title: Identification of fragile X syndrome specific molecular markers in human fibroblasts: a useful model to test the efficacy of therapeutic drugs.
abstract: Fragile X syndrome (FXS) is the most frequent cause of inherited intellectual disability and autism. It is caused by the absence of the fragile X mental retardation 1 (FMR1) gene product, fragile X mental retardation protein (FMRP), an RNA-binding protein involved in the regulation of translation of a subset of brain mRNAs. In Fmr1 knockout mice, the absence of FMRP results in elevated protein synthesis in the brain as well as increased signaling of many translational regulators. Whether protein synthesis is also dysregulated in FXS patients is not firmly established. Here, we demonstrate that fibroblasts from FXS patients have significantly elevated rates of basal protein synthesis along with increased levels of phosphorylated mechanistic target of rapamycin (p-mTOR), phosphorylated extracellular signal regulated kinase 1/2, and phosphorylated p70 ribosomal S6 kinase 1 (p-S6K1). The treatment with small molecules that inhibit S6K1 and a known FMRP target, phosphoinositide 3-kinase (PI3K) catalytic subunit p110β, lowered the rates of protein synthesis in both control and patient fibroblasts. Our data thus demonstrate that fibroblasts from FXS patients may be a useful in vitro model to test the efficacy and toxicity of potential therapeutics prior to clinical trials, as well as for drug screening and designing personalized treatment approaches.
authors.affiliation: Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Daman
authors.initials: D
authors.lastname: Kumari
authors.forename: Aditi
authors.initials: A
authors.lastname: Bhattacharya
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Nadel
authors.forename: Kristen
authors.initials: K
authors.lastname: Moulton
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Zeak
authors.forename: Anne
authors.initials: A
authors.lastname: Glicksman
authors.forename: Carl
authors.initials: C
authors.lastname: Dobkin
authors.forename: David J
authors.initials: DJ
authors.lastname: Brick
authors.forename: Philip H
authors.initials: PH
authors.lastname: Schwartz
authors.forename: Carolyn B
authors.initials: CB
authors.lastname: Smith
authors.forename: Eric
authors.initials: E
authors.lastname: Klann
authors.forename: Karen
authors.initials: K
authors.lastname: Usdin
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D007930:Leucine / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism
chemical_list: D015415:Biomarkers; D051860:Fragile X Messenger Ribonucleoprotein 1; D007930:Leucine; D019869:Phosphatidylinositol 3-Kinases; D012333:RNA, Messenger; D019893:Ribosomal Protein S6 Kinases; C497683:FMR1 protein, human
keywords: FMR1; FMRP; Fragile X syndrome; S6K1; fibroblasts; protein synthesis