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/b-catenin signaling. In conclusion, heterozygous WNT4 variants are likely to play a causative role in renal hypodysplasia.

Identification of 8 Novel Mutations in Nephrogenesis-Related Genes in Chinese Han Patients with Unilateral Renal Agenesis

“…1). Moreover, several of the variants identified in our study were close to or in the same domain as those sites reported in previous studies [10,11,17,18] as pathogenic mutations (online suppl. Fig.…”

“…In 2013, Vivante et al [17] reported a heterozygous missense mutation in WNT4 in 1 of 20 Israeli families with non-syndromic renal hypodysplasia. In the same year, Sanna-Cherchi et al [23] reported the effect of a specific DSTYK mutation in CAKUT.…”

CKD-Induced Wingless/Integration1 Inhibitors and Phosphorus Cause the CKD–Mineral and Bone Disorder

“…[27][28][29] Wnt9b, Wnt7b, and Wnt4 are indispensable in the inductive signals leading to the epithelia that form the nephron, 30,31 and they are reactivated during renal repair and in renal fibrosis. [32][33][34] In renal repair, Wnt4 stimulation contributes to cellular proliferation and epithelial reconstitution.…”

Wnt4 antagonises Wnt3a mediated increases in growth and glucose stimulated insulin secretion in the pancreatic beta-cell line, INS-1

“…In the nucleus β-catenin can act as a transcription factor (along with its cofactors TCF/LEF) to promote gene transcription of effectors of Wnt signalling, such as c-myc and cyclin D2. In contrast, the non-canonical pathways, such as those stimulated by Wnt4 are β-catenin independent and have been shown to antagonise the canonical Wnt pathway in several cell types [13,14,[19][20][21].…”