Genetic Variation in MSH3 That Lowers Its Expression Ameliorates Disease Course and Limits Repeat Expansion in Huntington’s Disease and Myotonic Dystrophy Type 1

Background: Huntington’s disease (HD) and myotonic dystrophy type 1 (DM1) are dominantly inherited diseases caused respectively by CAG and CTG repeat expansions. In both, inherited repeat length correlates positively with severity and negatively with onset. Expanded repeats are unstable through the germline, and somatically, likely contributing to onset and progression. Genetic: variation in MSH3, a DNA mismatch repair protein, is associated with slower HD progression and a lower rate of somatic expansion in DM1. The lead SNP in a GWAS of HD progression, rs557874766, is located in a polymorphic 9 bp tandem repeat in MSH3 exon 1. Msh3 inactivation in animal models of HD and DM1 is known to prevent repeat expansion and ameliorate disease phenotype. Aim: Determine the exact genotype of the MSH3 exon 1 repeat and conduct genotype-phenotype analysis in HD and DM1. Methods/techniques: We conducted next-generation sequencing of the MSH3 repeat region in cohorts of 218 HD and 200 DM1 patients. RNA-Seq was used to quantify whole blood MSH3 expression in HD subjects. In a transcriptome-wide association study (TWAS), MSH3 expression from human prefrontal cortex was imputed into HD GWAS data. Results/outcome: Rs557874766 was found to be an alignment artefact due to the sequence complexity of varying numbers of 9 bp tandem repeats. Individuals who appeared to have the rs557874766 minor allele, associated with delayed HD onset, had a three-repeat variant (allele frequency 26%). Fourteen MSH3 repeat alleles were observed, with the commonest containing six repeats and corresponding to the reference sequence. Each copy of the three-repeat allele slows HD progression by 0.34 UHDRS motor units and 0.1 functional capacity units per year (p=2.18E-7), and delays onset by 2.08 years (p=0.037). In DM1 each three-repeat allele correlates with a lower rate of somatic expansion (p=0.02) and later age of onset (p=0.04). Three-repeat homozygotes had significantly lower MSH3 expression in blood (p=0.028). The TWAS identified significant association of decreased MSH3 with slow progression (p=2.52E-6). Conclusion: A three-repeat variant in MSH3 exon 1 is associated with reduced MSH3 expression and slower progression in HD, reduced rate of somatic expansion in DM1 and delayed onset in both diseases. Genetic variation reducing MSH3 expression may reduce somatic expansion, delay onset and slow progression. Therapies reducing MSH3 could ameliorate several repeat expansion diseases.