1. Genetics and Genomics
  2. Structural Biology and Molecular Biophysics
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SLC6A14, an amino acid transporter, modifies the primary CF defect in fluid secretion

  1. Saumel Ahmadi
  2. Sunny Xia
  3. Yu-Sheng Wu
  4. Michelle Di Paola
  5. Randolph Kissoon
  6. Catherine Luk
  7. Fan Lin
  8. Kai Du
  9. Johanna Rommens
  10. Christine Bear  Is a corresponding author
  1. University of Toronto, Canada
  2. Hospital for Sick Children, Canada
Research Article
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Cite this article as: eLife 2018;7:e37963 doi: 10.7554/eLife.37963

Abstract

The severity of intestinal disease associated with Cystic Fibrosis (CF) is variable in the patient population and this variability is partially conferred by the influence of modifier genes. Genome-wide association studies have identified SLC6A14, an electrogenic amino acid transporter, as a genetic modifier of CF-associated meconium ileus. The purpose of the current work was to determine the biological role of Slc6a14, by disrupting its expression in CF mice bearing the major mutation, F508del. We found that disruption of Slc6a14 worsened the intestinal fluid secretion defect characteristic of these mice. In vitro studies of mouse intestinal organoids revealed that exacerbation of the primary defect was associated with reduced arginine uptake across the apical membrane, with aberrant nitric oxide and cyclic GMP mediated regulation of the major CF-causing mutant protein. Together, these studies highlight the role of this apical transporter in modifying cellular nitric oxide levels, residual function of the major CF mutant and potentially, its promise as a therapeutic target.

Data availability

All of the data is presented in the submitted figures (in the article file) and supplementary file

Article and author information

Author details

  1. Saumel Ahmadi

    Department of Physiology, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  2. Sunny Xia

    Department of Physiology, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Yu-Sheng Wu

    Department of Physiology, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Michelle Di Paola

    Programme in Molecular Medicine, Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. Randolph Kissoon

    Programme in Molecular Medicine, Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Catherine Luk

    Programme in Molecular Medicine, Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Fan Lin

    Department of Molecular Genetics, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  8. Kai Du

    Programme in Molecular Medicine, Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  9. Johanna Rommens

    Department of Molecular Genetics, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  10. Christine Bear

    Department of Physiology, University of Toronto, Toronto, Canada
    For correspondence
    bear@sickkids.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7063-3418

Funding

Canadian Institutes of Health Research (CIHR MOP-97954,CIHR GPG-102171)

  • Fan Lin

Cystic Fibrosis Canada (CFC-1)

  • Christine Bear

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: SickKids Animal Approval: #1000037433

Reviewing Editor

  1. Ralph DeBerardinis, UT Southwestern Medical Center, United States

Publication history

  1. Received: April 30, 2018
  2. Accepted: July 12, 2018
  3. Accepted Manuscript published: July 13, 2018 (version 1)
  4. Version of Record published: July 20, 2018 (version 2)

Copyright

© 2018, Ahmadi 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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