학술논문
SCGN deficiency results in colitis susceptibility
Document Type
article
Author
Luis F Sifuentes-Dominguez; Haiying Li; Ernesto Llano; Zhe Liu; Amika Singla; Ashish S Patel; Mahesh Kathania; Areen Khoury; Nicholas Norris; Jonathan J Rios; Petro Starokadomskyy; Jason Y Park; Purva Gopal; Qi Liu; Shuai Tan; Lillienne Chan; Theodora Ross; Steven Harrison; K Venuprasad; Linda A Baker; Da Jia; Ezra Burstein
Source
eLife, Vol 8 (2019)
Subject
Language
English
ISSN
2050-084X
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 ultra rare 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.