@article{ea585e5ff3b248978409a1aa82c1c423,
title = "SCGN deficiency results in colitis susceptibility",
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.",
author = "Luis Sifuentes-Dominguez and Haying Li and Ernesto Llano and Zhe Liu and Amika Singla and Patel, {Ashish S.} and Mahesh Kathania and Areen Khoury and Nicholas Norris and Rios, {Jonathan J.} and Petro Starokadomskyy and Park, {Jason Y.} and Purva Gopal and Qi Liu and Shuai Tan and Lillienne Chan and Theodora Ross and Steven Harrison and Venuprasad K and Baker, {Linda A.} and Da Jia and Ezra Burstein",
note = "Funding Information: Foundation to E.B. LS-D was supported through NIH 5 K12 HD-068369-05 and Children's Funding Information: We wish to thank patients and families involved in this study. We also acknowledge the help from John Shelton and the staff at UTSW?s molecular pathology core, the Children?s Health histology core with help with immunostaining, and the McDermott Center Bioinformatics Core facility. We also thank the McDermott Center Human Gene Discovery laboratory. We thank the transgenic core at UTSW for their help in generating animal models. We also want to thank Jonathan Cohen and Helen Hobbs at the McDermott Center for their invaluable comments throughout this project and for their support with genotyping of subjects in the DHS for the SCGN variants. This work was supported by the Pollock Family Center for Research in IBD, as well as generous gifts from Crowley Family Foundation, the McCune Family Foundation and the Lewis Family Foundation to E.B. LS-D was supported through NIH 5 K12 HD-068369-05 and Children's Health Clinical Research Advisory Committee: CCRAC 195. The work of L.A.B. is supported by NIH R01 DK105068, and the work of J.J.R. was supported by NIH grant UL1TR001105. D.J. is supported by Natural Science Foundation of China (NSFC) grants (#91854121, #31871429). Funding Information: NIH R01 DK105068, and the work of J.J.R. was supported by NIH grant UL1TR001105. D.J. is Funding Information: supported by Natural Science Foundation of China (NSFC) grants (#91854121, #31871429). Publisher Copyright: {\textcopyright} 2019, eLife Sciences Publications Ltd. All rights reserved.",
year = "2019",
month = oct,
doi = "10.7554/eLife.49910",
language = "English (US)",
volume = "8",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}