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Nat Commun. 2016 Feb 24;7:10822. doi: 10.1038/ncomms10822.

FAT1 mutations cause a glomerulotubular nephropathy.

Author information

  • 1Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 2Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Korea.
  • 3Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
  • 4University Freiburg Medical Center, Freiburg 79106, Germany.
  • 5Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • 6Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
  • 7MRC Centre for Regenerative Medicine, Multiple Sclerosis Society Centre for Translational Research, University of Edinburgh, Edinburgh EH16 4UU, UK.
  • 8School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK.
  • 9Department of Molecular Genetics, Samuel Lunenfeld-Tanenbaum Research Institute, University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
  • 10Department of Pediatrics II, University Hospital of Essen, Essen 45147, Germany.
  • 11Department of Pediatrics, Bethanien Hospital, Moers 47441, Germany.
  • 12Institute of Surgical Pathology, University Hospital Zurich, Zurich 8091, Switzerland.
  • 13Division of Nephrology, Kantonsspital Winterthur, Winterthur 8401, Switzerland.
  • 14Department of Paediatric Nephrology, Birmingham Children's Hospital, Birmingham B4 6NH, UK.
  • 15Children's and Academic Renal Unit, University of Bristol, Bristol BS1 5NB, UK.
  • 16Department of Genetics, Hospital Kuala Lumpur, Kuala Lumpur 50586, Malaysia.
  • 17Centre for Kidney Research, Children's Hospital at Westmead, Westmead 2145, Australia.
  • 18Department of Pediatrics, Division of Pediatric Nephrology, Children's Hospital of Michigan/Wayne State University, Detroit, Michigan 48201, USA.
  • 19Division of Nephrology, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada M5G 1X8.
  • 20Institute for Mother and Child Health Care of Serbia "Dr Vukan Čupić", Department of Nephrology, University of Belgrade, Faculty of Medicine, Belgrade 11000, Serbia.
  • 21Department of Experimental Immunobiology, Division of Transplantation Immunology &Mucosal Biology, King's College London, Faculty of Life Sciences &Medicine, 5th floor Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
  • 22Department of Pediatrics, Center of Pediatric Nephrology &Transplantation, Kasr Al Ainy School of Medicine, Cairo University, Cairo 11562, Egypt.
  • 23Egyptian Group for Orphan Renal Diseases, Cairo 11562, Egypt.
  • 24Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
  • 25Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
  • 26Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
  • 27Wilf Family Cardiovascular Research Institute and Department of Medicine/Cardiology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

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.

PMID:
26905694
PMCID:
PMC4770090
DOI:
10.1038/ncomms10822
[PubMed - indexed for MEDLINE]
Free PMC Article

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