Human Genetics

, Volume 133, Issue 10, pp 1311–1318 | Cite as

Modifiers of (CAG)n instability in Machado–Joseph disease (MJD/SCA3) transmissions: an association study with DNA replication, repair and recombination genes

  • Sandra Martins
  • Christopher E. Pearson
  • Paula Coutinho
  • Sylvie Provost
  • António Amorim
  • Marie-Pierre Dubé
  • Jorge Sequeiros
  • Guy A. Rouleau
Original Investigation

Abstract

Twelve neurological disorders are caused by gene-specific CAG/CTG repeat expansions that are highly unstable upon transmission to offspring. This intergenerational repeat instability is clinically relevant since disease onset, progression and severity are associated with repeat size. Studies of model organisms revealed the involvement of some DNA replication and repair genes in the process of repeat instability, however, little is known about their role in patients. Here, we used an association study to search for genetic modifiers of (CAG)n instability in 137 parent–child transmissions in Machado–Joseph disease (MJD/SCA3). With the hypothesis that variants in genes involved in DNA replication, repair or recombination might alter the MJD CAG instability patterns, we screened 768 SNPs from 93 of these genes. We found a variant in ERCC6 (rs2228528) associated with an expansion bias of MJD alleles. When using a gene–gene interaction model, the allele combination G–A (rs4140804–rs2972388) of RPA3–CDK7 is also associated with MJD instability in a direction-dependent manner. Interestingly, the transcription-coupled repair factor ERCC6 (aka CSB), the single-strand binding protein RPA, and the CDK7 kinase part of the TFIIH transcription repair complex, have all been linked to transcription-coupled repair. This is the first study performed in patient samples to implicate specific modifiers of CAG instability in humans. In summary, we found variants in three transcription-coupled repair genes associated with the MJD mutation that points to distinct mechanisms of (CAG)n instability.

Supplementary material

439_2014_1467_MOESM1_ESM.docx (31 kb)
Supplementary material 1 (DOCX 31 kb)
439_2014_1467_MOESM2_ESM.xlsx (40 kb)
Supplementary material 2 (XLSX 40 kb)

