| Objective: To characterize the craniofacial phenotype of FGFR2 S252W and P253R mouse models mimicking human Apert syndrome using quantitative analysis of skull morphology and to compare the skull features between mouse models and human Apert syndrome, this study is focused on validating whether the established mouse models can simulate human Apert syndrome phenotypically, and can be used as an appropriate tool for studying the etiopahagenisis and therapeutic strategies of Apert syndrome. In addition, the difference of craniofacial phenotype between S252W and P253R mice model was compared to provide insight into further research on etiopahagenisis of different phenotypes caused by different mutatuions in the same gene.Methods: Eâ…¡A-Cre transgenic mice were mated with the FGFR2-Ser252Trp,Pro253Arg knock-in mice respectively to establish the Apert syndrome mouse model, the genotype was identified by PCR. S252W and P253R Apert mouse and the normal littermates aged of 4 weeks and 8 weeks were used to observe the general skull shapes, the changes of body weight and cranial radiographs. Mouse skulls were prepared by a traditional way and a newly-developed method. The biologic landmarks were set according to the anatomy characteristics of the mouse skull by using anatomical microscope. The mouse skull was enlarged 400 times through versatile toolroom microscope, three-dimensional coordinate data of these landmarks on the skull was measured by Mahr PMC 800 multisensor 3D coordinate measuring machine, and space distances were calculated from each two landmarks through MarSoft Vision 3D software. All these measured data were analyzed by SAS 8.0 software.Results: the whole body size and weight were both reduced significantly in the S252W and P253R Apert mice when compared the wild-type mouse. Marked differences were found in nearly all craniofacial regions except that the mandibles have fairly normal size and shape. Skull length was decreased (90.2%)but Skull height(107.3%) and width(113.4%) were increased in mutant mice. The nasal bone length(67.6%)and the facial height(75.3%)reduced very significantly. Interorbital distance(118.8%)was also increased noticeably in the two Apert mouse skulls as compared with wild-type littermates. Maxillary length(88.5%)was shorter whereas the mandibular length(101.5%)was relative normal. The craniofacial phenotype of the two Apert mouse models highly resembled the clinical manifestation of the Apert patients'skull: brachycephalia and turricephaly, ocular hypertelorism, midface hypoplasia, shorten nasal bone, maxillary hypoplasia, exophthalmia, enlarged intracranial volume, malocclusion, normal size and shape of the mandible. The morphologic change of the Apert mouse skull at 8 weeks age was consistent with 4 weeks old Apert mouse, but varied in the magnitude. For the S252W and P253R Apert mouse models there were no marked difference between their skulls, just existed some subtle difference. Skull width was broader in the P253R mice than that in the S252W mice. On the contrary, the facial height was reduced severer and the fossa orbitalis region became shallower in the S252W mice than that in the P253R mice. The newly-developed method for preparing mouse skeleton by ants was simpler and faster than the traditional way.Conclusion: the S252W and P253R Apert mouse models showed craniofacial characteristics that phenocopied Apert syndrome patient phenotype. They can be used as a useful tool for research on the pathogenesis, therapeutic strategies and pharmacologic interventions of Apert syndrome patients in the future. It is suggested that craniofacial anomalies in Apert mice appeared before adulthood since the phenotype is consistent in the whole adult period, so it is necessary to analyze the craniofacial development at more stages from embryonic period to adulthood. The established data of skull morphologic characteristic of the wild-type and Apert mice at 4 and 8 weeks age provide the foundation for the further works on investigating the craniofacial dysmorphology of other mouse models with FGFR1,FGFR3 mutations.
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