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Congenital Diarrhea and Cholestatic Liver Disease: Phenotypic Spectrum Associated with MYO5B Mutations
Article

Advanced Microscopy for Liver and Gut Ultrastructural Pathology in Patients with MVID and PFIC Caused by MYO5B Mutations

1
Institute of Histology and Embryology, Medical University of Innsbruck, A-6020 Innsbruck, Austria
2
Austrian Drug Screening Institute, ADSI, A-6020 Innsbruck, Austria
3
Institute of Cell Biology, Medical University of Innsbruck, A-6020 Innsbruck, Austria
4
Department of Internal Medicine, Medical University of Innsbruck, A-6020 Innsbruck, Austria
5
Department of Paediatrics I, Medical University of Innsbruck, A-6020 Innsbruck, Austria
6
Department of Paediatric Gastroenterology and Hepatology, University Hospital for Children and Adolescents, University of Tübingen, D-72076 Tübingen, Germany
7
Department of Surgery and the Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232-8240, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Sven van IJzendoorn
J. Clin. Med. 2021, 10(9), 1901; https://doi.org/10.3390/jcm10091901
Received: 29 March 2021 / Revised: 22 April 2021 / Accepted: 23 April 2021 / Published: 28 April 2021
Mutations in the actin motor protein myosinVb (myo5b) cause aberrant apical cargo transport and the congenital enteropathy microvillus inclusion disease (MVID). Recently, missense mutations in myo5b were also associated with progressive familial intrahepatic cholestasis (MYO5B-PFIC). Here, we thoroughly characterized the ultrastructural and immuno-cytochemical phenotype of hepatocytes and duodenal enterocytes from a unique case of an adult MYO5B-PFIC patient who showed constant hepatopathy but only periodic enteric symptoms. Selected data from two other patients supported the findings. Advanced methods such as cryo-fixation, freeze-substitution, immuno-gold labeling, electron tomography and immuno-fluorescence microscopy complemented the standard procedures. Liver biopsies showed mislocalization of Rab11 and bile canalicular membrane proteins. Rab11-positive vesicles clustered around bile canaliculi and resembled subapical clusters of aberrant recycling endosomes in enterocytes from MVID patients. The adult patient studied in detail showed a severe, MVID-specific enterocyte phenotype, despite only a mild clinical intestinal presentation. This included mislocalization of numerous proteins essential for apical cargo transport and morphological alterations. We characterized the heterogeneous population of large catabolic organelles regarding their complex ultrastructure and differential distribution of autophagic and lysosomal marker proteins. Finally, we generated duodenal organoids/enteroids from biopsies that recapitulated all MVID hallmarks, demonstrating the potential of this disease model for personalized medicine. View Full-Text
Keywords: Rab11a; syntaxin3; myosinVb; NHE3; organoid; recycling endosome; progressive familial intrahepatic cholestasis; congenital diarrheal disorder; high-pressure freezing; immuno-electron microscopy Rab11a; syntaxin3; myosinVb; NHE3; organoid; recycling endosome; progressive familial intrahepatic cholestasis; congenital diarrheal disorder; high-pressure freezing; immuno-electron microscopy
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MDPI and ACS Style

Hess, M.W.; Krainer, I.M.; Filipek, P.A.; Witting, B.; Gutleben, K.; Vietor, I.; Zoller, H.; Aldrian, D.; Sturm, E.; Goldenring, J.R.; Janecke, A.R.; Müller, T.; Huber, L.A.; Vogel, G.F. Advanced Microscopy for Liver and Gut Ultrastructural Pathology in Patients with MVID and PFIC Caused by MYO5B Mutations. J. Clin. Med. 2021, 10, 1901. https://doi.org/10.3390/jcm10091901

AMA Style

Hess MW, Krainer IM, Filipek PA, Witting B, Gutleben K, Vietor I, Zoller H, Aldrian D, Sturm E, Goldenring JR, Janecke AR, Müller T, Huber LA, Vogel GF. Advanced Microscopy for Liver and Gut Ultrastructural Pathology in Patients with MVID and PFIC Caused by MYO5B Mutations. Journal of Clinical Medicine. 2021; 10(9):1901. https://doi.org/10.3390/jcm10091901

Chicago/Turabian Style

Hess, Michael W., Iris M. Krainer, Przemyslaw A. Filipek, Barbara Witting, Karin Gutleben, Ilja Vietor, Heinz Zoller, Denise Aldrian, Ekkehard Sturm, James R. Goldenring, Andreas R. Janecke, Thomas Müller, Lukas A. Huber, and Georg F. Vogel 2021. "Advanced Microscopy for Liver and Gut Ultrastructural Pathology in Patients with MVID and PFIC Caused by MYO5B Mutations" Journal of Clinical Medicine 10, no. 9: 1901. https://doi.org/10.3390/jcm10091901

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