References

  1. Abbasi R, Ramroth H, Becher H, Dietz A, Schmezer P, Popanda O (2009) Laryngeal cancer risk associated with smoking and alcohol consumption is modified by genetic polymorphisms in ERCC5, ERCC6 and RAD23B but not by polymorphisms in five other nucleotide excision repair genes. Int J Cancer 125:1431–1439PubMedCrossRefGoogle Scholar
  2. Angstadt AY, Thayanithy V, Subramanian S, Modiano JF, Breen M (2012) A genome-wide approach to comparative oncology: high-resolution oligonucleotide aCGH of canine and human osteosarcoma pinpoints shared microaberrations. Cancer Genet 205:572–587PubMedCrossRefGoogle Scholar
  3. Axford MM, Wang YH, Nakamori M, Zannis-Hadjopoulos M, Thornton CA, Pearson CE (2013) Detection of slipped-DNAs at the trinucleotide repeats of the myotonic dystrophy type I disease locus in patient tissues. PLoS Genet 9:e1003866PubMedCentralPubMedCrossRefGoogle Scholar
  4. Baas DC, Despriet DD, Gorgels TG et al (2010) The ERCC6 gene and age-related macular degeneration. PLoS One 5:e13786PubMedCentralPubMedCrossRefGoogle Scholar
  5. Barry KH, Koutros S, Andreotti G et al (2012) Genetic variation in nucleotide excision repair pathway genes, pesticide exposure and prostate cancer risk. Carcinogenesis 33:331–337PubMedCentralPubMedCrossRefGoogle Scholar
  6. Binz SK, Sheehan AM, Wold MS (2004) Replication protein a phosphorylation and the cellular response to DNA damage. DNA Repair (Amst) 3:1015–1024CrossRefGoogle Scholar
  7. Brown LY, Brown SA (2004) Alanine tracts: the expanding story of human illness and trinucleotide repeats. Trends Genet 20:51–58PubMedCrossRefGoogle Scholar
  8. Cancel G, Gourfinkel-An I, Stevanin G, Didierjean O, Abbas N, Hirsch E, Agid Y, Brice A (1998) Somatic mosaicism of the CAG repeat expansion in spinocerebellar ataxia type 3/Machado–Joseph disease. Hum Mutat 11:23–27PubMedCrossRefGoogle Scholar
  9. Carvalho DR, La Rocque-Ferreira A, Rizzo IM, Imamura EU, Speck-Martins CE (2008) Homozygosity enhances severity in spinocerebellar ataxia type 3. Pediatr Neurol 38:296–299PubMedCrossRefGoogle Scholar
  10. Chan NL, Hou C, Zhang T, Yuan F, Machwe A, Huang J, Orren DK, Gu L, Li GM (2012) The Werner syndrome protein promotes CAG/CTG repeat stability by resolving large (CAG)(n)/(CTG)(n) hairpins. J Biol Chem 287:30151–30156PubMedCentralPubMedCrossRefGoogle Scholar
  11. Chang CH, Chiu CF, Wang HC et al (2009) Significant association of ERCC6 single nucleotide polymorphisms with bladder cancer susceptibility in Taiwan. Anticancer Res 29:5121–5124PubMedGoogle Scholar
  12. Chiu CF, Tsai MH, Tseng HC, Wang CL, Tsai FJ, Lin CC, Bau DT (2008) A novel single nucleotide polymorphism in ERCC6 gene is associated with oral cancer susceptibility in Taiwanese patients. Oral Oncol 44:582–586PubMedCrossRefGoogle Scholar
  13. Compe E, Egly JM (2012) TFIIH: when transcription met DNA repair. Nat Rev Mol Cell Biol 13:343–354PubMedCrossRefGoogle Scholar
  14. Coutinho P (1992) Doença de Machado–Joseph—Tentativa de definição. University of Porto, PortugalGoogle Scholar
  15. Coutinho P, Andrade C (1978) Autosomal dominant system degeneration in Portuguese families of the Azores Islands. A new genetic disorder involving cerebellar, pyramidal, extrapyramidal and spinal cord motor functions. Neurology 28:703–709PubMedCrossRefGoogle Scholar
  16. Cunningham JM, Vierkant RA, Sellers TA et al (2009) Cell cycle genes and ovarian cancer susceptibility: a tagSNP analysis. Br J Cancer 101:1461–1468PubMedCentralPubMedCrossRefGoogle Scholar
  17. Curtin NJ (2012) DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer 12:801–817PubMedCrossRefGoogle Scholar
  18. Dudbridge F (2008) Likelihood-based association analysis for nuclear families and unrelated subjects with missing genotype data. Hum Hered 66:87–98PubMedCentralPubMedCrossRefGoogle Scholar
  19. Ezzatizadeh V, Pinto RM, Sandi C, Sandi M, Al-Mahdawi S, Te Riele H, Pook MA (2012) The mismatch repair system protects against intergenerational GAA repeat instability in a Friedreich ataxia mouse model. Neurobiol Dis 46:165–171PubMedCentralPubMedCrossRefGoogle Scholar
