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 Büscher, 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 () and Friedhelm Hildebrandt ()
Additional contact information
Heon Yung Gee: Boston Children's Hospital, Harvard Medical School
Carolin E. Sadowski: Boston Children's Hospital, Harvard Medical School
Pardeep K. Aggarwal: Yale University School of Medicine
Jonathan D. Porath: Boston Children's Hospital, Harvard Medical School
Toma A. Yakulov: University Freiburg Medical Center
Markus Schueler: Boston Children's Hospital, Harvard Medical School
Svjetlana Lovric: Boston Children's Hospital, Harvard Medical School
Shazia Ashraf: Boston Children's Hospital, Harvard Medical School
Daniela A. Braun: Boston Children's Hospital, Harvard Medical School
Jan Halbritter: Boston Children's Hospital, Harvard Medical School
Humphrey Fang: Boston Children's Hospital, Harvard Medical School
Rannar Airik: Boston Children's Hospital, Harvard Medical School
Virginia Vega-Warner: University of Michigan
Kyeong Jee Cho: Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine
Timothy A. Chan: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Luc G. T. Morris: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Charles ffrench-Constant: MRC Centre for Regenerative Medicine, Multiple Sclerosis Society Centre for Translational Research, University of Edinburgh
Nicholas Allen: School of Biosciences, Cardiff University
Helen McNeill: Samuel Lunenfeld-Tanenbaum Research Institute, University of Toronto, Mount Sinai Hospital
Rainer Büscher: University Hospital of Essen
Henriette Kyrieleis: Bethanien Hospital
Michael Wallot: Bethanien Hospital
Ariana Gaspert: Institute of Surgical Pathology, University Hospital Zurich
Thomas Kistler: Kantonsspital Winterthur
David V. Milford: Birmingham Children’s Hospital
Moin A. Saleem: Children’s and Academic Renal Unit, University of Bristol
Wee Teik Keng: Hospital Kuala Lumpur
Stephen I. Alexander: Centre for Kidney Research, Children's Hospital at Westmead
Rudolph P. Valentini: Children’s Hospital of Michigan/Wayne State University
Christoph Licht: The Hospital for Sick Children and University of Toronto
Jun C. Teh: The Hospital for Sick Children and University of Toronto
Radovan Bogdanovic: Institute for Mother and Child Health Care of Serbia “Dr Vukan Čupić”, University of Belgrade, Faculty of Medicine
Ania Koziell: King’s College London, Faculty of Life Sciences & Medicine
Agnieszka Bierzynska: Children’s and Academic Renal Unit, University of Bristol
Neveen A. Soliman: Center of Pediatric Nephrology & Transplantation, Kasr Al Ainy School of Medicine, Cairo University
Edgar A. Otto: University of Michigan
Richard P. Lifton: Yale University School of Medicine
Lawrence B. Holzman: Perelman School of Medicine, University of Pennsylvania
Nicholas E. S. Sibinga: Albert Einstein College of Medicine
Gerd Walz: University Freiburg Medical Center
Alda Tufro: Yale University School of Medicine
Friedhelm Hildebrandt: Boston Children's Hospital, Harvard Medical School

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10822

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