Abstract
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.
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References
Hegde MV, Saraph AA (2011) Unstable genes unstable mind: beyond the central dogma of molecular biology. Med Hypotheses 77:165–170
McMurray CT (2010) Mechanisms of trinucleotide repeat instability during human development. Nat Rev Genet 11:786–799
La Spada AR, Taylor JP (2010) Repeat expansion disease: progress and puzzles in disease pathogenesis. Nat Rev Genet 11:247–258
Toth G, Gaspari Z, Jurka J (2000) Microsatellites in different eukaryotic genomes: survey and analysis. Genome Res 10:967–981
Jurka J, Pethiyagoda C (1995) Simple repetitive DNA sequences from primates: compilation and analysis. J Mol Evol 40:120–126
Beckman JS, Weber JL (1992) Survey of human and rat microsatellites. Genomics 12:627–631
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 359:141–152
Kashi Y, King DG (2006) Simple sequence repeats as advantageous mutators in evolution. Trends Genet 22:253–259
Strachan T, Read AP (1999) Human molecular genetics, vol 2. Wiley-Liss, New York
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 93:417–421
Yant SR, Wu X, Huang Y et al (2005) High-resolution genome-wide mapping of transposon integration in mammals. Mol Cell Biol 25:2085–2094
Kohwi Y (2004) Trinucleotide repeat protocols, vol 277, Methods in molecular biology. Humana, Totowa, NJ
Friedman JE (2011) Anticipation in hereditary disease: the history of a biomedical concept. Hum Genet 130:705–714
Maltecca F, Filla A, Castaldo I et al (2003) Intergenerational instability and marked anticipation in SCA-17. Neurology 61:1441–1443
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 65:905–914
La Spada AR, Wilson EM, Lubahn DB et al (1991) Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352:77–79
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 255:1253–1255
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 72:971–983
Duyao M, Ambrose C, Myers R et al (1993) Trinucleotide repeat length instability and age of onset in Huntington’s disease. Nat Genet 4:387–392
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 71:295–301
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 59:554–560
Bovo D, Rugge M, Shiao YH (1999) Origin of spurious multiple bands in the amplification of microsatellite sequences. Mol Pathol 52:50–51
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 4:1519–1526
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 4:1–8
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 32:445–453
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) 86:485–490
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 5:109–114
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 90:434–444
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 7:71
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) 6:789–796
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 78:690–695
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 16:1133–1142
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 95:270–274
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 6:409–414
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:60–65
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 103:564–569
Goellner GM, Tester D, Thibodeau S et al (1997) Different mechanisms underlie DNA instability in Huntington disease and colorectal cancer. Am J Hum Genet 60:879–890
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 47:113–117
Martorell L, Gamez J, Cayuela ML et al (2004) Germline mutational dynamics in myotonic dystrophy type 1 males: allele length and age effects. Neurology 62:269–274
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 42:85–98
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 395:125–134
Savouret C, Brisson E, Essers J et al (2003) CTG repeat instability and size variation timing in DNA repair-deficient mice. EMBO J 22:2264–2273
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 9:439–445
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 8:99–106
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 9:2539–2544
Kaytor MD, Burright EN, Duvick LA et al (1997) Increased trinucleotide repeat instability with advanced maternal age. Hum Mol Genet 6:2135–2139
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 12:3359–3367
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 18:3039–3047
Dion V, Wilson JH (2009) Instability and chromatin structure of expanded trinucleotide repeats. Trends Genet 25:288–297
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:e1000257
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 91:4950–4954
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 30:4534–4547
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 26:816–823