  20. Gan W, Guan Z, Liu J, Gui T, Shen K, Manley JL, Li X (2011) R-loop-mediated genomic instability is caused by impairment of replication fork progression. Genes Dev 25:2041–2056PubMedCentralPubMedCrossRefGoogle Scholar
  21. Gao X, Starmer J, Martin ER (2008) A multiple testing correction method for genetic association studies using correlated single nucleotide polymorphisms. Genet Epidemiol 32:361–369PubMedCrossRefGoogle Scholar
  22. George Priya Doss C, Nagasundaram N, Chakraborty C, Chen L, Zhu H (2013) Extrapolating the effect of deleterious nsSNPs in the binding adaptability of flavopiridol with CDK7 protein: a molecular dynamics approach. Hum Genomics 7:10PubMedCentralPubMedCrossRefGoogle Scholar
  23. Goula AV, Berquist BR, Wilson DM 3rd, Wheeler VC, Trottier Y, Merienne K (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:e1000749PubMedCentralPubMedCrossRefGoogle Scholar
  24. Hubert L Jr, Lin Y, Dion V, Wilson JH (2011) Xpa deficiency reduces CAG trinucleotide repeat instability in neuronal tissues in a mouse model of SCA1. Hum Mol Genet 20:4822–4830PubMedCentralPubMedCrossRefGoogle Scholar
  25. Jeon S, Choi JY, Lee KM, Park SK, Yoo KY, Noh DY, Ahn SH, Kang D (2010) Combined genetic effect of CDK7 and ESR1 polymorphisms on breast cancer. Breast Cancer Res Treat 121:737–742PubMedCrossRefGoogle Scholar
  26. Jiang H, Tang B, Xu B, Zhao GH, Shen L, Tang JG, Li QH, Xia K (2005) Frequency analysis of autosomal dominant spinocerebellar ataxias in Han population in the Chinese mainland and clinical and molecular characterization of spinocerebellar ataxia type 6. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 22:1–4PubMedGoogle Scholar
  27. Jin T, Zhang J, Li G, Li S, Yang B, Chen C, Cai L (2013) TP53 and RPA3 gene variations were associated with risk of glioma in a Chinese Han population. Cancer Biother Radiopharm 28:248–253PubMedCrossRefGoogle Scholar
  28. Kawaguchi Y, Okamoto T, Taniwaki M et al (1994) CAG expansions in a novel gene for Machado–Joseph disease at chromosome 14q32.1. Nat Genet 8:221–228PubMedCrossRefGoogle Scholar
  29. Kovtun IV, McMurray CT (2001) Trinucleotide expansion in haploid germ cells by gap repair. Nat Genet 27:407–411PubMedCrossRefGoogle Scholar
  30. Kovtun IV, McMurray CT (2008) Features of trinucleotide repeat instability in vivo. Cell Res 18:198–213PubMedCrossRefGoogle Scholar
  31. Kovtun IV, Liu Y, Bjoras M, Klungland A, Wilson SH, McMurray CT (2007) OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells. Nature 447:447–452PubMedCentralPubMedCrossRefGoogle Scholar
  32. Kovtun IV, Johnson KO, McMurray CT (2011) Cockayne syndrome B protein antagonizes OGG1 in modulating CAG repeat length in vivo. Aging (Albany NY) 3:509–514Google Scholar
  33. Krasilnikova MM, Mirkin SM (2004) Replication stalling at Friedreich’s ataxia (GAA)n repeats in vivo. Mol Cell Biol 24:2286–2295PubMedCentralPubMedCrossRefGoogle Scholar
  34. Larsen E, Gran C, Saether BE, Seeberg E, Klungland A (2003) Proliferation failure and gamma radiation sensitivity of Fen1 null mutant mice at the blastocyst stage. Mol Cell Biol 23:5346–5353PubMedCentralPubMedCrossRefGoogle Scholar
  35. Laugel V, Dalloz C, Durand M et al (2010) Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in Cockayne syndrome. Hum Mutat 31:113–126PubMedCrossRefGoogle Scholar
  36. Li Y, Jin G, Wang H et al (2007) Polymorphisms of CAK genes and risk for lung cancer: a case-control study in Chinese population. Lung Cancer 58:171–183PubMedCrossRefGoogle Scholar
  37. 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 27:6209–6217PubMedCentralPubMedCrossRefGoogle Scholar
  38. Lin Z, Zhang X, Tuo J et al (2008) A variant of the Cockayne syndrome B gene ERCC6 confers risk of lung cancer. Hum Mutat 29:113–122PubMedCentralPubMedCrossRefGoogle Scholar
  39. Lopes-Cendes I, Maciel P, Kish S et al (1996) Somatic mosaicism in the central nervous system in spinocerebellar ataxia type 1 and Machado–Joseph disease. Ann Neurol 40:199–206PubMedCrossRefGoogle Scholar
  40. Lopez Castel A, Tomkinson AE, Pearson CE (2009) CTG/CAG repeat instability is modulated by the levels of human DNA ligase I and its interaction with proliferating cell nuclear antigen: a distinction between replication and slipped-DNA repair. J Biol Chem 284:26631–26645PubMedCentralPubMedCrossRefGoogle Scholar
