@article{b47dc25566a34ff59433d1025fdec234,
title = "A drosophila screen identifies nkcc1 as a modifier of ngly1 deficiency",
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 to 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.",
author = "Talsness, {Dana M.} and Owings, {Katie G.} and Emily Coelho and Gaelle Mercenne and Pleinis, {John M.} and Raghavendran Partha and Hope, {Kevin A.} and Zuberi, {Aamir R.} and Clark, {Nathan L.} and Lutz, {Cathleen M.} and Rodan, {Aylin R.} and Chow, {Clement Y.}",
note = "Funding Information: This study is dedicated to Bertrand Might, the first child diagnosed with NGLY1 deficiency. We thank Dr. Hamed Jafar-Nejad (Baylor College of Medicine) for the gift of immortalized NGLY1-null MEFs. This research was supported by the NIH through an NIGMS R35 award (R35GM124780) (CYC), NIDDK R01 award (R01 DK110358) (ARR), and NHGRI R01 award (R01 HG009299) (NLC). This work was also supported by a Glenn Award from the Glenn Foundation for Medical Research to CYC. CYC was the Mario R Capecchi Endowed Chair in Genetics. DMT and KSH were supported on an NIH/NHGRI Genomic Medicine T32 postdoctoral training grant from the University of Utah (T32 HG008962) and by a generous gift from the Might family through the Bertrand T Might Fellowship. KGO was supported by the NIH/NIGMS Genetics T32 Fellowship from the University of Utah (T32 GM007464). The MEFs were derived from NGLY1 knockout mice which were funded by the Grace Science Foundation to CML. Publisher Copyright: {\textcopyright} Talsness et al.",
year = "2020",
month = dec,
doi = "10.7554/eLife.57831",
language = "English (US)",
volume = "9",
pages = "1--22",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}