欧几里德几何距离矩阵法对FGFR2 Ser252Trp点突变小鼠头颅形状特征的分析

Skull morphology of mice carrying gain-of-function mutation of FGFR2 Ser252Trp by Euclidean distance matrix analysis

目的通过定量分析模拟Apert综合征患者的FGFR2 Ser252Trp突变小鼠模型和野生型小鼠头颅表型,并与Apert患者所表现出来的异常头颅颜面特征进行比较,探讨所建立的Apert小鼠模型能否真实地模拟Apert综合征患者的头颅表型。方法采用蚂蚁啃食的方法制备Ser252Trp突变小鼠和同窝对照小鼠头颅标本,用三维坐标测量仪检测头颅27个标记点的三维坐标值,用欧几里德几何距离矩阵法(euclidean distance matrix analysis,EDMA)对突变小鼠和对照小鼠头颅三维数据进行处理和统计分析。结果Ser252Trp突变小鼠头颅形状与同窝对照组相比具有统计学差异(P<0.01),突变小鼠头颅长度缩短,且头颅前端缩短比后部缩短更严重,头颅面部鼻骨长度、前颌骨、上颌骨及颧骨长度明显缩短(P<0.01),眼间距和额骨宽度变宽,颅腔长度有所缩短,宽度增加,颅顶升高(P<0.01),这与Apert患者颅面的临床表现高度相似:眼间距增宽,面中部发育不良,鼻骨缩短,上颌骨发育低下,突眼,颅腔变宽呈圆鼓状。结论FGFR2 Ser252Trp突变小鼠从表型上真实地反映Apert患者的头颅颜面特征,可以作为人类Apert综合征的较好模型用于有关疾病致病机制、手术及药物治疗的研究模型。

Objective To validate the mouse carrying Ser252Trp mutation in fibroblast growth factor receptor （FGFR2） as a model for human Apert syndrome resulting from equivalent mutation by quantitatively analyzing the morphologic changes of mouse skull. Methods Euclidean distance matrix analysis （EDMA） was used to quantitatively compare the morphologic difference between the skulls of mutants and their wild type con- trols by analyzing the 3 D coordinate data of skulls＇ 27 landmarks collected by a 3 D coordinate Measuring Ma- chine. Results There was significant differences in substantial morphology between skulls of mutants and their matched controls （P 〈 0.01 ）. The mutants showed shortened length along anterior-posterior axis, especially in the anterior portion of skulls. The mutants exhibited significantly decreased lengths in the nasal bone, premaxilla, maxilla and zygoma （P 〈0. 01 ）, as well as broadened interorbital and frontal bone width （P 〈0. 01 ）. All these anomalies subsequently led to shortened A-P length, as well as the increased width and height in mutant skulls, which highly similar to those skull features of humans with Apert syndrome such as brachycephaly, midface dysplasia, widened distance between eyes, shortened nasal bones, and expanded cranial volumes, etc.Conclusion The FGFR2 Ser252Trp mutation shows the characteristic skull phenotypes that resemble those of human with Apert syndrome. Our results indicate that this mouse strain can be used as a good model for human Apert syndrome.