Kidney Week

Abstract: SA-PO562

A Homozygous Missense Mutation in VWA2, Encoding an Interactor of the Fraser-Complex, as a Likely Cause of Vesico-Ureteral Reflux

Session Information

• Noncystic Mendelian Diseases
  November 04, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Genetic Diseases of the Kidney

• 802 Non-Cystic Mendelian Diseases

Authors

• Shril, Shirlee, Boston Children's Hospital, Boston, Massachusetts, United States

Shirlee Shril,

• van der Ven, Amelie, Boston Children's Hospital, Boston, Massachusetts, United States

Amelie van der Ven,

• Kobbe, Birgit, University of Cologne, Cologne, Germany

Birgit Kobbe,

• Kohl, Stefan, Boston Children's Hospital, Boston, Massachusetts, United States

Stefan Kohl,

• Pogoda, Hans-Martin, University of Cologne, Cologne, Germany

Hans-Martin Pogoda,

• Ityel, Hadas, Boston Children's Hospital, Boston, Massachusetts, United States

Hadas Ityel,

• Chen, Jing, Boston Children's Hospital, Boston, Massachusetts, United States

Jing Chen,

• Hwang, Daw-yang, Boston Children's Hospital, Boston, Massachusetts, United States

Daw-yang Hwang,

• Widmeier, Eugen, Boston Children's Hospital, Boston, Massachusetts, United States

Eugen Widmeier,

• Connaughton, Dervla M., Boston Children's Hospital, Boston, Massachusetts, United States

Dervla M. Connaughton,

• Mann, Nina, Boston Children's Hospital, Boston, Massachusetts, United States

Nina Mann,

• Hammerschmidt, Matthias, University of Cologne, Cologne, Germany

Matthias Hammerschmidt,

• Wagener, Raimund, University of Cologne, Cologne, Germany

Raimund Wagener,

• Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States

Friedhelm Hildebrandt,

Background

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first 3 decades of life. About 38 monogenic causes of CAKUT are known so far, explaining <20% of CAKUT cases.

Methods

To identify additional monogenic causes of CAKUT, we performed whole exome sequencing in a consanguineous patient with CAKUT from Indian origin.

Results

We identified a homozygous missense mutation (c.1336C>T, p.Arg446Cys) in the gene Von Willebrand factor A domain containing 2 (VWA2). By immunohistochemistry on kidneys of newborn mice, we show that Vwa2 and Fraser extracellular matrix complex subunit 1 (Fras1) co-localize in the nephrogenic zone of the renal cortex. There was pronounced staining for Vwa2 in the basement membrane of the UB and derivatives of the MM (comma-shaped and S-shaped bodies).
By applying cell-based protein expression studies, we demonstrate that the Arg446Cys mutation decreases secretion of the VWA2 protein into the extracellular space in vitro: Lack of secretion is most likely due to increased intracellular aggregate formation of VWA2 secondary to the additional, unpaired cysteine residue in the mutated protein. Recombinant mutant VWA2 additionally forms disulfide-linked higher aggregates in vitro.

Conclusion

VWA2 is a known, direct interactor of FRAS1 of the Fraser-Complex (FC). FC-encoding genes FRAS1, FREM1, FREM2 and interacting proteins GRIP1 and ITGA8 have previously been implicated in the pathogenesis of syndromic and isolated CAKUT phenotypes in humans (Kohl JASN 25, 2014). The results from in vitro experiments indicate a dose-dependent, gain-of-function effect of the Arg446Cys homozygous mutation in VWA2. VWA2 therefore constitutes a very strong candidate in the search for novel CAKUT-causing genes.

Funding

• NIDDK Support