SCGN deficiency results in colitis susceptibility

Luis Sifuentes-Dominguez; Haying 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; Venuprasad K; Linda A. Baker; Da Jia; Ezra Burstein

doi:10.7554/eLife.49910

SCGN deficiency results in colitis susceptibility

Luis Sifuentes-Dominguez, Haying 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, Venuprasad K, Linda A. BakerDa Jia, Ezra Burstein

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

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.

Original language	English (US)
Article number	e49910
Journal	eLife
Volume	8
DOIs	https://doi.org/10.7554/eLife.49910
State	Published - Oct 2019

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

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Sifuentes-Dominguez, L., Li, H., Llano, E., Liu, Z., Singla, A., Patel, A. S., Kathania, M., Khoury, A., Norris, N., Rios, J. J., Starokadomskyy, P., Park, J. Y., Gopal, P., Liu, Q., Tan, S., Chan, L., Ross, T., Harrison, S., K, V., ... Burstein, E. (2019). SCGN deficiency results in colitis susceptibility. eLife, 8, Article e49910. https://doi.org/10.7554/eLife.49910

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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",

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month = oct,

doi = "10.7554/eLife.49910",

language = "English (US)",

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T1 - SCGN deficiency results in colitis susceptibility

AU - Sifuentes-Dominguez, Luis

AU - Li, Haying

AU - Llano, Ernesto

AU - Liu, Zhe

AU - Singla, Amika

AU - Patel, Ashish S.

AU - Kathania, Mahesh

AU - Khoury, Areen

AU - Norris, Nicholas

AU - Rios, Jonathan J.

AU - Starokadomskyy, Petro

AU - Park, Jason Y.

AU - Gopal, Purva

AU - Liu, Qi

AU - Tan, Shuai

AU - Chan, Lillienne

AU - Ross, Theodora

AU - Harrison, Steven

AU - K, Venuprasad

AU - Baker, Linda A.

AU - Jia, Da

AU - Burstein, Ezra

PY - 2019/10

Y1 - 2019/10

N2 - 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.

AB - 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.

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SCGN deficiency results in colitis susceptibility

Abstract

ASJC Scopus subject areas

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