FAT1 mutations cause a glomerulotubular nephropathy Journal Article


Authors: Gee, H. Y.; Sadowski, C. E.; Aggarwal, P. K.; Porath, J. D.; Yakulov, T. A.; Schueler, M.; Lovric, S.; Ashraf, S.; Braun, D. A.; Halbritter, J.; Fang, H.; Airik, R.; Vega-Warner, V.; Jee Cho, K.; Chan, T. A.; Morris, L. G. T.; Ffrench-Constant, C.; Allen, N.; McNeill, H.; B├╝scher, R.; Kyrieleis, H.; Wallot, M.; Gaspert, A.; Kistler, T.; Milford, D. V.; Saleem, M. A.; Keng, W. T.; Alexander, S. I.; Valentini, R. P.; Licht, C.; Teh, J. C.; Bogdanovic, R.; Koziell, A.; Bierzynska, A.; Soliman, N. A.; Otto, E. A.; Lifton, R. P.; Holzman, L. B.; Sibinga, N. E. S.; Walz, G.; Tufro, A.; Hildebrandt, F.
Article Title: FAT1 mutations cause a glomerulotubular nephropathy
Abstract: 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.
Keywords: mus; danio rerio
Journal Title: Nature Communications
Volume: 7
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2016-02-24
Start Page: 10822
Language: English
DOI: 10.1038/ncomms10822
PROVIDER: scopus
PMCID: PMC4770090
PUBMED: 26905694
DOI/URL:
Notes: Article -- Export Date: 4 April 2016 -- Source: Scopus
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MSK Authors
  1. Timothy Chan
    266 Chan
  2. Luc Morris
    150 Morris