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 1:583–593
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 96:1504–1509
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 23:471–473
McMurray CT (2008) Hijacking of the mismatch repair system to cause CAG expansion and cell death in neurodegenerative disease. DNA Repair (Amst) 7:1121–1134
Kovtun IV, McMurray CT (2001) Trinucleotide expansion in haploid germ cells by gap repair. Nat Genet 27:407–411
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 11:191–198
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 13:1815–1825
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 33:37–47
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 27:6209–6217
Kovtun IV, Liu Y, Bjoras M et al (2007) OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells. Nature 447:447–452
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:e1000749
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) 10:887–896
Jung J, Bonini N (2007) CREB-binding protein modulates repeat instability in a Drosophila model for polyQ disease. Science 315:1857–1859
Lin Y, Dion V, Wilson JH (2006) Transcription promotes contraction of CAG repeat tracts in human cells. Nat Struct Mol Biol 13:179–180
Larkin K, Fardaei M (2001) Myotonic dystrophy—a multigene disorder. Brain Res Bull 56:389–395
Schneider-Gold C, Timchenko LT (2010) CCUG repeats reduce the rate of global protein synthesis in myotonic dystrophy type 2. Rev Neurosci 21:19–28
Dick KA, Margolis JM, Day JW et al (2006) Dominant non-coding repeat expansions in human disease. Genome Dyn 1:67–83
Echeverria GV, Cooper TA (2012) RNA-binding proteins in microsatellite expansion disorders: mediators of RNA toxicity. Brain Res 1462:100–111
Wojciechowska M, Krzyzosiak WJ (2011) Cellular toxicity of expanded RNA repeats: focus on RNA foci. Hum Mol Genet 20:3811–3821
Tan H, Xu Z, Jin P (2012) Role of noncoding RNAs in trinucleotide repeat neurodegenerative disorders. Exp Neurol 235(2):469–475
Todd PK, Paulson HL (2010) RNA-mediated neurodegeneration in repeat expansion disorders. Ann Neurol 67:291–300
Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795
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):2245–2262
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:e1002321
Jimenez-Sanchez M, Thompson F, Zavodsky E et al (2011) Autophagy and polyglutamine diseases. Prog Neurobiol 97(2):67–82
Schapira AH, Jenner P (2011) Etiology and pathogenesis of Parkinson’s disease. Mov Disord 26:1049–1055
Ravikumar B, Duden R, Rubinsztein DC (2002) Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet 11:1107–1117
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 11:165–170
Ranganathan S, Fischbeck KH (2010) Therapeutic approaches to spinal and bulbar muscular atrophy. Trends Pharmacol Sci 31:523–527
Schulz JB, Boesch S, Burk K et al (2009) Diagnosis and treatment of Friedreich ataxia: a European perspective. Nat Rev Neurol 5:222–234
Sah DW, Aronin N (2011) Oligonucleotide therapeutic approaches for Huntington disease. J Clin Invest 121:500–507
Fiszer A, Olejniczak M, Switonski PM et al (2012) An evaluation of oligonucleotide-based therapeutic strategies for polyQ diseases. BMC Mol Biol 13:6
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 17:1053–1063
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 102:5820–5825
Zhang Y, Friedlander RM (2011) Using non-coding small RNAs to develop therapies for Huntington’s disease. Gene Ther 18:1139–1149
Nakamori M, Gourdon G, Thornton CA (2011) Stabilization of expanded (CTG)*(CAG) repeats by antisense oligonucleotides. Mol Ther 19:2222–2227
Benraiss A, Goldman SA (2011) Cellular therapy and induced neuronal replacement for Huntington’s disease. Neurotherapeutics 8:577–590
Lindvall O, Bjorklund A (2011) Cell therapeutics in Parkinson’s disease. Neurotherapeutics 8:539–548
Daadi MM (2011) Novel paths towards neural cellular products for neurological disorders. Regen Med 6:25–30
Park IH, Zhao R, West JA et al (2008) Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451:141–146
Takahashi K, Tanabe K, Ohnuki M et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872
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 19:1757–1767
Acknowledgments
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.
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Budworth, H., McMurray, C.T. (2013). A Brief History of Triplet Repeat Diseases. In: Kohwi, Y., McMurray, C. (eds) Trinucleotide Repeat Protocols. Methods in Molecular Biology, vol 1010. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-411-1_1
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DOI: https://doi.org/10.1007/978-1-62703-411-1_1
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