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Gee, Heon Yung, Sadowski, Carolin E., Aggarwal, Pardeep K., Porath, Jonathan D., Yakulov, Toma A., Schueler, Markus, Lovric, Svjetlana, Ashraf, Shazia, Braun, Daniela A., Halbritter, Jan, Fang, Humphrey, Airik, Rannar, Vega-Warner, Virginia, Jee Cho, Kyeong, Chan, Timothy A., Morris, Luc G. T., ffrench-Constant, Charles 
ORCID: https://orcid.org/0000-0002-5621-3377, Allen, Nicholas, McNeill, Helen, Büscher, Rainer, Kyrieleis, Henriette, Wallot, Michael, Gaspert, Ariana, Kistler, Thomas, Milford, David V., Saleem, Moin A., Keng, Wee Teik, Alexander, Stephen I., Valentini, Rudolph P., Licht, Christoph, Teh, Jun C., Bogdanovic, Radovan, Koziell, Ania, Bierzynska, Agnieszka, Soliman, Neveen A., Otto, Edgar A., Lifton, Richard P., Holzman, Lawrence B., Sibinga, Nicholas E. S., Walz, Gerd, Tufro, Alda and Hildebrandt, Friedhelm
(2016)
FAT1 mutations cause a glomerulotubular nephropathy.
Nature Communications, 7.
ISSN 2041-1723
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.
| Item Type: | Article |
|---|---|
| Additional Information: | 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. |
| Uncontrolled Keywords: | chemistry(all),biochemistry, genetics and molecular biology(all),physics and astronomy(all) ,/dk/atira/pure/subjectarea/asjc/1600 |
| Faculty \ School: | Faculty of Medicine and Health Sciences > Norwich Medical School |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 15 Jul 2022 22:30 |
| Last Modified: | 22 Oct 2022 18:37 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/86252 |
| DOI: | 10.1038/ncomms10822 |
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