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 trans...

Full description

Saved in:
Bibliographic Details
Published in:Human mutation 2014-12, Vol.35 (12), p.1485-1494
Main Authors: Kumari, Daman, Bhattacharya, Aditi, Nadel, Jeffrey, Moulton, Kristen, Zeak, Nicole M., Glicksman, Anne, Dobkin, Carl, Brick, David J., Schwartz, Philip H., Smith, Carolyn B., Klann, Eric, Usdin, Karen
Format: Article
Language:English
Subjects:
Animals
Biomarkers - metabolism
Case-Control Studies
Cells, Cultured
Drug Evaluation, Preclinical
Drug therapy
fibroblasts
Fibroblasts - cytology
Fibroblasts - metabolism
FMR1
FMRP
Fragile X Mental Retardation Protein - genetics
Fragile X syndrome
Fragile X Syndrome - drug therapy
Fragile X Syndrome - genetics
Humans
Kinases
Leucine - metabolism
Male
Mental retardation
Mice
Mice, Knockout
Mutation
Phosphatidylinositol 3-Kinases - metabolism
Protein Biosynthesis
Protein synthesis
Proteins
Ribosomal Protein S6 Kinases - metabolism
RNA, Messenger - genetics
S6K1
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. We show that primary fibroblasts from fragile X syndrome (FXS) patients have elevated rates of protein synthesis and increased levels of translational regulators, p‐mTOR and p‐S6K1. Treatment with inhibitors of S6K1 and PI3K reduces rates of protein synthesis in these cells. Our data suggest that primary fibroblasts from FXS patients can be a useful cell‐based model for high‐throughput drug screens, evaluation of potential therapeutic compounds and designing personalized treatment approaches.
ISSN:1059-7794
1098-1004
DOI:10.1002/humu.22699