1.Generation of a transgenic mouse model to study cranial suture development; Apert syndrome.
Kee Joon LEE ; Chootima RATISOONTORN ; Hyoung Seon BAIK ; Young Chel PARK ; Kwang Kyun PARK ; Hyun Duck NAH
Korean Journal of Orthodontics 2003;33(6):485-497
The form and function of the craniofacial structure critically depend on genetic information. With recent advances in the molecular technology, genes that are important for normal growth and morphogenesis of the craniofacial skeleton are being rapidly uncovered, shaping up modern craniofacial biology. One of them is fibroblast growth factor receptor 2 (FGFR2). Specific point mutations in the FGFR2 gene have been linked to Apert syndrome, which is characterized by premature closure of cranial sutures and craniofacial anomalies as well as limb deformities. To study pathogenic mechanisms underlying craniosynostosis phenotype of Apert syndrome, we used a transgenic approach; an FGFR2 minigene construct containing an Apert mutation (a point mutation that substitute proline at the position 253 to arginine; P253R) was introduced into fertilized mouse germ cells by DNA microinjection. The injected cells were then allowed to develop into transgenic mice. We used a bone-specific promoter (a DNA fragment from the type I collagen gene) to confine the expression of mutant FGFR2 gene to the bone tissue, and asked whether expression of mutant FGFR2 in bone is sufficient to cause the craniosynostosis phenotype in mice. Initial characterization of these mice shows prematurely closed cranial sutures with facial deformities expected from Apert patients. We also demonstrate that the transgene produces mutant FGFR2 protein with increased functional activities. Having this useful mouse model, we now can ask questions regarding the role of FGFR2 in normal and abnormal development of cranial bones and sutures.
Acrocephalosyndactylia*
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Animals
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Arginine
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Biology
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Bone and Bones
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Collagen Type I
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Congenital Abnormalities
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Cranial Sutures*
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Craniosynostoses
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DNA
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Extremities
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Germ Cells
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Humans
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Mice
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Mice, Transgenic*
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Microinjections
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Morphogenesis
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Phenotype
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Point Mutation
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Proline
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Receptor, Fibroblast Growth Factor, Type 2
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Skeleton
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Sutures
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Transgenes
2.Craniofacial morphologic alteration induced by bone-targeted mutants of FGFR2 causing Apert and Crouzon syndrome.
Kee Joon LEE ; Hyun Duck NAH ; Stephen T J TJOA ; Young Chel PARK ; Hyoung Seon BAIK ; Tae Min YUN ; Jin Wook SONG
Korean Journal of Orthodontics 2006;36(4):284-294
OBJECTIVE: Activating mutations in the fibroblast growth factor receptor-2 (FGFR2) have been shown to cause syndromic craniosynostosis such as Apert and Crouzon syndromes. The purpose of this pilot study was to investigate the resultant phenotypes induced by the two distinctive bone-targeted gene constructs of FGFR2, Pro253Arg and Cys278Phe, corresponding to human Apert and Crouzon syndromes respectively. METHODS: Wild type and a transgenic mouse model with normal FGFR2 were used as controls to examine the validity of the microinjection. Micro-CT and morphometric analysis on the skull revealed the following results. RESULTS: Both Apert and Crouzon mutants of FGFR2 induced fusion of calvarial sutures and anteroposteriorly constricted facial dimension, with anterior crossbite present only in Apert mice. Apert mice differed from Crouzon mice and transgenic mice with normal FGFR2 in the anterior cranial base flexure and calvarial flexure angle which implies a possible difference in the pathogenesis of the two mutations. In contrast, the transgenic mice with normal FGFR2 displayed normal craniofacial phenotype. CONCLUSION: Apert and Crouzon mutations appear to lead to genotype-specific phenotypes, possibly causing the distinctive sites and sequence of synostosis in the calvaria and cranial base. The exact function of the altered FGFR2 at each suture needs further investigation.
Acrocephalosyndactylia
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Animals
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Craniofacial Dysostosis*
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Craniosynostoses
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Fibroblast Growth Factors
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Humans
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Malocclusion
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Mice
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Mice, Transgenic
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Microinjections
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Phenotype
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Pilot Projects
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Skull
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Skull Base
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Sutures
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Synostosis