Abstract
The fragile X-related disorders (FXDs) are a group of clinical conditions that result primarily from an unusual mutation, the expansion of a CGG-repeat tract in exon 1 of the FMR1 gene. Mouse models are proving useful for understanding many aspects of disease pathology in these disorders. There is also reason to think that such models may be useful for understanding the molecular basis of the unusual mutation responsible for these disorders. This review will discuss what has been learnt to date about mechanisms of repeat instability from a knock-in FXD mouse model and what the implications of these findings may be for humans carrying expansion-prone FMR1 alleles.
Highlights
IntroductionThe fragile X-related disorders (FXDs) are X-linked disorders that include a form of ovarian dysfunction known as fragile X-associated primary ovarian insufficiency (FXPOI; MIM# 311360), a neurodegenerative condition, fragile X-associated tremor/ataxia syndrome (FXTAS; MIM# 300623)
The fragile X-related disorders (FXDs) are X-linked disorders that include a form of ovarian dysfunction known as fragile X-associated primary ovarian insufficiency (FXPOI; MIM# 311360), a neurodegenerative condition, fragile X-associated tremor/ataxia syndrome (FXTAS; MIM# 300623)and fragile X syndrome (FXS; MIM# 300624), a major cause of intellectual disability and autism [1].FXPOI and FXTAS are seen in carriers of FMR1 premutation (PM) alleles, alleles that have a tandem array of 55–200 CGG repeats in exon 1
The fact that larger expansions and contractions that occur later in development are difficult to detect in mice, raises the possibility that some humans may be even more mosaic than analysis of their bulk DNA suggests
Summary
The fragile X-related disorders (FXDs) are X-linked disorders that include a form of ovarian dysfunction known as fragile X-associated primary ovarian insufficiency (FXPOI; MIM# 311360), a neurodegenerative condition, fragile X-associated tremor/ataxia syndrome (FXTAS; MIM# 300623). FXPOI and FXTAS are seen in carriers of FMR1 premutation (PM) alleles, alleles that have a tandem array of 55–200 CGG repeats in exon 1. In contrast PM alleles are transcriptionally active and can have transcript levels anywhere between 2 and 8 times the levels of normal alleles [2] Both FM and PM carriers show wide variability in their clinical presentation and both FXTAS and FXPOI show incomplete penetrance suggesting the contribution of other genetic factors to disease severity. Mouse models offer a number of clear advantages over some of these cell-based systems, including the high frequency of both expansions and contractions and the ability to examine instability in different biologically relevant organs at various stages of development. We will discuss some of the implications of this information for diagnosis and disease risk assessment in humans
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
