ARHGDIA: a novel gene implicated in nephrotic syndrome
Open Access
- 22 February 2013
- journal article
- research article
- Published by BMJ in Journal of Medical Genetics
- Vol. 50 (5), 330-338
- https://doi.org/10.1136/jmedgenet-2012-101442
Abstract
Background Congenital 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 results Whole 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 alpha (RhoGDI alpha, 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, RhoGDI alpha, 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 RhoGDI alpha, they are sequestered in an inactive, cytosolic pool. In the mouse kidney, RhoGDI alpha was highly expressed in podocytes, a critical cell within the glomerular filtration barrier. When transfected in HEK293T cells, the mutant RhoGDI alpha was unable to bind to the Rho-GTPases, RhoA, Rac1, and Cdc42, unlike the wild-type construct. When RhoGDI alpha was knocked down in podocytes, RhoA, Rac1, and Cdc42 were hyperactivated and podocyte motility was impaired. The proband's fibroblasts demonstrated mislocalisation of RhoGDI alpha 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. Conclusions Mutations in ARHGDIA need to be considered in the aetiology of heritable forms of nephrotic syndrome.Keywords
This publication has 39 references indexed in Scilit:
- MYO1EMutations and Childhood Familial Focal Segmental GlomerulosclerosisThe New England Journal of Medicine, 2011
- The 'invisible hand': regulation of RHO GTPases by RHOGDIsNature Reviews Molecular Cell Biology, 2011
- Integrative genomics viewerNature Biotechnology, 2011
- ANNOVAR: functional annotation of genetic variants from high-throughput sequencing dataNucleic Acids Research, 2010
- Inhibition of Podocyte FAK Protects against Proteinuria and Foot Process EffacementJournal of the American Society of Nephrology, 2010
- Mutations in the human laminin β2 (LAMB2) gene and the associated phenotypic spectrumaHuman Mutation, 2010
- Regulation of Rho GTPase crosstalk, degradation and activity by RhoGDI1Nature, 2010
- A method and server for predicting damaging missense mutationsNature Methods, 2010
- Morphological and proliferative abnormalities in renal mesangial cells lacking RhoGDICellular Signalling, 2009
- Congenital nephrotic syndromePediatric Nephrology, 2007