Lethality of mice bearing a knockout of the Ngly1-gene is partially rescued by the additional deletion of the Engase gene
2017
The cytoplasmic peptide:N-glycanase (
Ngly1in mammals) is a de-N-glycosylating enzyme that is highly conserved among eukaryotes. It was recently reported that subjects harboring mutations in the
NGLY1gene 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/6background. 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/6mice, 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/6and 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/6and ICR mixed background. The defects observed in
Ngly1/Engase-deficient mice (
C57BL/6background) and
Ngly1-deficient mice (
C57BL/6and 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.
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