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

<div><p>The cytoplasmic peptide:<i>N</i>-glycanase (Ngly1 in mammals) is a de-<i>N</i>-glycosylating enzyme that is highly conserved among eukaryotes. It was recently reported that subjects harboring mutations in the <i>NGLY1</i> gene exhibited severe systemic symptoms (<i>NGLY1</i>-deficiency). While the enzyme obviously has a critical role in mammals, its precise function remains unclear. In this study, we analyzed <i>Ngly1</i>-deficient mice and found that they are embryonic lethal in C57BL/6 background. Surprisingly, the additional deletion of the gene encoding endo-β-<i>N</i>-acetylglucosaminidase (<i>Engase</i>), which is another de-<i>N</i>-glycosylating enzyme but leaves a single GlcNAc at glycosylated Asn residues, resulted in the partial rescue of the lethality of the <i>Ngly1</i>-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 <i>Ngly1</i>-deficient mice. Viable <i>Ngly1</i>-deficient mice in a C57BL/6 and ICR mixed background, however, showed a very severe phenotype reminiscent of the symptoms of <i>NGLY1</i>-deficiency subjects. Again, many of those defects were strongly suppressed by the additional deletion of <i>Engase</i> in the C57BL/6 and ICR mixed background. The defects observed in <i>Ngly1/Engase</i>-deficient mice (C57BL/6 background) and <i>Ngly1</i>-deficient mice (C57BL/6 and ICR mixed background) closely resembled some of the symptoms of patients with an <i>NGLY1</i>-deficiency. These observations strongly suggest that the <i>Ngly1</i>- or <i>Ngly1/Engase</i>-deficient mice could serve as a valuable animal model for studies related to the pathogenesis of the <i>NGLY1-</i>deficiency, and that cytoplasmic ENGase represents one of the potential therapeutic targets for this genetic disorder.</p>