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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ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling

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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Figure 1

Mapping and WER reveal a novel single-gene cause of NS (ARHGDIA).

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Mapping and WER reveal a novel single-gene cause of NS (ARHGDIA). (A) ...
(A) Homozygosity mapping in family A1432 consisting of 2 siblings with SRNS. NPL scores are plotted across the human genome. The x-axis shows SNP marker positions on human chromosomes concatenated from p-ter (left) to q-ter (right). Genetic distance is given in centimorgans. Maximum NPL peaks indicate the candidate regions of homozygosity by descent (red circles). The gene ARHGDIA is positioned (arrowhead) within one of the mapped candidate regions. (B) Chromatograms of ARHGDIA mutations in SRNS families A1432 and A4578. Gene symbols (underlined), family numbers, mutations, and predicted translational changes are given (see also Table 1). Sequence traces are shown for mutations above normal controls. Mutated nucleotides are indicated by arrowheads. (C) Renal histology of individual A4578-21 with DMS and an ARHGDIA mutation. Right kidney explanted at 2 months of age reveals on H&E staining advanced tubular dilation, atrophy, and casts (left). Original magnification, ×50. PAS stain (right) reveals the characteristic pattern of DMS featuring a small, sclerosed, simplified glomerulus with a corona of vacuolized podocytes (arrowhead). Original magnification, ×630.