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.
authors.affiliation: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.|Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Korea.
authors.forename: Heon Yung
authors.initials: HY
authors.lastname: Gee
authors.affiliation: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Carolin E
authors.initials: CE
authors.lastname: Sadowski
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Pardeep K
authors.initials: PK
authors.lastname: Aggarwal
authors.affiliation: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Porath
authors.affiliation: University Freiburg Medical Center, Freiburg 79106, Germany.
authors.forename: Toma A
authors.initials: TA
authors.lastname: Yakulov
authors.affiliation: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Schueler
authors.affiliation: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Svjetlana
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authors.lastname: Lovric
authors.affiliation: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Shazia
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authors.lastname: Ashraf
authors.affiliation: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Daniela A
authors.initials: DA
authors.lastname: Braun
authors.affiliation: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Halbritter
authors.affiliation: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Humphrey
authors.initials: H
authors.lastname: Fang
authors.affiliation: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Rannar
authors.initials: R
authors.lastname: Airik
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Vega-Warner
authors.affiliation: Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Korea.
authors.forename: Kyeong Jee
authors.initials: KJ
authors.lastname: Cho
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Luc G T
authors.initials: LG
authors.lastname: Morris
authors.affiliation: MRC Centre for Regenerative Medicine, Multiple Sclerosis Society Centre for Translational Research, University of Edinburgh, Edinburgh EH16 4UU, UK.
authors.forename: Charles
authors.initials: C
authors.lastname: ffrench-Constant
authors.affiliation: School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Allen
authors.affiliation: Department of Molecular Genetics, Samuel Lunenfeld-Tanenbaum Research Institute, University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
authors.forename: Helen
authors.initials: H
authors.lastname: McNeill
authors.affiliation: Department of Pediatrics II, University Hospital of Essen, Essen 45147, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Büscher
authors.affiliation: Department of Pediatrics, Bethanien Hospital, Moers 47441, Germany.
authors.forename: Henriette
authors.initials: H
authors.lastname: Kyrieleis
authors.affiliation: Department of Pediatrics, Bethanien Hospital, Moers 47441, Germany.
authors.forename: Michael
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authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich 8091, Switzerland.
authors.forename: Ariana
authors.initials: A
authors.lastname: Gaspert
authors.affiliation: Division of Nephrology, Kantonsspital Winterthur, Winterthur 8401, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kistler
authors.affiliation: Department of Paediatric Nephrology, Birmingham Children's Hospital, Birmingham B4 6NH, UK.
authors.forename: David V
authors.initials: DV
authors.lastname: Milford
authors.affiliation: Children's and Academic Renal Unit, University of Bristol, Bristol BS1 5NB, UK.
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authors.initials: MA
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authors.affiliation: Department of Genetics, Hospital Kuala Lumpur, Kuala Lumpur 50586, Malaysia.
authors.forename: Wee Teik
authors.initials: WT
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authors.affiliation: Centre for Kidney Research, Children's Hospital at Westmead, Westmead 2145, Australia.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Alexander
authors.affiliation: Department of Pediatrics, Division of Pediatric Nephrology, Children's Hospital of Michigan/Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: Rudolph P
authors.initials: RP
authors.lastname: Valentini
authors.affiliation: Division of Nephrology, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Christoph
authors.initials: C
authors.lastname: Licht
authors.affiliation: Division of Nephrology, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Jun C
authors.initials: JC
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authors.affiliation: Institute for Mother and Child Health Care of Serbia "Dr Vukan Čupić", Department of Nephrology, University of Belgrade, Faculty of Medicine, Belgrade 11000, Serbia.
authors.forename: Radovan
authors.initials: R
authors.lastname: Bogdanovic
authors.affiliation: Department 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.
authors.forename: Ania
authors.initials: A
authors.lastname: Koziell
authors.affiliation: Children's and Academic Renal Unit, University of Bristol, Bristol BS1 5NB, UK.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Bierzynska
authors.affiliation: Department of Pediatrics, Center of Pediatric Nephrology &Transplantation, Kasr Al Ainy School of Medicine, Cairo University, Cairo 11562, Egypt.|Egyptian Group for Orphan Renal Diseases, Cairo 11562, Egypt.
authors.forename: Neveen A
authors.initials: NA
authors.lastname: Soliman
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Edgar A
authors.identifier: http://orcid.org/0000-0002-2387-9973
authors.initials: EA
authors.lastname: Otto
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
authors.forename: Richard P
authors.initials: RP
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authors.affiliation: Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Holzman
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authors.forename: Nicholas E S
authors.initials: NE
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authors.affiliation: University Freiburg Medical Center, Freiburg 79106, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Walz
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Alda
authors.initials: A
authors.lastname: Tufro
authors.affiliation: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics*; D002448:Cell Adhesion / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics*; D004108:Dilatation, Pathologic / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006417:Hematuria / Q000235:genetics; D006801:Humans; D007684:Kidney Tubules / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D054082:Lissencephaly / Q000235:genetics; D051379:Mice; D009154:Mutation; D009404:Nephrotic Syndrome / Q000151:congenital* / Q000235:genetics; D050199:Podocytes / Q000378:metabolism*; D013577:Syndrome; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D015820:Cadherins; C502403:FAT1 protein, human; D029961:Zebrafish Proteins; C502406:fat1 protein, mouse; C000609008:fat1a protein, zebrafish; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein