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Citations to this article

ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling
Heon Yung Gee, … , Edgar A. Otto, Friedhelm Hildebrandt
Heon Yung Gee, … , Edgar A. Otto, Friedhelm Hildebrandt
Published July 8, 2013
Citation Information: J Clin Invest. 2013;123(8):3243-3253. https://doi.org/10.1172/JCI69134.
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Research Article Article has an altmetric score of 17

ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling

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Abstract

Nephrotic syndrome (NS) is divided into steroid-sensitive (SSNS) and -resistant (SRNS) variants. SRNS causes end-stage kidney disease, which cannot be cured. While the disease mechanisms of NS are not well understood, genetic mapping studies suggest a multitude of unknown single-gene causes. We combined homozygosity mapping with whole-exome resequencing and identified an ARHGDIA mutation that causes SRNS. We demonstrated that ARHGDIA is in a complex with RHO GTPases and is prominently expressed in podocytes of rat glomeruli. ARHGDIA mutations (R120X and G173V) from individuals with SRNS abrogated interaction with RHO GTPases and increased active GTP-bound RAC1 and CDC42, but not RHOA, indicating that RAC1 and CDC42 are more relevant to the pathogenesis of this SRNS variant than RHOA. Moreover, the mutations enhanced migration of cultured human podocytes; however, enhanced migration was reversed by treatment with RAC1 inhibitors. The nephrotic phenotype was recapitulated in arhgdia-deficient zebrafish. RAC1 inhibitors were partially effective in ameliorating arhgdia-associated defects. These findings identify a single-gene cause of NS and reveal that RHO GTPase signaling is a pathogenic mediator of SRNS.

Authors

Heon Yung Gee, Pawaree Saisawat, Shazia Ashraf, Toby W. Hurd, Virginia Vega-Warner, Humphrey Fang, Bodo B. Beck, Olivier Gribouval, Weibin Zhou, Katrina A. Diaz, Sivakumar Natarajan, Roger C. Wiggins, Svjetlana Lovric, Gil Chernin, Dominik S. Schoeb, Bugsu Ovunc, Yaacov Frishberg, Neveen A. Soliman, Hanan M. Fathy, Heike Goebel, Julia Hoefele, Lutz T. Weber, Jeffrey W. Innis, Christian Faul, Zhe Han, Joseph Washburn, Corinne Antignac, Shawn Levy, Edgar A. Otto, Friedhelm Hildebrandt

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Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 2018 2017 2016 2015 2014 2013 2009 Total
Citations: 5 3 5 9 17 8 13 13 18 22 9 10 3 1 136
Citation information
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Citations to this article in year 2016 (22)

