Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Expandable DNA repeats and human disease

Abstract

Nearly 30 hereditary disorders in humans result from an increase in the number of copies of simple repeats in genomic DNA. These DNA repeats seem to be predisposed to such expansion because they have unusual structural features, which disrupt the cellular replication, repair and recombination machineries. The presence of expanded DNA repeats alters gene expression in human cells, leading to disease. Surprisingly, many of these debilitating diseases are caused by repeat expansions in the non-coding regions of their resident genes. It is becoming clear that the peculiar structures of repeat-containing transcripts are at the heart of the pathogenesis of these diseases.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Location of expandable repeats responsible for human diseases.
Figure 2: Unusual DNA structures formed by expandable repeats.
Figure 3: Replication mechanisms for repeat expansion.
Figure 4: Gap repair model for repeat expansions in non-dividing cells.
Figure 5: Recombination models for repeat expansions.
Figure 6: Loss of stabilizing interruptions within expandable repeats.
Figure 7: Three models of early events in repeat expansions.
Figure 8: Disease-associated RNA gain of function.

References

  1. Fleischer, B. Uber myotonische Dystrophie mit Katarakt. Albrecht Von Graefes Arch. Klin. Exp. Ophthalmol. 96, 91–133 (1918).

    Google Scholar 

  2. Sherman, S. L. et al. Further segregation analysis of the fragile X syndrome with special reference to transmitting males. Hum. Genet. 69, 289–299 (1985).

    CAS  PubMed  Google Scholar 

  3. Verkerk, A. J. et al. 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 (1991).

    CAS  PubMed  Google Scholar 

  4. Kremer, E. J. et al. Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n . Science 252, 1711–1714 (1991).

    ADS  CAS  PubMed  Google Scholar 

  5. La Spada, A. R., Wilson, E. M., Lubahn, D. B., Harding, A. E. & Fischbeck, K. H. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352, 77–79 (1991).

    ADS  CAS  PubMed  Google Scholar 

  6. Brook, J. D. et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member. Cell 68, 799–808 (1992).

    CAS  PubMed  Google Scholar 

  7. Mahadevan, M. et al. Myotonic dystrophy mutation: an unstable CTG repeat in the 3′ untranslated region of the gene. Science 255, 1253–1255 (1992).

    ADS  CAS  PubMed  Google Scholar 

  8. Mirkin, S. M. Molecular models for repeat expansions. Chemtracts Biochem. Mol. Biol. 17, 639–662 (2004).

    CAS  Google Scholar 

  9. Pearson, C. E., Nichol Edamura, K. & Cleary, J. D. Repeat instability: mechanisms of dynamic mutations. Nature Rev. Genet. 6, 729–742 (2005).

    CAS  PubMed  Google Scholar 

  10. Kunst, C. B. & Warren, S. T. Cryptic and polar variation of the fragile X repeat could result in predisposing normal alleles. Cell 77, 853–861 (1994).

    CAS  PubMed  Google Scholar 

  11. Jodice, C. et al. Effect of trinucleotide repeat length and parental sex on phenotypic variation in spinocerebellar ataxia I. Am. J. Hum. Genet. 54, 959–965 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Brown, L. Y. & Brown, S. A. Alanine tracts: the expanding story of human illness and trinucleotide repeats. Trends Genet. 20, 51–58 (2004).

    CAS  PubMed  Google Scholar 

  13. Wells, R. D., Dere, R., Hebert, M. L., Napierala, M. & Son, L.S. Advances in mechanisms of genetic instability related to hereditary neurological diseases. Nucleic Acids Res. 33, 3785–3798 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Mirkin, S. M. DNA structures, repeat expansions and human hereditary disorders. Curr. Opin. Struct. Biol. 16, 351–358 (2006).

    CAS  PubMed  Google Scholar 

  15. Ranum, L. P. & Cooper, T. A. RNA-mediated neuromuscular disorders. Annu. Rev. Neurosci. 29, 259–277 (2006).

    CAS  PubMed  Google Scholar 

  16. Kunkel, T. A. Slippery DNA and diseases. Nature 365, 207–208 (1993).

    ADS  CAS  PubMed  Google Scholar 

  17. McMurray, C. T. DNA secondary structure: a common and causative factor for expansion in human disease. Proc. Natl Acad. Sci. USA 96, 1823–1825 (1999).

