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 & 22 others 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

Research output: Contribution to journalArticle

31 Citations (Scopus)

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 languageEnglish (US)
Article number10822
JournalNature Communications
Volume7
DOIs
StatePublished - Feb 24 2016

Fingerprint

Podocytes
steroids
mutations
pathogenesis
Nephrotic Syndrome
Steroids
Mutation
causes
hematuria
kidney diseases
cells
Cell Movement
deletion
cysts
lumens
Monomeric GTP-Binding Proteins
Glomerular Filtration Barrier
Cell adhesion
fibroblasts
Fibroblasts

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Gee, H. Y., Sadowski, C. E., Aggarwal, P. K., Porath, J. D., Yakulov, T. A., Schueler, M., ... Hildebrandt, F. (2016). FAT1 mutations cause a glomerulotubular nephropathy. Nature Communications, 7, [10822]. https://doi.org/10.1038/ncomms10822

FAT1 mutations cause a glomerulotubular nephropathy. / 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; 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; Hildebrandt, Friedhelm.

In: Nature Communications, Vol. 7, 10822, 24.02.2016.

Research output: Contribution to journalArticle

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
Gee HY, Sadowski CE, Aggarwal PK, Porath JD, Yakulov TA, Schueler M et al. FAT1 mutations cause a glomerulotubular nephropathy. Nature Communications. 2016 Feb 24;7. 10822. https://doi.org/10.1038/ncomms10822
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 ; 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 ; Hildebrandt, Friedhelm. / FAT1 mutations cause a glomerulotubular nephropathy. In: Nature Communications. 2016 ; Vol. 7.
@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",
year = "2016",
month = "2",
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

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

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

U2 - 10.1038/ncomms10822

DO - 10.1038/ncomms10822

M3 - Article

VL - 7

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 10822

ER -