Year: 2020
Type: article
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 is misglycosylated and has reduced function, making it only the second confirmed NGLY1 enzymatic substrate. The misregulation of this ion transporter may explain the observed defects in secretory epithelium function in NGLY1 deficiency patients.
Source: eLife
DOI: 10.7554/elife.57831
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Awards: G1590088021, G1774981225, G2848036350, Training Program in Genetics, G5107705165, G6764753027, Investigating the impact of genetic variation on the ER stress response, protein folding, and disease, Regulation of WNK signaling by potassium and Mo25: structure, function and physiology, Training Program in Genomic Medicine, Title: Functional Annotation of Genomes via Phenotypic Convergence within Large Multi-species Alignments
OpenAlex ID: W3112210782