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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

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: 6 3 5 9 17 8 13 13 18 22 9 10 3 1 137
Citation information
This citation data is accumulated from CrossRef, which receives citation information from participating publishers, including this journal. Not all publishers participate in CrossRef, so this information is not comprehensive. Additionally, data may not reflect the most current citations to this article, and the data may differ from citation information available from other sources (for example, Google Scholar, Web of Science, and Scopus).

Citations to this article in year 2021 (17)

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Single-Cell Transcriptomics Reveal Disrupted Kidney Filter Cell-Cell Interactions after Early and Selective Podocyte Injury
AR Clark, J Marshall, Y Zhou, MS Montesinos, H Chen, L Nguyen, F Chen, A Greka
The American Journal of Pathology 2021
The glomerular filtration barrier: a structural target for novel kidney therapies
IS Daehn, JS Duffield
Nature Reviews Drug Discovery 2021
Abnormal Crosstalk between Endothelial Cells and Podocytes Mediates Tyrosine Kinase Inhibitor (TKI)-Induced Nephrotoxicity
X Gu, S Zhang, T Zhang
Cells 2021
TRPC5 Channel Inhibition Protects Podocytes in Puromycin-Aminonucleoside Induced Nephrosis Models
Y Zhou, C Kim, JL Pablo, F Zhang, JY Jung, L Xiao, S Bazua-Valenti, M Emani, CR Hopkins, A Weins, A Greka
Frontiers in Medicine 2021
The Mineralocorticoid Receptor in Salt-Sensitive Hypertension and Renal Injury
N Ayuzawa, T Fujita
Journal of the American Society of Nephrology : JASN 2021
Management of Steroid-Resistant Nephrotic Syndrome in Children
S Sachdeva, S Khan, C Davalos, C Avanthika, S Jhaveri, A Babu, D Patterson, AJ Yamani
Cureus 2021
Recessive Mutations in SYNPO2 as a Candidate of Monogenic Nephrotic Syndrome
Y Mao, R Schneider, PF van der Ven, M Assent, K Lohanadan, V Klämbt, F Buerger, TM Kitzler, K Deutsch, M Nakayama, AJ Majmundar, N Mann, T Hermle, AC Onuchic-Whitford, W Zhou, NN Margam, R Duncan, J Marquez, M Khokha, HM Fathy, JA Kari, SE Desoky, LA Eid, HS Awad, M Al-Saffar, S Mane, RP Lifton, DO Fürst, S Shril, F Hildebrandt
Kidney International Reports 2021
Rho GTPases in kidney physiology and diseases
C Steichen, JC Hervé, T Hauet, N Bourmeyster
Small GTPases 2021
Generation of Monogenic Candidate Genes for Human Nephrotic Syndrome Using 3 Independent Approaches
V Klämbt, Y Mao, R Schneider, F Buerger, H Shamseldin, AC Onuchic-Whitford, K Deutsch, TM Kitzler, M Nakayama, AJ Majmundar, N Mann, H Hugo, E Widmeier, W Tan, HL Rehm, S Mane, RP Lifton, FS Alkuraya, S Shril, F Hildebrandt
Kidney International Reports 2021
Urine-Derived Epithelial Cells as Models for Genetic Kidney Diseases
T Bondue, FO Arcolino, KR Veys, OC Adebayo, E Levtchenko, LP van den Heuvel, MA Elmonem
Cells 2021
Role of Rho in Salt-Sensitive Hypertension
W Kawarazaki, T Fujita
International journal of molecular sciences 2021
Recessive NOS1AP variants impair actin remodeling and cause glomerulopathy in humans and mice
AJ Majmundar, F Buerger, TA Forbes, V Klämbt, R Schneider, K Deutsch, TM Kitzler, SE Howden, M Scurr, KS Tan, M Krzeminski, E Widmeier, DA Braun, E Lai, I Ullah, A Amar, A Kolb, K Eddy, CH Chen, D Salmanullah, R Dai, M Nakayama, I Ottlewski, CM Kolvenbach, AC Onuchic-Whitford, Y Mao, N Mann, MM Nabhan, S Rosen, JD Forman-Kay, NA Soliman, A Heilos, R Kain, C Aufricht, S Mane, RP Lifton, S Shril, MH Little, F Hildebrandt
Science Advances 2021
Safety and Efficacy of GFB-887, a TRPC5 Channel Inhibitor, in Patients With Focal Segmental Glomerulosclerosis, Treatment-Resistant Minimal Change Disease, or Diabetic Nephropathy: TRACTION-2 Trial Design
L Walsh, JF Reilly, C Cornwall, GA Gaich, DS Gipson, HJ Heerspink, L Johnson, H Trachtman, KR Tuttle, YM Farag, K Padmanabhan, XR Pan-Zhou, JR Woodworth, FS Czerwiec
Kidney International Reports 2021
Rho-GTPase Activating Protein myosin MYO9A identified as a novel candidate gene for monogenic focal segmental glomerulosclerosis
Q Li, A Gulati, M Lemaire, T Nottoli, A Bale, A Tufro
Kidney International 2021
Identification of Potential miRNA-mRNA Regulatory Network Contributing to Hypertrophic Cardiomyopathy (HCM)
L Wang, F Lu, J Xu
Frontiers in Cardiovascular Medicine 2021
Nephrotic-syndrome-associated mutation of KANK2 induces pathologic binding competition with physiological interactor KIF21A
Y Xu, C Guo, W Pan, C Zhao, Y Ding, X Xie, Z Wei, Y Sun, C Yu
The Journal of biological chemistry 2021
End‐stage renal disease in a child with focal segmental glomerulosclerosis associated with a homozygous NUP93 variant
R Acharya, K Upadhyay
Clinical Case Reports 2021

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