[PMID]: | 29351342 |
[Au] Autor: | van der Ven AT; Kobbe B; Kohl S; Shril S; Pogoda HM; Imhof T; Ityel H; Vivante A; Chen J; Hwang DY; Connaughton DM; Mann N; Widmeier E; Taglienti M; Schmidt JM; Nakayama M; Senguttuvan P; Kumar S; Tasic V; Kehinde EO; Mane SM; Lifton RP; Soliman N; Lu W; Bauer SB; Hammerschmidt M; Wagener R; Hildebrandt F |
[Ad] Endereço: | Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America. |
[Ti] Título: | A homozygous missense variant in VWA2, encoding an interactor of the Fraser-complex, in a patient with vesicoureteral reflux. |
[So] Source: | PLoS One;13(1):e0191224, 2018. |
[Is] ISSN: | 1932-6203 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | 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. |
[Mh] Termos MeSH primário: |
Biomarcadores Tumorais/genética Síndrome de Fraser/genética Mutação de Sentido Incorreto Anormalidades Urogenitais/genética Refluxo Vesicoureteral/genética
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[Mh] Termos MeSH secundário: |
Sequência de Aminoácidos Substituição de Aminoácidos Animais Animais Recém-Nascidos Biomarcadores Tumorais/química Criança Consanguinidade Sequência Conservada Éxons Proteínas da Matriz Extracelular/genética Proteínas da Matriz Extracelular/metabolismo Regulação da Expressão Gênica no Desenvolvimento Homozigoto Seres Humanos Masculino Camundongos Modelos Animais Modelos Moleculares Linhagem Homologia de Sequência de Aminoácidos Sistema Urogenital/crescimento & desenvolvimento Sistema Urogenital/metabolismo
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[Pt] Tipo de publicação: | CASE REPORTS; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T |
[Nm] Nome de substância:
| 0 (Biomarkers, Tumor); 0 (Extracellular Matrix Proteins); 0 (Fras1 protein, mouse); 0 (VWA2 protein, human); 0 (Vwa2 protein, mouse) |
[Em] Mês de entrada: | 1802 |
[Cu] Atualização por classe: | 180221 |
[Lr] Data última revisão:
| 180221 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 180120 |
[St] Status: | MEDLINE |
[do] DOI: | 10.1371/journal.pone.0191224 |
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