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


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.


Nucleotide Excision Repair Huntington Disease Base Excision Repair Multiple Displacement Amplification Repeat Instability 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by the Canadian Institutes of Health Research; and the Levesque Chair for research in Neurogenetics [to G.A.R.]; and the Portuguese Foundation for Science and Technology [SFRH/BPD/77969/2011 to S.M].

Conflict of interest

The authors have declared that no competing interests exist.

Ethical standards

All experiments here described comply with the current laws of the countries in which they were performed.

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)


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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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