Abstract

The Known Unknowns: Missing Pieces in in vivo Models of Fragile X Syndrome

Highlights

  • Fragile X Syndrome (FXS) is one of the most studied monogenic neurological syndromes over the past few decades

  • Fragile X Syndrome (FXS) is a rare disease and the leading monogenic cause of Autism Spectrum Disorders (ASD). It is caused by the silencing of the Fragile X mental retardation (FMR1) gene and the subsequent reduction or loss of fragile X mental retardation protein (FMRP)

  • We have summarised the major clinical characteristics and possible mechanisms underlying clinical phenotypes associated with FXS and other disorders that arise from abnormalities in the FMR1 locus, such as fragile-X associated tremor/ataxia syndrome (FXTAS), fragile-X-associated neuropsychiatric disorders (FXAND) including ASD and fragile x-associated primary ovarian insufficiency (FXPOI)

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Summary

Introduction

Fragile X Syndrome (FXS) is one of the most studied monogenic neurological syndromes over the past few decades. With a carefully chosen combination of artificial repeat insertion, control of FMR1 RNA levels and manipulation of the DNA replication or repair pathways to promote slippage, it may be possible to develop such a model We believe that such studies can be conducted in simpler models like yeast[46], used to derive optimal conditions which may be moved into higher models like Zebrafish and mouse, to create true FXS models. It may be prudent to conduct such studies in models like Danio rerio (Zebrafish) where true “wild type” animals (wild caught) can be used (incorporating the genetic diversity present in the natural world), with as large a sample size as required to power the statistics Such an approach may allow one to incorporate the varied baselines in the population (for example, the median increase in anxiety in wild-caught vs lab-wild type strains50) and multi-factorial influences on the neurological phenotypes during the screening process to make results more robust[57]. Implementation of such strategies and the consequent identification of efficacious treatments may cause a paradigm shift in the way rare disease biology, modelling and drug development is practiced in the future

Funding and Acknowledgements
Conclusions and future outlook
Conflict of Interest Statement

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