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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.author T. van der Ven, Amelie
dc.contributor.author Kobbe, Birgit
dc.contributor.author Kohl, Stefan
dc.contributor.author Shril, Shirlee
dc.contributor.author Pogoda, Hans-Martin
dc.contributor.author Imhof, Thomas
dc.contributor.author Ityel, Hadas
dc.contributor.author Vivante, Asaf
dc.contributor.author Chen, Jing
dc.contributor.author Hwang, Daw-Yang
dc.contributor.author M. Connaughton, Dervla
dc.contributor.author Mann, Nina
dc.contributor.author Widmeier, Eugen
dc.contributor.author Taglienti, Mary
dc.contributor.author Schmidt, Johanna Magdalena
dc.contributor.author Nakayama, Makiko
dc.contributor.author Senguttuvan, Prabha
dc.contributor.author Kumar, Selvin
dc.contributor.author Tasic, Velibor
dc.contributor.author Kehinde, Elijah O.
dc.contributor.author M. Mane, Shrikant
dc.contributor.author P. Lifton, Richard
dc.contributor.author Soliman, Neveen
dc.contributor.author Lu, Weining
dc.contributor.author B. Bauer, Stuart
dc.contributor.author Hammerschmidt, Matthias
dc.contributor.author Wagener, Raimund
dc.contributor.author Hildebrandt, Friedhelm
dc.date.accessioned 2020-03-27T05:35:35Z
dc.date.available 2020-03-27T05:35:35Z
dc.date.issued 2018-01
dc.identifier.citation van 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.0191224 en_US
dc.identifier.issn 1932-6203
dc.identifier.other 10.1371/journal.pone.0191224
dc.identifier.uri https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0191224&type=printable
dc.identifier.uri http://nur.nu.edu.kz/handle/123456789/4554
dc.description https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191224 en_US
dc.description.abstract Congenital 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.language.iso en en_US
dc.publisher Public Library of Science en_US
dc.relation.ispartofseries PLoS ONE;
dc.rights Attribution-NonCommercial-ShareAlike 3.0 United States *
dc.rights.uri http://creativecommons.org/licenses/by-nc-sa/3.0/us/ *
dc.subject Research Subject Categories::MEDICINE en_US
dc.subject chronic kidney disease en_US
dc.subject CKD en_US
dc.subject congenital anomalies of the kidney and urinary tract en_US
dc.subject CAKUT en_US
dc.subject whole exome sequencing en_US
dc.subject WES en_US
dc.subject VWA2 en_US
dc.subject ureteric bud en_US
dc.subject UB en_US
dc.title A homozygous missense variant in VWA2, encoding an interactor of the Fraser-complex, in a patient with vesicoureteral refluxy en_US
dc.type Article en_US
workflow.import.source science

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