This report describes congenital disorder of deglycosylation 1 (CDDG1); CDDG1 exhibits autosomal recessive inheritance. The human gene implicated in this disease, NGLY1, encodes N-glycanase 1, a cytoplasmic component of the endoplasmic-reticulum-associated degradation pathway that identifies and degrades misfolded glycoproteins. There is a single orthologous gene in Drosophila, Pngl, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and loss-of-function mutations caused by imprecise excision of TE insertions have been generated.
Multiple UAS constructs of the human Hsap\NGLY1 gene have been introduced into flies, including wild-type and a construct carrying a variant implicated in this disease. Variant(s) implicated in human disease tested (as transgenic human gene, NGLY1): the NGLY1:p.Arg402del variant form has been introduced into flies. The Hsap\NGLY1 wild-type gene exhibits heterologous rescue (functional complementation) for the semi-lethality and sterility phenotypes of Dmel\Pngl. The mouse Mmus\Ngly1 gene has also been introduced into flies and also exhibits functional complementation for mutations of Dmel\Pngl.
Animals homozygous for loss-of-function mutations of Pngl exhibit global development delay and rarely survive to adulthood; escapers exhibit small body size, sterility, and a decreased lifespan. Abnormalities of the larval midgut are observed. Physical and genetic interactions of Dmel\Pngl have been described; see below and in the Pngl gene report.
[updated Aug. 2025 by FlyBase; FBrf0222196]
[CONGENITAL DISORDER OF DEGLYCOSYLATION 1; CDDG1](https://omim.org/entry/615273)
[N-GLYCANASE 1; NGLY1](https://omim.org/entry/610661)
Congenital disorder of deglycosylation is an autosomal recessive multisystem disorder characterized by global developmental delay, hypotonia, abnormal involuntary movements, and alacrima or poor tear production. Other common features include microcephaly, intractable seizures, abnormal eye movements, and evidence of liver dysfunction (summary by Enns et al., 2014; pubmed:24651605). [from MIM:615273; 2018.06.19]
Congenital disorder of deglycosylation (CDDG) is caused by homozygous or compound heterozygous mutation in the NGLY1 gene. [from MIM:615273; 2018.06.19]
Liver biopsy shows cytoplasmic accumulation of storage material in vacuoles (summary by Enns et al., 2014; pubmed:24651605). [from MIM:615273; 2018.06.19]
N-glycanase 1, the protein encoded by NGLY1, specifically deglycosylates the denatured form of N-linked glycoproteins in the cytoplasm and assists their proteasome-mediated degradation. Deglycosylation is a prerequisite for proteasome-mediated degradation of some, but not all, misfolded glycoproteins. [Gene Cards, NGLY1; 2018.06.19]
NGLY1 is a cytoplasmic component of the endoplasmic reticulum-associated degradation (ERAD) pathway that identifies and degrades misfolded glycoproteins (summary by Enns et al., 2014; pubmed:24651605). [from MIM:610661; 2018.06.19]
One to one (1 human to 1 Drosophila).
High-scoring ortholog of human NGLY1 (1 Drosophila to 1 human); Dmel\Pngl shares 34% identity and 52% similarity with the human gene.
