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FAT1 mutations cause a glomerulotubular nephropathy

Author

Listed:
  • Heon Yung Gee

    (Boston Children's Hospital, Harvard Medical School
    Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine)

  • 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
    Egyptian Group for Orphan Renal Diseases)

  • Edgar A. Otto

    (University of Michigan)

  • Richard P. Lifton

    (Yale University School of Medicine
    Howard Hughes Medical Institute)

  • 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
    Howard Hughes Medical Institute)

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.

Suggested Citation

  • 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 Fan, 2016. "FAT1 mutations cause a glomerulotubular nephropathy," Nature Communications, Nature, vol. 7(1), pages 1-11, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10822
    DOI: 10.1038/ncomms10822
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    Cited by:

    1. Ji-Hee Kim & Kyu-Hee Hwang & Bao T. N. Dang & Minseob Eom & In Deok Kong & Yousang Gwack & Seyoung Yu & Heon Yung Gee & Lutz Birnbaumer & Kyu-Sang Park & Seung-Kuy Cha, 2021. "Insulin-activated store-operated Ca2+ entry via Orai1 induces podocyte actin remodeling and causes proteinuria," Nature Communications, Nature, vol. 12(1), pages 1-13, December.

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