A Drosophila screen identifies NKCC1 as a modifier of NGLY1 deficiency
- University of Utah School of Medicine, United States
- University of Utah, United States
- University of Pittsburgh, United States
- The Jackson Laboratory, United States
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.
Article and author information
Author details
Raghavendran Partha
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.
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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