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

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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.

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Acknowledgments

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.

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Authors and Affiliations

  1. Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, 3801 rue University, Montreal, QC, H3A2B4, Canada

    Sandra Martins & Guy A. Rouleau

  2. IPATIMUP, Institute of Molecular Pathology and Immunology, University of Porto, 4200-465, Porto, Portugal

    Sandra Martins & António Amorim

  3. Genetics and Genome Biology, The Hospital for Sick Children, 686 Bay Street, Toronto, ON, M5G 0A4, Canada

    Christopher E. Pearson

  4. Program of Molecular Genetics, University of Toronto, Toronto, ON, M5S1A1, Canada

    Christopher E. Pearson

  5. Serviço Neurologia, Hospital São Sebastião, 4520-211, Feira, Portugal

    Paula Coutinho

  6. The Montreal Heart Institute Research Centre, Montreal, QC, H1T1C8, Canada

    Sylvie Provost & Marie-Pierre Dubé

  7. Faculdade de Ciências, Universidade do Porto, 4169-007, Porto, Portugal

    António Amorim

  8. Université de Montréal, Montreal, QC, H3T1J4, Canada

    Marie-Pierre Dubé

  9. UnIGENe, IBMC, 4150-180, Porto, Portugal

    Jorge Sequeiros

  10. ICBAS, Universidade do Porto, 4050-313, Porto, Portugal

    Jorge Sequeiros

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  1. Sandra Martins
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  2. Christopher E. Pearson
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  3. Paula Coutinho
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Correspondence to Christopher E. Pearson or Guy A. Rouleau.

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Martins, S., Pearson, C.E., Coutinho, P. et al. Modifiers of (CAG)n instability in Machado–Joseph disease (MJD/SCA3) transmissions: an association study with DNA replication, repair and recombination genes. Hum Genet 133, 1311–1318 (2014). https://doi.org/10.1007/s00439-014-1467-8

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