trinucleotide repeat expansion


Summary: An increased number of contiguous trinucleotide repeats in the DNA sequence from one generation to the next. The presence of these regions is associated with diseases such as FRAGILE X SYNDROME and MYOTONIC DYSTROPHY. Some CHROMOSOME FRAGILE SITES are composed of sequences where trinucleotide repeat expansion occurs.

Top Publications

  1. Bañez Coronel M, Porta S, Kagerbauer B, Mateu Huertas E, Pantano L, Ferrer I, et al. A pathogenic mechanism in Huntington's disease involves small CAG-repeated RNAs with neurotoxic activity. PLoS Genet. 2012;8:e1002481 pubmed publisher
    ..The identification of the specific cellular processes affected by sCAGs may provide insights into the pathogenic mechanisms underlying HD, offering opportunities to develop new therapeutic approaches. ..
  2. Rau F, Freyermuth F, Fugier C, Villemin J, Fischer M, Jost B, et al. Misregulation of miR-1 processing is associated with heart defects in myotonic dystrophy. Nat Struct Mol Biol. 2011;18:840-5 pubmed publisher
    ..CACNA1C and GJA1 encode the main calcium- and gap-junction channels in heart, respectively, and we propose that their misregulation may contribute to the cardiac dysfunctions observed in affected persons. ..
  3. Seixas A, Holmes S, Takeshima H, Pavlovich A, Sachs N, Pruitt J, et al. Loss of junctophilin-3 contributes to Huntington disease-like 2 pathogenesis. Ann Neurol. 2012;71:245-57 pubmed publisher
    ..Our results suggest that the pathogenic mechanism of HDL2 is multifactorial, involving both a toxic gain of function of JPH3 RNA and a toxic loss of JPH3 expression. ..
  4. Keryer G, Pineda J, Liot G, Kim J, Dietrich P, Benstaali C, et al. Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease. J Clin Invest. 2011;121:4372-82 pubmed publisher
    ..In HD, hypermorphic ciliogenesis may affect signaling and neuroblast migration so as to dysregulate brain homeostasis and exacerbate disease progression. ..
  5. Krzyzosiak W, Sobczak K, Wojciechowska M, Fiszer A, Mykowska A, Kozlowski P. Triplet repeat RNA structure and its role as pathogenic agent and therapeutic target. Nucleic Acids Res. 2012;40:11-26 pubmed publisher
    ..We describe various concepts and approaches aimed at the selective inhibition of mutant transcript activity in experimental therapies developed for repeat-associated diseases. ..
  6. Morales F, Couto J, Higham C, Hogg G, Cuenca P, Braida C, et al. Somatic instability of the expanded CTG triplet repeat in myotonic dystrophy type 1 is a heritable quantitative trait and modifier of disease severity. Hum Mol Genet. 2012;21:3558-67 pubmed publisher
  7. Panaite P, Kielar M, Kraftsik R, Gourdon G, Kuntzer T, Barakat Walter I. Peripheral neuropathy is linked to a severe form of myotonic dystrophy in transgenic mice. J Neuropathol Exp Neurol. 2011;70:678-85 pubmed publisher
    ..Pathologic alterations in the structure of hind limb neuromuscular junctions were also detected in the DMSXL mice. These results suggest that peripheral neuropathy can be linked to a large CTG expansion and a severe form of DM1. ..
  8. Yildirim I, Park H, Disney M, Schatz G. A dynamic structural model of expanded RNA CAG repeats: a refined X-ray structure and computational investigations using molecular dynamics and umbrella sampling simulations. J Am Chem Soc. 2013;135:3528-38 pubmed publisher
    ..These results are important to understand RNA dynamic-function relationships and to develop small molecules that target RNA dynamic ensembles. ..
  9. Tomé S, Panigrahi G, López Castel A, Foiry L, Melton D, Gourdon G, et al. Maternal germline-specific effect of DNA ligase I on CTG/CAG instability. Hum Mol Genet. 2011;20:2131-43 pubmed publisher
    ..Thus, unlike other DNA metabolizing enzymes studied to date, LigI has a highly specific role in CTG repeat maintenance in the maternal germline, involved in mediating CTG expansions and in the avoidance of maternal CTG contractions. ..

