Journal Article Ppublish 1 citation
PubMed: 40200693 DOI: 10.1242/dmm.052211
A homozygous human WNT11 variant is associated with laterality, heart and renal defects.
Dis Model Mech 18(5)
Authors: Henrike Berns, Damian Weber, Maximilian Haas, Zeineb Bakey, Magdalena Maria Brislinger-Engelhardt, Miriam Schmidts, Peter Walentek
Affiliations
- Internal Medicine IV, Medical Center - University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany.
- SGBM Spemann Graduate School for Biology and Medicine, University of Freiburg, Albertstrasse 19A, 79104 Freiburg, Germany.
- Center for Pediatrics and Adolescent Medicine, Medical Center - University of Freiburg, Breisacherstrasse 62, 79106 Freiburg, Germany.
- Human Genetics Department, Radboud University Medical Center Nijmegen and Radboud Institute for Molecular Life Sciences (RIMLS), Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands.
- CIBSS Centre for Integrative Biological Signalling Studies, University of Freiburg, Schänzlestrasse 18, 79104 Freiburg, Germany.
Abstract
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.
MeSH
Human Development, Disease Models, Animal, Heart, Ligands