Understanding the mutational mechanism responsible for the Repeat Expansion Diseases

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Background: The Repeat Expansion Diseases (REDs) are a group of >46 human genetic disorders caused by an expansion or an increase in the number of repeat units in a disease-specific short tandem repeat (STR) or microsatellite. In total, these diseases are thought to affect 1 in 283 people. The mechanism by which the expansions occur is not fully understood but is thought to differ from the generalized microsatellite instability (MSI) seen in many different cancers. Specifically, instability is confined to a single genetic locus and, as we and others have shown previously, genes involved in mismatch repair (MMR) that normally protect against MSI in cancer, are actually required to generate expansions in different models of the these diseases (reviewed in Zhao et. al., 2021). Recent genome wide association studies (GWAS) in REDs like Huntington’s disease (HD; OMIM #143100) have implicated single-nucleotide polymorphisms (SNPs) in some of the same MMR factors in somatic expansion in patients. Our recent candidate SNP approach extends these findings to the Fragile X-related disorders (FXDs: OMIM #311360; #300623 and #300624), a group of REDs caused by a CGG-repeat expansion in the FMR1 gene (Hwang et. al., 2022; Aishworiya et. al., 2023; Protic et. al., 2023). These data lend weight to the idea that many REDs may share a common expansion mechanism. Furthermore, the GWAS data support the hypothesis, that in some REDs expansion that occurs in somatic cells during an individual’s lifetime affects not only the age-at-disease-onset but disease severity as well. In the absence of effective treatments for the downstream consequences of repeat expansion in most of these diseases, therapeutic efforts to reduce or reverse the expansions has gained interest. Progress report: We have shown that PMS2, MLH3 and PMS1, the binding partners of MLH1 in the MutLalpha, MutLgamma and MutLbeta complexes respectively, are all required for expansion in stem cell models of the FXDs (Miller et. al., 2020), a glutaminase deficiency (OMIM # 618412)(Hayward et. al., 2024) and HD (manuscript in preparation). Since these factors have not previously been reported to act together, this unusual finding adds further support for a single expansion mechanism for all of these diseases. Not only does it suggest a novel co-operative role of the MutL complexes in expansion, but it is the first essential role for PMS1 reported. Since unlike the other MLH1 binding proteins, loss of PMS1 is not associated with elevated oncogenic risk, it also lends support for PMS1 as a therapeutic target for reducing repeat expansion. Our efforts to understand PMS1’s role in repeat expansion may also add to our understanding of the events associated with normal mismatch repair. We have also shown that PMS2 has seemingly paradoxical effects in different cell types, driving expansion in some and protecting against it in others. Our data suggests that this unexpected behavior depends on gene dosage and reconciles some of the differences reported for the effect of PMS2 in different diseases and disease models. The most parsimonious model to explain this effect is consistent with in vitro work demonstrating different cleavage preferences of MutLalpha and MutLgamma (Jimenez et. al., manuscript submitted). We also showed that the FANCJ helicase, which resolves DNA secondary structures, reduces the expansion rate in some cell types (Jimenez et. al., 2025). In contrast, we found that mutations in many pathways for the repair of double-strand breaks do not affect expansions, a finding with interesting implications for the expansion mechanism (Hayward et. al., 2025).