More Information


  1. Lee T, Li Y, Ingre C, Weber M, Grehl T, Gredal O, et al. Ataxin-2 intermediate-length polyglutamine expansions in European ALS patients. Hum Mol Genet. 2011;20:1697-700 pubmed publisher
    ..Our findings support the hypothesis that ataxin 2 plays an important role in predisposing to ALS and that polyQ expansions in ataxin 2 are a significant risk factor for the disease. ..
  2. de Mezer M, Wojciechowska M, Napierala M, Sobczak K, Krzyzosiak W. Mutant CAG repeats of Huntingtin transcript fold into hairpins, form nuclear foci and are targets for RNA interference. Nucleic Acids Res. 2011;39:3852-63 pubmed publisher
  3. Du J, Campau E, Soragni E, Ku S, Puckett J, Dervan P, et al. Role of mismatch repair enzymes in GAA·TTC triplet-repeat expansion in Friedreich ataxia induced pluripotent stem cells. J Biol Chem. 2012;287:29861-72 pubmed publisher
    ..These studies suggest that in FRDA, GAA·TTC triplet-repeat instability occurs in embryonic cells and involves the highly active mismatch repair system...
  4. Møllersen L, Rowe A, Larsen E, Rognes T, Klungland A. Continuous and periodic expansion of CAG repeats in Huntington's disease R6/1 mice. PLoS Genet. 2010;6:e1001242 pubmed publisher
    ..Expansion profiles displaying this kind of periodicity in the expansion process have not previously been reported. These in vivo findings imply that mechanistically distinct expansion processes occur in different tissues. ..
  5. Hubert L, Lin Y, Dion V, Wilson J. Xpa deficiency reduces CAG trinucleotide repeat instability in neuronal tissues in a mouse model of SCA1. Hum Mol Genet. 2011;20:4822-30 pubmed publisher
    ..These results validate our original findings in cultured human cells and suggest that transcription may induce NER-dependent TNR instability in neuronal tissues in humans. ..
  6. Liu J, Verma P, Evans Galea M, Delatycki M, Michalska A, Leung J, et al. Generation of induced pluripotent stem cell lines from Friedreich ataxia patients. Stem Cell Rev. 2011;7:703-13 pubmed publisher
    ..As such, iPS cell lines derived from FRDA patients, following correction of the mutated gene, could provide a useful source of immunocompatible cells for transplantation therapy...
  7. Hsu R, Hsiao K, Lin M, Li C, Wang L, Chen L, et al. Long tract of untranslated CAG repeats is deleterious in transgenic mice. PLoS ONE. 2011;6:e16417 pubmed publisher
    ..These data support the notion that expanded CAG repeat RNA can cause deleterious effects in mammals. They also suggest the possible involvement of an RNA mechanism in human diseases with long CAG repeats. ..
  8. Chan W, Tsoi H, Wu C, Wong C, Cheng T, Li H, et al. Expanded polyglutamine domain possesses nuclear export activity which modulates subcellular localization and toxicity of polyQ disease protein via exportin-1. Hum Mol Genet. 2011;20:1738-50 pubmed publisher
    ..polyQ) diseases are a group of late-onset, progressive neurodegenerative disorders caused by CAG trinucleotide repeat expansion in the coding region of disease genes...
  9. Lawlor K, O Keefe L, Samaraweera S, van Eyk C, McLeod C, Maloney C, et al. Double-stranded RNA is pathogenic in Drosophila models of expanded repeat neurodegenerative diseases. Hum Mol Genet. 2011;20:3757-68 pubmed publisher
    ..These data identify a novel pathway through which double-stranded repeat RNA is toxic and capable of eliciting symptoms common to neurodegenerative human diseases resulting from dominantly inherited expanded repeats. ..
  10. Wojciechowska M, Krzyzosiak W. CAG repeat RNA as an auxiliary toxic agent in polyglutamine disorders. RNA Biol. 2011;8:565-71 pubmed publisher
  11. Lai Y, Xu M, Zhang Z, Liu Y. Instability of CTG repeats is governed by the position of a DNA base lesion through base excision repair. PLoS ONE. 2013;8:e56960 pubmed publisher
    ..Our study indicates that the position of a DNA base lesion governs whether TNR is expanded or deleted through BER. ..
