A Brief History of Triplet Repeat Diseases

  • Helen Budworth
  • Cynthia T. McMurray
Part of the Methods in Molecular Biology book series (MIMB, volume 1010)


Instability of repetitive DNA sequences within the genome is associated with a number of human diseases. The expansion of trinucleotide repeats is recognized as a major cause of neurological and neuromuscular diseases, and progress in understanding the mutations over the last 20 years has been substantial. Here we provide a brief summary of progress with an emphasis on technical advances at different stages.

Key words

Trinucleotide repeat Genomic instability Triplet repeat expansion Huntington’s disease Fragile X syndrome Myotonic dystrophy Spinocerebellar ataxia Neurodegeneration 



I would like to thank Christie A. Canaria, Virginia Platt (NIH/NIA T32-AG00266), Do Yup Lee, Nelson Chan, Ella Xun, James Lim, and support from the National Institutes of Health Grants NS069177, NS40738, NS062384, and NS060115.


  1. 1.
    Hegde MV, Saraph AA (2011) Unstable genes unstable mind: beyond the central dogma of molecular biology. Med Hypotheses 77:165–170PubMedCrossRefGoogle Scholar
  2. 2.
    McMurray CT (2010) Mechanisms of trinucleotide repeat instability during human development. Nat Rev Genet 11:786–799PubMedCrossRefGoogle Scholar
  3. 3.
    La Spada AR, Taylor JP (2010) Repeat expansion disease: progress and puzzles in disease pathogenesis. Nat Rev Genet 11:247–258PubMedCrossRefGoogle Scholar
  4. 4.
    Toth G, Gaspari Z, Jurka J (2000) Microsatellites in different eukaryotic genomes: survey and analysis. Genome Res 10:967–981PubMedCrossRefGoogle Scholar
  5. 5.
    Jurka J, Pethiyagoda C (1995) Simple repetitive DNA sequences from primates: compilation and analysis. J Mol Evol 40:120–126PubMedCrossRefGoogle Scholar
  6. 6.
    Beckman JS, Weber JL (1992) Survey of human and rat microsatellites. Genomics 12:627–631PubMedCrossRefGoogle Scholar
  7. 7.
    Jeffreys AJ, Holloway JK, Kauppi L et al (2004) Meiotic recombination hot spots and human DNA diversity. Philos Trans R Soc Lond B Biol Sci 359:141–152PubMedCrossRefGoogle Scholar
  8. 8.
    Kashi Y, King DG (2006) Simple sequence repeats as advantageous mutators in evolution. Trends Genet 22:253–259PubMedCrossRefGoogle Scholar
  9. 9.
    Strachan T, Read AP (1999) Human molecular genetics, vol 2. Wiley-Liss, New YorkGoogle Scholar
  10. 10.
    Djian P, Hancock JM, Chana HS (1996) Codon repeats in genes associated with human diseases: fewer repeats in the genes of nonhuman primates and nucleotide substitutions concentrated at the sites of reiteration. Proc Natl Acad Sci U S A 93:417–421PubMedCrossRefGoogle Scholar
  11. 11.
    Yant SR, Wu X, Huang Y et al (2005) High-resolution genome-wide mapping of transposon integration in mammals. Mol Cell Biol 25:2085–2094PubMedCrossRefGoogle Scholar
  12. 12.
    Kohwi Y (2004) Trinucleotide repeat protocols, vol 277, Methods in molecular biology. Humana, Totowa, NJCrossRefGoogle Scholar
  13. 13.
    Friedman JE (2011) Anticipation in hereditary disease: the history of a biomedical concept. Hum Genet 130:705–714PubMedCrossRefGoogle Scholar
  14. 14.
    Maltecca F, Filla A, Castaldo I et al (2003) Intergenerational instability and marked anticipation in SCA-17. Neurology 61:1441–1443PubMedCrossRefGoogle Scholar
  15. 15.
    Verkerk AJ, Pieretti M, Sutcliffe JS et al (1991) Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65:905–914PubMedCrossRefGoogle Scholar
  16. 16.
    La Spada AR, Wilson EM, Lubahn DB et al (1991) Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352:77–79PubMedCrossRefGoogle Scholar
  17. 17.
    Mahadevan M, Tsilfidis C, Sabourin L et al (1992) Myotonic dystrophy mutation: an unstable CTG repeat in the 3′ untranslated region of the gene. Science 255:1253–1255PubMedCrossRefGoogle Scholar
  18. 18.
