Fragile X syndrome, the most common genetic disorder associated with mental retardation, is caused by an expansion of the unstable CGG repeat within the FMR1 gene. As a result of this expansion, the CGG repeat and the upstream CpG island are methylated and FMR1 expression is silenced. The absence of the FMR1 gene product, the fragile X mental retardation protein (FMRP), in neurons leads to cognitive impairment.

Since the identification of the FMR1 gene, basic research has been focused on the molecular characterization of the FMR1 gene product (FMRP), the fragile X related proteins (FXR1P and FXR2P), the mechanisms of repeat amplification and transcriptional silencing of the FMR1 gene.

Animal models in fragile X research have provided new insights and knowledge about the physiological function of FMRP in the cell and the nerve cell in particular. In addition, in vitro studies have been applied to gather knowledge about FMRP transport kinetics using primary neuronal cultures. Currently, compelling evidence suggests a role of FMRP in the transport/translation of dendritically localized mRNAs and has led to an increased interest in the role of FMRP in dendritic mRNA transport/translation in relation to synaptic plasticity, a molecular mechanism implicated in learning and memory.

Recently, a new neurodegenerative disorder (FXTAS) associated with the fragile X premutation has been recognized. FXTAS (fragile X associated tremor/ataxia syndrome) represents a severe form of neurodegenerative disorder associated with the fragile X premutation, including tremor and/or ataxia, neuropathy, autonomic dysfunction and memory and executive function deficits. We succeeded in the generation of a mouse model for FXTAS.

Schematic representation of the FMR1 gene with KH domain , RGG boxes and the nucleocyplasmic shuttling signals NLS and NES. In the 5’ part of the gene the CGG repeat is shown for control (N), premutation (P) and patients (F). The G-quartet structure present in the mRNA is depicted above the RGG box for which it encodes and to which it binds.