SCGN deficiency results in colitis susceptibility
- University of Texas Southwestern Medical Center, United States
- Sichuan University, China
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.
Data availability
Sequencing data have been deposited in GEO under accession code GSE134202.data generated during this study is included in the manuscript.
-
Transcriptome-wide gene-expression analysis of colonic epithelium from enteroendocrine cell-deficient miceNCBI Gene Expression Omnibus, GSE134202.
Article and author information
Author details
Luis F Sifuentes-Dominguez
Funding
Eunice Kennedy Shriver National Institute of Child Health and Human Development (5 K12 HD-068369-05)
- Luis F Sifuentes-Dominguez
Children's Health Clinical Research Advisory Committee (195)
- Luis F Sifuentes-Dominguez
National Institute of Diabetes and Digestive and Kidney Diseases (DK105068)
- Linda A Baker
National Center for Advancing Translational Sciences (UL1TR001105)
- Jonathan J Rios
Natural Science Foundation of China (91854121)
- Da Jia
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Murine studies were approved by the UT Southwestern Institutional Animal Care and Use Committee under study number APN 102011. All zebrafish (Danio rerio) experiments were performed according to standard procedures, and were performed in accordance with the guidelines of the animal ethical committee of Sichuan University.
Human subjects: All human studies were carried out in accordance with UT Southwestern Medical Center institutional review board guidelines under an approved protocol (STU 112010-130). All subjects agreed to participation and written informed consent was obtained from all participants or legal guardians. Assent was obtained from individuals older than 10 years of age at time of enrollment.
Copyright
© 2019, Sifuentes-Dominguez et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,493
- views
-
- 372
- downloads
-
- 20
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
SCGN deficiency results in colitis susceptibility
eLife 8:e49910.
https://doi.org/10.7554/eLife.49910
Further reading
-
- Genetics and Genomics
Resistance to anthelmintics, particularly the macrocyclic lactone ivermectin (IVM), presents a substantial global challenge for parasite control. We found that the functional loss of an evolutionarily conserved E3 ubiquitin ligase, UBR-1, leads to IVM resistance in Caenorhabditis elegans. Multiple IVM-inhibiting activities, including viability, body size, pharyngeal pumping, and locomotion, were significantly ameliorated in various ubr-1 mutants. Interestingly, exogenous application of glutamate induces IVM resistance in wild-type animals. The sensitivity of all IVM-affected phenotypes of ubr-1 is restored by eliminating proteins associated with glutamate metabolism or signaling: GOT-1, a transaminase that converts aspartate to glutamate, and EAT-4, a vesicular glutamate transporter. We demonstrated that IVM-targeted GluCls (glutamate-gated chloride channels) are downregulated and that the IVM-mediated inhibition of serotonin-activated pharynx Ca2+ activity is diminished in ubr-1. Additionally, enhancing glutamate uptake in ubr-1 mutants through ceftriaxone completely restored their IVM sensitivity. Therefore, UBR-1 deficiency-mediated aberrant glutamate signaling leads to ivermectin resistance in C. elegans.
-
- Genetics and Genomics
Osteoporosis, characterized by reduced bone density and strength, increases fracture risk, pain, and limits mobility. Established therapies of parathyroid hormone (PTH) analogs effectively promote bone formation and reduce fractures in severe osteoporosis, but their use is limited by potential adverse effects. In the pursuit of safer osteoporosis treatments, we investigated R25CPTH, a PTH variant wherein the native arginine at position 25 is substituted by cysteine. These studies were prompted by our finding of high bone mineral density in a hypoparathyroidism patient with the R25C homozygous mutation, and we explored its effects on PTH type-1 receptor (PTH1R) signaling in cells and bone metabolism in mice. Our findings indicate that R25CPTH(1–84) forms dimers both intracellularly and extracellularly, and the synthetic dimeric peptide, R25CPTH(1–34), exhibits altered activity in PTH1R-mediated cyclic AMP (cAMP) response. Upon a single injection in mice, dimeric R25CPTH(1–34) induced acute calcemic and phosphaturic responses comparable to PTH(1–34). Furthermore, repeated daily injections increased calvarial bone thickness in intact mice and improved trabecular and cortical bone parameters in ovariectomized (OVX) mice, akin to PTH(1–34). The overall results reveal a capacity of a dimeric PTH peptide ligand to activate the PTH1R in vitro and in vivo as PTH, suggesting a potential path of therapeutic PTH analog development.