    The Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983CrossRefGoogle Scholar
  19. 19.
    Duyao M, Ambrose C, Myers R et al (1993) Trinucleotide repeat length instability and age of onset in Huntington’s disease. Nat Genet 4:387–392PubMedCrossRefGoogle Scholar
  20. 20.
    Andresen JM, Gayan J, Djousse L et al (2007) The relationship between CAG repeat length and age of onset differs for Huntington’s disease patients with juvenile onset or adult onset. Ann Hum Genet 71:295–301PubMedCrossRefGoogle Scholar
  21. 21.
    Filla A, De Michele G, Cavalcanti F et al (1996) The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia. Am J Hum Genet 59:554–560PubMedGoogle Scholar
  22. 22.
    Bovo D, Rugge M, Shiao YH (1999) Origin of spurious multiple bands in the amplification of microsatellite sequences. Mol Pathol 52:50–51PubMedCrossRefGoogle Scholar
  23. 23.
    Leeflang EP, Zhang L, Tavare S et al (1995) Single sperm analysis of the trinucleotide repeats in the Huntington’s disease gene: quantification of the mutation frequency spectrum. Hum Mol Genet 4:1519–1526PubMedCrossRefGoogle Scholar
  24. 24.
    Monckton DG, Wong LJ, Ashizawa T et al (1995) Somatic mosaicism, germline expansions, germline reversions and intergenerational reductions in myotonic dystrophy males: small pool PCR analyses. Hum Mol Genet 4:1–8PubMedCrossRefGoogle Scholar
  25. 25.
    Gayan J, Brocklebank D, Andresen JM et al (2008) Genomewide linkage scan reveals novel loci modifying age of onset of Huntington’s disease in the Venezuelan HD kindreds. Genet Epidemiol 32:445–453PubMedCrossRefGoogle Scholar
  26. 26.
    Arning L, Monte D, Hansen W et al (2008) ASK1 and MAP2K6 as modifiers of age at onset in Huntington’s disease. J Mol Med (Berl) 86:485–490CrossRefGoogle Scholar
  27. 27.
    Djousse L, Knowlton B, Hayden MR et al (2004) Evidence for a modifier of onset age in Huntington disease linked to the HD gene in 4p16. Neurogenetics 5:109–114PubMedCrossRefGoogle Scholar
  28. 28.
    Lee JM, Gillis T, Mysore JS et al (2012) Common SNP-based haplotype analysis of the 4p16.3 Huntington disease gene region. Am J Hum Genet 90:434–444PubMedCrossRefGoogle Scholar
  29. 29.
    Li JL, Hayden MR, Warby SC et al (2006) Genome-wide significance for a modifier of age at neurological onset in Huntington’s disease at 6q23-24: the HD MAPS study. BMC Med Genet 7:71PubMedCrossRefGoogle Scholar
  30. 30.
    Veitch NJ, Ennis M, McAbney JP et al (2007) Inherited CAG.CTG allele length is a major modifier of somatic mutation length variability in Huntington disease. DNA Repair (Amst) 6:789–796CrossRefGoogle Scholar
  31. 31.
    Lee JM, Ramos EM, Lee JH et al (2012) CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. Neurology 78:690–695PubMedCrossRefGoogle Scholar
  32. 32.
    Shelbourne PF, Keller-McGandy C, Bi WL et al (2007) Triplet repeat mutation length gains correlate with cell-type specific vulnerability in Huntington disease brain. Hum Mol Genet 16:1133–1142PubMedCrossRefGoogle Scholar
  33. 33.
    De Rooij KE, De Koning Gans PA, Roos RA et al (1995) Somatic expansion of the (CAG)n repeat in Huntington disease brains. Hum Genet 95:270–274PubMedCrossRefGoogle Scholar
  34. 34.
    Telenius H, Kremer B, Goldberg YP et al (1994) Somatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm. Nat Genet 6:409–414PubMedCrossRefGoogle Scholar
  35. 35.
    Nolin SL, Ding XH, Houck GE et al (2008) Fragile X full mutation alleles composed of few alleles: implications for CGG repeat expansion. Am J Med Genet A 146A:60–65PubMedCrossRefGoogle Scholar
  36. 36.
    Koefoed P, Hasholt L, Fenger K et al (1998) Mitotic and meiotic instability of the CAG trinucleotide repeat in spinocerebellar ataxia type 1. Hum Genet 103:564–569PubMedCrossRefGoogle Scholar
  37. 37.
    Goellner GM, Tester D, Thibodeau S et al (1997) Different mechanisms underlie DNA instability in Huntington disease and colorectal cancer. Am J Hum Genet 60:879–890PubMedGoogle Scholar
  38. 38.
    Norremolle A, Sorensen SA, Fenger K et al (1995) Correlation between magnitude of CAG repeat length alterations and length of the paternal repeat in paternally inherited Huntington’s disease. Clin Genet 47:113–117PubMedCrossRefGoogle Scholar
  39. 39.
    Martorell L, Gamez J, Cayuela ML et al (2004) Germline mutational dynamics in myotonic dystrophy type 1 males: allele length and age effects. Neurology 62:269–274PubMedCrossRefGoogle Scholar
  40. 40.
    Qin M, Entezam A, Usdin K et al (2011) A mouse model of the fragile X premutation: effects on behavior, dendrite morphology, and regional rates of cerebral protein synthesis. Neurobiol Dis 42:85–98PubMedCrossRefGoogle Scholar
  41. 41.
    Entezam A, Biacsi R, Orrison B et al (2007) Regional FMRP deficits and large repeat expansions into the full mutation range in a new Fragile X premutation mouse model. Gene 395:125–134PubMedCrossRefGoogle Scholar
  42. 42.
    Savouret C, Brisson E, Essers J et al (2003) CTG repeat instability and size variation timing in DNA repair-deficient mice. EMBO J 22:2264–2273PubMedCrossRefGoogle Scholar
  43. 43.
    Fortune MT, Vassilopoulos C, Coolbaugh MI et al (2000) Dramatic, expansion-biased, age-dependent, tissue-specific somatic mosaicism in a transgenic mouse model of triplet repeat instability. Hum Mol Genet 9:439–445PubMedCrossRefGoogle Scholar
  44. 44.
    Sato T, Oyake M, Nakamura K et al (1999) Transgenic mice harboring a full-length human mutant DRPLA gene exhibit age-dependent intergenerational and somatic instabilities of CAG repeats comparable with those in DRPLA patients. Hum Mol Genet 8:99–106PubMedCrossRefGoogle Scholar
  45. 45.
    Kennedy L, Shelbourne PF (2000) Dramatic mutation instability in HD mouse striatum: does polyglutamine load contribute to cell-specific vulnerability in Huntington’s disease? Hum Mol Genet 9:2539–2544PubMedCrossRefGoogle Scholar
  46. 46.
    Kaytor MD, Burright EN, Duvick LA et al (1997) Increased trinucleotide repeat instability with advanced maternal age. Hum Mol Genet 6:2135–2139PubMedCrossRefGoogle Scholar
  47. 47.
    Kennedy L, Evans E, Chen CM et al (2003) Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis. Hum Mol Genet 12:3359–3367PubMedCrossRefGoogle Scholar
  48. 48.
    Swami M, Hendricks AE, Gillis T et al (2009) Somatic expansion of the Huntington’s disease CAG repeat in the brain is associated with an earlier age of disease onset. Hum Mol Genet 18:3039–3047PubMedCrossRefGoogle Scholar
  49. 49.
    Dion V, Wilson JH (2009) Instability and chromatin structure of expanded trinucleotide repeats. Trends Genet 25:288–297PubMedCrossRefGoogle Scholar
  50. 50.
    Libby RT, Hagerman KA, Pineda VV et al (2008) CTCF cis-regulates trinucleotide repeat instability in an epigenetic manner: a novel basis for mutational hot spot determination. PLoS Genet 4:e1000257PubMedCrossRefGoogle Scholar
  51. 51.
    Fry M, Loeb LA (1994) The fragile X syndrome d(CGG)n nucleotide repeats form a stable tetrahelical structure. Proc Natl Acad Sci U S A 91:4950–4954PubMedCrossRefGoogle Scholar
  52. 52.
    Pearson CE, Tam M, Wang YH et al (2002) Slipped-strand DNAs formed by long (CAG)*(CTG) repeats: slipped-out repeats and slip-out junctions. Nucleic Acids Res 30:4534–4547PubMedCrossRefGoogle Scholar
  53. 53.
    Pearson CE, Wang YH, Griffith JD et al (1998) Structural analysis of slipped-strand DNA (S-DNA) formed in (CTG)n. (CAG)n repeats from the myotonic dystrophy locus. Nucleic Acids Res 26:816–823PubMedCrossRefGoogle Scholar
  54. 54.
    Gacy AM, Goellner GM, Spiro C et al (1998) GAA instability in Friedreich’s Ataxia shares a common, DNA-directed and intraallelic mechanism with other trinucleotide diseases. Mol Cell 1:583–593PubMedCrossRefGoogle Scholar
  55. 55.
