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.
| Original language | English |
|---|---|
| Article number | 10822 |
| Journal | Nature Communications |
| Volume | 7 |
| DOIs | |
| Publication status | Published - 24 Feb 2016 |
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FAT1 mutations cause a glomerulotubular nephropathy. / Gee, Heon Yung; Sadowski, Carolin E.; Aggarwal, Pardeep K. et al.
In: Nature Communications, Vol. 7, 10822, 24.02.2016.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - FAT1 mutations cause a glomerulotubular nephropathy
AU - Gee, Heon Yung
AU - Sadowski, Carolin E.
AU - Aggarwal, Pardeep K.
AU - Porath, Jonathan D.
AU - Yakulov, Toma A.
AU - Schueler, Markus
AU - Lovric, Svjetlana
AU - Ashraf, Shazia
AU - Braun, Daniela A.
AU - Halbritter, Jan
AU - Fang, Humphrey
AU - Airik, Rannar
AU - Vega-Warner, Virginia
AU - Jee Cho, Kyeong
AU - Chan, Timothy A.
AU - Morris, Luc G. T.
AU - ffrench-Constant, Charles
AU - Allen, Nicholas
AU - McNeill, Helen
AU - Büscher, Rainer
AU - Kyrieleis, Henriette
AU - Wallot, Michael
AU - Gaspert, Ariana
AU - Kistler, Thomas
AU - Milford, David V.
AU - Saleem, Moin A.
AU - Keng, Wee Teik
AU - Alexander, Stephen I.
AU - Valentini, Rudolph P.
AU - Licht, Christoph
AU - Teh, Jun C.
AU - Bogdanovic, Radovan
AU - Koziell, Ania
AU - Bierzynska, Agnieszka
AU - Soliman, Neveen A.
AU - Otto, Edgar A.
AU - Lifton, Richard P.
AU - Holzman, Lawrence B.
AU - Sibinga, Nicholas E. S.
AU - Walz, Gerd
AU - Tufro, Alda
AU - Hildebrandt, Friedhelm
N1 - Funding Information: We thank the families who contributed to this study, UK Renal Rare Disease Registry (www.renalradar.org) and Dr Susan Arbuckle (Children''s Hospital Westmead) and Dr David Manson (Toronto) for contributing renal pathology materials and radiology materials, respectively. Sequencing of UK patients was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy''s and St Thomas'' NHS Foundation Trust and King''s College London and the Guys and St Thomas'' Hospital Charity. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. We thank Maria Ericsson (Harvard Medical School Electron Microscopy Facility) for technical assistance. This research was supported by grants from the National Institutes of Health to F.H. (DK076683, DK068306), to E.A.O. (DK090917), to A.T. (DK059333), to N.E.S (HL104518) and by a grant from the Nephcure Foundation (to F.H.). H.Y.G. was supported by an OFD/CTREC/RRRC Career Development Fellowship, a Nephcure-ASN Foundation Kidney Research Grant and Basic Science Research Program through the National Research Foundation of Korea by the Ministry of Science, ICT & Future planning (2015R1D1A1A01056685). G.W. was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 1140), and from the European Community''s Seventh Framework Programme (grant agreement 241955, SYSCILIA). F.H. is the Warren E. Grupe Professor of Pediatrics at Harvard Medical School. Funding Information: We thank the families who contributed to this study, UK Renal Rare Disease Registry (www.renalradar.org) and Dr Susan Arbuckle (Children’s Hospital Westmead) and Dr David Manson (Toronto) for contributing renal pathology materials and radiology materials, respectively. Sequencing of UK patients was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London and the Guys and St Thomas’ Hospital Charity. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. We thank Maria Ericsson (Harvard Medical School Electron Microscopy Facility) for technical assistance. This research was supported by grants from the National Institutes of Health to F.H. (DK076683, DK068306), to E.A.O. (DK090917), to A.T. (DK059333), to N.E.S (HL104518) and by a grant from the Nephcure Foundation (to F.H.). H.Y.G. was supported by an OFD/CTREC/RRRC Career Development Fellowship, a Nephcure—ASN Foundation Kidney Research Grant and Basic Science Research Program through the National Research Foundation of Korea by the Ministry of Science, ICT & Future planning (2015R1D1A1A01056685). G.W. was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 1140), and from the European Community’s Seventh Framework Programme (grant agreement 241955, SYSCILIA). F.H. is the Warren E. Grupe Professor of Pediatrics at Harvard Medical School.
PY - 2016/2/24
Y1 - 2016/2/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84959378120&partnerID=8YFLogxK
U2 - 10.1038/ncomms10822
DO - 10.1038/ncomms10822
M3 - Article
C2 - 26905694
AN - SCOPUS:84959378120
VL - 7
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 10822
ER -