Cerebral protein synthesis in a knockin mouse model of the fragile X premutation.

Mei Qin,Tianjian Huang,Renate K Hukema,Thomas Burlin,Zhonghua Liu,Michael Kader,Carolyn B Smith,Zachary Zeidler,Zengyan Xia

doi:10.1177/1759091414551957

Abstract

The (CGG)n-repeat in the 5′-untranslated region of the fragile X mental retardation gene (FMR1) 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 FMR1 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. FMR1 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 FMR1 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 Fmr1 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.

Highlights

The (CGG)n-repeat sequence in the 50-untranslated region of the fragile X mental retardation gene (FMR1) on Xq27.3 is polymorphic
The number of CGG repeats ranged from 114 to 279, and fragile X mental retardation protein (FMRP) levels decreased from 59% to 14% of the mean of three wild type (WT) values (Figure 1(a) and (b))
In our previous study of the KINIH mouse model of fragile X premutation (FXPM) with CGG repeat lengths between 120 and 140, we found that FMRP levels in brain were reduced by 80% to 90% of WT and rates of cerebral protein synthesis (rCPS) were increased (106– 120% of WT) similar to changes we had seen in Fmr1 KO mice

Summary

Introduction

The (CGG)n-repeat sequence in the 50-untranslated region of the fragile X mental retardation gene (FMR1) on Xq27.3 is polymorphic. The repeat sequence length is 5 to 54 and the gene product, fragile X mental retardation protein (FMRP) has normal expression (Fu et al, 1991). Individuals with fragile X syndrome (FXS), the most common form of hereditary intellectual disability and monogenic cause of autism, have more than 200 CGG repeats resulting in gene methylation, transcriptional silencing, and absence of FMRP (Verkerk et al, 1991). This is known as the full mutation. Because the prevalence of FXPM in the general population, approximately 1/290 males and 1/148 females (Maenner et al, 2013), is much higher than that of FXS, FXPM may have a greater impact on the general population than FXS

Methods

Results

Conclusion