WDR73 Depletion Destabilizes PIP4K2C Activity and Impairs Focal Adhesion Formation in Galloway–Mowat Syndrome
Hongyan Li,
Fang Liu,
Hanzhe Kuang,
Hua Teng,
Siyi Chen,
Sijing Zeng,
Qimin Zhou,
Zhaokai Li,
Desheng Liang,
Zhuo Li,
Lingqian Wu
Affiliations
Hongyan Li
Center for Medical Genetics, Hunan Key Laboratory of Medical Genetics & Hunan Key Laboratory of Animal Models for Human Disease, School of Life Sciences, Central South University, Changsha 410000, China
Fang Liu
Center for Medical Genetics, Hunan Key Laboratory of Medical Genetics & Hunan Key Laboratory of Animal Models for Human Disease, School of Life Sciences, Central South University, Changsha 410000, China
Hanzhe Kuang
Center for Medical Genetics, Hunan Key Laboratory of Medical Genetics & Hunan Key Laboratory of Animal Models for Human Disease, School of Life Sciences, Central South University, Changsha 410000, China
Hua Teng
Center for Medical Genetics, Hunan Key Laboratory of Medical Genetics & Hunan Key Laboratory of Animal Models for Human Disease, School of Life Sciences, Central South University, Changsha 410000, China
Siyi Chen
Center for Medical Genetics, Hunan Key Laboratory of Medical Genetics & Hunan Key Laboratory of Animal Models for Human Disease, School of Life Sciences, Central South University, Changsha 410000, China
Sijing Zeng
Center for Medical Genetics, Hunan Key Laboratory of Medical Genetics & Hunan Key Laboratory of Animal Models for Human Disease, School of Life Sciences, Central South University, Changsha 410000, China
Qimin Zhou
Center for Medical Genetics, Hunan Key Laboratory of Medical Genetics & Hunan Key Laboratory of Animal Models for Human Disease, School of Life Sciences, Central South University, Changsha 410000, China
Zhaokai Li
Center for Medical Genetics, Hunan Key Laboratory of Medical Genetics & Hunan Key Laboratory of Animal Models for Human Disease, School of Life Sciences, Central South University, Changsha 410000, China
Desheng Liang
Center for Medical Genetics, Hunan Key Laboratory of Medical Genetics & Hunan Key Laboratory of Animal Models for Human Disease, School of Life Sciences, Central South University, Changsha 410000, China
Zhuo Li
Center for Medical Genetics, Hunan Key Laboratory of Medical Genetics & Hunan Key Laboratory of Animal Models for Human Disease, School of Life Sciences, Central South University, Changsha 410000, China
Lingqian Wu
Center for Medical Genetics, Hunan Key Laboratory of Medical Genetics & Hunan Key Laboratory of Animal Models for Human Disease, School of Life Sciences, Central South University, Changsha 410000, China
(1) Background: Galloway–Mowat syndrome (GAMOS) is a rare genetic disease, classically characterized by a combination of various neurological symptoms and nephrotic syndrome. WDR73 is the pathogenic gene responsible for GAMOS1. However, the pathological and molecular mechanisms of GAMOS1, especially nephrotic syndrome caused by WDR73 deficiency, remain unknown. (2) Methods and Results: In this study, we first observed remarkable cellular morphological changes including impaired cell adhesion, decreased pseudopodia, and G2/M phase arrest in WDR73 knockout (KO) HEK 293 cells. The differentially expressed genes in WDR73 KO cells were enriched in the focal adhesion (FA) pathway. Additionally, PIP4K2C, a phospholipid kinase also involved in the FA pathway, was subsequently validated to interact with WDR73 via protein microarray and GST pulldown. WDR73 regulates PIP4K2C protein stability through the autophagy–lysosomal pathway. The stability of PIP4K2C was significantly disrupted by WDR73 KO, leading to a remarkable reduction in PIP2 and thus weakening the FA formation. In addition, we found that podocyte-specific conditional knockout (Wdr73 CKO) mice showed high levels of albuminuria and podocyte foot process injury in the ADR-induced model. FA formation was impaired in primary podocytes derived from Wdr73 CKO mice. (3) Conclusions: Since FA has been well known for its critical roles in maintaining podocyte structures and function, our study indicated that nephrotic syndrome in GAMOS1 is associated with disruption of FA caused by WDR73 deficiency.
