ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling

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 GoebelJulia Hoefele, Lutz T. Weber, Jeffrey W. Innis, Christian Faul, Zhe Han, Joseph Washburn, Corinne Antignac, Shawn Levy, Edgar A. Otto, Friedhelm Hildebrandt

Research output: Contribution to journalArticle

119 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3243-3253
Number of pages11
JournalJournal of Clinical Investigation
Volume123
Issue number8
DOIs
Publication statusPublished - 2013 Aug 1

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GTP Phosphohydrolases
Nephrotic Syndrome
Podocytes
Mutation
Exome
Zebrafish
Guanosine Triphosphate
Genes
Chronic Kidney Failure
Steroids
Phenotype

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Gee, H. Y., Saisawat, P., Ashraf, S., Hurd, T. W., Vega-Warner, V., Fang, H., ... Hildebrandt, F. (2013). ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling. Journal of Clinical Investigation, 123(8), 3243-3253. https://doi.org/10.1172/JCI69134
Gee, Heon Yung ; Saisawat, Pawaree ; Ashraf, Shazia ; Hurd, Toby W. ; Vega-Warner, Virginia ; Fang, Humphrey ; Beck, Bodo B. ; Gribouval, Olivier ; Zhou, Weibin ; Diaz, Katrina A. ; Natarajan, Sivakumar ; Wiggins, Roger C. ; Lovric, Svjetlana ; Chernin, Gil ; Schoeb, Dominik S. ; Ovunc, Bugsu ; Frishberg, Yaacov ; Soliman, Neveen A. ; Fathy, Hanan M. ; Goebel, Heike ; Hoefele, Julia ; Weber, Lutz T. ; Innis, Jeffrey W. ; Faul, Christian ; Han, Zhe ; Washburn, Joseph ; Antignac, Corinne ; Levy, Shawn ; Otto, Edgar A. ; Hildebrandt, Friedhelm. / ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 8. pp. 3243-3253.
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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.",
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Gee, HY, Saisawat, P, Ashraf, S, Hurd, TW, Vega-Warner, V, Fang, H, Beck, BB, Gribouval, O, Zhou, W, Diaz, KA, Natarajan, S, Wiggins, RC, Lovric, S, Chernin, G, Schoeb, DS, Ovunc, B, Frishberg, Y, Soliman, NA, Fathy, HM, Goebel, H, Hoefele, J, Weber, LT, Innis, JW, Faul, C, Han, Z, Washburn, J, Antignac, C, Levy, S, Otto, EA & Hildebrandt, F 2013, 'ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling', Journal of Clinical Investigation, vol. 123, no. 8, pp. 3243-3253. https://doi.org/10.1172/JCI69134

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

In: Journal of Clinical Investigation, Vol. 123, No. 8, 01.08.2013, p. 3243-3253.

Research output: Contribution to journalArticle

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T1 - ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling

AU - Gee, Heon Yung

AU - Saisawat, Pawaree

AU - Ashraf, Shazia

AU - Hurd, Toby W.

AU - Vega-Warner, Virginia

AU - Fang, Humphrey

AU - Beck, Bodo B.

AU - Gribouval, Olivier

AU - Zhou, Weibin

AU - Diaz, Katrina A.

AU - Natarajan, Sivakumar

AU - Wiggins, Roger C.

AU - Lovric, Svjetlana

AU - Chernin, Gil

AU - Schoeb, Dominik S.

AU - Ovunc, Bugsu

AU - Frishberg, Yaacov

AU - Soliman, Neveen A.

AU - Fathy, Hanan M.

AU - Goebel, Heike

AU - Hoefele, Julia

AU - Weber, Lutz T.

AU - Innis, Jeffrey W.

AU - Faul, Christian

AU - Han, Zhe

AU - Washburn, Joseph

AU - Antignac, Corinne

AU - Levy, Shawn

AU - Otto, Edgar A.

AU - Hildebrandt, Friedhelm

PY - 2013/8/1

Y1 - 2013/8/1

N2 - 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.

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