    ADS  CAS  PubMed  Google Scholar 

  18. Gacy, A. M., Goellner, G., Juranic, N., Macura, S. & McMurray, C. T. Trinucleotide repeats that expand in human disease form hairpin structures in vitro. Cell 81, 533–540 (1995).

    CAS  PubMed  Google Scholar 

  19. Dere, R., Napierala, M., Ranum, L. P. & Wells, R. D. Hairpin structure-forming propensity of the (CCTG·CAGG) tetranucleotide repeats contributes to the genetic instability associated with myotonic dystrophy type 2. J. Biol. Chem. 279, 41715–41726 (2004).

    CAS  PubMed  Google Scholar 

  20. Usdin, K. & Woodford, K. J. CGG repeats associated with DNA instability and chromosome fragility from structures that block DNA synthesis in vitro. Nucleic Acids Res. 23, 4202–4209 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Fry, M. & Loeb, L. A. The fragile X syndrome d(CGG)n nucleotide repeats form a stable tetrahelical structure. Proc. Natl Acad. Sci. USA 91, 4950–4954 (1994).

    ADS  CAS  PubMed  Google Scholar 

  22. Pearson, C. E. & Sinden, R. R. Alternative structures in duplex DNA formed within the trinucleotide repeats of the myotonic dystrophy and fragile X loci. Biochemistry 35, 5041–5053 (1996).

    CAS  PubMed  Google Scholar 

  23. Pearson, C. E. et al. Slipped-strand DNAs formed by long (CAG)·(CTG) repeats: slipped-out repeats and slip-out junctions. Nucleic Acids Res. 30, 4534–4547 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Gacy, A. M. et al. GAA instability in Friedreich's ataxia shares a common, DNA-directed and intraallelic mechanism with other trinucleotide diseases. Mol. Cell 1, 583–593 (1998).

    CAS  PubMed  Google Scholar 

  25. Sakamoto, N. et al. Sticky DNA: self association properties of long (GAA)·(TTC) repeats in R·R·Y triplex structures from Friedreich's ataxia. Mol. Cell 3, 465–475 (1999).

    CAS  PubMed  Google Scholar 

  26. Vetcher, A. A. et al. Sticky DNA, a long (GAA·GAA·TTC) triplex that is formed intramolecularly, in the sequence of intron 1 of the frataxin gene. J. Biol. Chem. 277, 39217–39227 (2002).

    CAS  PubMed  Google Scholar 

  27. Potaman, V. N. et al. Unpaired structures in SCA10 (ATTCT)n·(AGAAT)n repeats. J. Mol. Biol. 326, 1095–1111 (2003).

    CAS  PubMed  Google Scholar 

  28. Moore, H., Greenwell, P. W., Liu, C. P., Arnheim, N. & Petes, T. D. Triplet repeats form secondary structures that escape DNA repair in yeast. Proc. Natl Acad. Sci. USA 96, 1504–1509 (1999).

    ADS  CAS  PubMed  Google Scholar 

  29. Sakamoto, N. et al. GGA·TCC-interrupted triplets in long GAA·TTC repeats inhibit the formation of triplex and sticky DNA structures, alleviate transcription inhibition, and reduce genetic instabilities. J. Biol. Chem. 276, 27178–27187 (2001).

    CAS  PubMed  Google Scholar 

  30. Kang, S., Jaworski, A., Ohshima, K. & Wells, R. D. Expansion and deletion of CTG repeats from human disease genes are determined by the direction of replication in E. coli. Nature Genet. 10, 213–218 (1995).

    CAS  PubMed  Google Scholar 

  31. Ohshima, K. & Wells, R. D. Hairpin formation during DNA synthesis primer realignment in vitro in triplet repeat sequences from human hereditary disease genes. J. Biol. Chem. 272, 16798–16806 (1997).

    CAS  PubMed  Google Scholar 

  32. Freudenreich, C. H., Stavenhagen, J. B. & Zakian, V. A. Stability of a CTG·CAG trinucleotide repeat in yeast is dependent on its orientation in the genome. Mol. Cell. Biol. 17, 2090–2098 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Miret, J. J., Pessoa-Brandao, L. & Lahue, R. S. Orientation-dependent and sequence-specific expansions of CTG·CAG trinucleotide repeats in Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 95, 12438–12443 (1998).

