Mechanisms of Genome Instability in the Fragile X-Related Disorders.

Bruce E Hayward,Karen Usdin

doi:10.3390/genes12101633

Abstract

The Fragile X-related disorders (FXDs), which include the intellectual disability fragile X syndrome (FXS), are disorders caused by expansion of a CGG-repeat tract in the 5′ UTR of the X-linked FMR1 gene. These disorders are named for FRAXA, the folate-sensitive fragile site that localizes with the CGG-repeat in individuals with FXS. Two pathological FMR1 allele size classes are distinguished. Premutation (PM) alleles have 54–200 repeats and confer the risk of fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). PM alleles are prone to both somatic and germline expansion, with female PM carriers being at risk of having a child with >200+ repeats. Inheritance of such full mutation (FM) alleles causes FXS. Contractions of PM and FM alleles can also occur. As a result, many carriers are mosaic for different sized alleles, with the clinical presentation depending on the proportions of these alleles in affected tissues. Furthermore, it has become apparent that the chromosomal fragility of FXS individuals reflects an underlying problem that can lead to chromosomal numerical and structural abnormalities. Thus, large numbers of CGG-repeats in the FMR1 gene predisposes individuals to multiple forms of genome instability. This review will discuss our current understanding of these processes.

Highlights

The repeat tract, which is coincident with the fragile site at Xq27.3, explains the unusual inheritance pattern that had become known as the Sherman paradox; the repeat is expansion prone, tending to gain repeats with each successive generation, with symptoms of fragile X syndrome (FXS) only becoming apparent when the repeat number exceeds 200 [5]
FX cells treated with 5-fluoro-20 -deoxyuridine (FdU), a direct inhibitor of thymidylate synthase, show an increase in the expression of the fragile site, and in the incidence of ultrafine anaphase bridges arising at the FMR1 locus [47]
Fragile X-related disorders (FXDs),the thesecond secondin inthe the form form of of deletions of FXS, and the third in the form of chromosomal structural and numerical abnormalities of FXS, and the third in the form of chromosomal structural and numerical abnormalities that can result from problems associated with replication the repeats including fragile that can result from problems associated with replication ofof the repeats including fragile site expression

Summary

Introduction

The repeat tract, which is coincident with the fragile site at Xq27.3, explains the unusual inheritance pattern that had become known as the Sherman paradox; the repeat is expansion prone, tending to gain repeats with each successive generation, with symptoms of FXS only becoming apparent when the repeat number exceeds 200 [5] Such alleles are known as full mutation (FM) alleles and the symptoms of this disorder arise because the FM allele undergoes a process of repeat-mediated gene silencing that results in a deficit of FMRP [6]. In addition to the expansions that cause these disorders, contractions of the repeat and deletions associated with the loss of flanking sequences are associated with PM and FM alleles In some cases, this generates a normal sized allele [8,9,10,11]. This review will discuss evidence from PM and FM carriers and patients with other repeat expansion diseases that allows us to narrow our focus to a subset of possible mechanisms that account for these events

FRAXA Chromosome Fragility

Repeat

Repeat Expansions

Repeat Contractions

Findings

Concluding Remarks