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 (Zhao 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 (Zhao et. al., 2015; 2018), 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 evidence that some of the same genes are also implicated in expansions in the FXDs (Hwang et. al., 2022; Aishworiya et. al., 2023; Protic et. al., 2023). 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. This work also showed a correlation between increased somatic expansion and attention deficit hyperactivity disorder (ADHD) seen in some carriers (Aishworiya et. al., 2023). 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 and also may be useful for use in clinical trials of compounds that affect repeat expansion.