    ADS  CAS  PubMed  Google Scholar 

  34. Cleary, J. D., Nichol, K., Wang, Y. H. & Pearson, C. E. Evidence of cis-acting factors in replication-mediated trinucleotide repeat instability in primate cells. Nature Genet. 31, 37–46 (2002).

    CAS  PubMed  Google Scholar 

  35. Rindler, M. P., Clark, R. M., Pollard, L. M., De Biase, I. & Bidichandani, S. I. Replication in mammalian cells recapitulates the locus-specific differences in somatic instability of genomic GAA triplet-repeats. Nucleic Acids Res. 34, 6352–6361 (2006).

    CAS  Google Scholar 

  36. Bhattacharyya, S. & Lahue, R. S. Saccharomyces cerevisiae Srs2 DNA helicase selectively blocks expansions of trinucleotide repeats. Mol. Cell. Biol. 24, 7324–7330 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Daee, D. L., Mertz, T., Collins, N. & Lahue, R. S. Post-replication repair inhibits CAG·CTG repeat expansions in Saccharomyces cerevisiae. Mol. Cell. Biol. 27, 102–110 (2007).

    CAS  PubMed  Google Scholar 

  38. Samadashwily, G. M., Raca, G. & Mirkin, S. M. Trinucleotide repeats affect DNA replication in vivo. Nature Genet. 17, 298–304 (1997).

    CAS  PubMed  Google Scholar 

  39. Krasilnikova, M. M. & Mirkin, S. M. Replication stalling at Friedreich's ataxia (GAA)n repeats in vivo. Mol. Cell. Biol. 24, 2286–2295 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Pelletier, R., Krasilnikova, M. M., Samadashwily, G. M., Lahue, R. S. & Mirkin, S. M. Replication and expansion of trinucleotide repeats in yeast. Mol. Cell. Biol. 23, 1349–1357 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Fouche, N., Ozgur, S., Roy, D. & Griffith, J. D. Replication fork regression in repetitive DNAs. Nucleic Acids Res. 34, 6044–6050 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Manley, K., Shirley, T. L., Flaherty, L. & Messer, A. Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice. Nature Genet. 23, 471–473 (1999).

    CAS  PubMed  Google Scholar 

  43. Savouret, C. et al. CTG repeat instability and size variation timing in DNA repair-deficient mice. EMBO J. 22, 2264–2273 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. van den Broek, W. J. et al. 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 (2002).

    CAS  PubMed  Google Scholar 

  45. Kovtun, I. V. & McMurray, C. T. Trinucleotide expansion in haploid germ cells by gap repair. Nature Genet. 27, 407–411 (2001).

    CAS  PubMed  Google Scholar 

  46. Owen, B. A. et al. (CAG)n-hairpin DNA binds to Msh2–Msh3 and changes properties of mismatch recognition. Nature Struct. Mol. Biol. 12, 663–670 (2005).

    CAS  Google Scholar 

  47. Savouret, C. et al. MSH2-dependent germinal CTG repeat expansions are produced continuously in spermatogonia from DM1 transgenic mice. Mol. Cell. Biol. 24, 629–637 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Yoon, S. R., Dubeau, L., de Young, M., Wexler, N. S. & Arnheim, N. Huntington disease expansion mutations in humans can occur before meiosis is completed. Proc. Natl Acad. Sci. USA 100, 8834–8838 (2003).

    ADS  CAS  PubMed  Google Scholar 

  49. Anvret, M. et al. Larger expansions of the CTG repeat in muscle compared to lymphocytes from patients with myotonic dystrophy. Hum. Mol. Genet. 2, 1397–1400 (1993).

    CAS  PubMed  Google Scholar 

  50. Kennedy, L. et al. Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis. Hum. Mol. Genet. 12, 3359–3367 (2003).

    CAS  PubMed  Google Scholar 

  51. Lia, A. S. et al. Somatic instability of the CTG repeat in mice transgenic for the myotonic dystrophy region is age dependent but not correlated to the relative intertissue transcription levels and proliferative capacities. Hum. Mol. Genet. 7, 1285–1291 (1998).

