A Novel WT1 Variant in a New Zealand Pedigree with Syndromic Focal Segmental Glomerulosclerosis

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dc.contributor.advisor Davidson, A en
dc.contributor.advisor Holm, T en
dc.contributor.author Dodd, Rachel en
dc.date.accessioned 2020-04-08T21:36:09Z en
dc.date.issued 2019 en
dc.identifier.uri http://hdl.handle.net/2292/50286 en
dc.description.abstract The focus of this project was to identify the genetic factors underlying disease presentation in a New Zealand family with a novel syndrome characterized by focal segmental glomerular sclerosis (FSGS) and bicornuate uterus (a developmental reproductive system anomaly caused by defects in fusion of the Mullerian ducts). FSGS refers to the scarring of the glomerular blood filters in the kidney, which impairs their ability to function normally. FSGS occurs as a result of injury to podocytes (specialised epithelial cells in the glomerular blood filter), nephrotic syndrome (leaking protein into the urine), and can eventually lead to renal failure. While drug-based treatments are available, these are not effective in all cases and progression to end stage kidney disease is relatively common. Through whole exome sequencing of individuals in the affected pedigree, we identified a novel candidate variant in the Wilms’ Tumour 1 (WT1) gene. Previously reported mutations in this gene cause a variety of syndromes with effects on genitourinary development, consistent with the phenotype observed in the pedigree. Analysis of the WT1 variant function using reporter assays and kidney organoid model of podocyte biology demonstrated marked effects on expression of key components of podocyte cell architecture. Moreover, these effects were partially rescued by pharmacological treatment with 1-azakenpaullone, a GSK3ß inhibitor with stabilizing effects on the podocyte actin cytoskeleton. Together, the work in this thesis supports the hypothesis that the WT1-variant discovered in the NZ pedigree is a hypomorph (has reduced function), and is causative for the pathology observed in affected family members. This variant represents a novel addition to the growing number of WT1 variants with known pathology, and a novel genetic cause of adult onset FSGS and bicornuate uterus. Ultimately, better understanding of the genetic causes in cases such as these may lead to improved understanding of FSGS etiology for treatment and screening purposes. en
dc.publisher ResearchSpace@Auckland en
dc.relation.ispartof PhD Thesis - University of Auckland en
dc.relation.isreferencedby UoA en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm en
dc.rights.uri http://creativecommons.org/licenses/by-nc-sa/3.0/nz/ en
dc.title A Novel WT1 Variant in a New Zealand Pedigree with Syndromic Focal Segmental Glomerulosclerosis en
dc.type Thesis en
thesis.degree.discipline Molecular Medicine en
thesis.degree.grantor The University of Auckland en
thesis.degree.level Doctoral en
thesis.degree.name PhD en
dc.rights.holder Copyright: The author en
dc.rights.accessrights http://purl.org/eprint/accessRights/OpenAccess en
pubs.elements-id 797681 en
pubs.record-created-at-source-date 2020-04-09 en


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http://creativecommons.org/licenses/by-nc-sa/3.0/nz/ Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by-nc-sa/3.0/nz/

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