Disrupted apical exocytosis of cargo vesicles causes enteropathy in FHL5 patients with Munc18-2 mutations

Vogel, Georg F.; Rijn, Jorik M. van; Krainer, Iris M.; Janecke, Andreas; Posovszky, Carsten; Cohen, Marta C.; Searle, Claire; Jantchou, P; Escher, Johanna C.; Patey, Natalie; Cutz, Ernest; Müller, Thomas; Middendorp, Sabine; Hess, Michael W.; Huber, Lukas A.

doi:10.1172/jci.insight.94564

Cited by 45 publications

(72 citation statements)

References 49 publications

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“…Recently, mutations in two other genes have been associated with variant forms of MVID: STX3 (chromosome 11q12.1; MIM# 600876) (Wiegerinck et al., ) and STXBP2 (chromosome 19p13.2; MIM# 601717) (Stepensky et al., ; Vogel et al., ). STX3 encodes the syntaxin‐3 protein, which is a member of the Qa‐SNARE protein family that contributes a glutamine (Q) residue for the formation of the assembled core SNARE complex.…”

Section: Microvillus Inclusion Disease: An Expanding Spectrum Of Genementioning

confidence: 99%

“…Therapies targeted against FHL5 failed to resolve the diarrhea which persisted even after full hematopoietic stem cell transplantation (Pagel et al., ), indicating that the intestinal symptoms are independent of immune cell defects. Immunohistochemical analyses of intestinal biopsies of these patients revealed the intracellular retention of apical brush border proteins such as CD10 and PAS‐positive material, variable microvillus atrophy and microvillus inclusions (Stepensky et al., ; Vogel et al., ). Thus, these patients show all intestine‐related clinical and cellular hallmarks of MVID (Stepensky et al., ; Vogel et al., ).…”

Section: Microvillus Inclusion Disease: An Expanding Spectrum Of Genementioning

confidence: 99%

“…Immunohistochemical analyses of intestinal biopsies of these patients revealed the intracellular retention of apical brush border proteins such as CD10 and PAS‐positive material, variable microvillus atrophy and microvillus inclusions (Stepensky et al., ; Vogel et al., ). Thus, these patients show all intestine‐related clinical and cellular hallmarks of MVID (Stepensky et al., ; Vogel et al., ).…”

Section: Microvillus Inclusion Disease: An Expanding Spectrum Of Genementioning

confidence: 99%

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MYO5B,STX3, andSTXBP2mutations reveal a common disease mechanism that unifies a subset of congenital diarrheal disorders: A mutation update

et al. 2018

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Microvillus inclusion disease (MVID) is a rare but fatal autosomal recessive congenital diarrheal disorder caused by MYO5B mutations. In 2013, we launched an open‐access registry for MVID patients and their MYO5B mutations (www.mvid-central.org). Since then, additional unique MYO5B mutations have been identified in MVID patients, but also in non‐MVID patients. Animal models have been generated that formally prove the causality between MYO5B and MVID. Importantly, mutations in two other genes, STXBP2 and STX3, have since been associated with variants of MVID, shedding new light on the pathogenesis of this congenital diarrheal disorder. Here, we review these additional genes and their mutations. Furthermore, we discuss recent data from cell studies that indicate that the three genes are functionally linked and, therefore, may constitute a common disease mechanism that unifies a subset of phenotypically linked congenital diarrheal disorders. We present new data based on patient material to support this. To congregate existing and future information on MVID geno‐/phenotypes, we have updated and expanded the MVID registry to include all currently known MVID‐associated gene mutations, their demonstrated or predicted functional consequences, and associated clinical information.

