Modifiers of (CAG)n instability in Machado–Joseph disease (MJD/SCA3) transmissions: an association study with DNA replication, repair and recombination genes
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.
KeywordsNucleotide Excision Repair Huntington Disease Base Excision Repair Multiple Displacement Amplification Repeat Instability
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.
All experiments here described comply with the current laws of the countries in which they were performed.
- 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
- Coutinho P (1992) Doença de Machado–Joseph—Tentativa de definição. University of Porto, PortugalGoogle Scholar
- 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
- 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
- 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
- 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
- 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
- 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
- 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