DDOD综合征又称显性遗传耳聋-甲发育不全综合征，其致病基因ATP6V1B2 由申请人团队鉴定，已报道的国内外所有患者均携带该基因c.1516C>T突变。对DDOD综合征患者进行人工耳蜗术后7年随访，发现其言语康复效果欠佳，经过系统表型再评估证实患者存在学习记忆障碍。我们前期在斑马鱼中研究了atp6v1b2基因对发育的影响，明确其与听觉、脑发育、四肢、血管生成等有关，为管家基因；构建了Atp6v1b2 c.1516C>T突变knockin小鼠模型，该模型表现为听力正常、学习记忆障碍和自发性癫痫。本课题拟研究该模型小鼠听觉补偿机制、学习记忆障碍的病理基础，分析管家基因ATP6V1B2异常在不同器官的功能调控和阈值效应；构建患者皮肤成纤维细胞来源的iPS细胞并进行突变修复和定向分化，探讨生物学治疗方案。本研究意义在于拓展DDOD综合征表型特征、明确其发病机制，为精准治疗、预后评估提供理论依据。

DDOD (Dominant deafness-onychodystrophy，MIM 124480) syndrome is a kind of rare disease. The pathogenetic gene was identified as ATP6V1B2 by the applicant’s team. The common c.1516C>T mutation in ATP6V1B2 was reported in patients diagnosed DDOD syndrome worldwide. Through a 7-year-follow-up after cochlear implantation operation and systematic phenotype analysis in DDOD syndrome patients, the dysfunctions of learning and memory were discovered. Our previous work in zebrafish showed that atp6v1b2 is a housekeeping gene which plays important roles in the development. Knockdown of atp6v1b2 resulted in hair cell loss, pericardial oedema, a non-inflated swim bladder, shorter pectoral fins and impairment of angiogenic vessel growth. We then constructed the Atp6v1b2 c.1516C>T mutation knockin mouse model. The major phenotypes of the knockin mouse model include dysfunctions of learning and memory, idiopathic epilepsy and normal hearing. In this study, we will investigate the mechanism of hearing compensation, the pathological basis of dysfunctions of learning and memory in the knockin mouse model to clarify the regulatory factors and its threshold effect of Atp6v1b2 in different organs. The iPS cells derived from skin mechanocytes of DDOD syndrome patients will be constructed, mutation corrected and directionally differentiated. The biotherapy for DDOD syndrome will then be explored. The meaning of this study lies in two aspects, the phenotype expansions and pathogenesis illumination for DDOD syndrome. The results will provide theoretical basis for precise treatment and prognosis evaluation.