先天性肾脏和尿路异常是常见的出生缺陷，也是导致儿童肾衰竭的首要原因。该病分子机理仍不透彻，目前还不能有效预防，治疗也无特殊手段。GEN1是新发现Holliday 交叉解构酶。我们前期研究观察到GEN1突变小鼠肾脏和输尿管异常高发，并发现了携带GEN1无义突变的先天性肾脏和尿路异常患者，为培育新的疾病动物模型奠定了良好基础。本项目将一方面深入研究突变小鼠肾脏和尿路的异常改变，另一方面分析疾病患者GEN1基因序列和功能的变化，从表型和病因两方面入手评估突变小鼠与患者的相似性，评价GEN1突变体作为疾病模型的价值。项目将以动物模型为基础，研究GEN1影响肾脏发育和疾病的分子机理，为先天性肾脏和尿路异常的遗传预警和干预研究提供线索。

Congenital anomalies of the kidney and urinary tract (CAKUT) is a common birth defect and the leading cause of renal failure in children. Molecular mechanisms underlying CAKUT have not been well defined, nor do we have effective methods for the prevention and early intervention of the disease. We have found the mutation of GEN1, a recently discovered Holliday Junction resolvase, frequently leads to kidney and unrinary tract defects in mice. In addition, GEN1 mutations have been detected in CAKUT patients as well. In order to develop a new animal model model for CAKUT, we propose a detailed comparison between mouse mutants and human patients. Pathological and physiological changes of the mouse mutants will be characterized and compared to the symptoms found in patients. On the other hand, more patients will be screened for GEN1 mutations. Patient specific mutations will be evaluated for their effects on GEN1 activities. Finally, we will explore the mechanistic relation through which GEN1 could affect the development and disease of the kidney and uniary tract.