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Microvillus inclusion disease (MVID) is an autosomal recessive congenital diarrheal disorder characterized by intractable neonatal-onset watery diarrhea and malabsorption. While most cases are due to biallelic MYO5B mutations, pathogenic variants in STXBP2 have been reported in a small number of unrelated MVID patients (PMID:29266534; PMID:38307491). These biallelic STXBP2 variants disrupt Munc18-2 function in enterocytes, supporting a Limited ClinGen gene–disease association based on the small cohort size and absence of extensive segregation data. Reported mutations include c.1214G>C (p.Arg405Pro), consistent with loss of apical trafficking.
Functional studies demonstrate that Munc18-2 forms a complex with syntaxin 3 to regulate apical membrane delivery in epithelial cells, with STXBP2 mutants showing impaired binding and altered hemagglutinin transport in Caco-2 cells (PMID:10788461). In Munc18-2–deficient intestinal organoids, loss of STXBP2 phenocopies MVID features—microvillus inclusions arise dynamically during enterocyte differentiation and are rescued by wild-type but not patient variants (PMID:30364784). Taken together, genetic and experimental evidence converge on a pathogenic mechanism of defective apical vesicular trafficking. Key Take-home: STXBP2 testing may inform diagnosis of MVID cases negative for MYO5B and guide tailored management of severe congenital diarrhea.
Gene–Disease AssociationLimitedSTXBP2 variants reported in a small number of MVID patients ([PMID:29266534]; [PMID:38307491]) Genetic EvidenceLimitedBiallelic STXBP2 variants identified in few probands with MVID Functional EvidenceModerateEpithelial assays show Munc18-2/STX3 interaction defects ([PMID:10788461]); organoid models recapitulate MVID and rescue by wild-type STXBP2 ([PMID:30364784]) |