Repeat-mediated genetic and epigenetic changes at the FMR1 locus in the Fragile X-related disorders

Abstract

The Fragile X-related disorders are a group of genetic conditions that include the neurodegenerative disorder, Fragile X-associated tremor/ataxia syndrome (FXTAS), the fertility disorder, Fragile X-associated primary ovarian insufficiency (FXPOI) and the intellectual disability, Fragile X syndrome (FXS). The pathology in all these diseases is related to the number of CGG/CCG-repeats in the 5′ UTR of the Fragile X mental retardation 1 (FMR1) gene. The repeats are prone to continuous expansion and the increase in repeat number has paradoxical effects on gene expression increasing transcription on mid-sized alleles and decreasing it on longer ones. In some cases the repeats can simultaneously both increase FMR1 mRNA production and decrease the levels of the FMR1 gene product, Fragile X mental retardation 1 protein (FMRP). Since FXTAS and FXPOI result from the deleterious consequences of the expression of elevated levels of FMR1 mRNA and FXS is caused by an FMRP deficiency, the clinical picture is turning out to be more complex than once appreciated. Added complications result from the fact that increasing repeat numbers make the alleles somatically unstable. Thus many individuals have a complex mixture of different sized alleles in different cells. Furthermore, it has become apparent that the eponymous fragile site, once thought to be no more than a useful diagnostic criterion, may have clinical consequences for females who inherit chromosomes that express this site. This review will cover what is currently known about the mechanisms responsible for repeat instability, for the repeat-mediated epigenetic changes that affect expression of the FMR1 gene, and for chromosome fragility. It will also touch on what current and future options are for ameliorating some of these effects.

Fragility Extraordinaire: Unsolved Mysteries of Chromosome Fragile Sites

“…For instance, in the case of the FMR1 gene at FRAXA, a full mutation (>200 CGG repeats) induces FMR1 gene silencing and results in the fragile X syndrome, while premutation alleles (55–200 CGG repeats) cause fragile X-associated ataxia/tremor syndrome and fragile X-associated primary ovarian insufficiency [note: premutation alleles do not cause chromosome fragility] (Galloway and Nelson 2009; Garcia-Arocena and Hagerman 2010; Santoro et al 2012; Usdin et al 2014). These observations suggest that impaired function of the RFS-associated genes can also impact organs other than the brain.…”

Fragile X spectrum disorders

“…There are at least 3 mechanisms that could explain the elevation of FMR1 mRNA (89). One suggests that the observed increase of acetylated histones at the FMR1 promoter (118) could increase the FMR1 gene transcription.…”

“…Premutation carries can present with facial dysmorphic features and the most common finding is prominent ears (89,90). Recently a study of premutation carriers found that 33% of postpubertal carrier males had macroorchidism (93).…”

“…Colak et al (2014), suggested an RNA mediated mechanism of silencing, in which the FMR1 gene is silenced through a hybridization of the complementary CGG-repeat track of the FMR1 mRNA (92). Other RNA-mediated mechanisms have been suggested to involve the formation of RNA hairpins subtracts of the enzyme Dicer, RNA-DNA hybrids for chromatin compaction and promoter antisensetranscripts (89). The silencing mechanisms of FMR1 are potential targets for drug therapy.…”

“…There are mechanisms that could explain the reduced transcription of the FMR1 gene in the full mutation; these mechanisms can be divided in two groups: DNA-mediated and RNA-mediated (89). A model in which hairpin aggregation by the CGG repeats results in the DeNovo methylation has been suggested because tridimensional CGG-structures can trigger their own methylation by DNA methyltransferases in vitro (90); another suggested DNA-mediated model involves repeat-binding transcription factors which in turn can aggregate other proteins and prevent transcription.…”