A homozygous missense variant in VWA2, encoding an interactor of the Fraser-complex, in a patient with vesicoureteral reflux
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A homozygous missense variant in VWA2, encoding an interactor of the Fraser-complex, in a patient with vesicoureteral reflux. / 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; Taglienti, Mary; Schmidt, Johanna Magdalena; Nakayama, Makiko; Senguttuvan, Prabha; Kumar, Selvin; Tasic, Velibor; Kehinde, Elijah O; Mane, Shrikant M; Lifton, Richard P; Soliman, Neveen; Lu, Weining; Bauer, Stuart B; Hammerschmidt, Matthias; Wagener, Raimund; Hildebrandt, Friedhelm.
In: PLOS ONE, Vol. 13, No. 1, 2018, p. e0191224.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - A homozygous missense variant in VWA2, encoding an interactor of the Fraser-complex, in a patient with vesicoureteral reflux
AU - van der Ven, Amelie T
AU - Kobbe, Birgit
AU - Kohl, Stefan
AU - Shril, Shirlee
AU - Pogoda, Hans-Martin
AU - Imhof, Thomas
AU - Ityel, Hadas
AU - Vivante, Asaf
AU - Chen, Jing
AU - Hwang, Daw-Yang
AU - Connaughton, Dervla M
AU - Mann, Nina
AU - Widmeier, Eugen
AU - Taglienti, Mary
AU - Schmidt, Johanna Magdalena
AU - Nakayama, Makiko
AU - Senguttuvan, Prabha
AU - Kumar, Selvin
AU - Tasic, Velibor
AU - Kehinde, Elijah O
AU - Mane, Shrikant M
AU - Lifton, Richard P
AU - Soliman, Neveen
AU - Lu, Weining
AU - Bauer, Stuart B
AU - Hammerschmidt, Matthias
AU - Wagener, Raimund
AU - Hildebrandt, Friedhelm
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - Amino Acid Sequence
KW - Amino Acid Substitution
KW - Animals
KW - Animals, Newborn
KW - Biomarkers, Tumor/chemistry
KW - Child
KW - Consanguinity
KW - Conserved Sequence
KW - Exons
KW - Extracellular Matrix Proteins/genetics
KW - Fraser Syndrome/genetics
KW - Gene Expression Regulation, Developmental
KW - Homozygote
KW - Humans
KW - Male
KW - Mice
KW - Models, Animal
KW - Models, Molecular
KW - Mutation, Missense
KW - Pedigree
KW - Sequence Homology, Amino Acid
KW - Urogenital Abnormalities/genetics
KW - Urogenital System/growth & development
KW - Vesico-Ureteral Reflux/genetics
U2 - 10.1371/journal.pone.0191224
DO - 10.1371/journal.pone.0191224
M3 - SCORING: Journal article
C2 - 29351342
VL - 13
SP - e0191224
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 1
ER -
