A homozygous missense variant in VWA2, encoding an interactor of the Fraser-complex, in a patient with vesicoureteral reflux
| Autor: | 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, Matthias Hammerschmidt |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
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 |
| Zdroj: | PLoS ONE PLoS ONE, Vol 13, Iss 1, p e0191224 (2018) |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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