The consequences of the unusual mutation responsible for the Repeat Expansion Diseases

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Background: The REDs are a group of 45+ incurable human disorders that are caused by expansions of a disease-specific tandem repeat or microsatellite. These diseases include 11 that result from the presence of a large CGG-repeat tract present with the transcriptional unit of the affected gene. In those diseases involving very large repeats, referred to as full mutation (FM) alleles, repeat-mediated gene silencing occurs. This results in a deficiency of the protein product of the affected gene that is the proximal cause of disease pathology. In the case of Fragile X syndrome (FXS), the most common heritable cause of intellectual disability and autism, the silenced gene is the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene. As a result, the amount of the protein product of FMR1, FMRP, is severely reduced. FMRP is involved in, amongst many other things, the regulation of translation in the brain. In contrast, mid-size repeat tracts, so-called premutation (PM) alleles, are often hyper-expressed, with pathology arising via some deleterious consequence of the expression of transcripts with larger than normal numbers of CGG-repeats, the nature of which is the subject of much debate. This results in a form of neurodegeneration known as Fragile X associated tremor/ataxia syndrome (FXTAS) and a form of ovarian dysfunction known as Fragile X associated primary ovarian insufficiency (FXPOI). Other CGG-REDs show a similar pattern of hyper-expression of mid-size alleles and silencing of larger ones. In addition, the large and silent alleles in many of these diseases are associated with a folate-sensitive fragile site that colocalizes with the affected gene. Our previous work has helped define the heterochromatin landscape associated with Fragile X alleles (Biacsi et. al., 2008; Kumari and Usdin, 2010; Kumari et. al., 2014; Zhou et. al., 2016; Kumari et. al., 2020), identified the likely timing of the silencing window (Zhou et. al., 2016) and implicated the FMR1 transcript in the silencing process (Kumari and Usdin, 2014). We were also amongst the first to show that repeat-mediated gene silencing also occurs in Friedreich ataxia, a disorder resulting from a GAA-repeat expansion in the first intron of the frataxin (FXN) gene (Greene et. al., 2007) and more recently we showed that epigenetic silencing is also seen in a glutaminase deficiency disorder resulting from a CAG (GCA)-expansion in the 5 UTR of the Glutaminase 1 (GLS1) gene (van Kuilenberg et. al., 2019). In this review period we have continued our studies on the molecular events associated with gene silencing and reactivation in FXS and on the identification of new small molecules that can block gene silencing. In the process we have uncovered new evidence for the effect of long CGG-repeats on chromosomal integrity and the processes involved in preventing deleterious chromosomal rearrangements (manuscript in preparation). We are also continuing our efforts to identify new Repeat Expansion Diseases and to help with the diagnosis of unusual cases of previously identified diseases (e.g., Fazal et. al., 2023).