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Apical Membrane Alterations in Non-intestinal Organs in Microvillus Inclusion Disease

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Microvillus inclusion disease (MVID) is a severe form of neonatal diarrhea, caused mainly by mutations in MYO5B. Inactivating mutations in MYO5B causes depolarization of enterocytes in the small intestine, which gives rise to chronic, unremitting secretory diarrhea. While the pathology of the small intestine in MVID patients is well described, little is known about extraintestinal effects of MYO5B mutation.


We examined stomach, liver, pancreas, colon, and kidney in Navajo MVID patients, who share a single homozygous MYO5B-P660L (1979C>T p.Pro660Leu, exon 16). Sections were stained for markers of the apical membrane to assess polarized trafficking.


Navajo MVID patients showed notable changes in H/K-ATPase-containing tubulovesicle structure in the stomach parietal cells. Colonic mucosa was morphologically normal, but did show losses in apical ezrin and Syntaxin 3. Hepatocytes in the MVID patients displayed aberrant canalicular expression of the essential transporters MRP2 and BSEP. The pancreas showed small fragmented islets and a decrease in apical ezrin in pancreatic ducts. Kidney showed normal primary cilia.


These findings indicate that the effects of the P660L mutation in MYO5B in Navajo MVID patients are not limited to the small intestine, but that certain tissues may be able to compensate functionally for alterations in apical trafficking.

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This work was supported by the NIH Grant RO1 DK70856 and RO1 DK48370 to J.R.G and RAC Awards to M.S. from Phoenix Children’s Hospital for initial support of this project. V.G.S. and C.S. were supported by NIH Postdoctoral Fellowships (T32 DK007673). Confocal and structured illumination fluorescence microscopy imaging was performed through the use of the VUMC Cell Imaging Shared Resource, and histological sectioning was performed by Translational Pathology Shared Resource, both supported by National Institute of Health (NIH) Grants CA68485, DK20593, DK58404 and HD15052. Fluorescence slide imaging was performed on an Ariol SL-50 digitizing scanner in the VUMC Digital Histology Shared Resource. We thank G. Silber, K. Ingebo, and D. Ursea for the outstanding care that they have provided over the years for the Navajo patients with MVID. We thank all of the families of our Navajo patients, who consented to allow archived tissue samples from their children to be used in this study.

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Correspondence to James R. Goldenring.

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Supplemental Figure 1. Alterations in pancreas morphologies in MVID patient samples. (A) Insulin stains beta cells specifically in normal and MVID patient samples, with small collection of insulin-staining cells are observed throughout the MVID pancreas. (B) Apical Ezrin staining was lost in MVID patient, with basolateral and cytoplasmic redistribution. Notable intracellular distribution of p120 and loss of lateral staining was demonstrated in MVID pancreas samples compared to control, with loss of MYO5B. Higher magnification images are shown as insets in the merged panels. Scale bars are 100 µm in both panels (TIFF 5463 kb)


Supplemental Figure 2: Immunofluorescence of the kidney demonstrates no significant pathology in MVID patients compared to control (Acyl-tub and Arl13B). Sections of normal kidney and biopsied kidney from a Navajo MVID patient were stained for Acetylated tubulin (green) and Arl13b (red) to visualize the primary cilia. Renal primary cilia demonstrated no changes in length or structure in MVID patients by Arl13b or acetylated tubulin (acetyl-tubulin) immunofluorescence. Scale bars are 10 µm in all panels (TIFF 4361 kb)

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Schlegel, C., Weis, V.G., Knowles, B.C. et al. Apical Membrane Alterations in Non-intestinal Organs in Microvillus Inclusion Disease. Dig Dis Sci 63, 356–365 (2018).

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