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.
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
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
-
- 2,419
- views
-
- 363
- downloads
-
- 19
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
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)
Further reading
-
- Genetics and Genomics
- Microbiology and Infectious Disease
Schistosoma mansoni is a parasitic flatworm that causes the major neglected tropical disease schistosomiasis. The miracidium is the first larval stage of the life cycle. It swims and infects a freshwater snail, transforms into a mother sporocyst, where its stem cells generate daughter sporocysts that give rise to human-infective cercariae larvae. To understand the miracidium at cellular and molecular levels, we created a whole-body atlas of its ~365 cells. Single-cell RNA sequencing identified 19 transcriptionally distinct cell clusters. In situ hybridisation of tissue-specific genes revealed that 93% of the cells in the larva are somatic (57% neural, 19% muscle, 13% epidermal or tegument, 2% parenchyma, and 2% protonephridia) and 7% are stem. Whereas neurons represent the most diverse somatic cell types, trajectory analysis of the two main stem cell populations indicates that one of them is the origin of the tegument lineage and the other likely contains pluripotent cells. Furthermore, unlike the somatic cells, each of these stem populations shows sex-biased transcriptional signatures suggesting a cell-type-specific gene dosage compensation for sex chromosome-linked loci. The miracidium represents a simple developmental stage with which to gain a fundamental understanding of the molecular biology and spatial architecture of schistosome cells.
-
- Genetics and Genomics
- Microbiology and Infectious Disease
Klebsiella pneumoniae is a global public health concern due to the rising myriad of hypervirulent and multidrug-resistant clones both alarmingly associated with high mortality. The molecular mechanisms underpinning these recalcitrant K. pneumoniae infection, and how virulence is coupled with the emergence of lineages resistant to nearly all present-day clinically important antimicrobials, are unclear. In this study, we performed a genome-wide screen in K. pneumoniae ECL8, a member of the endemic K2-ST375 pathotype most often reported in Asia, to define genes essential for growth in a nutrient-rich laboratory medium (Luria-Bertani [LB] medium), human urine, and serum. Through transposon directed insertion-site sequencing (TraDIS), a total of 427 genes were identified as essential for growth on LB agar, whereas transposon insertions in 11 and 144 genes decreased fitness for growth in either urine or serum, respectively. These studies not only provide further knowledge on the genetics of this pathogen but also provide a strong impetus for discovering new antimicrobial targets to improve current therapeutic options for K. pneumoniae infections.