外胚层发育不良常染色体显性遗传耳聋-甲发育不全综合征(dominant deafness and onychodystrohy syndrome，DDOD)病因不明，表现为先天性重度感音神经性耳聋、甲发育不全或缺失、指骨融合或增多、牙齿畸形或缺失，严重影响患者的认知和劳动能力。我们前期利用外显子组测序技术在三个中国DDOD家系检测到ATP6V1B2基因新生突变p.R506X，发现该基因编码的H+转运蛋白V-ATPase在小鼠内耳毛细胞及神经元高表达，体外细胞模型证实该突变导致溶酶体酸度异常、细胞消化功能紊乱进而细胞损伤。上述结果显示ATP6V1B2基因缺陷与DDOD发病密切相关。本课题拟构建Atp6v1b2基因耳蜗选择性Knockdown小鼠模型及突变Knockin小鼠模型,对动物模型进行表型鉴定及在体病理、电生理、生化研究，明确DDOD的致病机制。研究结果将为该病的生物学治疗奠定基础。

The deafness and onychodystrohy syndrome (DDOD) is a kind of hereditary ectodermal dysplasia disease which affects patients'cognition development and work capacity. DDOD shows autosomal dominant inheritance of congenital deafness and onychodystrophy. Conical, hypoplastic teeth are also a feature. We have identified a mutation c.1516C>T (p.R506X) in ATP6V1B2 gene in three Chinese DDOD pedigrees through the whole human exome sequencing and bioinformatics technique. This ATP6V1B2 c.1516 C>T (p.R506X) mutation was absent in the parents, indicating the de novo nature of the mutation. The newly identified gene,ATP6V1B2, encodes V-ATPase,a H+ transporter.It expresses widely in tissues developing from ectoderm. Our former results show it expresses in the mouse cochlea,especially in organ of Corti and spiral ganglian neurons.Preliminary in vitro experiments in HEK293 cells showed that the ATP6V1B2 p.R506X causes PH abnormity in lysosome which further lead to the disorders of cell digestion and cell injury. All the above results show ATP6V1B2 gene deficiency correlates with DDOD.In this study, we will investigate on the function of the newly identified deafness gene responsible for DDOD syndrome by making a conditional cochlea Atp6v1b2 Knockdown mouse model and an Atp6v1b2 c.1516 C>T (p.R506X) mutation Knockin mouse model. Systemic phenotype,pathophysiology and biochemistry study will then be performed on the models. The results of this study will reveal the pathogenesis and molecular pathway of DDOD syndrome,help deepen the understanding of DDOD and provide basis for the biological treatment on DDOD.In addition, this study will underlie the development of preimplantation diagnosis and prenatal diagnosis for DDOD.