2025/04/09 by Henrike Berns, Dominik Weber, Maximilian Haas +4 · 1 voice · 1 citation
Biochemistry, Genetics and Molecular Biology · Medicine · #Congenital Heart Disease Studies #Congenital heart defects research #Genetics and Neurodevelopmental Disorders
paper · pdf · doi:10.1242/dmm.052211
openalex publication_date 2025/04/09 · openalex created_date 2025/04/10 · openalex updated_date 2026/08/01
Wnt signaling plays important roles during vertebrate development, including left-right axis specification as well as heart and kidney organogenesis. We identified a homozygous human WNT11 variant in an infant with situs inversus totalis, complex heart defects and renal hypodysplasia, and used Xenopus embryos to functionally characterize this variant. WNT11c.814delG encodes a protein with reduced stability that lost signaling activity in vivo. This is remarkable, because the variant encodes a truncated ligand with nearly identical length and predicted structure to dominant-negative Wnts. Furthermore, we demonstrate that alteration of the truncated C-terminal end can restore stability and signaling activity similarly to Xenopus dominant-negative Wnt11b. Our study also suggests similar functions for WNT11 in human development as those described in model organisms. Therefore, biallelic WNT11 dysfunction should be considered a novel genetic cause of syndromal human phenotypes presenting with congenital heart defects and renal hypoplasia, with or without laterality defects. The work presented here enhances our understanding of human development and structure-function relationships in Wnt ligands.