    CAS  PubMed  Google Scholar 

  52. Fortune, M. T., Vassilopoulos, C., Coolbaugh, M. I., Siciliano, M. J. & Monckton, D. G. Dramatic, expansion-biased, age-dependent, tissue-specific somatic mosaicism in a transgenic mouse model of triplet repeat instability. Hum. Mol. Genet. 9, 439–445 (2000).

    CAS  PubMed  Google Scholar 

  53. Kovtun, I. V. et al. OGG1 initiates age-dependent CAG expansion in somatic cells during base excision repair of oxidized bases in vitro and in vivo. Nature 447, 447–452 (2007).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  54. Spiro, C. et al. Inhibition of FEN-1 processing by DNA secondary structure at trinucleotide repeats. Mol. Cell 4, 1079–1085 (1999).

    CAS  PubMed  Google Scholar 

  55. Henricksen, L. A., Tom, S., Liu, Y. & Bambara, R. A. Inhibition of flap endonuclease 1 by flap secondary structure and relevance to repeat sequence expansion. J. Biol. Chem. 275, 16420–16427 (2000).

    CAS  PubMed  Google Scholar 

  56. Panigrahi, G. B., Lau, R., Montgomery, S. E., Leonard, M. R. & Pearson, C. E. Slipped (CTG)·(CAG) repeats can be correctly repaired, escape repair or undergo error-prone repair. Nature Struct. Mol. Biol. 12, 654–662 (2005).

    CAS  Google Scholar 

  57. Liu, Y., Zhang, H., Veeraraghavan, J., Bambara, R. A. & Freudenreich, C. H. Saccharomyces cerevisiae flap endonuclease 1 uses flap equilibration to maintain triplet repeat stability. Mol. Cell. Biol. 24, 4049–4064 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. van den Broek, W. J., Nelen, M. R., van der Heijden, G. W., Wansink, D. G. & Wieringa, B. Fen1 does not control somatic hypermutability of the (CTG)n·(CAG)n repeat in a knock-in mouse model for DM1. FEBS Lett. 580, 5208–5214 (2006).

    CAS  PubMed  Google Scholar 

  59. Warren, S. T. Polyalanine expansion in synpolydactyly might result from unequal crossing-over of HOXD13. Science 275, 408–409 (1997).

    CAS  PubMed  Google Scholar 

  60. Richards, R. I. et al. Evidence of founder chromosomes in fragile X syndrome. Nature Genet. 1, 257–260 (1992).

    CAS  PubMed  Google Scholar 

  61. Jakupciak, J. P. & Wells, R. D. Genetic instabilities in (CTG)·(CAG) repeats occur by recombination. J. Biol. Chem. 274, 23468–23479 (1999).

    CAS  PubMed  Google Scholar 

  62. Napierala, M., Dere, R., Vetcher, A. & Wells, R. D. Structure-dependent recombination hot spot activity of GAA·TTC sequences from intron 1 of the Friedreich's ataxia gene. J. Biol. Chem. 279, 6444–6454 (2004).

    CAS  PubMed  Google Scholar 

  63. Dere, R. & Wells, R. D. DM2 CCTG·CAGG repeats are crossover hotspots that are more prone to expansions than the DM1 CTG·CAG repeats in Escherichia coli. J. Mol. Biol. 360, 21–36 (2006).

    CAS  PubMed  Google Scholar 

  64. Freudenreich, C. H., Kantrow, S. M. & Zakian, V. A. Expansion and length-dependent fragility of CTG repeats in yeast. Science 279, 853–856 (1998).

    ADS  CAS  PubMed  Google Scholar 

  65. Nag, D. K., Suri, M. & Stenson, E. K. Both CAG repeats and inverted DNA repeats stimulate spontaneous unequal sister-chromatid exchange in Saccharomyces cerevisiae. Nucleic Acids Res. 32, 5677–5684 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Richard, G.-F., Goellner, G. M., McMurray, C. T. & Haber, J. E. Recombination-induced CAG trinucleotide repeat expansions in yeast involve the MRE11–RAD50–XRS2 complex. EMBO J. 19, 2381–2390 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Richard, G.-F., Cyncynatus, C. & Dujon, B. Contractions and expansions of CAG·CTG trinucleotide repeats occur during ectopic gene conversion in yeast, by a MUS81-independent mechanism. J. Mol. Biol. 326, 769–782 (2003).

