PUBLICATION
SCGN deficiency results in colitis susceptibility
- Authors
- Sifuentes-Dominguez, L.F., 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., Venuprasad, K., Baker, L.A., Jia, D., Burstein, E.
- ID
- ZDB-PUB-191031-10
- Date
- 2019
- Source
- eLIFE 8: (Journal)
- Registered Authors
- Keywords
- genetics, genomics, human, immunology, inflammation, mouse, zebrafish
- MeSH Terms
-
- Animals
- Cell Membrane/metabolism
- Colitis, Ulcerative/genetics*
- Cytoplasmic Vesicles/metabolism
- Disease Models, Animal
- Genetic Predisposition to Disease*
- Humans
- Membrane Fusion
- Mice
- Mutation, Missense
- Protein Transport
- SNARE Proteins/metabolism
- Secretagogins/deficiency*
- Secretagogins/genetics
- Synaptosomal-Associated Protein 25/metabolism
- PubMed
- 31663849 Full text @ Elife
Citation
Sifuentes-Dominguez, L.F., 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., Venuprasad, K., Baker, L.A., Jia, D., Burstein, E. (2019) SCGN deficiency results in colitis susceptibility. eLIFE. 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 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping