eLife (Oct 2019)
SCGN deficiency results in colitis susceptibility
- 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
Affiliations
- Luis F Sifuentes-Dominguez
- ORCiD
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United States
- Haiying Li
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
- Ernesto Llano
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
- Zhe Liu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
- Amika Singla
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
- Ashish S Patel
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United States
- Mahesh Kathania
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
- Areen Khoury
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
- Nicholas Norris
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United States
- Jonathan J Rios
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United States; McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United States; Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, United States
- Petro Starokadomskyy
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
- Jason Y Park
- McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United States; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States
- Purva Gopal
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States
- Qi Liu
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
- Shuai Tan
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States; Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
- Lillienne Chan
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United States
- Theodora Ross
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
- Steven Harrison
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, United States
- K Venuprasad
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
- Linda A Baker
- ORCiD
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, United States
- Da Jia
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
- Ezra Burstein
- ORCiD
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
- DOI
- https://doi.org/10.7554/eLife.49910
- Journal volume & issue
-
Vol. 8
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.
Keywords
