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Updated: May 1, 2026
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
Loss of syntaxin 3 causes variant microvillus inclusion disease
Caroline L Wiegerinck1, Andreas R Janecke2, Kerstin Schneeberger1
1Division of Pediatrics, Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
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.
Insights
Microvillus inclusion disease (MVID) is a rare intestinal disorder. Loss of syntaxin 3 (STX3) function causes a variant form of MVID, leading to severe diarrhea.
Area of Science:
- Gastroenterology
- Cell Biology
- Genetics
Background:
- Microvillus inclusion disease (MVID) is a severe congenital enteropathy.
- It is characterized by impaired intestinal epithelial differentiation and intractable diarrhea.
- Previous research linked MVID to mutations in myosin Vb, affecting apical vesicle recycling.
Observation:
- A subset of MVID patients presented with a distinct clinical and ultrastructural phenotype.
- Whole-exome sequencing identified homozygous truncating mutations in syntaxin 3 (STX3) in these patients.
- Syntaxin 3 is crucial for apical vesicle fusion in enterocytes.
Findings:
- Loss of STX3 function leads to defective apical vesicle fusion in intestinal epithelial cells.
- Patient-derived organoid cultures and cell models recapitulated key MVID features.
- This confirms syntaxin 3 as a critical gene in MVID pathogenesis.
Implications:
- Identifies syntaxin 3 as a novel causative gene for a variant form of MVID.
- Provides a molecular basis for understanding MVID pathophysiology.
- Opens avenues for potential diagnostic and therapeutic strategies for MVID patients.
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