A homozygous missense variant in VWA2, encoding an interactor of the Fraser-complex, in a patient with vesicoureteral refluxy
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Date
2018-01
Authors
T. van der Ven, Amelie
Kobbe, Birgit
Kohl, Stefan
Shril, Shirlee
Pogoda, Hans-Martin
Imhof, Thomas
Ityel, Hadas
Vivante, Asaf
Chen, Jing
Hwang, Daw-Yang
Journal Title
Journal ISSN
Volume Title
Publisher
Public Library of Science
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.
Description
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191224
Keywords
Research Subject Categories::MEDICINE, chronic kidney disease, CKD, congenital anomalies of the kidney and urinary tract, CAKUT, whole exome sequencing, WES, VWA2, ureteric bud, UB
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