A homozygous missense variant in VWA2, encoding an interactor of the Fraser-complex, in a patient with vesicoureteral refluxy

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dc.contributor.authorT. van der Ven, Amelie
dc.contributor.authorKobbe, Birgit
dc.contributor.authorKohl, Stefan
dc.contributor.authorShril, Shirlee
dc.contributor.authorPogoda, Hans-Martin
dc.contributor.authorImhof, Thomas
dc.contributor.authorItyel, Hadas
dc.contributor.authorVivante, Asaf
dc.contributor.authorChen, Jing
dc.contributor.authorHwang, Daw-Yang
dc.contributor.authorM. Connaughton, Dervla
dc.contributor.authorMann, Nina
dc.contributor.authorWidmeier, Eugen
dc.contributor.authorTaglienti, Mary
dc.contributor.authorSchmidt, Johanna Magdalena
dc.contributor.authorNakayama, Makiko
dc.contributor.authorSenguttuvan, Prabha
dc.contributor.authorKumar, Selvin
dc.contributor.authorTasic, Velibor
dc.contributor.authorKehinde, Elijah O.
dc.contributor.authorM. Mane, Shrikant
dc.contributor.authorP. Lifton, Richard
dc.contributor.authorSoliman, Neveen
dc.contributor.authorLu, Weining
dc.contributor.authorB. Bauer, Stuart
dc.contributor.authorHammerschmidt, Matthias
dc.contributor.authorWagener, Raimund
dc.contributor.authorHildebrandt, Friedhelm
dc.date.accessioned2020-03-27T05:35:35Z
dc.date.available2020-03-27T05:35:35Z
dc.date.issued2018-01
dc.descriptionhttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191224en_US
dc.description.abstractCongenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause (40–50%) of chronic kidney disease (CKD) in children. About 40 monogenic causes of CAKUT have so far been discovered. To date less than 20% of CAKUT cases can be explained by mutations in these 40 genes. To identify additional monogenic causes of CAKUT, we performed whole exome sequencing (WES) and homozygosity mapping (HM) in a patient with CAKUT from Indian origin and consanguineous descent. We identified a homozygous missense mutation (c.1336C>T, p.Arg446Cys) in the gene Von Willebrand factor A domain containing 2 (VWA2). With immunohistochemistry studies on kidneys of newborn (P1) mice, we show that Vwa2 and Fraser extracellular matrix complex subunit 1 (Fras1) co-localize in the nephrogenic zone of the renal cortex. We identified a pronounced expression of Vwa2 in the basement membrane of the ureteric bud (UB) and derivatives of the metanephric mesenchyme (MM). By applying in vitro assays, we demonstrate that the Arg446Cys mutation decreases translocation of monomeric VWA2 protein and increases translocation of aggregated VWA2 protein into the extracellular space. This is potentially due to the additional, unpaired cysteine residue in the mutated protein that is used for intermolecular disulfide bond formation. VWA2 is a known, direct interactor of FRAS1 of the Fraser-Complex (FC). FC-encoding genes and interacting proteins have previously been implicated in the pathogenesis of syndromic and/or isolated CAKUT phenotypes in humans. VWA2 therefore constitutes a very strong candidate in the search for novel CAKUT-causing genes. Our results from in vitro experiments indicate a dose-dependent neomorphic effect of the Arg446Cys homozygous mutation in VWA2.en_US
dc.identifier.citationvan der Ven, A. T., Kobbe, B., Kohl, S., Shril, S., Pogoda, H.-M., Imhof, T., Ityel, H., Vivante, A., Chen, J., Hwang, D.-Y., Connaughton, D. M., Mann, N., Widmeier, E., Taglienti, M., Schmidt, J. M., Nakayama, M., Senguttuvan, P., Kumar, S., Tasic, V., … Hildebrandt, F. (2018). A homozygous missense variant in VWA2, encoding an interactor of the Fraser-complex, in a patient with vesicoureteral reflux. PLOS ONE, 13(1), e0191224. https://doi.org/10.1371/journal.pone.0191224en_US
dc.identifier.issn1932-6203
dc.identifier.other10.1371/journal.pone.0191224
dc.identifier.urihttps://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0191224&type=printable
dc.identifier.urihttp://nur.nu.edu.kz/handle/123456789/4554
dc.language.isoenen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.ispartofseriesPLoS ONE;
dc.rightsAttribution-NonCommercial-ShareAlike 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/3.0/us/*
dc.subjectResearch Subject Categories::MEDICINEen_US
dc.subjectchronic kidney diseaseen_US
dc.subjectCKDen_US
dc.subjectcongenital anomalies of the kidney and urinary tracten_US
dc.subjectCAKUTen_US
dc.subjectwhole exome sequencingen_US
dc.subjectWESen_US
dc.subjectVWA2en_US
dc.subjectureteric buden_US
dc.subjectUBen_US
dc.titleA homozygous missense variant in VWA2, encoding an interactor of the Fraser-complex, in a patient with vesicoureteral refluxyen_US
dc.typeArticleen_US
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