1. Cell Biology
  2. Genetics and Genomics
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A Drosophila screen identifies NKCC1 as a modifier of NGLY1 deficiency

  1. Dana M Talsness  Is a corresponding author
  2. Katie G Owings
  3. Emily Coelho
  4. Gaelle Mercenne
  5. John M Pleinis
  6. Raghavendran Partha
  7. Kevin A Hope
  8. Aamir R Zuberi
  9. Nathan L Clark
  10. Cathleen M Lutz
  11. Aylin R Rodan
  12. Clement Y Chow  Is a corresponding author
  1. University of Utah, United States
  2. University of Pittsburgh, United States
  3. The Jackson Laboratory, United States
Research Article
  • Cited 8
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Cite this article as: eLife 2020;9:e57831 doi: 10.7554/eLife.57831

Abstract

N-Glycanase 1 (NGLY1) is a cytoplasmic deglycosylating enzyme. Loss-of-function mutations in the NGLY1 gene cause NGLY1 deficiency, which is characterized by developmental delay, seizures, and a lack of sweat and tears. To model the phenotypic variability observed among patients, we crossed a Drosophila model of NGLY1 deficiency onto a panel of genetically diverse strains. The resulting progeny showed a phenotypic spectrum from 0-100% lethality. Association analysis on the lethality phenotype, as well as an evolutionary rate covariation analysis, generated lists of modifying genes, providing insight into NGLY1 function and disease. The top association hit was Ncc69 (human NKCC1/2), a conserved ion transporter. Analyses in NGLY1 -/- mouse cells demonstrated that NKCC1 has an altered average molecular weight and reduced function. The misregulation of this ion transporter may explain the observed defects in secretory epithelium function in NGLY1 deficiency patients.

Data availability

All data generated by this study are included in the manuscript and supporting files.

The following previously published data sets were used

Article and author information

Author details

  1. Dana M Talsness

    Human Genetics, University of Utah, Salt Lake City, United States
    For correspondence
    dana.talsness@genetics.utah.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7823-1616
  2. Katie G Owings

    Human Genetics, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Emily Coelho

    Human Genetics, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Gaelle Mercenne

    Internal Medicine, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. John M Pleinis

    Internal Medicine, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Raghavendran Partha

    Computational and Systems Biology, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7900-4375
  7. Kevin A Hope

    Human Genetics, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Aamir R Zuberi

    The Jackson Laboratory, Bar Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Nathan L Clark

    Department of Human Genetics, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Cathleen M Lutz

    The Jackson Laboratory, Bar Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Aylin R Rodan

    Internal Medicine, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9202-2378
  12. Clement Y Chow

    Department of Human Genetics, University of Utah, Salt Lake City, United States
    For correspondence
    cchow@genetics.utah.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3104-7923

Funding

National Institute of General Medical Sciences (R35GM124780)

  • Clement Y Chow

National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK110358)

  • Aylin R Rodan

National Human Genome Research Institute (R01 HG009299)

  • Nathan L Clark

Glenn Foundation for Medical Research (Glenn Award)

  • Clement Y Chow

National Human Genome Research Institute (T32 HG008962)

  • Dana M Talsness
  • Kevin A Hope

Might family (Bertrand T Might Fellowship)

  • Dana M Talsness

National Institute of General Medical Sciences (T32 GM007464)

  • Katie G Owings

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

Reviewing Editor

  1. Hugo J Bellen, Baylor College of Medicine, United States

Publication history

  1. Received: April 14, 2020
  2. Accepted: December 12, 2020
  3. Accepted Manuscript published: December 14, 2020 (version 1)
  4. Accepted Manuscript updated: December 17, 2020 (version 2)
  5. Version of Record published: December 23, 2020 (version 3)

Copyright

© 2020, Talsness 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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