Vogel, GF;
Janecke, AR;
Krainer, IM;
Gutleben, K;
Witting, B;
Mitton, SG;
Mansour, S;
Ballauff, A;
Roland, JT;
Engevik, AC;
et al.
Vogel, GF; Janecke, AR; Krainer, IM; Gutleben, K; Witting, B; Mitton, SG; Mansour, S; Ballauff, A; Roland, JT; Engevik, AC; Cutz, E; Müller, T; Goldenring, JR; Huber, LA; Hess, MW
(2017)
Abnormal Rab11-Rab8-vesicles cluster in enterocytes of patients with microvillus inclusion disease.
Traffic, 18 (7).
pp. 453-464.
ISSN 1600-0854
https://doi.org/10.1111/tra.12486
SGUL Authors: Mitton, Sally Gay Mansour, Sahar Mansour, Sahar
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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.
Item Type: | Article | |||||||||||||||
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Additional Information: | This is the peer reviewed version of the following article: Vogel GF, Janecke AR, Krainer IM, Gutleben K, Witting B, Mitton SG, Mansour S, Ballauff A, Roland JT, Engevik AC, Cutz E, Müller T, Goldenring JR, Huber LA and Hess MW. Abnormal Rab11‐Rab8‐vesicles cluster in enterocytes of patients with microvillus inclusion disease. Traffic. 2017;18:453–464, which has been published in final form at https://doi.org/10.1111/tra.12486. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. | |||||||||||||||
Keywords: | Myo5b, NHE3, Rab Small GTPases, Rab11a, Rab8a, Stx3, congenital diarrheal disorder, electron tomography, hereditary enteropathy, immunoelectron microscopy, Caco-2 Cells, Cell Membrane, Enterocytes, Humans, Malabsorption Syndromes, Male, Microvilli, Mucolipidoses, Mutation, Myosin Type V, Protein Transport, Qa-SNARE Proteins, Secretory Vesicles, rab GTP-Binding Proteins, Enterocytes, Caco-2 Cells, Cell Membrane, Microvilli, Secretory Vesicles, Humans, Mucolipidoses, Malabsorption Syndromes, Myosin Type V, rab GTP-Binding Proteins, Protein Transport, Mutation, Male, Qa-SNARE Proteins, congenital diarrheal disorder, electron tomography, hereditary enteropathy, immunoelectron microscopy, Myo5b, NHE3, Rab Small GTPases, Rab11a, Rab8a, Stx3, Myo5b, NHE3, Rab Small GTPases, Rab11a, Rab8a, Stx3, congenital diarrheal disorder, electron tomography, hereditary enteropathy, immunoelectron microscopy, 0601 Biochemistry And Cell Biology, Developmental Biology | |||||||||||||||
SGUL Research Institute / Research Centre: | Academic Structure > Institute of Medical & Biomedical Education (IMBE) Academic Structure > Institute of Medical & Biomedical Education (IMBE) > Centre for Clinical Education (INMECE ) Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) |
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Journal or Publication Title: | Traffic | |||||||||||||||
ISSN: | 1600-0854 | |||||||||||||||
Language: | eng | |||||||||||||||
Dates: |
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Publisher License: | Publisher's own licence | |||||||||||||||
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PubMed ID: | 28407399 | |||||||||||||||
Web of Science ID: | WOS:000403215100005 | |||||||||||||||
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URI: | https://openaccess.sgul.ac.uk/id/eprint/110384 | |||||||||||||||
Publisher's version: | https://doi.org/10.1111/tra.12486 |
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