Galloway-Mowat综合征（GAMOS）是一种早发的致愚、致死性常染色体隐性遗传病，主要表现为神经系统多发异常和肾病综合征。WDR73是GAMOS1型的致病基因，其致病机制研究有限。本课题组报道了首个中国人群GAMOS1家系，研究发现携带WDR73纯合错义突变（p.Trp371Gly）患者生存时间长，且表达上调，与以往报道尤其是截短突变间存在较大的异质性。因此，为深入了解WDR73突变导致GAMOS1的病理基础和潜在分子机制，本项目拟诱导患者特异性iPSCs和建立WDR73敲除的iPSCs并模拟不同发育阶段，比较错义突变和截短突变之间的差异；同时在我们已建立Wdr73敲除小鼠模型的基础上，研究GAMOS1在不同发育阶段组织器官的病理特征；最后结合在体和离体实验，探究WDR73的生物学功能及其缺陷导致GAMOS1的分子机制，从而为GAMOS1这类严重遗传病的预防和诊治提供理论依据。

Galloway-Mowat syndrome (GAMOS) is a rare autosomal recessive neurodegenerative disorder characterized by infantile onset of central nervous system abnormalities and nephrotic syndrome. WDR73 is the first reported gene which causes GAMOS1, and yet its pathogenesis remains poorly understood. It is hard to make a diagnosis due to the clinical and genetic heterogeneity of GAMOS1. We previously reported the first Chinese GAMOS1 family, and found that patients with homozygous missense mutation (p.Trp371Gly) of WDR73 displayed milder kidney dysfunction and longer lifespan, compared with other reported patients, especially in those patients with truncating mutation. Additionally, the expression of WDR73 was surprisingly increased. Therefore, in order to understand the pathological features and molecular mechanism of GAMOS1 caused by WDR73 mutation, our study intends to induce patient-specific iPSCs and establish WDR73 knockout iPSCs to understand and compare the difference of influence between missense mutation and truncating mutation. Meanwhile, we have established the Wdr73 knockout mice model to study the pathological features of GAMOS1 at different developmental stages. Finally, combined with in vivo and in vitro experiments, we will explore the biological function of WDR73 and the molecular mechanism of the GAMOS1 development, so as to provide theoretical basis for the prevention and treatment of severe genetic diseases such as GAMOS1.