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

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.

Repeat instability during DNA repair: Insights from model systems

“…The loss of the fly XPG homolog, Mus201, reduced expansion in a Drosophila model of SCA3 (Jung & Bonini, 2007) while the loss of CSB in a mouse model for FXS led to a lower frequency of germ-line expansions in older females and a reduction in the extent of somatic expansions in some tissues (Zhao & Usdin, 2014). A role for CSB in expansions is appealing given the demonstration that a CSB variant is associated with increased expansion risk in humans with SCA3 (Martins et al ., 2014). However, in a HD mouse model, the loss of CSB alone had no significant effect on somatic expansions in a wild-type background, although it did increase the somatic expansion frequency in Ogg1 null mice (Kovtun et al ., 2011).…”

The Repeat Expansion Diseases: The dark side of DNA repair

“…It could also act via its ability to modify chromatin and/or increase transcription elongation [95, 96]. While very few genetic modifiers of expansion risk in humans have thus far been identified, it is interesting to note that single nucleotide polymorphisms (SNPs) in three TCR-related genes are associated with an increased expansion risk in Machado-Joseph Disease (MJD/SCA3) alleles, including one in the ERCC6/CSB gene [97]. …”

Modulation of trinucleotide repeat instability by DNA polymerase β polymorphic variant R137Q

“…This includes the polymorphisms in OGG1(Rs1052133) (Ser326Cys) [77, 78], MSH3 (Rs26279) [56], XPC [78] and ERCC6 (rs2228528) [60]. This suggests that the polymorphisms of proteins of BER, mismatch repair (MMR) and nucleotide excision repair (NER) pathways can modulate TNR instability.…”

“…polymorphism of DNA repair enzymes and cofactors, 8-oxoguanine DNA glycosylase (OGG1) [48, 49], APE1 [50], X-ray repair cross-complementing protein 1 (XRCC1) [51–53], XPC [54, 55], MSH3 [56–59], RPA-CDK7 [60] among others have been reported to be associated with cancer and neurodegenerative diseases. However, some studies do not support the notion [61–63].…”