基于人源性FGF23基因C35A突变Knock-in小鼠研究下颌前突致病机制

下颌前突（Mandibular prognathism, MP）是一类常见颌面部发育畸形，在我国发病率超过10%，严重影响患者口颌功能和颜面美观。通常认为MP是由遗传和环境因素共同作用引起的。近年来国内外学者对MP的遗传因素进行了大量研究，但至今尚未确定致病基因。本课题组通过家系连锁分析发现一个MP可疑致病突变基因FGF23，突变位点为C35A，并在转染的293T细胞中证实该突变可干扰FGF23蛋白分泌。为了进一步明确该突变对于MP发生的作用，我们通过CRISPR/Cas9技术成功构建了人源性FGF23 C35A突变Knock-in小鼠。本项目将以此为基础，利用模式小鼠，通过影像学、免疫组织化学、分子生物学等技术，从宏观到微观各层面解析此突变基因对颅颌面的影响，阐明FGF23 C35A突变对于MP发生的作用机制。研究结果将为MP的预防、诊断和治疗提供理论依据。

Mandibular prognathism（MP）is a kind of developmental craniofacial deformity, prevailing in more than 10% of the Chinese Han population, and seriously affects oral function and facial appearance of the affected individuals. MP is suggested to be caused by both hereditary and environmental factors. Although has been extensively investigated, the MP-causing gene has not been well defined. Our previous study identified a putative MP-causing mutation, C35A in FGF23 gene, by family linkage analysis. This mutation impaired the secretion of FGF23 protein in transfected 293T cells. We have also established a FGF23 C35A Knock-in mouse model expressing human mutant FGF23 signal peptide by CRISPR/Cas9 technique. Basing on our preliminary studies, this proposal intends to further investigate the function and mechanism of FGF23 C35A mutant in the pathogenesis of MP using radiography, immunohistochemistry, and molecular biology, from macroscopic to microscopic perspectives. The experimental results will provide a reliable theoretical basis of prevention, diagnosis and treatment of MP.