Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

A genome-wide CRISPR screen identifies the glycosylation enzyme DPM1 as a modifier of DPAGT1 deficiency and ER stress

View ORCID ProfileHans M. Dalton, Raghuvir Viswanatha, Ricky Brathwaite Jr., Jae Sophia Zuno, Stephanie E. Mohr, Norbert Perrimon, View ORCID ProfileClement Y. Chow
doi: https://doi.org/10.1101/2021.12.03.471178
Hans M. Dalton
1Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Hans M. Dalton
Raghuvir Viswanatha
2Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ricky Brathwaite Jr.
2Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jae Sophia Zuno
1Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stephanie E. Mohr
2Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Norbert Perrimon
2Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
3Howard Hughes Medical Institute, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Clement Y. Chow
1Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Clement Y. Chow
  • For correspondence: cchow@genetics.utah.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Partial loss-of-function mutations in glycosylation pathways underlie a set of rare diseases called Congenital Disorders of Glycosylation (CDGs). In particular, DPAGT1-CDG is caused by mutations in the gene encoding the first step in N-glycosylation, DPAGT1, and this disorder currently lacks effective therapies. To identify potential therapeutic targets for DPAGT1-CDG, we performed CRISPR knockout screens in Drosophila cells for genes associated with better survival and glycoprotein levels under DPAGT1 inhibition. We identified hundreds of candidate genes that may be of therapeutic benefit. Intriguingly, inhibition of the mannosyltransferase Dpm1, or its downstream glycosylation pathways, could rescue two in vivo models of DPAGT1 inhibition and ER stress, even though impairment of these pathways alone usually cause CDGs. While both in vivo models ostensibly cause ER stress (through DPAGT1 inhibition or a misfolded protein), we found a novel difference in fructose metabolism that may indicate glycolysis as a modulator of DPAGT1-CDG. Our results provide new therapeutic targets for DPAGT1-CDG, include the unique finding of Dpm1-related pathways rescuing DPAGT1 inhibition, and reveal a novel interaction between fructose metabolism and ER stress.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Back to top
PreviousNext
Posted December 04, 2021.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
A genome-wide CRISPR screen identifies the glycosylation enzyme DPM1 as a modifier of DPAGT1 deficiency and ER stress
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
A genome-wide CRISPR screen identifies the glycosylation enzyme DPM1 as a modifier of DPAGT1 deficiency and ER stress
Hans M. Dalton, Raghuvir Viswanatha, Ricky Brathwaite Jr., Jae Sophia Zuno, Stephanie E. Mohr, Norbert Perrimon, Clement Y. Chow
bioRxiv 2021.12.03.471178; doi: https://doi.org/10.1101/2021.12.03.471178
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
A genome-wide CRISPR screen identifies the glycosylation enzyme DPM1 as a modifier of DPAGT1 deficiency and ER stress
Hans M. Dalton, Raghuvir Viswanatha, Ricky Brathwaite Jr., Jae Sophia Zuno, Stephanie E. Mohr, Norbert Perrimon, Clement Y. Chow
bioRxiv 2021.12.03.471178; doi: https://doi.org/10.1101/2021.12.03.471178

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Genetics
Subject Areas
All Articles
  • Animal Behavior and Cognition (3505)
  • Biochemistry (7346)
  • Bioengineering (5323)
  • Bioinformatics (20260)
  • Biophysics (10016)
  • Cancer Biology (7743)
  • Cell Biology (11300)
  • Clinical Trials (138)
  • Developmental Biology (6437)
  • Ecology (9951)
  • Epidemiology (2065)
  • Evolutionary Biology (13321)
  • Genetics (9361)
  • Genomics (12583)
  • Immunology (7701)
  • Microbiology (19021)
  • Molecular Biology (7441)
  • Neuroscience (41036)
  • Paleontology (300)
  • Pathology (1229)
  • Pharmacology and Toxicology (2137)
  • Physiology (3160)
  • Plant Biology (6860)
  • Scientific Communication and Education (1272)
  • Synthetic Biology (1896)
  • Systems Biology (5311)
  • Zoology (1089)