Lethality of mice bearing a knockout of the Ngly1-gene is partially rescued by the additional deletion of the Engase gene

The cytoplasmic peptide:n-glycanase (ngly1 in mammals) is a de-n-glycosylating enzyme that is highly conserved among eukaryotes. it was recently reported that subjects harboring mutations in the ngly1 gene exhibited severe systemic symptoms (ngly1-deficiency). while the enzyme obviously has a critical role in mammals,its precise function remains unclear. in this study,we analyzed ngly1-deficient mice and found that they are embryonic lethal in c57bl/6 background. surprisingly,the additional deletion of the gene encoding endo-β-n-acetylglucosaminidase (engase),which is another de-n-glycosylating enzyme but leaves a single glcnac at glycosylated asn residues,resulted in the partial rescue of the lethality of the ngly1-deficient mice. additionally,we also found that a change in the genetic background of c57bl/6 mice,produced by crossing the mice with an outbred mouse strain (icr) could partially rescue the embryonic lethality of ngly1-deficient mice. viable ngly1-deficient mice in a c57bl/6 and icr mixed background,however,showed a very severe phenotype reminiscent of the symptoms of ngly1-deficiency subjects. again,many of those defects were strongly suppressed by the additional deletion of engase in the c57bl/6 and icr mixed background. the defects observed in ngly1/engase-deficient mice (c57bl/6 background) and ngly1-deficient mice (c57bl/6 and icr mixed background) closely resembled some of the symptoms of patients with an ngly1-deficiency. these observations strongly suggest that the ngly1- or ngly1/engase-deficient mice could serve as a valuable animal model for studies related to the pathogenesis of the ngly1-deficiency,and that cytoplasmic engase represents one of the potential therapeutic targets for this genetic disorder. © 2017 fujihira et al.