    Moore H, Greenwell PW, Liu CP et al (1999) Triplet repeats form secondary structures that escape DNA repair in yeast. Proc Natl Acad Sci U S A 96:1504–1509PubMedCrossRefGoogle Scholar
  56. 56.
    Manley K, Shirley TL, Flaherty L et al (1999) Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice. Nat Genet 23:471–473PubMedCrossRefGoogle Scholar
  57. 57.
    McMurray CT (2008) Hijacking of the mismatch repair system to cause CAG expansion and cell death in neurodegenerative disease. DNA Repair (Amst) 7:1121–1134CrossRefGoogle Scholar
  58. 58.
    Kovtun IV, McMurray CT (2001) Trinucleotide expansion in haploid germ cells by gap repair. Nat Genet 27:407–411PubMedCrossRefGoogle Scholar
  59. 59.
    van den Broek WJ, Nelen MR, Wansink DG et al (2002) Somatic expansion behaviour of the (CTG)n repeat in myotonic dystrophy knock-in mice is differentially affected by Msh3 and Msh6 mismatch-repair proteins. Hum Mol Genet 11:191–198PubMedCrossRefGoogle Scholar
  60. 60.
    Gomes-Pereira M, Fortune MT, Ingram L et al (2004) Pms2 is a genetic enhancer of trinucleotide CAG.CTG repeat somatic mosaicism: implications for the mechanism of triplet repeat expansion. Hum Mol Genet 13:1815–1825PubMedCrossRefGoogle Scholar
  61. 61.
    Dragileva E, Hendricks A, Teed A et al (2009) Intergenerational and striatal CAG repeat instability in Huntington’s disease knock-in mice involve different DNA repair genes. Neurobiol Dis 33:37–47PubMedCrossRefGoogle Scholar
  62. 62.
    Lin Y, Wilson JH (2007) Transcription-induced CAG repeat contraction in human cells is mediated in part by transcription-coupled nucleotide excision repair. Mol Cell Biol 27:6209–6217PubMedCrossRefGoogle Scholar
  63. 63.
    Kovtun IV, Liu Y, Bjoras M et al (2007) OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells. Nature 447:447–452PubMedCrossRefGoogle Scholar
  64. 64.
    Goula AV, Berquist BR, Wilson DM 3rd et al (2009) Stoichiometry of base excision repair proteins correlates with increased somatic CAG instability in striatum over cerebellum in Huntington’s disease transgenic mice. PLoS Genet 5:e1000749PubMedCrossRefGoogle Scholar
  65. 65.
    Jarem DA, Wilson NR, Schermerhorn KM et al (2011) 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) 10:887–896CrossRefGoogle Scholar
  66. 66.
    Jung J, Bonini N (2007) CREB-binding protein modulates repeat instability in a Drosophila model for polyQ disease. Science 315:1857–1859PubMedCrossRefGoogle Scholar
  67. 67.
    Lin Y, Dion V, Wilson JH (2006) Transcription promotes contraction of CAG repeat tracts in human cells. Nat Struct Mol Biol 13:179–180PubMedCrossRefGoogle Scholar
  68. 68.
    Larkin K, Fardaei M (2001) Myotonic dystrophy—a multigene disorder. Brain Res Bull 56:389–395PubMedCrossRefGoogle Scholar
  69. 69.
    Schneider-Gold C, Timchenko LT (2010) CCUG repeats reduce the rate of global protein synthesis in myotonic dystrophy type 2. Rev Neurosci 21:19–28PubMedGoogle Scholar
  70. 70.
    Dick KA, Margolis JM, Day JW et al (2006) Dominant non-coding repeat expansions in human disease. Genome Dyn 1:67–83PubMedCrossRefGoogle Scholar
  71. 71.
    Echeverria GV, Cooper TA (2012) RNA-binding proteins in microsatellite expansion disorders: mediators of RNA toxicity. Brain Res 1462:100–111PubMedCrossRefGoogle Scholar
  72. 72.
    Wojciechowska M, Krzyzosiak WJ (2011) Cellular toxicity of expanded RNA repeats: focus on RNA foci. Hum Mol Genet 20:3811–3821PubMedCrossRefGoogle Scholar
  73. 73.
    Tan H, Xu Z, Jin P (2012) Role of noncoding RNAs in trinucleotide repeat neurodegenerative disorders. Exp Neurol 235(2):469–475PubMedCrossRefGoogle Scholar
  74. 74.
    Todd PK, Paulson HL (2010) RNA-mediated neurodegeneration in repeat expansion disorders. Ann Neurol 67:291–300PubMedGoogle Scholar
  75. 75.
    Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795PubMedCrossRefGoogle Scholar
  76. 76.
