The (CGG)n-repeat in the 5’-untransiated region of the fragile X mental retardation gene (FMRi) gene is polymorphic and may become unstable on transmission to the next generation. In fragile X syndrome, CGG repeat lengths exceed 200, resulting in silencing of FMRi and absence of its protein product, fragile X mental retardation protein (FMRP). CGG repeat lengths between 55 and 200 occur in fragile X premutation (FXPM) carriers and have a high risk of expansion to a full mutation on maternal transmission. FXPM carriers have an increased risk for developing progressive neurodegenerative syndromes and neuropsychological symptoms. FMRi mRNA levels are elevated in FXPM, and it is thought that clinical symptoms might be caused by a toxic gain of function due to elevated FMRi mRNA. Paradoxically, FMRP levels decrease moderately with increasing CGG repeat length in FXPM. Lowered FMRP levels may also contribute to the appearance of clinical problems. We previously reported increases in regional rates of cerebral protein synthesis (rCPS) in the absence of FMRP in an Fmri knockout mouse model and in a FXPM knockin (KI) mouse model with 120 to 140 CGG repeats in which FMRP levels are profoundly reduced (80%-90%). To explore whether the concentration of FMRP contributes to the rCPS changes, we measured rCPS in another FXPM KI model with a similar CGG repeat length and a 50% reduction in FMRP. In all 24 brain regions examined, rCPS were unaffected. These results suggest that even with 50% reductions in FMRP, normal protein synthesis rates are maintained.

Fmri, FMRP, Fragile X premutation, Fragile X syndrome, FXTAS, Protein synthesis
dx.doi.org/10.1177/1759091414551957, hdl.handle.net/1765/87462
ASN Neuro
Erasmus MC: University Medical Center Rotterdam

Qin, M, Huang, T, Liu, Z, Kader, M, Burlin, T, Xia, Z, … Smith, C.B. (2014). Cerebral protein synthesis in a knockin mouse model of the fragile X premutation. ASN Neuro, 6(5). doi:10.1177/1759091414551957