Int J Biol Sci 2018; 14(1):10-20. doi:10.7150/ijbs.22768 This issue

Research Paper

Disruption of Gen1 Causes Congenital Anomalies of the Kidney and Urinary Tract in Mice

Herui Wang1,2,5*, Chi Zhang1,2,6*, Xiaowen Wang2,7, Yaru Lian1,3, Bin Guo1, Miao Han1,3, Xiaoe Zhang2, Xiaoting Zhu1, Sixian Xu1, Zengli Guo1, Yunli Bi2, Qian Shen2, Xiang Wang2, Jiaojiao Liu2, Yuan Zhuang1,4, Ting Ni1,3, Hong Xu2✉, Xiaohui Wu1,2✉

1. State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China;
2. Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Children's Hospital of Fudan University, Shanghai 201102, China;
3. MOE Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai 200433, China;
4. Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA;
5. Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA;
6. Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309, USA;
7. Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430000, China.
* These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( See for full terms and conditions.
Wang H, Zhang C, Wang X, Lian Y, Guo B, Han M, Zhang X, Zhu X, Xu S, Guo Z, Bi Y, Shen Q, Wang X, Liu J, Zhuang Y, Ni T, Xu H, Wu X. Disruption of Gen1 Causes Congenital Anomalies of the Kidney and Urinary Tract in Mice. Int J Biol Sci 2018; 14(1):10-20. doi:10.7150/ijbs.22768. Available from

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Graphic abstract

Congenital anomalies of the kidney and urinary tract (CAKUT) are among the most common developmental defects in humans. Despite of several known CAKUT-related loci (HNF1B, PAX2, EYA1, etc.), the genetic etiology of CAKUT remains to be elucidated for most patients. In this study, we report that disruption of the Holliday Junction resolvase gene Gen1 leads to renal agenesis, duplex kidney, hydronephrosis, and vesicoureteral reflux (VUR) in mice. GEN1 interacts with SIX1 and enhances the transcriptional activity of SIX1/EYA1, a key regulatory complex of the GDNF morphogen. Gen1 mutation impairs Grem1 and Gdnf expression, resulting in excessive ureteric bud formation and defective ureteric bud branching during early kidney development. These results revealed an unidentified role of GEN1 in kidney development and suggested its contribution to CAKUT.