FAT1 mutations cause a glomerulotubular nephropathy

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 Fang; Rannar Airik; Virginia Vega-Warner; Kyeong Jee Cho; Timothy A. Chan; Luc G.T. Morris; Charles Ffrench-Constant; Nicholas Allen; Helen McNeill; Rainer Büscher; Henriette Kyrieleis; Michael Wallot; Ariana Gaspert; Thomas Kistler; David V. Milford; Moin A. Saleem; Wee Teik Keng; Stephen I. Alexander; Rudolph P. Valentini; Christoph Licht; Jun C. Teh; Radovan Bogdanovic; Ania Koziell; Agnieszka Bierzynska; Neveen A. Soliman; Edgar A. Otto; Richard P. Lifton; Lawrence B. Holzman; Nicholas E.S. Sibinga; Gerd Walz; Alda Tufro; Friedhelm Hildebrandt

doi:10.1038/ncomms10822

FAT1 mutations cause a glomerulotubular nephropathy

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 Fang, Rannar Airik, Virginia Vega-Warner, Kyeong Jee Cho, Timothy A. Chan, Luc G.T. Morris, Charles Ffrench-Constant, Nicholas Allen, Helen McNeill, Rainer BüscherHenriette Kyrieleis, Michael Wallot, Ariana Gaspert, Thomas Kistler, David V. Milford, Moin A. Saleem, Wee Teik Keng, Stephen I. Alexander, Rudolph P. Valentini, Christoph Licht, Jun C. Teh, Radovan Bogdanovic, Ania Koziell, Agnieszka Bierzynska, Neveen A. Soliman, Edgar A. Otto, Richard P. Lifton, Lawrence B. Holzman, Nicholas E.S. Sibinga, Gerd Walz, Alda Tufro, Friedhelm Hildebrandt

Medicine

Research output: Contribution to journal › Article › peer-review

85 Scopus citations

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 (US)
Article number	10822
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10822
State	Published - Feb 24 2016

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/ncomms10822

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Gee, H. Y., Sadowski, C. E., Aggarwal, P. K., Porath, J. D., Yakulov, T. A., Schueler, M., Lovric, S., Ashraf, S., Braun, D. A., Halbritter, J., Fang, H., Airik, R., Vega-Warner, V., Jee Cho, K., Chan, T. A., Morris, L. G. T., Ffrench-Constant, C., Allen, N., McNeill, H., ... Hildebrandt, F. (2016). FAT1 mutations cause a glomerulotubular nephropathy. Nature communications, 7, Article 10822. https://doi.org/10.1038/ncomms10822

Gee, HY, Sadowski, CE, Aggarwal, PK, Porath, JD, Yakulov, TA, Schueler, M, Lovric, S, Ashraf, S, Braun, DA, Halbritter, J, Fang, H, Airik, R, Vega-Warner, V, Jee Cho, K, Chan, TA, Morris, LGT, Ffrench-Constant, C, Allen, N, McNeill, H, Büscher, R, Kyrieleis, H, Wallot, M, Gaspert, A, Kistler, T, Milford, DV, Saleem, MA, Keng, WT, Alexander, SI, Valentini, RP, Licht, C, Teh, JC, Bogdanovic, R, Koziell, A, Bierzynska, A, Soliman, NA, Otto, EA, Lifton, RP, Holzman, LB, Sibinga, NES, Walz, G, Tufro, A & Hildebrandt, F 2016, 'FAT1 mutations cause a glomerulotubular nephropathy', Nature communications, vol. 7, 10822. https://doi.org/10.1038/ncomms10822

@article{c226c61ecbb04ccc95e22cf79a7c273c,

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.",

author = "Gee, {Heon Yung} and Sadowski, {Carolin E.} and Aggarwal, {Pardeep K.} and Porath, {Jonathan D.} and Yakulov, {Toma A.} and Markus Schueler and Svjetlana Lovric and Shazia Ashraf and Braun, {Daniela A.} and Jan Halbritter and Humphrey Fang and Rannar Airik and Virginia Vega-Warner and {Jee Cho}, Kyeong and Chan, {Timothy A.} and Morris, {Luc G.T.} and Charles Ffrench-Constant and Nicholas Allen and Helen McNeill and Rainer B{\"u}scher and Henriette Kyrieleis and Michael Wallot and Ariana Gaspert and Thomas Kistler and Milford, {David V.} and Saleem, {Moin A.} and Keng, {Wee Teik} and Alexander, {Stephen I.} and Valentini, {Rudolph P.} and Christoph Licht and Teh, {Jun C.} and Radovan Bogdanovic and Ania Koziell and Agnieszka Bierzynska and Soliman, {Neveen A.} and Otto, {Edgar A.} and Lifton, {Richard P.} and Holzman, {Lawrence B.} and Sibinga, {Nicholas E.S.} and Gerd Walz and Alda Tufro and Friedhelm Hildebrandt",

note = "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{\textquoteright}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{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust and King{\textquoteright}s College London and the Guys and St Thomas{\textquoteright} 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{\textquoteright}s Seventh Framework Programme (grant agreement 241955, SYSCILIA). F.H. is the Warren E. Grupe Professor of Pediatrics at Harvard Medical School.",

year = "2016",

month = feb,

day = "24",

doi = "10.1038/ncomms10822",

language = "English (US)",

volume = "7",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

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.

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UR - http://www.scopus.com/inward/citedby.url?scp=84959378120&partnerID=8YFLogxK

U2 - 10.1038/ncomms10822

DO - 10.1038/ncomms10822

M3 - Article

C2 - 26905694

AN - SCOPUS:84959378120

SN - 2041-1723

VL - 7

JO - Nature communications

JF - Nature communications

M1 - 10822

ER -

FAT1 mutations cause a glomerulotubular nephropathy

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