  12. Groh W, Groh M, Shen C, Monckton D, Bodkin C, Pascuzzi R. Survival and CTG repeat expansion in adults with myotonic dystrophy type 1. Muscle Nerve. 2011;43:648-51 pubmed publisher
    ..There was an inverse relationship between all-cause survival and CTG length (relative risk 5.4 per log repeat, 95% confidence interval 2.9-10.2, P < 0.001). The data demonstrate a genotype-mortality association in DM1. ..
  13. Lahue R, Frizzell A. Histone deacetylase complexes as caretakers of genome stability. Epigenetics. 2012;7:806-10 pubmed publisher
    ..These new findings highlight certain HDACs as caretakers of genome stability, and also underscore the potential medical complexities in using HDAC inhibitors for treatment of disease. ..
  14. Palomaki G, Richards C. Assessing the analytic validity of molecular testing for Huntington disease using data from an external proficiency testing survey. Genet Med. 2012;14:69-75 pubmed publisher
    ..Analytic validity is high for Huntington disease testing among US laboratories. International survey participants had lower analytic validity and a higher proportion of poorly performing laboratories. The reasons for this are unclear. ..
  15. Nalavade R, Griesche N, Ryan D, Hildebrand S, Krauss S. Mechanisms of RNA-induced toxicity in CAG repeat disorders. Cell Death Dis. 2013;4:e752 pubmed publisher
    ..In addition, therapeutic approaches for CAG repeat disorders are discussed. Together, all the findings summarized here show that mutant mRNA has a fundamental role in the pathogenesis of CAG repeat diseases. ..
  16. Carroll J, Warby S, Southwell A, Doty C, Greenlee S, Skotte N, et al. Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the Huntington disease gene / allele-specific silencing of mutant huntingtin. Mol Ther. 2011;19:2178-85 pubmed publisher
    ..We demonstrate that potent and selective allele-specific knockdown of the mHTT protein can be achieved at therapeutically relevant SNP sites using ASOs in vitro and in vivo. ..
  17. Yrigollen C, Durbin Johnson B, Gane L, Nelson D, Hagerman R, Hagerman P, et al. AGG interruptions within the maternal FMR1 gene reduce the risk of offspring with fragile X syndrome. Genet Med. 2012;14:729-36 pubmed publisher
    ..2 AGG) exceeding 60% for alleles in the 70- to 80-CGG repeat range. ..
  18. Yu Z, Zhu Y, Chen Plotkin A, Clay Falcone D, McCluskey L, Elman L, et al. PolyQ repeat expansions in ATXN2 associated with ALS are CAA interrupted repeats. PLoS ONE. 2011;6:e17951 pubmed publisher
  19. Liu Y, Wilson S. DNA base excision repair: a mechanism of trinucleotide repeat expansion. Trends Biochem Sci. 2012;37:162-72 pubmed publisher
  20. Martelli A, Napierala M, Puccio H. Understanding the genetic and molecular pathogenesis of Friedreich's ataxia through animal and cellular models. Dis Model Mech. 2012;5:165-76 pubmed publisher
    ..This review provides an update on the understanding of frataxin function, developments of animal and cellular models of the disease, and recent advances in trying to uncover potential molecules for therapy. ..
  21. Wilburn B, Rudnicki D, Zhao J, Weitz T, Cheng Y, Gu X, et al. An antisense CAG repeat transcript at JPH3 locus mediates expanded polyglutamine protein toxicity in Huntington's disease-like 2 mice. Neuron. 2011;70:427-40 pubmed publisher
    ..These results suggest overlapping polyQ-mediated pathogenic mechanisms in HD and HDL2...
  22. Qurashi A, Liu H, Ray L, Nelson D, Duan R, Jin P. Chemical screen reveals small molecules suppressing fragile X premutation rCGG repeat-mediated neurodegeneration in Drosophila. Hum Mol Genet. 2012;21:2068-75 pubmed publisher
    ..Our results demonstrate the utility of Drosophila models for unbiased small molecule screens and point to PLA(2) as a possible therapeutic target to treat FXTAS. ..