    Vidal RL, Figueroa A, Court FA et al (2012) Targeting the UPR transcription factor XBP1 protects against Huntington’s disease through the regulation of FoxO1 and autophagy. Hum Mol Genet 21(10):2245–2262PubMedCrossRefGoogle Scholar
  77. 77.
    Yu Z, Wang AM, Adachi H et al (2011) Macroautophagy is regulated by the UPR-mediator CHOP and accentuates the phenotype of SBMA mice. PLoS Genet 7:e1002321PubMedCrossRefGoogle Scholar
  78. 78.
    Jimenez-Sanchez M, Thompson F, Zavodsky E et al (2011) Autophagy and polyglutamine diseases. Prog Neurobiol 97(2):67–82PubMedCrossRefGoogle Scholar
  79. 79.
    Schapira AH, Jenner P (2011) Etiology and pathogenesis of Parkinson’s disease. Mov Disord 26:1049–1055PubMedCrossRefGoogle Scholar
  80. 80.
    Ravikumar B, Duden R, Rubinsztein DC (2002) Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet 11:1107–1117PubMedCrossRefGoogle Scholar
  81. 81.
    Lopez Castel A, Cleary JD, Pearson CE (2010) Repeat instability as the basis for human diseases and as a potential target for therapy. Nat Rev Mol Cell Biol 11:165–170PubMedCrossRefGoogle Scholar
  82. 82.
    Ranganathan S, Fischbeck KH (2010) Therapeutic approaches to spinal and bulbar muscular atrophy. Trends Pharmacol Sci 31:523–527PubMedCrossRefGoogle Scholar
  83. 83.
    Schulz JB, Boesch S, Burk K et al (2009) Diagnosis and treatment of Friedreich ataxia: a European perspective. Nat Rev Neurol 5:222–234PubMedCrossRefGoogle Scholar
  84. 84.
    Sah DW, Aronin N (2011) Oligonucleotide therapeutic approaches for Huntington disease. J Clin Invest 121:500–507PubMedCrossRefGoogle Scholar
  85. 85.
    Fiszer A, Olejniczak M, Switonski PM et al (2012) An evaluation of oligonucleotide-based therapeutic strategies for polyQ diseases. BMC Mol Biol 13:6PubMedCrossRefGoogle Scholar
  86. 86.
    Boudreau RL, McBride JL, Martins I et al (2009) Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington’s disease mice. Mol Ther 17:1053–1063PubMedCrossRefGoogle Scholar
  87. 87.
    Harper SQ, Staber PD, He X et al (2005) RNA interference improves motor and neuropathological abnormalities in a Huntington’s disease mouse model. Proc Natl Acad Sci USA 102:5820–5825PubMedCrossRefGoogle Scholar
  88. 88.
    Zhang Y, Friedlander RM (2011) Using non-coding small RNAs to develop therapies for Huntington’s disease. Gene Ther 18:1139–1149PubMedCrossRefGoogle Scholar
  89. 89.
    Nakamori M, Gourdon G, Thornton CA (2011) Stabilization of expanded (CTG)*(CAG) repeats by antisense oligonucleotides. Mol Ther 19:2222–2227PubMedCrossRefGoogle Scholar
  90. 90.
    Benraiss A, Goldman SA (2011) Cellular therapy and induced neuronal replacement for Huntington’s disease. Neurotherapeutics 8:577–590PubMedCrossRefGoogle Scholar
  91. 91.
    Lindvall O, Bjorklund A (2011) Cell therapeutics in Parkinson’s disease. Neurotherapeutics 8:539–548PubMedCrossRefGoogle Scholar
  92. 92.
    Daadi MM (2011) Novel paths towards neural cellular products for neurological disorders. Regen Med 6:25–30PubMedCrossRefGoogle Scholar
  93. 93.
    Park IH, Zhao R, West JA et al (2008) Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451:141–146PubMedCrossRefGoogle Scholar
  94. 94.
    Takahashi K, Tanabe K, Ohnuki M et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872PubMedCrossRefGoogle Scholar
  95. 95.
    Chen SJ, Chang CM, Tsai SK et al (2010) Functional improvement of focal cerebral ischemia injury by subdural transplantation of induced pluripotent stem cells with fibrin glue. Stem Cells Dev 19:1757–1767PubMedCrossRefGoogle Scholar

Copyright information

© Springer New York 2013

Authors and Affiliations

  • Helen Budworth
    • 1
  • Cynthia T. McMurray
    • 2
  1. 1.Life Sciences DivisionLawrence Berkeley National LaboratoryBerkeleyUSA
  2. 2.Life Sciences DivisionLawrence Berkeley National laboratoryBerkeleyUSA

Personalised recommendations