Cameron Schlegel1,2, Victoria G Weis1,2, Byron C Knowles3,2, Lynne A Lapierre1,2, Martin G Martin4, Paul Dickman5,6, James R Goldenring7,8,9, Mitchell D Shub10,6. 1. Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA. 2. Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. 3. Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA. 4. Department of Pediatrics, Division of Gastroenterology and Nutrition, Mattel Children's Hospital, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. 5. Division of Pathology and Laboratory Medicine, Phoenix Children's Hospital, Phoenix, AZ, USA. 6. Department of Child Health, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA. 7. Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA. jim.goldenring@vanderbilt.edu. 8. Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA. jim.goldenring@vanderbilt.edu. 9. Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. jim.goldenring@vanderbilt.edu. 10. Division of Gastroenterology, Phoenix Children's Hospital, Phoenix, AZ, USA.
Abstract
OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
OBJECTIVES: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 MVIDpatients is well described, little is known about extraintestinal effects of MYO5B mutation. METHODS: We examined stomach, liver, pancreas, colon, and kidney in Navajo MVIDpatients, 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. RESULTS: Navajo MVIDpatients 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 MVIDpatients 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. CONCLUSIONS: These findings indicate that the effects of the P660L mutation in MYO5B in Navajo MVIDpatients 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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