CNS expression of murine fragile X protein (FMRP) as a function of CGG-repeat size

Large expansions of a CGG-repeat element (>200 repeats; full mutation) in the fragile X mental retardation 1 (FMR1) gene cause fragile X syndrome (FXS), the leading single-gene form of intellectual disability and of autism spectrum disorder. Smaller expansions (55-200CGGrepeats; premutation) result in theneurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). Whereas FXS is caused by gene silencing and insufficient FMR1 protein (FMRP), FXTAS is thought to be caused by 'toxicity' of expanded-CGG-repeat mRNA. However, as FMRP expression levels decrease with increasing CGG-repeat length, lowered protein may contribute to premutation-associated clinical involvement. To address this issue, we measured brain Fmr1 mRNA and FMRP levels as a function of CGG-repeat length in a congenic (CGG-repeat knock-in) mouse model using 57 wild-type and 97 expanded-CGG-repeat mice carrying up tõ250 CGG repeats. While Fmr1message levels increasedwith repeat length,FMRPlevels trended downward over thesamerange, subject to significant inter-subject variation.Human comparisons of protein levels in the frontal cortex of 7 normal and 17 FXTAS individuals revealed that the mildFMRPdecrease in mice mirrored the more limited data forFMRP expression in thehumansamples. In addition,FMRPexpression levels varied in a subset ofmiceacross the cerebellum, frontal cortex,andhippocampus,aswell asat different ages.Theseresults provide a foundation for understandingboth the CGG-repeat-dependence of FMRP expression and for interpreting clinical phenotypes in premutation carriers in terms of the balance between elevated mRNA and lowered FMRP expression levels.