    CAS  PubMed  Google Scholar 

  68. Meservy, J. L. et al. Long CTG tracts from the myotonic dystrophy gene induce deletions and rearrangements during recombination at the APRT locus in CHO cells. Mol. Cell. Biol. 23, 3152–3162 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Bacolla, A., Wojciechowska, M., Kosmider, B., Larson, J. E. & Wells, R. D. The involvement of non-B DNA structures in gross chromosomal rearrangements. DNA Repair (Amst.) 5, 1161–1170 (2006).

    CAS  Google Scholar 

  70. Rolfsmeier, M. L., Dixon, M. J. & Lahue, R. S. Mismatch repair blocks expansions of interrupted trinucleotide repeats in yeast. Mol. Cell 6, 1501–1507 (2000).

    CAS  PubMed  Google Scholar 

  71. Mirkin, S. M. & Smirnova, E. V. Positioned to expand. Nature Genet. 31, 5–6 (2002).

    CAS  PubMed  Google Scholar 

  72. Cleary, J. D. & Pearson, C. E. Replication fork dynamics and dynamic mutations: the fork-shift model of repeat instability. Trends Genet. 21, 272–280 (2005).

    CAS  PubMed  Google Scholar 

  73. Abu-Baker, A. & Rouleau, G. A. in Genetic Instabilities and Neurological Diseases (eds Wells, R. D. & Ashizawa, T.) 487–513 (Elsevier, Amsterdam, 2006).

    Google Scholar 

  74. Davis, B. M., McCurrach, M. E., Taneja, K. L., Singer, R. H. & Housman, D. E. Expansion of a CUG trinucleotide repeat in the 3′ untranslated region of myotonic dystrophy protein kinase transcripts results in nuclear retention of transcripts. Proc. Natl Acad. Sci. USA 94, 7388–7393 (1997).

    ADS  CAS  PubMed  Google Scholar 

  75. Amack, J. D. & Mahadevan, M. S. The myotonic dystrophy expanded CUG repeat tract is necessary but not sufficient to disrupt C2C12 myoblast differentiation. Hum. Mol. Genet. 10, 1879–1887 (2001).

    CAS  PubMed  Google Scholar 

  76. Mankodi, A. et al. Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat. Science 289, 1769–1772 (2000).

    ADS  CAS  PubMed  Google Scholar 

  77. Tassone, F. et al. Elevated levels of FMR1 mRNA in carrier males: a new mechanism of involvement in the fragile-X syndrome. Am. J. Hum. Genet. 66, 6–15 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Jin, P. et al. RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in Drosophila. Neuron 39, 739–747 (2003).

    CAS  PubMed  Google Scholar 

  79. Mutsuddi, M., Marshall, C. M., Benzow, K. A., Koob, M. D. & Rebay, I. The spinocerebellar ataxia 8 noncoding RNA causes neurodegeneration and associates with staufen in Drosophila. Curr. Biol. 14, 302–308 (2004).

    CAS  PubMed  Google Scholar 

  80. Lin, X. & Ashizawa, T. Recent progress in spinocerebellar ataxia type-10 (SCA10). Cerebellum 4, 37–42 (2005).

    CAS  PubMed  Google Scholar 

  81. Napierala, M. & Krzyzosiak, W. J. CUG repeats present in myotonin kinase RNA form metastable “slippery” hairpins. J. Biol. Chem. 272, 31079–31085 (1997).

    CAS  PubMed  Google Scholar 

  82. Sobczak, K., de Mezer, M., Michlewski, G., Krol, J. & Krzyzosiak, W. J. RNA structure of trinucleotide repeats associated with human neurological diseases. Nucleic Acids Res. 31, 5469–5482 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Handa, V., Yeh, H. J., McPhie, P. & Usdin, K. The AUUCU repeats responsible for spinocerebellar ataxia type 10 form unusual RNA hairpins. J. Biol. Chem. 280, 29340–29345 (2005).

