ArticleJCI insight2017
Disrupted apical exocytosis of cargo vesicles causes enteropathy in FHL5 patients with Munc18-2 mutations.
Article in JCI insight, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 58 citations in OpenAlex.
- UNCP-18 is amicroPublication biology · 2026Article
- Congenital enteropathy caused by ezrin deficiency.Human genetics · 2025Article
- Paediatric Congenital Enteropathies: Clinical and Histological Review.Diagnostics (Basel, Switzerland) · 2025Review
- Altered chaperone-nonmuscle myosin II interactions drive pathogenicity of the UNC45A c.710T>C variant in osteo-oto-hepato-enteric syndrome.JCI insight · 2025Article
- Enrichment of Rare Variants of Hemophagocytic Lymphohistiocytosis Genes in Systemic Juvenile Idiopathic Arthritis.Arthritis & rheumatology (Hoboken, N.J.) · 2024Article
- Breaking Down Barriers: Epithelial Contributors to Monogenic IBD Pathogenesis.Inflammatory bowel diseases · 2024Review
- Modeling the cell biology of monogenetic intestinal epithelial disorders.The Journal of cell biology · 2024Review
- Inverted apicobasal polarity in health and disease.Journal of cell science · 2024Review
- A CRISPR screen in intestinal epithelial cells identifies novel factors for polarity and apical transport.eLife · 2023Article
- Fetal Bowel Abnormalities Suspected by Ultrasonography in Microvillus Inclusion Disease: Prevalence and Clinical Significance.Journal of clinical medicine · 2022Article
- UNC45A deficiency causes microvillus inclusion disease-like phenotype by impairing myosin VB-dependent apical trafficking.The Journal of clinical investigation · 2022Article
- Theratyping of the Rare CFTR Variants E193K and R334W in Rectal Organoid-Derived Epithelial Monolayers.Journal of personalized medicine · 2022Article
- Understanding inborn errors of immunity: A lens into the pathophysiology of monogenic inflammatory bowel disease.Frontiers in immunology · 2022Review
- Variants in STXBP3 are Associated with Very Early Onset Inflammatory Bowel Disease, Bilateral Sensorineural Hearing Loss and Immune Dysregulation.Journal of Crohn's & colitis · 2021Article
- Intestinal immunoregulation: lessons from human mendelian diseases.Mucosal immunology · 2021Review
- Advanced Microscopy for Liver and Gut Ultrastructural Pathology in Patients with MVID and PFIC Caused by MYO5B Mutations.Journal of clinical medicine · 2021Article
- Congenital Diarrhea and Cholestatic Liver Disease: Phenotypic Spectrum Associated with MYO5B Mutations.Journal of clinical medicine · 2021Article
- Pharmacological and Parenteral Nutrition-Based Interventions in Microvillus Inclusion Disease.Journal of clinical medicine · 2020Review
- Enhanced Collagen Deposition in the Duodenum of Patients with Hyaline Fibromatosis Syndrome and Protein Losing Enteropathy.International journal of molecular sciences · 2020Article
- AP1S1 missense mutations cause a congenital enteropathy via an epithelial barrier defect.Human genetics · 2020Article
Corrections and comments
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Authors and funding
15 authors at 8 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Familial hemophagocytic lymphohistiocytosis 5 (FHL5) is an autosomal recessive disease caused by mutations in STXBP2, coding for Munc18-2, which is required for SNARE-mediated membrane fusion. FHL5 causes hematologic and gastrointestinal symptoms characterized by chronic enteropathy that is reminiscent of microvillus inclusion disease (MVID). However, the molecular pathophysiology of FHL5-associated diarrhea is poorly understood. Five FHL5 patients, including four previously unreported patients, were studied. Morphology of duodenal sections was analyzed by electron and fluorescence microscopy. Small intestinal enterocytes and organoid-derived monolayers displayed the subcellular characteristics of MVID. For the analyses of Munc18-2-dependent SNARE-protein interactions, a Munc18-2 CaCo2-KO model cell line was generated by applying CRISPR/Cas9 technology. Munc18-2 is required for Slp4a/Stx3 interaction in fusion of cargo vesicles with the apical plasma membrane. Cargo trafficking was investigated in patient biopsies, patient-derived organoids, and the genome-edited model cell line. Loss of Munc18-2 selectively disrupts trafficking of certain apical brush-border proteins (NHE3 and GLUT5), while transport of DPPIV remained unaffected. Here, we describe the molecular mechanism how the loss of function of Munc18-2 leads to cargo-selective mislocalization of brush-border components and a subapical accumulation of cargo vesicles, as it is known from the loss of polarity phenotype in MVID.
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