A Genetic Modifier of DM1

Need to Identify Genetic Modifiers for DM

One need look no further than Duchenne muscular dystrophy to understand the power of genetic modifiers, where variants in SPP1, LTBP4, CD40, ACTN3, and THBS1 impact disease phenotype. At least two of these modifiers, SPP1 and LTBP4, impact patient phenotypes to the extent that they should be controlled for in interventional clinical trials. By contrast, the literature around putative genetic modifiers of the pathogenesis of DM1 is sparse. Most recently, data suggest that the rbFOX1 RNA binding protein can compete with MBNL1 for binding to expanded CCUG repeats, potentially mitigating the phenotype of DM2 versus DM1 flies (Sellier et al., 2018). The relative dearth of knowledge is an important gap in mechanistic understanding of DM, as genetic modifiers may prove important in stratification of subjects in clinical trials, as well as representing putative therapeutic development targets.

Extensive literature supports a key genetic modifier role for DNA mismatch repair (MMR) proteins in microsatellite expansion disorders, as these proteins are essential for triplet repeat instability. Previously, a variant of the MMR, MSH3, was associated with somatic expansion rate in DM1 (Morales et al., 2016). The validation of a putative genetic modifier acting at such an early stage in the pathogenic cascade in DM1 would have considerable value.

MSH3 Variant: A Modifier of Somatic Instability and Disease Severity

Studies by Drs. Sarah Tabrizi (University College London), Darren Monckton (University of Glasgow), and colleagues have examined whether an MSH3 variant may indeed modify the instability of the CAG·CTG expansions that underlie Huntington’s disease (HD) and DM1 (Flower et al., 2019). The research team conducted Illumina sequencing of DNA from HD (n = 218) and DM1 (two cohorts, n = 247 and n = 199, as well as a meta-analysis that included the Morales et al. cohort) subjects and showed that a three-repeat allele in MSH3 exon 1 (3a allele) is associated with a reduced relative rate of somatic CAG·CTG expansion and delayed disease age of onset for HD and DM1. These data were supported by further studies in HD subjects.

The mechanism of action of the MSH3 variant in regulating triplet repeat stability is not yet known. The MSH3 3a allele might alter the MMR protein expression level or, alternatively, compromise its recognition and repair functions and thereby impact repeat length. Overall, the team suggests that a common MMR mechanism operating in HD and DM1 mediates trinucleotide repeat expansion and that this mechanism may be a viable target in therapeutic development for these two diseases, if not additional diseases.


rbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophytype 1/type 2 differences.
Sellier C, Cerro-Herreros E, Blatter M, Freyermuth F, Gaucherot A, Ruffenach F, Sarkar P, Puymirat J, Udd B, Day JW, Meola G, Bassez G, Fujimura H, Takahashi MP, Schoser B, Furling D, Artero R, Allain FHT, Llamusi B, Charlet-Berguerand N.
Nat Commun. 2018 May 22;9(1):2009. doi: 10.1038/s41467-018-04370-x.

A polymorphism in the MSH3 mismatch repair gene is associated with the levels of somatic instability of the expanded CTG repeat in the blood DNA of myotonic dystrophy type 1 patients.
Morales F, Vásquez M, Santamaría C, Cuenca P, Corrales E, Monckton DG.
DNA Repair (Amst). 2016 Apr;40:57-66. doi: 10.1016/j.dnarep.2016.01.001. Epub 2016 Mar 8.

MSH3 modifies somatic instability and disease severity in Huntington's and myotonic dystrophy type 1.
Flower M, Lomeikaite V, Ciosi M, Cumming S, Morales F, Lo K, Hensman Moss D, Jones L, Holmans P; TRACK-HD Investigators; OPTIMISTIC Consortium, Monckton DG, Tabrizi SJ.
Brain. 2019 Jun 19. pii: awz115. doi: 10.1093/brain/awz115. [Epub ahead of print]

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