SCGN deficiency results in colitis susceptibility
- University of Texas Southwestern Medical Center, United States
- Sichuan University, China
Abstract
Inflammatory bowel disease (IBD) affects 1.5-3.0 million people in the United States. IBD is genetically determined and many common risk alleles have been identified. Yet, a large proportion of genetic predisposition remains unexplained. In this study we report the identification of an ultrarare missense variant (NM_006998.3:c.230G>A;p.Arg77His) in the SCGN gene causing Mendelian early-onset ulcerative colitis. SCGN encodes a calcium sensor that is exclusively expressed in neuroendocrine lineages, including enteroendocrine cells and gut neurons. SCGN interacts with the SNARE complex, which is required for vesicle fusion with the plasma membrane. We show that the SCGN mutation identified impacted the localization of the SNARE complex partner, SNAP25, leading to impaired hormone release. Finally, we show that mouse models of Scgn deficiency recapitulate impaired hormone release and susceptibility to DSS-induced colitis. Altogether, these studies demonstrate that functional deficiency in SCGN can result in intestinal inflammation and implicates the neuroendocrine cellular compartment in IBD.
Data availability
Sequencing data have been deposited in GEO under accession code GSE134202.data generated during this study is included in the manuscript.
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Transcriptome-wide gene-expression analysis of colonic epithelium from enteroendocrine cell-deficient miceNCBI Gene Expression Omnibus, GSE134202.
Article and author information
Author details
Luis F Sifuentes-Dominguez
Funding
Eunice Kennedy Shriver National Institute of Child Health and Human Development (5 K12 HD-068369-05)
- Luis F Sifuentes-Dominguez
Children's Health Clinical Research Advisory Committee (195)
- Luis F Sifuentes-Dominguez
National Institute of Diabetes and Digestive and Kidney Diseases (DK105068)
- Linda A Baker
National Center for Advancing Translational Sciences (UL1TR001105)
- Jonathan J Rios
Natural Science Foundation of China (91854121)
- Da Jia
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Murine studies were approved by the UT Southwestern Institutional Animal Care and Use Committee under study number APN 102011. All zebrafish (Danio rerio) experiments were performed according to standard procedures, and were performed in accordance with the guidelines of the animal ethical committee of Sichuan University.
Human subjects: All human studies were carried out in accordance with UT Southwestern Medical Center institutional review board guidelines under an approved protocol (STU 112010-130). All subjects agreed to participation and written informed consent was obtained from all participants or legal guardians. Assent was obtained from individuals older than 10 years of age at time of enrollment.
Copyright
© 2019, Sifuentes-Dominguez et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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