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Section: Microvillus Inclusion Disease: An Expanding Spectrum Of Genementioning

confidence: 99%

Section: Microvillus Inclusion Disease: An Expanding Spectrum Of Genementioning

confidence: 99%

Section: Microvillus Inclusion Disease: An Expanding Spectrum Of Genementioning

confidence: 99%

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MYO5B,STX3, andSTXBP2mutations reveal a common disease mechanism that unifies a subset of congenital diarrheal disorders: A mutation update

et al. 2018

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“…Acquisition was controlled by VisiView software (Visitron Systems GmbH). Single plane confocal images were acquired using a Laser Scanning Confocal Microscope (SP5, Leica) with a 63× oil immersion objective (NA 1.4) using the LAS AF acquisition software …”

Section: Methodsmentioning

confidence: 99%

Combining high‐pressure freezing with pre‐embedding immunogold electron microscopy and tomography

Hess

Vogel

Yordanov

et al. 2018

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Immunogold labeling of permeabilized whole-mount cells or thin-sectioned material is widely used for the subcellular localization of biomolecules at the high spatial resolution of electron microscopy (EM). Those approaches are well compatible with either 3-dimensional (3D) reconstruction of organelle morphology and antigen distribution or with rapid cryofixation-but not easily with both at once. We describe here a specimen preparation and labeling protocol for animal cell cultures, which represents a novel blend of specifically adapted versions of established techniques. It combines the virtues of reliably preserved organelle ultrastructure, as trapped by rapid freezing within milliseconds followed by freeze-substitution and specimen rehydration, with the advantages of robust labeling of intracellular constituents in 3D through means of pre-embedding NANOGOLD-silver immunocytochemistry. So obtained thin and semi-thick epoxy resin sections are suitable for transmission EM imaging, as well as tomographic reconstruction and modeling of labeling patterns in the 3D cellular context.

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“…In intestinal organoids derived from syntaxin binding protein 2-null mice, Mosa et al (2018) observed microvillus inclusion formation both de novo in the cytoplasm and through internalization of the apical or basolateral plasma membrane. Loss of function mutations in syntaxin binding protein 2 result in familial hemophagocytic lymphohistiocytosis type 5, a disease that manifests gastrointestinal symptoms similar to MVID (Davidson et al, 1978;Côte et al, 2009;Pagel et al, 2012;Stepensky et al, 2013;Vogel et al, 2017;Mosa et al, 2018). Silencing of the V0-ATPase in Caenorhabditis elegans also revealed microvillus inclusion formation de novo in the cytoplasm or from internalization of large structures from the apical or basolateral plasma membrane (Bidaud-Meynard et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Loss of myosin Vb promotes apical bulk endocytosis in neonatal enterocytes

Engevik

Kaji

Postema

et al. 2019

Journal of Cell Biology

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In patients with inactivating mutations in myosin Vb (Myo5B), enterocytes show large inclusions lined by microvilli. The origin of inclusions in small-intestinal enterocytes in microvillus inclusion disease is currently unclear. We postulated that inclusions in Myo5b KO mouse enterocytes form through invagination of the apical brush border membrane. 70-kD FITC-dextran added apically to Myo5b KO intestinal explants accumulated in intracellular inclusions. Live imaging of Myo5b KO–derived enteroids confirmed the formation of inclusions from the apical membrane. Treatment of intestinal explants and enteroids with Dyngo resulted in accumulation of inclusions at the apical membrane. Inclusions in Myo5b KO enterocytes contained VAMP4 and Pacsin 2 (Syndapin 2). Myo5b;Pacsin 2 double-KO mice showed a significant decrease in inclusion formation. Our results suggest that apical bulk endocytosis in Myo5b KO enterocytes resembles activity-dependent bulk endocytosis, the primary mechanism for synaptic vesicle uptake during intense neuronal stimulation. Thus, apical bulk endocytosis mediates the formation of inclusions in neonatal Myo5b KO enterocytes.

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Disrupted apical exocytosis of cargo vesicles causes enteropathy in FHL5 patients with Munc18-2 mutations

Cited by 45 publications

References 49 publications

MYO5B,STX3, andSTXBP2mutations reveal a common disease mechanism that unifies a subset of congenital diarrheal disorders: A mutation update

MYO5B,STX3, andSTXBP2mutations reveal a common disease mechanism that unifies a subset of congenital diarrheal disorders: A mutation update

Combining high‐pressure freezing with pre‐embedding immunogold electron microscopy and tomography

Loss of myosin Vb promotes apical bulk endocytosis in neonatal enterocytes

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