Reduced excitatory amino acid transporter 1 and metabotropic glutamate receptor 5 expression in the cerebellum of fragile X mental retardation gene 1 premutation carriers with fragile X-associated tremor/ataxia syndrome.

A premutation (PM) expansion (55-200 CGG) in the fragile X mental retardation gene 1 causes elevated messenger RNA and reduced fragile X mental retardation gene 1 protein. Young PM carriers can develop characteristic physical features and mild cognitive disabilities. In addition, individuals with PM, particularly male carriers, are at high risk to develop fragile X-associated tremor/ataxia syndrome (FXTAS) with aging. Human postmortem FXTAS brains show extensive white matter disease in the cerebellum and the presence of intranuclear inclusions throughout the brain, although their etiologic significance is unknown. In the current work, expression levels of the metabotropic glutamate (Glu) receptor 5 and the Glu transporter excitatory amino acid transporter 1, examined by reverse transcription polymerase chain reaction and western blot analyses, were found to be reduced in the postmortem cerebellum of PM carriers with FXTAS compared with age matched controls, with higher CGG repeat number having greater reductions in both proteins. These data suggests a dysregulation of Glu signaling in PM carriers, which would likely contribute to the development and severity of FXTAS.