{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T02:40:58Z","timestamp":1793932858131,"version":"4.8.0"},"reference-count":40,"publisher":"BMJ","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2013,1,31]]},"published-print":{"date-parts":[[2013,5]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>\n                      Whole exome sequencing identified five genes with diallelic mutations that were shared by the sisters, and Sanger sequencing revealed that\n                      <jats:italic>ARHGDIA<\/jats:italic>\n                      that encodes Rho GDP (guanosine diphosphate) dissociation inhibitor \u03b1 (RhoGDI\u03b1, OMIM 601925) was the most likely candidate. Mice with targeted inactivation of\n                      <jats:italic>ARHGDIA<\/jats:italic>\n                      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\u03b1, 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\u03b1, they are sequestered in an inactive, cytosolic pool. In the mouse kidney, RhoGDI\u03b1 was highly expressed in podocytes, a critical cell within the glomerular filtration barrier. When transfected in HEK293T cells, the mutant RhoGDI\u03b1 was unable to bind to the Rho-GTPases, RhoA, Rac1, and Cdc42, unlike the wild-type construct. When RhoGDI\u03b1 was knocked down in podocytes, RhoA, Rac1, and Cdc42 were hyperactivated and podocyte motility was impaired. The proband's fibroblasts demonstrated mislocalisation of RhoGDI\u03b1 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Mutations in\n                      <jats:italic>ARHGDIA<\/jats:italic>\n                      need to be considered in the aetiology of heritable forms of nephrotic syndrome.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jmedgenet-2012-101442","type":"journal-article","created":{"date-parts":[[2013,2,23]],"date-time":"2013-02-23T07:42:29Z","timestamp":1361605349000},"page":"330-338","source":"Crossref","is-referenced-by-count":107,"title":["<i>ARHGDIA<\/i>\n                    : a novel gene implicated in nephrotic syndrome"],"prefix":"10.1136","volume":"50","author":[{"given":"Indra Rani","family":"Gupta","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Nephrology, McGill University, Montreal, Quebec, Canada"},{"name":"Research Institute of McGill University Health Centre, Montr\u00e9al, Qu\u00e9bec, Canada"},{"name":"Department of Human Genetics, McGill University, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cindy","family":"Baldwin","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Nephrology, McGill University, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Auguste","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Nephrology, McGill University, Montreal, Quebec, Canada"},{"name":"Department of Physiology, McGill University, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin C H","family":"Ha","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, McGill University, Montreal, Quebec, Canada"},{"name":"McGill University and Genome Qu\u00e9bec Innovation Centre, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmine","family":"El Andalousi","sequence":"additional","affiliation":[{"name":"Research Institute of McGill University Health Centre, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Somayyeh","family":"Fahiminiya","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, McGill University, Montreal, Quebec, Canada"},{"name":"McGill University and Genome Qu\u00e9bec Innovation Centre, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Bitzan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Nephrology, McGill University, Montreal, Quebec, Canada"},{"name":"Research Institute of McGill University Health Centre, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chantal","family":"Bernard","sequence":"additional","affiliation":[{"name":"Department of Pathology, Montreal Children's Hospital, McGill University, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Reza","family":"Akbari","sequence":"additional","affiliation":[{"name":"Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, Ontario, Canada"},{"name":"Faculty of Medicine, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, 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