A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion

This study identifies biallelic mutations in the WLS gene, encoding the Wnt ligand secretion mediator, as the cause of a novel pleiotropic multiorgan syndrome termed Zaki syndrome. Affected individuals exhibited microcephaly, facial dysmorphism, foot syndactyly, renal agenesis, and other structural defects. Using exome sequencing and linkage analysis across five families, researchers identified homozygous WLS mutations impairing Wnt secretion and signaling. Knock-in mouse models recapitulated patient phenotypes, including neural tube, kidney, and limb defects, with globally reduced Wnt activity. Treatment with the Wnt agonist CHIR99021 partially rescued developmental defects in embryoid bodies and mutant mice, suggesting potential therapeutic avenues. The findings highlight WLS as a critical regulator of embryogenesis and propose targeted Wnt activation as a strategy for preventing certain structural birth defects.

This study identifies biallelic mutations in the WLS gene, encoding the Wnt ligand secretion mediator, as the cause of a novel pleiotropic multiorgan syndrome termed Zaki syndrome. Affected individuals exhibited microcephaly, facial dysmorphism, foot syndactyly, renal agenesis, and other structural defects. Using exome sequencing and linkage analysis across five families, researchers identified homozygous WLS mutations impairing Wnt secretion and signaling. Knock-in mouse models recapitulated patient phenotypes, including neural tube, kidney, and limb defects, with globally reduced Wnt activity. Treatment with the Wnt agonist CHIR99021 partially rescued developmental defects in embryoid bodies and mutant mice, suggesting potential therapeutic avenues. The findings highlight WLS as a critical regulator of embryogenesis and propose targeted Wnt activation as a strategy for preventing certain structural birth defects.