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RNA interference and inhibition of MEK-ERK signaling prevent abnormal skeletal phenotypes in a mouse model of craniosynostosis.
Nat Genet. 2007 Sep; 39(9):1145-50.NGen

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.

Authors+Show Affiliations

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.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural

Language

eng

PubMed ID

17694057

Citation

Shukla, Vivek, et al. "RNA Interference and Inhibition of MEK-ERK Signaling Prevent Abnormal Skeletal Phenotypes in a Mouse Model of Craniosynostosis." Nature Genetics, vol. 39, no. 9, 2007, pp. 1145-50.
Shukla V, Coumoul X, Wang RH, et al. RNA interference and inhibition of MEK-ERK signaling prevent abnormal skeletal phenotypes in a mouse model of craniosynostosis. Nat Genet. 2007;39(9):1145-50.
Shukla, V., Coumoul, X., Wang, R. H., Kim, H. S., & Deng, C. X. (2007). RNA interference and inhibition of MEK-ERK signaling prevent abnormal skeletal phenotypes in a mouse model of craniosynostosis. Nature Genetics, 39(9), 1145-50.
Shukla V, et al. RNA Interference and Inhibition of MEK-ERK Signaling Prevent Abnormal Skeletal Phenotypes in a Mouse Model of Craniosynostosis. Nat Genet. 2007;39(9):1145-50. PubMed PMID: 17694057.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - RNA interference and inhibition of MEK-ERK signaling prevent abnormal skeletal phenotypes in a mouse model of craniosynostosis. AU - Shukla,Vivek, AU - Coumoul,Xavier, AU - Wang,Rui-Hong, AU - Kim,Hyun-Seok, AU - Deng,Chu-Xia, Y1 - 2007/08/12/ PY - 2007/04/26/received PY - 2007/06/06/accepted PY - 2007/8/19/pubmed PY - 2007/12/6/medline PY - 2007/8/19/entrez SP - 1145 EP - 50 JF - Nature genetics JO - Nat. Genet. VL - 39 IS - 9 N2 - 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. SN - 1061-4036 UR - https://www.unboundmedicine.com/medline/citation/17694057/RNA_interference_and_inhibition_of_MEK_ERK_signaling_prevent_abnormal_skeletal_phenotypes_in_a_mouse_model_of_craniosynostosis_ L2 - http://dx.doi.org/10.1038/ng2096 DB - PRIME DP - Unbound Medicine ER -