Title and authors Publication Year
A role for genetic susceptibility in sporadic focal segmental glomerulosclerosis
Haiyang Yu, Mykyta Artomov, Sebastian Brähler, M. Christine Stander, Ghaidan Shamsan, Matthew G. Sampson, Michael White, Matthias Kretzler, Jeffrey H. Miner, sanjay jain, Cheryl Winkler, Robi Mitra, Jeffrey B. Kopp, Mark J. Daly, Andrey Shaw
Journal of Clinical Investigation 2016
Podocytes
J Reiser, MM Altintas
F1000Research 2016
Drug discovery in focal and segmental glomerulosclerosis
N Pullen, A Fornoni
Kidney International 2016
Targeting the podocyte cytoskeleton: from pathogenesis to therapy in proteinuric kidney disease
X Tian, S Ishibe
Nephrology Dialysis Transplantation 2016
Podocyte–actin dynamics in health and disease
L Perico, S Conti, A Benigni, G Remuzzi
Nature Reviews Nephrology 2016
Podocytes: the Weakest Link in Diabetic Kidney Disease?
JS Lin, K Susztak
Current Diabetes Reports 2016
Human genetics of nephrotic syndrome and the quest for precision medicine:
A Greka
Current Opinion in Nephrology and Hypertension 2016
Synaptopodin Is a Coincidence Detector of Tyrosine versus Serine/Threonine Phosphorylation for the Modulation of Rho Protein Crosstalk in Podocytes
L Buvall, H Wallentin, J Sieber, S Andreeva, HY Choi, P Mundel, A Greka
Journal of the American Society of Nephrology : JASN 2016
The etiology of congenital nephrotic syndrome: current status and challenges
JJ Wang, JH Mao
World Journal of Pediatrics 2016
Cell biology and genetics of minimal change disease
MA Saleem, Y Kobayashi
F1000Research 2016
FAT1 mutations cause a glomerulotubular nephropathy
HY Gee, CE Sadowski, PK Aggarwal, JD Porath, TA Yakulov, M Schueler, S Lovric, S Ashraf, DA Braun, J Halbritter, H Fang, R Airik, V Vega-Warner, KJ Cho, TA Chan, LG Morris, C ffrench-Constant, N Allen, H McNeill, R Büscher, H Kyrieleis, M Wallot, A Gaspert, T Kistler, DV Milford, MA Saleem, WT Keng, SI Alexander, RP Valentini, C Licht, JC Teh, R Bogdanovic, A Koziell, A Bierzynska, NA Soliman, EA Otto, RP Lifton, LB Holzman, NE Sibinga, G Walz, A Tufro, F Hildebrandt
Nature Communications 2016
Dosage-dependent Role of RAC1 in Podocyte Injury
X Wan, MS Lee, W Zhou
American journal of physiology. Renal physiology 2016
Exploring the genetic basis of early-onset chronic kidney disease
A Vivante, F Hildebrandt
Nature Reviews Nephrology 2016
APOL1-G1 in Nephrocytes Induces Hypertrophy and Accelerates Cell Death
Y Fu, J Zhu, A Richman, Y Zhang, X Xie, JR Das, J Li, PE Ray, Z Han
Journal of the American Society of Nephrology : JASN 2016
Disease-causing mutations of RhoGDIα induce Rac1 hyperactivation in podocytes
D Auguste, M Maier, C Baldwin, L Aoudjit, R Robins, IR Gupta, T Takano
Small GTPases 2016
Functional validation of tensin2 SH2-PTB domain by CRISPR/Cas9-mediated genome editing
K MARUSUGI, K NAKANO, H SASAKI, J KIMURA, R YANOBU-TAKANASHI, T OKAMURA, N SASAKI
Journal of Veterinary Medical Science 2016
Mutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-resistant nephrotic syndrome
DA Braun, CE Sadowski, S Kohl, S Lovric, SA Astrinidis, WL Pabst, HY Gee, S Ashraf, JA Lawson, S Shril, M Airik, W Tan, D Schapiro, J Rao, WI Choi, T Hermle, MJ Kemper, M Pohl, F Ozaltin, M Konrad, R Bogdanovic, R Büscher, U Helmchen, E Serdaroglu, RP Lifton, W Antonin, F Hildebrandt
Nature Genetics 2016
Pathogenesis of Focal Segmental Glomerulosclerosis
BJ Lim, JW Yang, WS Do, AB Fogo
Journal of Pathology and Translational Medcine 2016
Modeling Monogenic Human Nephrotic Syndrome in the Drosophila Garland Cell Nephrocyte
T Hermle, DA Braun, M Helmsta dter, TB Huber, F Hildebrandt
Journal of the American Society of Nephrology : JASN 2016
A small molecule screening to detect potential therapeutic targets in human podocytes
E Widmeier, W Tan, M Airik, F Hildebrandt
American journal of physiology. Renal physiology 2016
Loss of endogenous thymosin β4 accelerates glomerular disease
E Vasilopoulou, M Kolatsi-Joannou, MT Lindenmeyer, KE White, MG Robson, CD Cohen, NJ Sebire, PR Riley, PJ Winyard, DA Long
Kidney International 2016
Steroid-resistant nephrotic syndrome: a persistent challenge for pediatric nephrology
S Dogra, F Kaskel
Pediatric Nephrology 2016

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