遗传性多发性外生骨疣（Hereditary Multiple Exostosis, HME）是影响软骨化骨过程而造成骨骼系统产生多发性外生骨疣的常染色体显性遗传病。EXT1和EXT2基因突变是引起HME的遗传因素。申请者在广西地区发现了一例HME家系，其致病突变位点仍不清楚。本项目拟测序分析HME家系成员EXT1和EXT2基因外显子以及内含子外显子拼接区域的DNA序列，鉴定致病突变位点。然后基于CRISPR/Cas9基因编辑系统制备与该家系具有相同突变特征的精准基因编辑小鼠，并通过免疫组化、X光分析、病理切片染色等方法研究HME小鼠的病理特征，分析其病理表现与HME家系的相似度，验证鉴定位点的致病性，揭示HME家系致病的遗传病因，证明基因编辑小鼠可以模拟人类HME疾病，为探索HME发生和发展机理、研制新的治疗方法、发现药物新靶点以及临床前药效学评价等生物医学研究奠定基础。

Hereditary Multiple Exostosis is an autosomal dominant disease which induces the multiple exostosis in skeletal system by influencing cartilaginous bone process. The mutations of EXT1 and EXT2 are the genetic cause of HME. We found a HME family in Guangxi Zhuang Autonomous Region, and the pathogenic mutation is still undiscovered. Here, we plan to screen the DNA sequence of exons, intron and exon spliced regions of EXT1 and EXT2 in HME family in order to screen pathogenic mutation site. After that, precise gene editing mouse model harboring the same mutant characteristics with HME family was established via CRISPR/Cas9 gene editing system. We will investigate the pathological characteristics of HME gene editing mouse by immunohistochemical, X-ray and pathological section staining and compare with that of HME family, for revealing the genetic cause and also for certificating the established gene editing mouse is a reliable disease model for precise recapitulation of human HME. HME mouse model is an important biomedical research basis of investigation into pathogenesis and disease development mechanism，development of new therapy, discovery of new drug targets and evaluation of preclinical pharmacodynamics.