Renal hypodysplasia associates with a wnt4 variant that causes aberrant canonical wnt signaling

Asaf Vivante, Michal Mark-Danieli, Miriam Davidovits, Orit Harari-Steinberg, Dorit Omer, Yehudit Gnatek, Roxana Cleper, Daniel Landau, Yael Kovalski, Irit Weissman, Israel Eisenstein, Michalle Soudack, Haike Reznik Wolf, Naomi Issler, Danny Lotan, Yair Anikster, Benjamin Dekel

    Research output: Contribution to journalArticlepeer-review

    40 Scopus citations


    Abnormal differentiation of the renal stem/progenitor pool into kidney tissue can lead to renal hypodysplasia (RHD), but the underlying causes of RHD are not well understood. In this multicenter study, we identified 20 Israeli pedigrees with isolated familial, nonsyndromic RHD and screened for mutations in candidate genes involved in kidney development, including PAX2, HNF1B, EYA1, SIX1, SIX2, SALL1, GDNF,WNT4, and WT1. In addition to previously reported RHD-causing genes, we found that two affected brothers were heterozygous for a missense variant in the WNT4 gene. Functional analysis of this variant revealed both antagonistic and agonistic canonicalWNT stimuli, dependent on cell type. InHEK293 cells,WNT4 inhibited WNT3A induced canonical activation, and the WNT4 variant significantly enhanced this inhibition of the canonical WNT pathway. In contrast, in primary cultures of human fetal kidney cells, which maintain WNT activation and more closely represent WNT signaling in renal progenitors during nephrogenesis, this mutation caused significant loss of function, resulting in diminished canonical WNT/β-catenin signaling. In conclusion, heterozygous WNT4 variants are likely to play a causative role in renal hypodysplasia.

    Original languageEnglish
    Pages (from-to)550-558
    Number of pages9
    JournalJournal of the American Society of Nephrology : JASN
    Issue number4
    StatePublished - 29 Mar 2013

    ASJC Scopus subject areas

    • Nephrology


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