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

Sébastien Jacquemont, Laura Pacini, Aia E. Jønch, Giulia Cencelli, Izabela Rozenberg, Yunsheng He, Laura D'Andrea, Giorgia Pedini, Marwa Eldeeb, Rob Willemsen, Fabrizio Gasparini, Flora Tassone, Randi J Hagerman, Baltazar Gomez-Mancilla, Claudia Bagni

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2039-2051
Number of pages13
JournalHuman Molecular Genetics
Issue number12
StatePublished - Jun 15 2018

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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