Fragile X syndrome (FXS) in UK is a common and important disease, affecting 2.5% of males with learning disabilities. Expansion of the CGG repeat within the human FMR1 gene gives rise to Fragile X syndrome (FXS) through the elimination of FMR1 RNA by a silencing effect upon the gene promoter when the repeat length increases beyond 200 repeats. The causes of this silencing are unknown, but CGG repeat length is critical and silencing occurs through modification of local chromatin structure and DNA methylation. FXS carriers carry lengths of CGG between 55 and 200 repeats. The repeat is unstable between generations, expanding progressively to reach the threshold at which gene silencing occurs. The transition to over 200 repeats occurs exclusively upon transmission from female carriers.
The FMR1 gene encodes the fragile X mental retardation protein (FMRP), which is a RNA-binding protein. FMRP has been proposed to be involved in modulating translation through its binding to cellular RNAs and ribosomes. FMRP is found associated with ribosomal components at the base of dendritic spines, and it has been proposed that it is involved in the regulation of local translation of mRNA in response to synaptic stimulation signals. This suggests that FMRP has a role to play in the normal mechanism of synaptic plasticity. The FMR1 RNA can also be found located in dendrites and that its translation could be modulated by group 1 metabotropic glutamate receptor (Gp1 mGluR) agonists. LTD that is associated with the activation of metabotrophic glutamate receptors and requires protein synthesis, has been reported to be increased in the hippocampus of the FMRP deficient mouse. In FXS, neurons exhibit long, spindly dendritic spines that appear to be morphologically immature. The role of FMRP in regulation of translation of many other mRNAs has been supported by its association with components of the RNAi machinery, strongly suggesting that its role could be to interact with regulatory MiRNAs.
There are a growing number of reports of clinical phenotypes associated with FX carrier status: FX-associated primary ovarian insufficiency (FX-POI) in 20% carrier females and a form of ataxia, found predominantly in males (FXTAS) that is associated with the presence of neuronal inclusions post-mortem. Evidence that the cellular defects that underlie these phenotypes are due to the presence of the expanded CGG repeat within the FMR1 mRNA (rCGG) has come from models in both mouse and fly, where expression is associated with neuronal degeneration and inclusion formation. This suggests that the toxic rCGG effect might be a clinically important cause of early onset menopause in women in the UK and also a cause of ataxia.
Research related to Fragile X syndrome is being carried out into:
- DNA instability in CGG and other triplet repeats (Hirst, Murphy)
- The effects of neuronal physiology on DNA damage & repair and the effects upon triplet repeat expansion (Hirst, Murphy)
- Dendritic spine dynamics in learning and memory models (Stewart)
- Cellular and molecular neurophysiology in the prefrontal cortex (Murphy)
Dr Mark Hirst is a scientific advisor to the UK Fragile X Society (
http://www.fragilex.org.uk/)
