title: Functional characterization of a novel FGFR2 mutation, E731K, in craniosynostosis.
abstract: 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.
authors.affiliation: Department of Molecular Genetics, School of Dentistry and Dental Research Institute, BK21 Program, Seoul National University, Seoul, Korea.
authors.forename: Jounghyen
authors.initials: J
authors.lastname: Park
authors.forename: Ok-Jin
authors.initials: OJ
authors.lastname: Park
authors.forename: Won-Joon
authors.initials: WJ
authors.lastname: Yoon
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Kang-Young
authors.initials: KY
authors.lastname: Choi
authors.forename: Tae-Joon
authors.initials: TJ
authors.lastname: Cho
authors.forename: Hyun-Mo
authors.initials: HM
authors.lastname: Ryoo
mesh_terms: D016475:3T3 Cells; D000168:Acrocephalosyndactylia / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D002460:Cell Line; D049109:Cell Proliferation; D017124:Conserved Sequence; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D003394:Craniofacial Dysostosis / Q000175:diagnosis / Q000235:genetics; D004252:DNA Mutational Analysis; D004789:Enzyme Activation; D056726:Genetic Association Studies; D005819:Genetic Markers; D006801:Humans; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010766:Phosphorylation; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D005819:Genetic Markers; C493709:RUNX2 protein, human; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3