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.

The following data sets were generated

Article and author information

Author details

  1. Luis F Sifuentes-Dominguez

    Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9525-071X
  2. Haiying Li

    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ernesto Llano

    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. 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 Inn, Sichuan University, Chendu, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Amika Singla

    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Ashish S Patel

    Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Mahesh Kathania

    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Areen Khoury

    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Nicholas Norris

    Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Jonathan J Rios

    Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Petro Starokadomskyy

    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Jason Y Park

    Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Purva Gopal

    Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Qi Liu

    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Shuai Tan

    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Lillienne Chan

    Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Theodora Ross

    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Steven Harrison

    Department of Urology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. K Venuprasad

    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Linda A Baker

    Department of Urology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8272-4886
  21. 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 Inn, Sichuan University, Chendu, China
    Competing interests
    The authors declare that no competing interests exist.
  22. Ezra Burstein

    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    ezra.burstein@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4341-6367

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.

Reviewing Editor

  1. Andrew J MacPherson, University of Bern, Switzerland

Publication history

  1. Received: July 3, 2019
  2. Accepted: October 27, 2019
  3. Accepted Manuscript published: October 30, 2019 (version 1)
  4. Version of Record published: November 8, 2019 (version 2)
  5. Version of Record updated: November 12, 2019 (version 3)

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.

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  1. Luis F Sifuentes-Dominguez
  2. Haiying Li
  3. Ernesto Llano
  4. Zhe Liu
  5. Amika Singla
  6. Ashish S Patel
  7. Mahesh Kathania
  8. Areen Khoury
  9. Nicholas Norris
  10. Jonathan J Rios
  11. Petro Starokadomskyy
  12. Jason Y Park
  13. Purva Gopal
  14. Qi Liu
  15. Shuai Tan
  16. Lillienne Chan
  17. Theodora Ross
  18. Steven Harrison
  19. K Venuprasad
  20. Linda A Baker
  21. Da Jia
  22. Ezra Burstein
(2019)
SCGN deficiency results in colitis susceptibility
eLife 8:e49910.
https://doi.org/10.7554/eLife.49910
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