Abstract
Premature fusion of one or more of the cranial sutures (craniosynostosis) in humans causes over 100 skeletal diseases, which occur in 1 of approximately 2,500 live births. Among them is Apert syndrome, one of the most severe forms of craniosynostosis, primarily caused by missense mutations leading to amino acid changes S252W or P253R in fibroblast growth factor receptor 2 (FGFR2). Here we show that a small hairpin RNA targeting the dominant mutant form of Fgfr2 (Fgfr2(S252W)) completely prevents Apert-like syndrome in mice. Restoration of normal FGFR2 signaling is manifested by an alteration of the activity of extracellular signal-regulated kinases 1 and 2 (ERK1/2), implicating the gene encoding ERK and the genes downstream of it in disease expressivity. Furthermore, treatment of the mutant mice with U0126, an inhibitor of mitogen-activated protein (MAP) kinase kinase 1 and 2 (MEK1/2) that blocks phosphorylation and activation of ERK1/2, significantly inhibits craniosynostosis. These results illustrate a pathogenic role for ERK activation in craniosynostosis resulting from FGFR2 with the S252W substitution and introduce a new concept of small-molecule inhibitor-mediated prevention and therapy for diseases caused by gain-of-function mutations in the human genome.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Base Sequence
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Butadienes / pharmacology
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Craniosynostoses / genetics*
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Craniosynostoses / pathology
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Craniosynostoses / prevention & control
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Enzyme Inhibitors / pharmacology
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / genetics*
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Gene Expression / drug effects
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Immunoblotting
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Male
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Mice
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Mice, Inbred Strains
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Mice, Transgenic
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / genetics*
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Nitriles / pharmacology
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Phenotype
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Phosphorylation / drug effects
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RNA Interference*
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Receptor, Fibroblast Growth Factor, Type 2 / antagonists & inhibitors
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Receptor, Fibroblast Growth Factor, Type 2 / genetics
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Receptor, Fibroblast Growth Factor, Type 2 / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / drug effects
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Signal Transduction / genetics*
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Signal Transduction / physiology
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Time Factors
Substances
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Butadienes
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Enzyme Inhibitors
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Nitriles
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U 0126
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Receptor, Fibroblast Growth Factor, Type 2
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Extracellular Signal-Regulated MAP Kinases
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Mitogen-Activated Protein Kinase Kinases