Abnormal Rab11‐Rab8‐vesicles cluster in enterocytes of patients with microvillus inclusion disease. (17th May 2017) - Vogel, Georg F.
Abstract : Microvillus inclusion disease (MVID) is a congenital enteropathy characterized by accumulation of vesiculo‐tubular endomembranes in the subapical cytoplasm of enterocytes, historically termed "secretory granules." However, neither their identity nor pathophysiological significance is well defined. Using immunoelectron microscopy and tomography, we studied biopsies from MVID patients (3× Myosin 5b mutations and 1× Syntaxin3 mutation) and compared them to controls and genome‐edited CaCo2 cell models, harboring relevant mutations. Duodenal biopsies from 2 patients with novel Myosin 5b mutations and typical clinical symptoms showed unusual ultrastructural phenotypes: aberrant subapical vesicles and tubules were prominent in the enterocytes, though other histological hallmarks of MVID were almost absent (ectopic intra‐/intercellular microvilli, brush border atrophy). We identified these enigmatic vesiculo‐tubular organelles as Rab11‐Rab8‐positive recycling compartments of altered size, shape and location harboring the apical SNARE Syntaxin3, apical transporters sodium‐hydrogen exchanger 3 (NHE3) and cystic fibrosis transmembrane conductance regulator. Our data strongly indicate that in MVID disrupted trafficking between cargo vesicles and the apical plasma membrane is the primary cause of a defect of epithelial polarity and subsequent facultative loss of brush border integrity, leading to malabsorption. Furthermore, they support the notion that mislocalization of transporters, such as NHE3 substantially contributes to the reported sodium loss diarrhea. Abstract : Microvillus Inclusion Disease (MVID) is a fatal hereditary diarrheal disorder caused by Myosin 5b or Syntaxin3 mutations, characterized by facultative brush border atrophy and pathological accumulation of vesiculo‐tubular endomembranes in the small intestinal enterocytes of neonates. Here we identified these ill‐defined, subapical organelles as aberrant Rab11‐Rab8‐positive recycling compartments, harboring pivotal apical membrane proteins. This provides further substantial evidence for the concept of disrupted apical traffic and mistargeting of apical transporters as the primary cause of diarrhea and malabsorption in MVID.