ArticleJournal of medical genetics2013
ARHGDIA: a novel gene implicated in nephrotic syndrome.
Article in Journal of medical genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed.
- Transcriptomic analysis identifies immune-related clusters and PPP2R1A as a candidate gene associated with venous thromboembolism recurrence.Archives of pharmacal research · 2026Article
- Gene-disease relationships for glomerular phenotypes: expert recommendations from ClinGen.Nature reviews. Nephrology · 2026Review
- Review
- Intersecting transcriptomic landscapes of hypertension and kidney function in African American women.American journal of physiology. Renal physiology · 2025Article
- Rac1 Suppression by the Focal Adhesion Protein GIT ArfGAP2 and Podocyte Protection.Journal of the American Society of Nephrology : JASN · 2025Article
- When should the nephrologist think about genetics in patients with glomerular diseases?Clinical kidney journal · 2025Review
- Actin Cytoskeleton and Integrin Components Are Interdependent for Slit Diaphragm Maintenance inCells · 2024Article
- Reovirus infection induces transcriptome-wide unique A-to-I editing changes in the murine fibroblasts.Virus research · 2024Article
- RhoGDI1 regulates cell-cell junctions in polarized epithelial cells.Frontiers in cell and developmental biology · 2024Article
- Mineralocorticoid Receptor Antagonists for Preventing Chronic Kidney Disease Progression: Current Evidence and Future Challenges.International journal of molecular sciences · 2023Review
- Homozygous ARHGDIA Gene Mutation in an 11-Month-Old Infant with Steroid-Resistant Nephrotic Syndrome.Indian journal of pediatrics · 2022Article
- Rho GTPases in kidney physiology and diseases.Small GTPases · 2022Article
- High detection rate for disease-causing variants in a cohort of 30 Iranian pediatric steroid resistant nephrotic syndrome cases.Frontiers in pediatrics · 2022Article
- Neurological involvement in monogenic podocytopathies.Pediatric nephrology (Berlin, Germany) · 2021Review
- Role of Rho in Salt-Sensitive Hypertension.International journal of molecular sciences · 2021Review
- Targeted broad-based genetic testing by next-generation sequencing informs diagnosis and facilitates management in patients with kidney diseases.Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · 2021Article
- Phosphorylation of ACTN4 Leads to Podocyte Vulnerability and Proteinuric Glomerulosclerosis.Journal of the American Society of Nephrology : JASN · 2020Article
- ARHGEF7 (Journal of the American Society of Nephrology : JASN · 2020Article
- TRPC Channels in Proteinuric Kidney Diseases.Cells · 2019Review
- Article
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Authors and funding
13 authors.
Funding
Abstract
backgroundCongenital nephrotic syndrome arises from a defect in the glomerular filtration barrier that permits the unrestricted passage of protein across the barrier, resulting in proteinuria, hypoalbuminaemia, and severe oedema. While most cases are due to mutations in one of five genes, in up to 15% of cases, a genetic cause is not identified. We investigated two sisters with a presumed recessive form of congenital nephrotic syndrome. METHODS AND
resultsWhole exome sequencing identified five genes with diallelic mutations that were shared by the sisters, and Sanger sequencing revealed that ARHGDIA that encodes Rho GDP (guanosine diphosphate) dissociation inhibitor α (RhoGDIα, OMIM 601925) was the most likely candidate. Mice with targeted inactivation of ARHGDIA are known to develop severe proteinuria and nephrotic syndrome, therefore this gene was pursued in functional studies. The sisters harbour a homozygous in-frame deletion that is predicted to remove a highly conserved aspartic acid residue within the interface where the protein, RhoGDIα, interacts with the Rho family of small GTPases (c.553_555del(p.Asp185del)). Rho-GTPases are critical regulators of the actin cytoskeleton and when bound to RhoGDIα, they are sequestered in an inactive, cytosolic pool. In the mouse kidney, RhoGDIα was highly expressed in podocytes, a critical cell within the glomerular filtration barrier. When transfected in HEK293T cells, the mutant RhoGDIα was unable to bind to the Rho-GTPases, RhoA, Rac1, and Cdc42, unlike the wild-type construct. When RhoGDIα was knocked down in podocytes, RhoA, Rac1, and Cdc42 were hyperactivated and podocyte motility was impaired. The proband's fibroblasts demonstrated mislocalisation of RhoGDIα to the nucleus, hyperactivation of the three Rho-GTPases, and impaired cell motility, suggesting that the in-frame deletion leads to a loss of function.
conclusionsMutations in ARHGDIA need to be considered in the aetiology of heritable forms of nephrotic syndrome.
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