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Functional characterization of a novel FGFR2 mutation, E731K, in craniosynostosis
Author(s) -
Park Jounghyen,
Park OkJin,
Yoon WonJoon,
Kim HyunJung,
Choi KangYoung,
Cho TaeJoon,
Ryoo HyunMo
Publication year - 2012
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.23368
Subject(s) - craniosynostosis , crouzon syndrome , apert syndrome , fibroblast growth factor receptor 1 , fibroblast growth factor receptor , fibroblast growth factor receptor 2 , fibroblast growth factor , mutation , biology , runx2 , signal transduction , genetics , microbiology and biotechnology , cancer research , transcription factor , gene , receptor
Craniosynostosis is a condition in which some or all of the sutures in the skull of an infant close prematurely. Fibroblast growth factor receptor 2 (FGFR2) mutations are a well‐known cause of craniosynostosis. Many syndromes that comprise craniosynostosis, such as Apert syndrome, Crouzon syndrome, and Pfeiffer syndrome, have one of the phenotypes that have been reported in FGFR2 mutant patients. FGFRs have been reported in four types (FGFR1–4), and upon binding with FGF ligands, signal transduction occurs inside of cells. Activated FGFR stimulates an osteogenic master transcription factor, Runx2, through the MAP kinase and PKC pathways. We obtained a genetic analysis of six Korean patients who have craniosynostosis as a phenotype. All of the patients had at least one mutation in the FGFR2 gene; five of those mutations have already been reported elsewhere, while one mutation is novel and was hypothesized to lead to Apert syndrome. In this study, we reported and functionally analyzed a novel mutation of the FGFR2 gene found in a craniosynostosis patient, E731K. The mutation is in the 2nd tyrosine kinase domain in the C‐terminal cytoplasmic region of the molecule. The mutation caused an enhanced phosphorylation of the FGFR2 E731K and ERK‐MAP kinase, the stimulation of transcriptional activity of Runx2, and consequently, the enhancement of osteogenic marker gene expression. We conclude that the substitution of E731K in FGFR2 is a novel mutation that resulted in a constitutive activation of the receptor and ultimately resulted in premature suture obliteration. J. Cell. Biochem. 113: 457–464, 2012. © 2011 Wiley Periodicals, Inc.