利用Ano5基因C360Y突变敲入小鼠模型研究中国GDD的发病机制

颌骨和骨干发育不良（GDD） 是一种病变累及口腔和长骨骨干的常染色体显性遗传病。口腔主要表现为牙骨质-骨化纤维瘤和颌骨骨髓炎；长骨主要表现为骨皮质增厚和骨硬化。ANO5是GDD的致病基因，但是ANO5基因突变导致GDD的分子机制尚不明确。申请人前期首次报道中国GDD家系中ANO5基因新突变C360Y，并成功建立Ano5基因C360Y突变敲入小鼠模型。功能研究表明，突变小鼠的成骨能力增强而骨吸收能力减弱，与成骨密切相关的柠檬酸代谢通路关键酶基因（Aco2）和与破骨细胞融合分化相关的基因（Rank、Nfatc1和Dcstamp）表达均降低，并且有miRNAs参与调控。本研究拟利用C360Y突变敲入小鼠模型，对Aco2-柠檬酸代谢和破骨分化的相关因子、信号通路及差异miRNAs进行深入研究，揭示C360Y突变导致中国GDD疾病发生的分子机制，为开发针对中国GDD患者特异性的治疗靶点提供理论依据。

Gnathodiaphyseal dysplasia(GDD) is an autosomal dominantly inherited disorder characterized by cemento-ossifying fibroma, purulent osteomyelitis, cortical thickening and diaphyseal sclerosis of tubular bones. Although ANO5 has been identified to be causative gene, the molecular mechanism of GDD which is associated with mutations in ANO5 remains unclear. We previously for the first time reported a novel missense mutation C360Y in a Chinese family with GDD and established C360Y mutation knock in mouse model. Functional study showed that the bone formation of mice with mutation was increased significantly and bone resorption attenuated contrarily. We also found that the expression of Aco2 gene which plays a vital role in citrate metablism was decreased. Concertedly, the genes related to osteoclast fusion and differentiation including Rank、Nfatc1 and Dcstamp expressed with reduction. Moreover, differentially expressed microRNAs have been proved to be involved in above processes. Now we plan to carry out further research into the relative factors, microRNAs and signaling pathways, which are associated with Aco2-citrate metabolism, and osteoclastogenesis respectively utilizing the C360Y mutation knock in mouse model. Our achievements will contribute to elucidating the molecular mechanism of GDD in China and excavating a specific approach for target treatment.