van der Ven, Amelie T., Kobbe, Birgit, Kohl, Stefan, Shril, Shirlee, Pogoda, Hans-Martin, Imhof, Thomas, Ityel, Hadas, Vivante, Asaf, Chen, Jing, Hwang, Daw-Yang, Connaughton, Dervla M., Mann, Nina, Widmeier, Eugen ORCID: 0000-0002-7773-5190, Taglienti, Mary, Schmidt, Johanna Magdalena, Nakayama, Makiko, Senguttuvan, Prabha, Kumar, Selvin, Tasic, Velibor ORCID: 0000-0002-3377-1245, Kehinde, Elijah O., Mane, Shrikant M., Lifton, Richard P., Soliman, Neveen ORCID: 0000-0002-8942-1973, Lu, Weining ORCID: 0000-0002-6570-3044, Bauer, Stuart B., Hammerschmidt, Matthias, Wagener, Raimund and Hildebrandt, Friedhelm (2018). A homozygous missense variant in VWA2, encoding an interactor of the Fraser-complex, in a patient with vesicoureteral refluxy. PLoS One, 13 (1). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
van der Ven, Amelie T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kobbe, BirgitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kohl, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shril, ShirleeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pogoda, Hans-MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Imhof, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ityel, HadasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vivante, AsafUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, JingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hwang, Daw-YangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Connaughton, Dervla M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mann, NinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Widmeier, EugenUNSPECIFIEDorcid.org/0000-0002-7773-5190UNSPECIFIED
Taglienti, MaryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, Johanna MagdalenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nakayama, MakikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Senguttuvan, PrabhaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kumar, SelvinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tasic, VeliborUNSPECIFIEDorcid.org/0000-0002-3377-1245UNSPECIFIED
Kehinde, Elijah O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mane, Shrikant M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lifton, Richard P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Soliman, NeveenUNSPECIFIEDorcid.org/0000-0002-8942-1973UNSPECIFIED
Lu, WeiningUNSPECIFIEDorcid.org/0000-0002-6570-3044UNSPECIFIED
Bauer, Stuart B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hammerschmidt, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagener, RaimundUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hildebrandt, FriedhelmUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-198667
DOI: 10.1371/journal.pone.0191224
Journal or Publication Title: PLoS One
Volume: 13
Number: 1
Date: 2018
Publisher: PUBLIC LIBRARY SCIENCE
Place of Publication: SAN FRANCISCO
ISSN: 1932-6203
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
EXTRACELLULAR-MATRIX PROTEIN; URINARY-TRACT MALFORMATIONS; MULTIPOINT LINKAGE ANALYSIS; CONGENITAL-ANOMALIES; RECESSIVE MUTATIONS; KIDNEY-DISEASES; IDENTIFICATION; DYSREGULATION; NEPHRONECTIN; EXPRESSIONMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/19866

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