds to trinucleotide-repeat containing cellular RNAs and translocates to the early oocyte

Drosophila Pur-α binds to trinucleotide-repeat containing cellular RNAs and translocates to the early oocyte

DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

Distribution of AGG interruption patterns within nine world populations

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