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Hum Mol Genet. 2018 Jun 15;27(12):2039-2051. doi: 10.1093/hmg/ddy099.

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

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Sainte-Justine University Hospital Research Centre, Montreal, QC H3T 1C5.
University of Montreal, Montreal, QC H3T 1J4, Canada.
Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy.
Department of Clinical Genetics, Odense University Hospital.
Human Genetics, Department of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark.
Neuroscience Translational Medicine, Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4056 Basel, Switzerland.
Biomarker Development, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California, Davis Medical Center, Sacramento, CA 95817, USA.
Department of Clinical Genetics, Erasmus Medical Center, 1738, 3000DR Rotterdam, The Netherlands.
Neuroscience Discovery, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
Department of Biochemistry and Molecular Medicine and Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, Sacramento, CA 95817, USA.
Department of Pediatric and Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, School of Medicine, Sacramento, CA 95817, USA.
Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 0G4, Canada.
Department of Fundamental Neuroscience, University of Lausanne, 1005 Lausanne, Switzerland.


Fragile X syndrome (FXS) is a monogenic form of intellectual disability and autism spectrum disorder caused by the absence of the fragile X mental retardation protein (FMRP). In biological models for the disease, this leads to upregulated mRNA translation and as a consequence, deficits in synaptic architecture and plasticity. Preclinical studies revealed that pharmacological interventions restore those deficits, which are thought to mediate the FXS cognitive and behavioral symptoms. Here, we characterized the de novo rate of protein synthesis in patients with FXS and their relationship with clinical 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 of protein synthesis are increased in fibroblasts of individuals with FXS and Fmr1 KO mice. However, this cellular phenotype displays a broad distribution and a proportion of fragile X individuals and Fmr1 KO mice do not show increased levels of protein synthesis, having measures in the normal range. Because the same Fmr1 KO animal measures in fibroblasts predict those in neurons we suggest the validity of this peripheral biomarker. Our study offers a potential explanation for the comprehensive drug development program undertaken thus far yielding negative results and suggests that a significant proportion, but not all individuals with FXS, may benefit from the reduction of excessive levels of protein synthesis.

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