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

Amelie T. Van Der Ven, Birgit Kobbe, Stefan Kohl, Shirlee Shril, Hans Martin Pogoda, Thomas Imhof, Hadas Ityel, Asaf Vivante, Jing Chen, Daw Yang Hwang, Dervla M. Connaughton, Nina Mann, Eugen Widmeier, Mary Taglienti, Johanna Magdalena Schmidt, Makiko Nakayama, Prabha Senguttuvan, Selvin Kumar, Velibor Tasic, Elijah O. KehindeShrikant M. Mane, Richard P. Lifton, Neveen Soliman, Weining Lu, Stuart B. Bauer, Matthias Hammerschmidt, Raimund Wagener*, Friedhelm Hildebrandt

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article numbere0191224
JournalPLoS ONE
Volume13
Issue number1
DOIs
StatePublished - Jan 2018
Externally publishedYes

Funding

FundersFunder number
National Institutes of Health
National Institute of Diabetes and Digestive and Kidney DiseasesR01DK088767
National Academy of SciencesLPDS 2015-07
California Department of Fish and GameVE916/1-1
Boston Children's Hospital
Intelligence Community Postdoctoral Research Fellowship Program
Deutsche ForschungsgemeinschaftSFB829/B2, SFB829/A9

    Fingerprint

    Dive into the research topics of 'A homozygous missense variant in VWA2, encoding an interactor of the Fraser-complex, in a patient with vesicoureteral reflux'. Together they form a unique fingerprint.

    Cite this