  23. Jarem D, Wilson N, Schermerhorn K, Delaney S. Incidence and persistence of 8-oxo-7,8-dihydroguanine within a hairpin intermediate exacerbates a toxic oxidation cycle associated with trinucleotide repeat expansion. DNA Repair (Amst). 2011;10:887-96 pubmed publisher
    ..This damage-containing hairpin can then be incorporated into duplex, resulting in an expanded TNR tract that now contains an oxidative lesion. Thus, the cycle restarts and the DNA can incrementally expand. ..
  24. Loomis E, Eid J, Peluso P, Yin J, Hickey L, Rank D, et al. Sequencing the unsequenceable: expanded CGG-repeat alleles of the fragile X gene. Genome Res. 2013;23:121-8 pubmed publisher
    ..These observations provide a baseline for future kinetic studies of repeat elements, as well as for studies of epigenetic and other chemical modifications thereof. ..
  25. Kovtun I, Johnson K, McMurray C. Cockayne syndrome B protein antagonizes OGG1 in modulating CAG repeat length in vivo. Aging (Albany NY). 2011;3:509-14 pubmed
    ..These results raise a possibility that actions of transcription-coupled and base excision repair pathways lead to different outcomes at CAG tracts in vivo. ..
  26. Mootha V, Gong X, Ku H, Xing C. Association and familial segregation of CTG18.1 trinucleotide repeat expansion of TCF4 gene in Fuchs' endothelial corneal dystrophy. Invest Ophthalmol Vis Sci. 2014;55:33-42 pubmed publisher
    ..1 allele conferring significant risk for FECD (>30-fold increase). The expanded allele cosegregates with the trait with complete penetrance in a majority of families, but we also document cases of incomplete penetrance. ..
  27. Lee J, Bennett C, Cooper T. RNase H-mediated degradation of toxic RNA in myotonic dystrophy type 1. Proc Natl Acad Sci U S A. 2012;109:4221-6 pubmed publisher
    ..Additional optimization will be required for systemic delivery; however, our study provides an alternative strategy for the use of ASOs in DM1 therapy...
  28. Bayot A, Reichman S, Lebon S, Csaba Z, Aubry L, Sterkers G, et al. Cis-silencing of PIP5K1B evidenced in Friedreich's ataxia patient cells results in cytoskeleton anomalies. Hum Mol Genet. 2013;22:2894-904 pubmed publisher
    ..In addition to provide new insights into the consequences of the FXN gene expansion, these findings raise the question whether PIP5K1B silencing may contribute to the variable manifestation of this complex disease. ..
  29. Tsoi H, Chan H. Expression of expanded CAG transcripts triggers nucleolar stress in Huntington's disease. Cerebellum. 2013;12:310-2 pubmed publisher
  30. Tsoi H, Lau T, Tsang S, Lau K, Chan H. CAG expansion induces nucleolar stress in polyglutamine diseases. Proc Natl Acad Sci U S A. 2012;109:13428-33 pubmed publisher
    ..Our work provides in vivo evidence that expanded CAG RNAs trigger nucleolar stress and induce apoptosis via p53 and describes a polyQ pathogenic mechanism that involves the nucleolus...
  31. Furrer S, Waldherr S, Mohanachandran M, Baughn T, Nguyen K, Sopher B, et al. Reduction of mutant ataxin-7 expression restores motor function and prevents cerebellar synaptic reorganization in a conditional mouse model of SCA7. Hum Mol Genet. 2013;22:890-903 pubmed publisher
  32. Ku S, Soragni E, Campau E, Thomas E, Altun G, Laurent L, et al. Friedreich's ataxia induced pluripotent stem cells model intergenerational GAA?TTC triplet repeat instability. Cell Stem Cell. 2010;7:631-7 pubmed publisher
  33. Stochmanski S, Therrien M, Laganiere J, Rochefort D, Laurent S, Karemera L, et al. Expanded ATXN3 frameshifting events are toxic in Drosophila and mammalian neuron models. Hum Mol Genet. 2012;21:2211-8 pubmed publisher
    ..Hence, we propose that -1 ribosomal frameshifting contributes to the toxicity associated with (exp)CAG repeats. ..
