Loss of syntaxin 3 causes variant microvillus inclusion disease

Gastroenterology. 2014 Jul;147(1):65-68.e10. doi: 10.1053/j.gastro.2014.04.002.

Caroline L Wiegerinck ¹, Andreas R Janecke ², Kerstin Schneeberger ¹, Georg F Vogel ³, Désirée Y van Haaften-Visser ⁴, Johanna C Escher ⁵, Rüdiger Adam ⁶, Cornelia E Thöni ⁷, Kristian Pfaller ⁸, Alexander J Jordan ⁶, Cleo-Aron Weis ⁹, Isaac J Nijman ¹⁰, Glen R Monroe ¹⁰, Peter M van Hasselt ¹¹, Ernest Cutz ¹², Judith Klumperman ¹³, Hans Clevers ¹⁴, Edward E S Nieuwenhuis ¹, Roderick H J Houwen ¹, Gijs van Haaften ¹⁰, Michael W Hess ⁸, Lukas A Huber ¹⁵, Janneke M Stapelbroek ¹, Thomas Müller ¹⁶, Sabine Middendorp ¹⁷

Affiliations

1 Division of Pediatrics, Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
2 Division of Human Genetics, Biocenter Innsbruck, Innsbruck, Austria; Department of Pediatrics I, Biocenter Innsbruck, Innsbruck, Austria.
3 Division of Cell Biology, Biocenter Innsbruck, Innsbruck, Austria; Division of Histology and Embryology, Innsbruck Medical University, Innsbruck, Austria.
4 Division of Pediatrics, Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Cell Biology, University Medical Center Utrecht, Utrecht, The Netherlands.
5 Pediatric Gastroenterology, Sophia Children's Hospital, Erasmus MC, Rotterdam, The Netherlands.
6 Pediatric Gastroenterology, Department of Pediatric and Adolescent Medicine, University Medical Centre, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
7 Division of Cell Biology, Biocenter Innsbruck, Innsbruck, Austria; Division of Pathology, Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Canada.
8 Division of Histology and Embryology, Innsbruck Medical University, Innsbruck, Austria.
9 Institute of Pathology, University Medical Centre, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
10 Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
11 Division of Pediatrics, Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
12 Division of Pathology, Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Canada.
13 Department of Cell Biology, University Medical Center Utrecht, Utrecht, The Netherlands; University Medical Center Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands.
14 Hubrecht Institute for Developmental Biology and Stem Cell Research, Royal Dutch Academy of Sciences, University Medical Center Utrecht, Utrecht, The Netherlands.
15 Division of Cell Biology, Biocenter Innsbruck, Innsbruck, Austria.
16 Department of Pediatrics I, Biocenter Innsbruck, Innsbruck, Austria. Electronic address: [email protected].
17 Division of Pediatrics, Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: [email protected].

PMID: 24726755 DOI: 10.1053/j.gastro.2014.04.002

Abstract

Microvillus inclusion disease (MVID) is a disorder of intestinal epithelial differentiation characterized by life-threatening intractable diarrhea. MVID can be diagnosed based on loss of microvilli, microvillus inclusions, and accumulation of subapical vesicles. Most patients with MVID have mutations in Myosin Vb that cause defects in recycling of apical vesicles. Whole-exome sequencing of DNA from patients with variant MVID showed homozygous truncating mutations in syntaxin 3 (STX3). STX3 is an apical receptor involved in membrane fusion of apical vesicles in enterocytes. Patient-derived organoid cultures and overexpression of truncated STX3 in Caco-2 cells recapitulated most characteristics of variant MVID. We conclude that loss of STX3 function causes variant MVID.

Keywords

Epithelial Polarity; Syntaxin 3; Variant Microvillus Inclusion Disease.

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