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

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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	https://doi.org/10.1038/ncomms10822
Publication status	Published - 24 Feb 2016

Keywords

Animals
Cadherins
Cell Adhesion
Cell Movement
Dilatation, Pathologic
Fibroblasts
Gene Knockdown Techniques
Hematuria
Humans
Kidney Tubules
Lissencephaly
Mice
Mutation
Nephrotic Syndrome
Podocytes
Syndrome
Zebrafish
Zebrafish Proteins
cdc42 GTP-Binding Protein
rac1 GTP-Binding Protein
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

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10.1038/ncomms10822

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Saleem, M. (Principal Investigator)
1/09/09 → 1/09/12
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Professor Moin Saleem
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- Bristol Medical School (THS) - Professor
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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., Cho, K. J., 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

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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.",

keywords = "Animals, Cadherins, Cell Adhesion, Cell Movement, Dilatation, Pathologic, Fibroblasts, Gene Knockdown Techniques, Hematuria, Humans, Kidney Tubules, Lissencephaly, Mice, Mutation, Nephrotic Syndrome, Podocytes, Syndrome, Zebrafish, Zebrafish Proteins, cdc42 GTP-Binding Protein, rac1 GTP-Binding Protein, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't",

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 Cho, {Kyeong Jee} 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",

year = "2016",

month = feb,

day = "24",

doi = "10.1038/ncomms10822",

language = "English",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Springer Nature",

}

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, Cho, KJ, 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

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 - Cho, Kyeong Jee

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

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.

KW - Animals

KW - Cadherins

KW - Cell Adhesion

KW - Cell Movement

KW - Dilatation, Pathologic

KW - Fibroblasts

KW - Gene Knockdown Techniques

KW - Hematuria

KW - Humans

KW - Kidney Tubules

KW - Lissencephaly

KW - Mice

KW - Mutation

KW - Nephrotic Syndrome

KW - Podocytes

KW - Syndrome

KW - Zebrafish

KW - Zebrafish Proteins

KW - cdc42 GTP-Binding Protein

KW - rac1 GTP-Binding Protein

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/ncomms10822

DO - 10.1038/ncomms10822

M3 - Article (Academic Journal)

C2 - 26905694

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 10822

ER -

FAT1 mutations cause a glomerulotubular nephropathy

Abstract

Keywords

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