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FAT1 mutations cause a glomerulotubular nephropathy

 Heon Yung Gee  ;  Carolin E. Sadowski  ;  Pardeep K. Aggarwal  ;  Jonathan D. Porath  ;  Toma A. Yakulov  ;  Markus Schueler  ;  Svjetlana Lovric  ;  Shazia Ashraf  ;  Daniela A. Braun  ;  Jan Halbritter  ;  Humphrey Fang  ;  Rannar Airik  ;  Virginia Vega-Warner  ;  Kyeong Jee Cho  ;  Timothy A. Chan  ;  Luc G.T. Morris  ;  Charles ffrench-Constant  ;  Nicholas Allen  ;  Helen McNeill  ;  Rainer Bu¨scher  ;  Henriette Kyrieleis  ;  Michael Wallot  ;  Ariana Gaspert  ;  Thomas Kistler  ;  David V. Milford  ;  Moin A. Saleem  ;  Wee Teik Keng  ;  Stephen I. Alexander  ;  Rudolph P. Valentini  ;  Christoph Licht  ;  Jun C. Teh  ;  Radovan Bogdanovic  ;  Ania Koziell  ;  Agnieszka Bierzynska  ;  Neveen A. Soliman  ;  Edgar A. Otto  ;  Richard P. Lifton  ;  Lawrence B. Holzman  ;  Nicholas E. S. Sibinga  ;  Gerd Walz  ;  Alda Tufro  ;  Friedhelm Hildebrandt 
 NATURE COMMUNICATIONS, Vol.7 : 10822, 2016 
Journal Title
Issue Date
Animals ; Cadherins/genetics* ; Cell Adhesion/genetics* ; Cell Movement/genetics* ; Dilatation, Pathologic/genetics ; Fibroblasts/metabolism* ; Gene Knockdown Techniques ; Hematuria/genetics ; Humans ; Kidney Tubules/cytology ; Kidney Tubules/metabolism ; Kidney Tubules/pathology ; Lissencephaly/genetics ; Mice ; Mutation ; Nephrotic Syndrome/congenital* ; Nephrotic Syndrome/genetics ; Podocytes/metabolism* ; Syndrome ; Zebrafish ; Zebrafish Proteins/genetics* ; cdc42 GTP-Binding Protein/metabolism ; rac1 GTP-Binding Protein/metabolism
Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease (CKD). Here we show that recessive mutations in FAT1 cause a distinct renal disease entity in four families with a combination of SRNS, tubular ectasia, haematuria and facultative neurological involvement. Loss of FAT1 results in decreased cell adhesion and migration in fibroblasts and podocytes and the decreased migration is partially reversed by a RAC1/CDC42 activator. Podocyte-specific deletion of Fat1 in mice induces abnormal glomerular filtration barrier development, leading to podocyte foot process effacement. Knockdown of Fat1 in renal tubular cells reduces migration, decreases active RAC1 and CDC42, and induces defects in lumen formation. Knockdown of fat1 in zebrafish causes pronephric cysts, which is partially rescued by RAC1/CDC42 activators, confirming a role of the two small GTPases in the pathogenesis. These findings provide new insights into the pathogenesis of SRNS and tubulopathy, linking FAT1 and RAC1/CDC42 to podocyte and tubular cell function.
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1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Gee, Heon Yung(지헌영) ORCID logo https://orcid.org/0000-0002-8741-6177
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