LEF1 Gene Mutation Impairs Intestinal Barrier and Causes Diarrhea

Through investigating pediatric intractable chronic diarrhea, we identified a de novo, unreported heterozygous missense mutation in LEF1 (c.880C > T, p.Pro294Ser) via whole-exome sequencing in a 1.5-year-old boy with 4-year persistent yellow-green watery diarrhea, complicated by protein-energy malnutrition and growth retardation refractory to conventional therapies. Gastrointestinal endoscopy revealed mucosal swelling with mild chronic inflammation, and the variant was absent from public databases. Functional validation using Lef1 P292S (human P294S ortholog) knock-in mice demonstrated increased DSS-induced diarrhea susceptibility, inherent intestinal structural defects, and compromised barrier integrity. Molecular and proteomic analyses confirmed downregulated tight junction protein and aquaporin 4 in mutant mice and patient tissues, alongside dysregulated ion transport, epithelial adhesion, and inflammatory pathways. Mechanistically, the conserved regulatory domain-localized LEF1 P294S mutation disrupts Wnt/β-catenin transcriptional regulation, impairing intestinal barrier function and water-electrolyte balance. Our study establishes LEF1 P294S as a pathogenic variant for pediatric chronic diarrhea, expands LEF1’s role in intestinal homeostasis, and provides a novel diagnostic marker and therapeutic target.