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.
Highlights
Huntington’s disease and myotonic dystrophy type 1 (DM1) are autosomal dominant disorders caused by CAGÁCTG trinucleotide repeat expansions
Illumina sequencing revealed that rs557874766 (Moss et al, 2017) was not a single nucleotide polymorphism (SNP), but an alignment artefact resulting from the complex 9-bp repeat sequence (Fig. 1C)
MSH3 has recently been identified as a genetic modifier of somatic instability in DM1 (Morales et al, 2016), and progression in Huntington’s disease (Moss et al, 2017)
Summary
Huntington’s disease and myotonic dystrophy type 1 (DM1) are autosomal dominant disorders caused by CAGÁCTG trinucleotide repeat expansions. Repeat tracts are unstable in somatic cells, tending to expand over time, in Huntington’s disease striatum (Kennedy et al, 2003) and DM1 muscle (Ashizawa et al, 1993), the most prominently affected tissues in each disease. Such expansion-biased, age-dependent and tissue-specific somatic instability is thought to contribute to disease onset and progression (Kennedy et al, 2003; Shelbourne et al, 2007; Swami et al, 2009; Morales et al, 2012)
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