Protein synthesis levels are increased in a subset of individuals with Fragile X syndrome

Fragile X syndrome (FXS) is a monogenic form of intellectual disability and autism spectrum disorder caused by the absenceof the fragile X mental retardation protein (FMRP). In biological models for the disease, this leads to upregulated mRNAtranslation and as a consequence, deficits in synaptic architecture and plasticity. Preclinical studies revealed thatpharmacological interventions restore those deficits, which are thought to mediate the FXS cognitive and behavioralsymptoms. Here, we characterized the de novo rate of protein synthesis in patients with FXS and their relationship withclinical severity.We measured the rate of protein synthesis in fibroblasts derived from 32 individuals with FXS and from 17 controls as well as in fibroblasts and primary neurons of 27 Fmr1 KO mice and 20 controls. Here, we show that levels ofprotein synthesis are increased in fibroblasts of individuals with FXS and Fmr1 KO mice. However, this cellular phenotypedisplays a broad distribution and a proportion of fragile X individuals and Fmr1 KO mice do not show increased levels ofprotein synthesis, having measures in the normal range. Because the same Fmr1 KO animal measures in fibroblasts predictthose in neurons we suggest the validity of this peripheral biomarker. Our study offers a potential explanation for thecomprehensive drug development program undertaken thus far yielding negative results and suggests that a significantproportion, but not all individuals with FXS, may benefit from the reduction of excessive levels of protein synthesis.