    CAS  PubMed  Google Scholar 

  84. Napierala, M., Michalowski, D., de Mezer, M. & Krzyzosiak, W. J. Facile FMR1 mRNA structure regulation by interruptions in CGG repeats. Nucleic Acids Res. 33, 451–463 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Fardaei, M. et al. Three proteins, MBNL, MBLL and MBXL, co-localize in vivo with nuclear foci of expanded-repeat transcripts in DM1 and DM2 cells. Hum. Mol. Genet. 11, 805–814 (2002).

    CAS  PubMed  Google Scholar 

  86. Miller, J. W. et al. Recruitment of human muscleblind proteins to (CUG)n expansions associated with myotonic dystrophy. EMBO J. 19, 4439–4448 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Lu, X., Timchenko, N. A. & Timchenko, L. T. Cardiac elav-type RNA-binding protein (ETR-3) binds to RNA CUG repeats expanded in myotonic dystrophy. Hum. Mol. Genet. 8, 53–60 (1999).

    CAS  PubMed  Google Scholar 

  88. Philips, A. V., Timchenko, L. T. & Cooper, T. A. Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science 280, 737–741 (1998).

    ADS  CAS  PubMed  Google Scholar 

  89. Thornton, C. A., Swanson, M. S. & Cooper, T. A. in Genetic Instabilities and Neurological Diseases (eds Wells, R. D. & Ashizawa, T.) 37–54 (Elsevier, Amsterdam, 2006).

    Google Scholar 

  90. Ho, T. H. et al. Muscleblind proteins regulate alternative splicing. EMBO J. 23, 3103–3112 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Kino, Y. et al. Muscleblind protein, MBNL1/EXP, binds specifically to CHHG repeats. Hum. Mol. Genet. 13, 495–507 (2004).

    CAS  PubMed  Google Scholar 

  92. Kanadia, R. N. et al. A muscleblind knockout model for myotonic dystrophy. Science 302, 1978–1980 (2003).

    ADS  CAS  PubMed  Google Scholar 

  93. Kanadia, R. N. et al. Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy. Proc. Natl Acad. Sci. USA 103, 11748–11753 (2006).

    ADS  CAS  PubMed  Google Scholar 

  94. Iwahashi, C. K. et al. Protein composition of the intranuclear inclusions of FXTAS. Brain 129, 256–271 (2006).

    CAS  PubMed  Google Scholar 

  95. Malinina, L. Possible involvement of the RNAi pathway in trinucleotide repeat expansion diseases. J. Biomol. Struct. Dyn. 23, 233–235 (2005).

    CAS  PubMed  Google Scholar 

  96. Handa, V., Saha, T. & Usdin, K. The fragile X syndrome repeats form RNA hairpins that do not activate the interferon-inducible protein kinase, PKR, but are cut by Dicer. Nucleic Acids Res. 31, 6243–6248 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Krol, J. et al. Ribonuclease Dicer cleaves triplet repeat hairpins into shorter repeats which silence specific targets. Mol. Cell 25, 575–586 (2007).

    CAS  PubMed  Google Scholar 

  98. Cho, D. H. et al. Antisense transcription and heterochromatin at the DM1 CTG repeats are constrained by CTCF. Mol. Cell 20, 483–489 (2005).

    CAS  PubMed  Google Scholar 

  99. Moseley, M. L. et al. Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8. Nature Genet. 38, 758–769 (2006).

    CAS  PubMed  Google Scholar 

  100. Gray, S. J., Gerhardt, J., Doerfler, W., Small, L. E. & Fanning, E. An origin of DNA replication in the promoter region of the human fragile X mental retardation (FMR1) gene. Mol. Cell. Biol. 27, 426–437 (2007).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I thank W. Krzyzosiak, R. Lahue, K. Lobachev, C. McMurray, D. Monckton, C. Pearson, M. Swanson, K. Usdin and R. Wells for sharing their ideas and unpublished results. I also extend my gratitude to all the participants of the 5th International Conference on Unstable Microsatellites and Human Disease (Granada, Spain, 2006) for their intense and productive discussions, which helped to shape this review. I am indebted to my wife, Kate, for her invaluable critical comments. I thank J. White and P. White for their generous support. This work was supported by the National Institutes of Health.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Mirkin, S. Expandable DNA repeats and human disease. Nature 447, 932–940 (2007). https://doi.org/10.1038/nature05977

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature05977

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing