LEF1 gene mutation impairs the intestinal barrier and causes diarrhea

Whole-exome sequencing identified a novel de novo heterozygous LEF1 variant (c.880 C > T; p.Pro294Ser) in a male pediatric patient who presented with intractable chronic yellow-green watery diarrhea with onset at 18 months of age. The condition persisted for 4 years and was complicated by protein-energy malnutrition and growth failure refractory to standard therapy. Gastrointestinal endoscopy showed mucosal edema accompanied by mild chronic inflammation, and this variant was not present in public population genomic databases. Functional validation was performed in Lef1 (c.876 C > G; p.Pro292Ser) knock-in mice (the murine ortholog of the human LEF1 p.Pro294Ser variant), and revealed increased susceptibility to dextran sulfate sodium (DSS)-induced diarrhea, intrinsic intestinal structural abnormalities, and impaired intestinal barrier integrity. Molecular and proteomic analyses revealed downregulated expression of tight junction proteins and aquaporin − 4 in both mutant mice and patient-derived intestinal tissues, concomitant with dysregulated ion transport, and aberrant inflammatory pathways. Mechanistically, the LEF1 variant enhances its own expression and nuclear accumulation, driving Epithelial-Mesenchymal Transition (EMT) and subsequent intestinal barrier disruption. Collectively, these findings establish LEF1 variant as a pathogenic driver of pediatric chronic diarrhea, broaden the functional role of LEF1 in intestinal homeostasis, and identifies its potential utility as a diagnostic biomarker and therapeutic target for this disorder.