1. A homozygous missense variant in VWA2, encoding an interactor of the Fraser-complex, in a patient with vesicoureteral reflux
- Author
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Richard P. Lifton, Elijah O. Kehinde, Shirlee Shril, Amelie T. van der Ven, Mary E. Taglienti, Raimund Wagener, Weining Lu, Neveen A. Soliman, Asaf Vivante, Birgit Kobbe, Makiko Nakayama, Selvin Kumar, Shrikant M. Mane, Nina Mann, Jing Chen, Stuart B. Bauer, Hadas Ityel, Thomas Imhof, Hans-Martin Pogoda, Dervla M. Connaughton, Eugen Widmeier, Johanna Magdalena Schmidt, Velibor Tasic, Daw-Yang Hwang, Friedhelm Hildebrandt, Prabha Senguttuvan, Stefan Kohl, and Matthias Hammerschmidt
- Subjects
0301 basic medicine ,Male ,Models, Molecular ,030232 urology & nephrology ,lcsh:Medicine ,medicine.disease_cause ,Biochemistry ,Exon ,Database and Informatics Methods ,Consanguinity ,Mice ,0302 clinical medicine ,Chronic Kidney Disease ,Medicine and Health Sciences ,Missense mutation ,Amino Acids ,Post-Translational Modification ,lcsh:Science ,Child ,Exome sequencing ,Conserved Sequence ,Mutation ,Extracellular Matrix Proteins ,Multidisciplinary ,Organic Compounds ,Homozygote ,Gene Expression Regulation, Developmental ,Exons ,Disease gene identification ,Pedigree ,Chemistry ,Protein Transport ,Nephrology ,Cell Processes ,Ureteric bud ,Physical Sciences ,Models, Animal ,Disulfide Bonds ,Anatomy ,Fraser Syndrome ,Research Article ,Missense Mutation ,Mutation, Missense ,Urogenital System ,Biology ,Research and Analysis Methods ,03 medical and health sciences ,medicine ,Genetics ,Biomarkers, Tumor ,Sulfur Containing Amino Acids ,Animals ,Humans ,Cysteine ,Amino Acid Sequence ,Vesico-Ureteral Reflux ,Sequence Homology, Amino Acid ,lcsh:R ,Organic Chemistry ,Calcium-Binding Proteins ,Chemical Compounds ,Biology and Life Sciences ,Proteins ,Protein Secretion ,Kidneys ,Renal System ,Cell Biology ,Molecular biology ,030104 developmental biology ,Biological Databases ,Amino Acid Substitution ,Animals, Newborn ,Urogenital Abnormalities ,Mutation Databases ,FRAS1 ,lcsh:Q ,VWA2 - 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.
- Published
- 2018