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.
Highlights
N-Glycanase 1 (NGLY1) deficiency (OMIM 615273) is a rare, autosomal recessive disorder caused by loss-of-function mutations in the NGLY1 gene
Together these two genetic analyses have generated a list of genes that (1) may explain some of the variation seen between NGLY1 patients, (2) may encode proteins that physically interact with NGLY1 in ERAD or other cellular processes, and (3) may be direct deglycosylation targets of NGLY1
We found that NKCC1 modifies multiple phenotypes in Drosophila, and in NGLY1 -/- mammalian cells, NKCC1 displays abnormal average molecular weight and has reduced activity
Summary
Dana M Talsness1†, Katie G Owings1†, Emily Coelho, Gaelle Mercenne, John M Pleinis, Raghavendran Partha, Kevin A Hope, Aamir R Zuberi, Nathan L Clark, Cathleen M Lutz, Aylin R Rodan, Clement Y Chow1*.
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