title: Renal hypodysplasia associates with a WNT4 variant that causes aberrant canonical WNT signaling.
abstract: 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 canonical WNT stimuli, dependent on cell type. In HEK293 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.
authors.affiliation: Department of Pediatrics, Talpiot Medical Leadership Program, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Asaf
authors.initials: A
authors.lastname: Vivante
authors.forename: Michal
authors.initials: M
authors.lastname: Mark-Danieli
authors.forename: Miriam
authors.initials: M
authors.lastname: Davidovits
authors.forename: Orit
authors.initials: O
authors.lastname: Harari-Steinberg
authors.forename: Dorit
authors.initials: D
authors.lastname: Omer
authors.forename: Yehudit
authors.initials: Y
authors.lastname: Gnatek
authors.forename: Roxana
authors.initials: R
authors.lastname: Cleper
authors.forename: Daniel
authors.initials: D
authors.lastname: Landau
authors.forename: Yael
authors.initials: Y
authors.lastname: Kovalski
authors.forename: Irit
authors.initials: I
authors.lastname: Weissman
authors.forename: Israel
authors.initials: I
authors.lastname: Eisenstein
authors.forename: Michalle
authors.initials: M
authors.lastname: Soudack
authors.forename: Haike Reznik
authors.initials: HR
authors.lastname: Wolf
authors.forename: Naomi
authors.initials: N
authors.lastname: Issler
authors.forename: Danny
authors.initials: D
authors.lastname: Lotan
authors.forename: Yair
authors.initials: Y
authors.lastname: Anikster
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dekel
mesh_terms: D000293:Adolescent; D002454:Cell Differentiation / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D007557:Israel; D007674:Kidney Diseases / Q000235:genetics*; D008297:Male; D009154:Mutation; D051762:PAX2 Transcription Factor / Q000235:genetics; D017422:Sequence Analysis, DNA; D060449:Wnt Signaling Pathway / Q000235:genetics*; D060528:Wnt4 Protein / Q000235:genetics*; D055815:Young Adult
chemical_list: D051762:PAX2 Transcription Factor; C555581:WNT4 protein, human; D060528:Wnt4 Protein