MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1

Abstract

The mismatch repair gene MSH3 has been implicated as a genetic modifier of the CAG·CTG repeat expansion disorders Huntington’s disease and myotonic dystrophy type 1. A recent Huntington’s disease genome-wide association study found rs557874766, an imputed single nucleotide polymorphism located within a polymorphic 9 bp tandem repeat in MSH3/DHFR, as the variant most significantly associated with progression in Huntington’s disease. Using Illumina sequencing in Huntington’s disease and myotonic dystrophy type 1 subjects, we show that rs557874766 is an alignment artefact, the minor allele for which corresponds to a three-repeat allele in MSH3 exon 1 that is associated with a reduced rate of somatic CAG·CTG expansion (P = 0.004) and delayed disease onset (P = 0.003) in both Huntington’s disease and myotonic dystrophy type 1, and slower progression (P = 3.86 × 10−7) in Huntington’s disease. RNA-Seq of whole blood in the Huntington’s disease subjects found that repeat variants are associated with MSH3 and DHFR expression. A transcriptome-wide association study in the Huntington’s disease cohort found increased MSH3 and DHFR expression are associated with disease progression. These results suggest that variation in the MSH3 exon 1 repeat region influences somatic expansion and disease phenotype in Huntington’s disease and myotonic dystrophy type 1, and suggests a common DNA repair mechanism operates in both repeat expansion diseases.

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

“…Given the lack of experimental data, analysis of big data sets can address this question. Numerous genome-wide association studies have found that SNPs in the MLH1 and MSH3 genes act as genetic modifiers of HD's age of onset (128,130,(325)(326)(327)440). Likewise, an SNP in PMS2 modifies age of onset in several other poly(Q) diseases (441).…”

“…Likewise, an SNP in PMS2 modifies age of onset in several other poly(Q) diseases (441). Furthermore, an SNP in MSH3 affects the CTG repeat somatic instability level in DM1 patients (28,440).…”

Expanded CAG/CTG Repeats Resist Gene Silencing Mediated by Targeted Epigenome Editing

“…The case of HDAC5 is possibly more complex as its partner, HDAC3, has been speculated to play a role in the deacetylation of MSH3 [32], which is a known modifier of repeat instability [32,55,[58][59][60][61][62][63][64][65][66][67]. The results obtained with PInT are concordant with a role for HDAC5 in trans, which may be that it helps control the deacetylation of MSH3 before it binds to the repeat tract.…”

DM1 Phenotype Variability and Triplet Repeat Instability: Challenges in the Development of New Therapies

“…In trinucleotide repeat mouse models, MSH3 expression is an important parameter in the degree of triplet instability and is considered as a limiting factor in this process [59,[63][64][65]. Recent data revealed that MSH3 single-nucleotide polymorphisms are associated with somatic mosaicism rates by potentially modifying MSH3 expression and/or activity in DM1 large cohorts [66,67]. In addition, genetic association analyses suggest that MSH3/DHFR three tandem repeat alleles, named 3a alleles, may reduce somatic rates but also delay the onset in DM1 patients [67].…”

“…Recent data revealed that MSH3 single-nucleotide polymorphisms are associated with somatic mosaicism rates by potentially modifying MSH3 expression and/or activity in DM1 large cohorts [66,67]. In addition, genetic association analyses suggest that MSH3/DHFR three tandem repeat alleles, named 3a alleles, may reduce somatic rates but also delay the onset in DM1 patients [67]. MSH3 is clearly a genetic modifier of somatic instability in DM1 but also in other CTG•CAG trinucleotide repeat diseases, suggesting a common mechanism [66,67].…”