  34. Gagnon K, Pendergraff H, Deleavey G, Swayze E, Potier P, Randolph J, et al. Allele-selective inhibition of mutant huntingtin expression with antisense oligonucleotides targeting the expanded CAG repeat. Biochemistry. 2010;49:10166-78 pubmed publisher
    ..ASOs targeted to the CAG repeat of HTT provide a starting point for the development of oligonucleotide-based therapeutics that can inhibit gene expression with allelic discrimination in patients with HD. ..
  35. Kumar R, Atamna H, Zakharov M, Bhasin S, Khan S, Jasuja R. Role of the androgen receptor CAG repeat polymorphism in prostate cancer, and spinal and bulbar muscular atrophy. Life Sci. 2011;88:565-71 pubmed publisher
  36. Querido E, Gallardo F, Beaudoin M, Ménard C, Chartrand P. Stochastic and reversible aggregation of mRNA with expanded CUG-triplet repeats. J Cell Sci. 2011;124:1703-14 pubmed publisher
    ..Our data reveal that nuclear CUG-repeat RNA aggregates are labile, constantly forming and disaggregating structures, and that the Mbnl1 splicing factor is directly involved in the aggregation process. ..
  37. Nolin S, Glicksman A, Ding X, Ersalesi N, Brown W, Sherman S, et al. Fragile X analysis of 1112 prenatal samples from 1991 to 2010. Prenat Diagn. 2011;31:925-31 pubmed publisher
    ..Thus, lower risk estimates for full mutation expansion may be appropriate for women newly identified as premutation carriers through routine screening. ..
  38. Kelly M, Bagnall R, Peverill R, Donelan L, Corben L, Delatycki M, et al. A polymorphic miR-155 binding site in AGTR1 is associated with cardiac hypertrophy in Friedreich ataxia. J Mol Cell Cardiol. 2011;51:848-54 pubmed publisher
    ..The AGTR1 polymorphism rs5186 appears to modify the FRDA cardiac phenotype independently of GAA1. This study supports the role of RAAS polymorphisms as modifiers of cardiac phenotype in FRDA patients. ..
  39. Schuring A, Welp A, Gromoll J, Zitzmann M, Sonntag B, Nieschlag E, et al. Role of the CAG repeat polymorphism of the androgen receptor gene in polycystic ovary syndrome (PCOS). Exp Clin Endocrinol Diabetes. 2012;120:73-9 pubmed publisher
    ..We investigated the role of the CAG repeat polymorphism of the androgen receptor in PCOS...
  40. Ezzatizadeh V, Pinto R, Sandi C, Sandi M, Al Mahdawi S, te Riele H, et al. The mismatch repair system protects against intergenerational GAA repeat instability in a Friedreich ataxia mouse model. Neurobiol Dis. 2012;46:165-71 pubmed publisher
    ..These findings reveal substantial differences in the intergenerational dynamics of expanded GAA repeat sequences compared with expanded CAG/CTG repeats, where Msh2 and Msh3 are thought to actively promote repeat expansions. ..
  41. Debacker K, Frizzell A, Gleeson O, Kirkham McCarthy L, Mertz T, Lahue R. Histone deacetylase complexes promote trinucleotide repeat expansions. PLoS Biol. 2012;10:e1001257 pubmed publisher
    ..This relationship further implies that HDAC3 inhibitors being tested for relief of expansion-associated gene silencing may also suppress somatic expansions that contribute to disease progression. ..
  42. Shieh S, Bonini N. Genes and pathways affected by CAG-repeat RNA-based toxicity in Drosophila. Hum Mol Genet. 2011;20:4810-21 pubmed publisher
    ..These findings suggest an overlap in the mechanisms of RNA and protein-based toxicity, providing insights into the pathogenicity of the RNA in polyQ disease. ..
  43. Sicot G, Gourdon G, Gomes Pereira M. Myotonic dystrophy, when simple repeats reveal complex pathogenic entities: new findings and future challenges. Hum Mol Genet. 2011;20:R116-23 pubmed publisher
    ..This review describes some of the recent advances in the understanding of the molecular mechanisms behind DM and other RNA-dominant disorders. ..