  41. 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
  42. Ma H, Hu Z, Wang H et al (2009) ERCC6/CSB gene polymorphisms and lung cancer risk. Cancer Lett 273:172–176PubMedCrossRefGoogle Scholar
  43. Ma H, Chen J, Pan S, Dai J, Jin G, Hu Z, Shen H, Shu Y (2011) Potentially functional polymorphisms in cell cycle genes and the survival of non-small cell lung cancer in a Chinese population. Lung Cancer 73:32–37PubMedCrossRefGoogle Scholar
  44. Maciel P, Gaspar C, DeStefano AL et al (1995) Correlation between CAG repeat length and clinical features in Machado–Joseph disease. Am J Hum Genet 57:54–61PubMedCentralPubMedGoogle Scholar
  45. Maciel P, Costa MC, Ferro A et al (2001) Improvement in the molecular diagnosis of Machado–Joseph disease. Arch Neurol 58:1821–1827PubMedCrossRefGoogle Scholar
  46. Manley K, Shirley TL, Flaherty L, Messer A (1999) Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice. Nat Genet 23:471–473PubMedCrossRefGoogle Scholar
  47. Martins S, Coutinho P, Silveira I, Giunti P, Jardim LB, Calafell F, Sequeiros J, Amorim A (2008) Cis-acting factors promoting the CAG intergenerational instability in Machado–Joseph disease. Am J Med Genet B Neuropsychiatr Genet 147B:439–446PubMedCrossRefGoogle Scholar
  48. Maruyama H, Nakamura S, Matsuyama Z et al (1995) Molecular features of the CAG repeats and clinical manifestation of Machado–Joseph disease. Hum Mol Genet 4:807–812PubMedCrossRefGoogle Scholar
  49. Mason AG, Tome S, Simard JP, Libby RT, Bammler TK, Beyer RP, Morton AJ, Pearson CE, La Spada AR (2014) Expression levels of DNA replication and repair genes predict regional somatic repeat instability in the brain but are not altered by polyglutamine disease protein expression or age. Hum Mol Genet 23:1606–1618PubMedCrossRefGoogle Scholar
  50. Michiels S, Danoy P, Dessen P, Bera A, Boulet T, Bouchardy C, Lathrop M, Sarasin A, Benhamou S (2007) Polymorphism discovery in 62 DNA repair genes and haplotype associations with risks for lung and head and neck cancers. Carcinogenesis 28:1731–1739PubMedCrossRefGoogle Scholar
  51. Mittal U, Srivastava AK, Jain S, Mukerji M (2005) Founder haplotype for Machado–Joseph disease in the Indian population: novel insights from history and polymorphism studies. Arch Neurol 62:637–640PubMedCrossRefGoogle Scholar
  52. Moe SE, Sorbo JG, Holen T (2008) Huntingtin triplet-repeat locus is stable under long-term Fen1 knockdown in human cells. J Neurosci Methods 171:233–238PubMedCrossRefGoogle Scholar
  53. Mu D, Wakasugi M, Hsu DS, Sancar A (1997) Characterization of reaction intermediates of human excision repair nuclease. J Biol Chem 272:28971–28979PubMedCrossRefGoogle Scholar
  54. Nakamori M, Pearson CE, Thornton CA (2011) Bidirectional transcription stimulates expansion and contraction of expanded (CTG)*(CAG) repeats. Hum Mol Genet 20:580–588PubMedCentralPubMedCrossRefGoogle Scholar
  55. Oakley GG, Patrick SM (2010) Replication protein A: directing traffic at the intersection of replication and repair. Front Biosci (Landmark Ed) 15:883–900CrossRefGoogle Scholar
  56. O’Hoy KL, Tsilfidis C, Mahadevan MS, Neville CE, Barcelo J, Hunter AG, Korneluk RG (1993) Reduction in size of the myotonic dystrophy trinucleotide repeat mutation during transmission. Science 259:809–812PubMedCrossRefGoogle Scholar
  57. Pearson CE (2003) Slipping while sleeping? Trinucleotide repeat expansions in germ cells. Trends Mol Med 9:490–495PubMedCrossRefGoogle Scholar
  58. Pearson CE, Nichol Edamura K, Cleary JD (2005) Repeat instability: mechanisms of dynamic mutations. Nat Rev Genet 6:729–742PubMedCrossRefGoogle Scholar
  59. Pinto RM, Dragileva E, Kirby A et al (2013) Mismatch repair genes Mlh1 and Mlh3 modify CAG instability in Huntington’s disease mice: genome-wide and candidate approaches. PLoS Genet 9:e1003930PubMedCentralPubMedCrossRefGoogle Scholar
  60. Pritchard C, Zhu N, Zuo J et al (1992) Recombination of 4p16 DNA markers in an unusual family with Huntington disease. Am J Hum Genet 50:1218–1230PubMedCentralPubMedGoogle Scholar
