Letter abstract
Nature Genetics 39, 1145 - 1150 (2007)
Published online: 12 August 2007 | doi:10.1038/ng2096
RNA interference and inhibition of MEK-ERK signaling prevent abnormal skeletal phenotypes in a mouse model of craniosynostosis
Vivek Shukla1,3, Xavier Coumoul1,2,3, Rui-Hong Wang1, Hyun-Seok Kim1 & Chu-Xia Deng1
Premature fusion of one or more of the cranial sutures (craniosynostosis) in humans causes over 100 skeletal diseases, which occur in 1 of 
2,500 live births1, 2, 3. 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)4, 5, 6. Here we show that a small hairpin RNA targeting the dominant mutant form of Fgfr2 (Fgfr2S252W) 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.
- Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, US National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
- Present address: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR-S 747, Unité de Pharmacologie, Toxicologie et Signalisation Cellulaire, Centre Universitaire des Saints-Pères, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France.
- These authors contributed equally to this work.
Correspondence to: Chu-Xia Deng1 e-mail: chuxiad@bdg10.niddk.nih.gov
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