  44. Suenaga K, Lee K, Nakamori M, Tatsumi Y, Takahashi M, Fujimura H, et al. Muscleblind-like 1 knockout mice reveal novel splicing defects in the myotonic dystrophy brain. PLoS ONE. 2012;7:e33218 pubmed publisher
    Myotonic dystrophy type 1 (DM1) is a multi-systemic disorder caused by a CTG trinucleotide repeat expansion (CTG(exp)) in the DMPK gene...
  45. Nagashima Y, Kowa H, Tsuji S, Iwata A. FAT10 protein binds to polyglutamine proteins and modulates their solubility. J Biol Chem. 2011;286:29594-600 pubmed publisher
    ..These findings were similar to those for huntingtin. Our new finding will provide a new role for FAT10 in the pathogenesis of polyglutamine diseases. ..
  46. Kim E, Napierala M, Dent S. Hyperexpansion of GAA repeats affects post-initiation steps of FXN transcription in Friedreich's ataxia. Nucleic Acids Res. 2011;39:8366-77 pubmed publisher
  47. Lu C, Lin L, Tan H, Wu H, Sherman S, Gao F, et al. Fragile X premutation RNA is sufficient to cause primary ovarian insufficiency in mice. Hum Mol Genet. 2012;21:5039-47 pubmed publisher
    ..These results together suggest that FMR1 premutation RNA could cause the POI associated with FMR1 premutation carriers, and the Akt/mTOR pathway may serve as a therapeutic target for FXPOI...
  48. Wieben E, Aleff R, Tosakulwong N, Butz M, Highsmith W, Edwards A, et al. A common trinucleotide repeat expansion within the transcription factor 4 (TCF4, E2-2) gene predicts Fuchs corneal dystrophy. PLoS ONE. 2012;7:e49083 pubmed publisher
    ..The TGC trinucleotide repeat expansion in TCF4 is strongly associated with FECD, and a repeat length >50 is highly specific for the ..
  49. Van Damme P, Veldink J, van Blitterswijk M, Corveleyn A, van Vught P, Thijs V, et al. Expanded ATXN2 CAG repeat size in ALS identifies genetic overlap between ALS and SCA2. Neurology. 2011;76:2066-72 pubmed publisher
    ..Intermediate CAG repeat expansions in ataxin 2 (ATXN2), the causative gene of spinocerebellar ataxia type 2 (SCA2), have been implicated in sporadic ALS. We studied ATXN2 in a large cohort of patients with sporadic and familial ALS...
  50. Corrado L, Mazzini L, Oggioni G, Luciano B, Godi M, Brusco A, et al. ATXN-2 CAG repeat expansions are interrupted in ALS patients. Hum Genet. 2011;130:575-80 pubmed publisher
    ..In conclusion, the findings of ATXN-2 expansions in pure ALS cases suggest that ALS may be a third phenotype (alongside ataxia/parkinsonism and pure Parkinson) associated with ATXN-2 interrupted alleles. ..
  51. Moyer M, Berger D, Ladd A, van Lunteren E. Differential susceptibility of muscles to myotonia and force impairment in a mouse model of myotonic dystrophy. Muscle Nerve. 2011;43:818-27 pubmed publisher
    ..In an expanded repeats model of DM the EDL is more susceptible to myotonia and force impairment than muscles with lower proportions of fast-twitch fibers. ..
  52. Lee J, Ramos E, Lee J, Gillis T, Mysore J, Hayden M, et al. CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. Neurology. 2012;78:690-5 pubmed publisher
  53. López Castel A, Nakamori M, Tomé S, Chitayat D, Gourdon G, Thornton C, et al. Expanded CTG repeat demarcates a boundary for abnormal CpG methylation in myotonic dystrophy patient tissues. Hum Mol Genet. 2011;20:1-15 pubmed publisher
    ..Thus, in humans, the CpG-free expanded CTG repeat appears to maintain a highly polarized pattern of CpG methylation at the DM1 locus, which varies markedly with age and tissues. ..