  61. Richards RI, Sutherland GR (1992) Dynamic mutations: a new class of mutations causing human disease. Cell 70:709–712PubMedCrossRefGoogle Scholar
  62. Rosenberg RN (1983) Dominant ataxias. Res Publ Assoc Res Nerv Ment Dis 60:195–213PubMedGoogle Scholar
  63. Sequeiros J, Martins S, Silveira I (2011) Epidemiology and population genetics of degenerative ataxias. In: Subramony S, Durr A (eds) Ataxic disorders, Chap. 14, Handbook of Clinical Neurology, Vol. 103 (3rd series). Elsevier, Edinburgh, pp 225–248Google Scholar
  64. Shah KA, Shishkin AA, Voineagu I, Pavlov YI, Shcherbakova PV, Mirkin SM (2012) Role of DNA polymerases in repeat-mediated genome instability. Cell Rep 2:1088–1095PubMedCentralPubMedCrossRefGoogle Scholar
  65. Silva-Fernandes A, Costa Mdo C, Duarte-Silva S et al (2010) Motor uncoordination and neuropathology in a transgenic mouse model of Machado–Joseph disease lacking intranuclear inclusions and ataxin-3 cleavage products. Neurobiol Dis 40:163–176PubMedCrossRefGoogle Scholar
  66. Takano H, Onodera O, Takahashi H et al (1996) Somatic mosaicism of expanded CAG repeats in brains of patients with dentatorubral-pallidoluysian atrophy: cellular population-dependent dynamics of mitotic instability. Am J Hum Genet 58:1212–1222PubMedCentralPubMedGoogle Scholar
  67. Tanaka F, Sobue G, Doyu M et al (1996) Differential pattern in tissue-specific somatic mosaicism of expanded CAG trinucleotide repeats in dentatorubral-pallidoluysian atrophy, Machado–Joseph disease, and X-linked recessive spinal and bulbar muscular atrophy. J Neurol Sci 135:43–50PubMedCrossRefGoogle Scholar
  68. Tanaka F, Ito Y, Sobue G (1999) Somatic mosaicism of expanded CAG trinucleotide repeat in the neural and nonneural tissues of Machado–Joseph disease (MJD). Nihon Rinsho 57:838–842PubMedGoogle Scholar
  69. Tome S, Manley K, Simard JP et al (2013) MSH3 polymorphisms and protein levels affect CAG repeat instability in Huntington’s disease mice. PLoS Genet 9:e1003280PubMedCentralPubMedCrossRefGoogle Scholar
  70. Tuo J, Ning B, Bojanowski CM et al (2006) Synergic effect of polymorphisms in ERCC6 5′ flanking region and complement factor H on age-related macular degeneration predisposition. Proc Natl Acad Sci USA 103:9256–9261PubMedCentralPubMedCrossRefGoogle Scholar
  71. van de Warrenburg BP, Hendriks H, Durr A, van Zuijlen MC, Stevanin G, Camuzat A, Sinke RJ, Brice A, Kremer BP (2005) Age at onset variance analysis in spinocerebellar ataxias: a study in a Dutch–French cohort. Ann Neurol 57:505–512PubMedCrossRefGoogle Scholar
  72. van den Broek WJ, Nelen MR, van der Heijden GW, Wansink DG, Wieringa B (2006) Fen1 does not control somatic hypermutability of the (CTG)(n)*(CAG)(n) repeat in a knock-in mouse model for DM1. FEBS Lett 580:5208–5214PubMedCrossRefGoogle Scholar
  73. Wold MS (1997) Replication protein A: a heterotrimeric, single-stranded DNA-binding protein required for eukaryotic DNA metabolism. Annu Rev Biochem 66:61–92PubMedCrossRefGoogle Scholar
  74. Yoon SR, Dubeau L, de Young M, Wexler NS, Arnheim N (2003) Huntington disease expansion mutations in humans can occur before meiosis is completed. Proc Natl Acad Sci USA 100:8834–8838PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Sandra Martins
    • 1
    • 2
  • Christopher E. Pearson
    • 3
    • 4
  • Paula Coutinho
    • 5
  • Sylvie Provost
    • 6
  • António Amorim
    • 2
    • 7
  • Marie-Pierre Dubé
    • 6
    • 8
  • Jorge Sequeiros
    • 9
    • 10
  • Guy A. Rouleau
    • 1
  1. 1.Department of Neurology and Neurosurgery, Montreal Neurological Institute and HospitalMcGill UniversityMontrealCanada
  2. 2.IPATIMUP, Institute of Molecular Pathology and ImmunologyUniversity of PortoPortoPortugal
  3. 3.Genetics and Genome BiologyThe Hospital for Sick ChildrenTorontoCanada
  4. 4.Program of Molecular GeneticsUniversity of TorontoTorontoCanada
  5. 5.Serviço Neurologia, Hospital São SebastiãoFeiraPortugal
  6. 6.The Montreal Heart Institute Research CentreMontrealCanada
  7. 7.Faculdade de CiênciasUniversidade do PortoPortoPortugal
  8. 8.Université de MontréalMontrealCanada
  9. 9.UnIGENeIBMCPortoPortugal
  10. 10.ICBASUniversidade do PortoPortoPortugal

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