Journal
ELIFE
Volume 8, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.49910
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Funding
- Eunice Kennedy Shriver National Institute of Child Health and Human Development [5 K12 HD-068369-05]
- Children's Health Clinical Research Advisory Committee [195]
- National Institute of Diabetes and Digestive and Kidney Diseases [DK105068]
- National Center for Advancing Translational Sciences [UL1TR001105]
- National Natural Science Foundation of China [91854121]
- UT Southwestern Pollock Family Center for Research in Inflammatory BowelDisease
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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 ultr arare 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.
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