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

120 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

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    Gee, H. Y., Saisawat, P., Ashraf, S., Hurd, T. W., Vega-Warner, V., Fang, H., Beck, B. B., Gribouval, O., Zhou, W., Diaz, K. A., Natarajan, S., Wiggins, R. C., Lovric, S., Chernin, G., Schoeb, D. S., Ovunc, B., Frishberg, Y., Soliman, N. A., Fathy, H. M., ... 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