Talsness, D.M., Owings, K.G., Coelho, E., Mercenne, G., Pleinis, J.M., Partha, R., Hope, K.A., Zuberi, A.R., Clark, N.L., Lutz, C.M., Rodan, A.R., Chow, C.Y. (2020). A Drosophila screen identifies NKCC1 as a modifier of NGLY1 deficiency.  eLife 9(): e57831.

FBrf0247621

Research paper

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.

PMC7758059 (PMC) (EuropePMC)