Abstract
BackgroundFragile X syndrome (FXS) is the leading inherited cause of intellectual disability and is caused by the loss of expression of the Fragile X mental retardation protein (FMRP). In animal model of FXS, the absence of FMRP leads to an aberrant rate of neuronal protein synthesis, which in turn is believed to be at the origin of defects regarding spine morphology and synaptic plasticity. Normalisation of protein synthesis in these models has been associated with a rescue of FXS behavioral and biochemicals phenotype, thus establishing the rate of protein synthesis as one of the most promising monitoring biomarker for FXS. However, rate of protein synthesis alteration in fragile X individuals is not well characterized.MethodWe applied a robust radiolabeled assay to measure rate of protein synthesis in freshly extracted peripheral blood mononuclear cells (PBMCs) and blood platelets. We ultimately settle on PBMCs to measure and compare rate of protein synthesis in 13 males with fragile X and 14 matched controls individuals.ResultsUsing this method, we measured a 26.9% decrease (p = 0,0193) in the rate of protein synthesis in fragile X individuals PBMCs. Furthermore, the rate of protein synthesis measurements obtained were highly reproducible, highlighting the robustness of the method.ConclusionOur work presents the first evidence of a diminution of the rate of protein synthesis in a human peripheral model of fragile X. Our results also support the finding of previous studies using brain PET imaging in Fragile X individuals. Since our assay only requires a simple venous puncture, it could be used in other cases of intellectual disability in order to determine if an aberrant rate of protein synthesis is a common general mechanism leading to impairment in synaptic plasticity and to intellectual disability.
Highlights
Intellectual disability (ID) is a developmental condition characterized by significant deficit in intellectual functioning (IQ score below 70) and adaptive behaviour affecting approximately 1% of males
Our work presents the first evidence of a diminution of the rate of protein synthesis in a human peripheral model of fragile X
Since our assay only requires a simple venous puncture, it could be used in other cases of intellectual disability in order to determine if an aberrant rate of protein synthesis is a common general mechanism leading to impairment in synaptic plasticity and to intellectual disability
Summary
Intellectual disability (ID) is a developmental condition characterized by significant deficit in intellectual functioning (IQ score below 70) and adaptive behaviour affecting approximately 1% of males. Fragile X syndrome (FXS) is the most common monogenic cause of intellectual disabilities (ID) affecting 1 per 5000 males [1]. The vast majority (> 99%) of FX cases arise from the runaway expansion of CGG repeats found in the 5’ UTR of the FMR1 gene and by the subsequent methylation of CpG islands in its promoter This phenomenon results in the transcriptional silencing of FMR1 and subsequent loss of expression of the Fragile X mental retardation protein (FMRP) [4,5,6]. Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability and is caused by the loss of expression of the Fragile X mental retardation protein (FMRP). Rate of protein synthesis alteration in fragile X individuals is not well characterized
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