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 caused by increases in the size of a disease-specific microsatellite. The Fragile X-related disorders (FXDs) arise from expansion of a CG -repeat in the 5' UTR of the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene. Carriers of alleles with 55-200 repeats, so-called premutation (PM) alleles, are at risk for a neurodegenerative disorder, Fragile X-associated tremor-ataxia syndrome (FXTAS), and a form of ovarian dysfunction known as Fragile X-associated primary ovarian insufficiency (FXPOI). Furthermore, in females, the PM allele can undergo expansion on intergenerational transfer that can result in their children having alleles with >200 repeats. This expanded allele is known as a full mutation (FM) and, with very few exceptions, all individuals who inherit such alleles have Fragile X syndrome (FXS), the leading heritable cause of intellectual disability and autism. FXS symptoms arise because repeat expansion leads to gene silencing and the subsequent absence of FMRP, the FMR1 gene product. The mechanism by which is expansion occurs is not fully understood but is thought to differ from the generalized microsatellite instability (MSI) seen in many different cancers in that instability is confined to a single genetic locus and, as we have shown previously, genes involved in mismatch repair (MMR) that normally protect against MSI in cancer are actually required to generate the FX mutation in a mouse model of the FXDs (sZhao et. al., 2021). Progress report: Recently, some of the MMR genes shown by us and others to be important for expansion in different mouse models, were shown to be some of the most impactful modifiers of age at onset of many other REDS. This effect was subsequently shown to be related to their involvement in protecting against or promoting somatic expansion. In a collaboration with the Tassone lab (UC Davis), we have carried out the first detailed characterization of somatic instability in 400+ women carrying Fragile X PM alleles and provided preliminary evidence that some of the same genes are also implicated in expansions in the FXDs (Hwang et. al., 2022). This lends weight to the idea that the REDs share a common expansion mechanism and that our mouse model is relevant for understanding this process. In this review period we also showed that FAN1, a nuclease first shown to be involved in the Fanconia anemia pathway of DNA repair, requires its nuclease activity for the protective effect we had previously demonstrated (Zhao and Usdin, 2018; Zhao, Lu and Usdin, 2021). Furthermore, we showed that this protective effect is independent of the Fanconi anemia pathway (Zhao, Lu and Usdin, 2021). While this work was in progress it was shown that FAN1 also plays a role in MMR. Thus, the simplest explanation for our observations is that FAN1, like EXO1 which we have also shown to be important in protecting against expansion (Zhao et. al., 2018), does so, at least in part, by facilitating canonical MMR. We have also shown that for a number of mouse models of different REDs, stool is a much better source of DNA for studying expansions than is blood (Zhao et. al., 2022). It allows potential genetic and environmental modifiers of expansion risk to be rapidly evaluated in the same animal over time (Zhao et. al., 2022).