ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling
| العنوان: | ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling |
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| المؤلفون: | Virginia Vega-Warner, Toby W. Hurd, Friedhelm Hildebrandt, Jeffrey W. Innis, Neveen A. Soliman, Weibin Zhou, Christian Faul, Yaacov Frishberg, Bodo B. Beck, Olivier Gribouval, Katrina A. Diaz, Gil Chernin, Zhe Han, Shawn Levy, Edgar A. Otto, Dominik S. Schoeb, Heike Goebel, Heon Yung Gee, Joseph Washburn, Pawaree Saisawat, Sivakumar Natarajan, Lutz T. Weber, Hanan M. Fathy, Shazia Ashraf, Bugsu Ovunc, Humphrey Fang, Roger C. Wiggins, Svjetlana Lovric, Corinne Antignac, Julia Hoefele |
| المصدر: | 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, Goebel, H, Hoefele, J, Weber, L T, Innis, J W, Faul, C, Han, Z, Washburn, J, Antignac, C, Levy, S, Otto, E A & Hildebrandt, F 2013, ' ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling ', Journal of Clinical Investigation, vol. 123, no. 8, pp. 3243-53 . https://doi.org/10.1172/JCI69134 |
| بيانات النشر: | American Society for Clinical Investigation, 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | rac1 GTP-Binding Protein, Nephrotic Syndrome, RHOA, Mutation, Missense, RAC1, CDC42, GTPase, medicine.disease_cause, Consanguinity, Cell Movement, Protein Interaction Mapping, medicine, Animals, Humans, Missense mutation, cdc42 GTP-Binding Protein, Cells, Cultured, Genetic Association Studies, Zebrafish, rho Guanine Nucleotide Dissociation Inhibitor alpha, Mutation, Base Sequence, biology, Podocytes, Homozygote, Chromosome Mapping, Sequence Analysis, DNA, General Medicine, Phenotype, Protein Transport, Cdc42 GTP-Binding Protein, Case-Control Studies, Gene Knockdown Techniques, biology.protein, Cancer research, rhoA GTP-Binding Protein, Protein Binding, Signal Transduction, Research Article |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| تدمد: | 0021-9738 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3e4c29ebf2b0e00f6b6980f0ac1cef8b https://doi.org/10.1172/jci69134 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....3e4c29ebf2b0e00f6b6980f0ac1cef8b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00219738 |
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