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dc.contributor.authorFalcone, Sara
dc.contributor.authorNicol, Thomas
dc.contributor.authorBlease, Andrew
dc.contributor.authorRandles, Michael J.
dc.contributor.authorAngus, Elizabeth
dc.contributor.authorPage, Anton
dc.contributor.authorTam, Frederick W. K.
dc.contributor.authorPusey, Charles D.
dc.contributor.authorLennon, Rachel
dc.contributor.authorPotter, Paul K.
dc.date.accessioned2022-08-01T14:24:09Z
dc.date.available2022-08-01T14:24:09Z
dc.date.issued2021-11-10
dc.identifierhttps://chesterrep.openrepository.com/bitstream/handle/10034/627061/1-s2.0-S0085253821010589-main.pdf?sequence=1
dc.identifier.citationFalcone, S., Nicol, T., Blease, A., Randles, M. J., Angus, E., Page, A., Tam, F. W. K., Pusey, C. D., Lennon, R., & Potter, P. K. (2022). A novel model of nephrotic syndrome results from a point mutation in Lama5 and is modified by genetic background. Kidney International, 101(3), 527-540. https://doi.org/10.1016/j.kint.2021.10.031en_US
dc.identifier.issn0085-2538
dc.identifier.doi10.1016/j.kint.2021.10.031
dc.identifier.urihttp://hdl.handle.net/10034/627061
dc.description.abstractNephrotic syndrome is characterized by severe proteinuria, hypoalbuminaemia, edema and hyperlipidaemia. Genetic studies of nephrotic syndrome have led to the identification of proteins playing a crucial role in slit diaphragm signaling, regulation of actin cytoskeleton dynamics and cell-matrix interactions. The laminin α5 chain is essential for embryonic development and, in association with laminin β2 and laminin γ1, is a major component of the glomerular basement membrane, a critical component of the glomerular filtration barrier. Mutations in LAMA5 were recently identified in children with nephrotic syndrome. Here, we have identified a novel missense mutation (E884G) in the uncharacterized L4a domain of LAMA5 where homozygous mice develop nephrotic syndrome with severe proteinuria with histological and ultrastructural changes in the glomerulus mimicking the progression seen in most patients. The levels of LAMA5 are reduced in vivo and the assembly of the laminin 521 heterotrimer significantly reduced in vitro. Proteomic analysis of the glomerular extracellular fraction revealed changes in the matrix composition. Importantly, the genetic background of the mice had a significant effect on aspects of disease progression from proteinuria to changes in podocyte morphology. Thus, our novel model will provide insights into pathologic mechanisms of nephrotic syndrome and pathways that influence the response to a dysfunctional glomerular basement membrane that may be important in a range of kidney diseases.en_US
dc.publisherElsevieren_US
dc.relation.urlhttps://www.sciencedirect.com/science/article/pii/S0085253821010589?via%3Dihuben_US
dc.relation.urlhttps://pubmed.ncbi.nlm.nih.gov/34774562/
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.subjectalbuminuriaglomerulusnephrotic syndromeproteinuriaproteomic analysisen_US
dc.subjectalbuminuriaen_US
dc.subjectglomerulusen_US
dc.subjectnephrotic syndromeen_US
dc.subjectproteinuriaen_US
dc.subjectproteomic analysisen_US
dc.titleA novel model of nephrotic syndrome results from a point mutation in Lama5 and is modified by genetic backgrounden_US
dc.typeArticleen_US
dc.identifier.eissn1523-1755en_US
dc.contributor.departmentMedical Research Council Harwell Institute; University of Oxford; The University of Manchester; University of Southampton; Imperial College London; Oxford Brookes University; University of Chesteren_US
dc.identifier.journalKidney Internationalen_US
or.grant.openaccessYesen_US
rioxxterms.funderMCU142684172en_US
rioxxterms.identifier.projectMCU142684172en_US
rioxxterms.versionVoRen_US
rioxxterms.versionofrecord10.1016/j.kint.2021.10.031en_US
dcterms.dateAccepted2021-10-18
rioxxterms.publicationdate2022-11-10
dc.date.deposited2022-08-01en_US
dc.indentifier.issn0085-2538en_US


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Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International