Alternative titles; symbols
HGNC Approved Gene Symbol: NGLY1
SNOMEDCT: 768846004;
Cytogenetic location: 3p24.2 Genomic coordinates (GRCh38): 3:25,718,944-25,790,039 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p24.2 | Congenital disorder of deglycosylation 1 | 615273 | Autosomal recessive | 3 |
The NGLY1 gene encodes N-glycanase (EC 3.5.1.52), a highly conserved enzyme that catalyzes deglycosylation of misfolded N-linked glycoproteins by cleaving the glycan chain before the proteins are degraded by the proteasome (Zhou et al., 2006). 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).
By EST database analysis, Suzuki et al. (2000) identified several homologs of yeast Png1, including human NGLY1. In yeast, Png1 was expressed in both the cytoplasm and nucleus.
Suzuki et al. (2003) cloned mouse Ngly1, and by database analysis, they identified human NGLY1. The deduced 654-amino acid human protein contains an N-terminal PUB/PUG protein-protein interaction domain and a central transglutaminase-like motif containing the catalytic triad of the active site. Mouse and human NGLY1 share 98% identity in these 2 domains. Northern blot analysis detected Ngly1 expression in all mouse tissues examined, with highest expression in testis.
Zhou et al. (2006) resolved the crystal structure of the C-terminal domain of mouse Ngly1 to 2-angstrom resolution. The C-terminal domain has a beta-sandwich architecture composed of 2 layers containing 9 and 8 antiparallel beta strands, respectively, and 3 additional short helices. Zhou et al. (2006) identified several solvent-exposed residues involved in binding the mannose moieties of N-linked oligosaccharide chains. Biochemical analysis indicated that the C-terminal domain enhances the catalytic activity of Ngly1.
Suzuki et al. (2003) determined that the NGLY1 gene contains 12 exons and spans about 70 kb. The mouse gene has a similar organization.
By radiation hybrid analysis, Suzuki et al. (2003) mapped the human and mouse NGLY1 genes to chromosomes 3 and 14, respectively. Database analysis suggested that the human gene maps to chromosome 3p24.
Suzuki et al. (2000) found that recombinant yeast Png1 was soluble. Deletion of Png1 in yeast delayed degradation of a mutant form of carboxypeptidase Y.
Using phylogenetic and mutational analyses, Lehrbach et al. (2019) identified 4 conserved N-glycosylation sites on C. elegans Skn1a (POU2F3; 607394). Following release of N-glycosylated Skn1a from the ER, C. elegans Skn1a was deglycosylated by Png1 to convert asparagine residues to aspartate residues. Subsequently, the deglycosylated Skn1a underwent proteolytic cleavage by the Ddi1 aspartic protease to generate a truncated and activated form of Skn1a. Ddi1-dependent protease cleavage removed the N-terminal ER-targeting domain of Skn1a, which allowed the protein to escape from proteasomal degradation. Lehrbach et al. (2019) suggested that conversion of 4 asparagine residues to aspartate residues likely introduced a new function to this domain, e.g., a binding site for cofactors that are critical for transcriptional regulation of proteasome subunit genes. In line with these results, truncated and deglycosylated Skn1a constitutively increased proteasome levels and enhanced proteostasis in C. elegans, and protected them against protein aggregation.
By whole-exome sequencing in a family in which a child had a congenital disorder of deglycosylation (CDDG1; 615273), Need et al. (2012) found that the boy was compound heterozygous for 2 mutations in the NGLY1 gene: a frameshift mutation in exon 12 (610661.0001) inherited from his mother, and a nonsense mutation in exon 8 (R401X; 610661.0002) inherited from his father. Need et al. (2012) compared NGLY1 protein expression in leukocytes extracted from blood from the patient, his parents, and 3 controls. Both parents showed reduced expression compared with controls, and the patient had barely discernible levels of NGLY1.
In 5 patients from 3 families with CDDG1, Enns et al. (2014) identified a homozygous R401X mutation in the NGLY1 gene. All of the patients were Caucasian and of European descent, suggesting the possibility of a founder mutation. Two additional patients were found to carry biallelic NGLY1 mutations (610661.0003-610661.0005). The patients had global developmental delay, hypotonia, and a movement disorder. Other features included hypolacrima or alacrima, abnormal liver enzymes, microcephaly, and seizures. Liver biopsy showed cytoplasmic accumulation of storage material in vacuoles, consistent with accumulation of intact but misfolded glycoproteins. Enns et al. (2014) concluded that the disorder is caused by dysfunction of the ERAD pathway and the cytosolic proteasome.
By whole-exome sequencing, Panneman et al. (2020) identified homozygous or compound heterozygous mutations in the NGYL1 gene (610661.0002; 610661.0006-610661.0008) in 4 patients with CDDG1. Western blot analysis in muscle tissue and fibroblasts from all 4 patients showed absence of NGLY1 protein expression. Evidence was found for mitochondrial dysfunction in patient fibroblasts and muscle tissue. In patients 2 and 4, fibroblast mitochondria were smaller and less branched compared to controls, and maximal respiration and basal respiration were reduced in fibroblasts from patient 4 compared to controls. Biochemical evaluation in muscle tissue from all 4 patients showed reduced mitochondrial ATP production from oxidation of pyruvate and malate.
Using whole-exome sequencing, in a boy with congenital disorder of deglycosylation (CDDG1; 615273) and his parents, Need et al. (2012) found that the boy was compound heterozygous for 2 mutations in the NGLY1 gene: a frameshift mutation in exon 12 inherited from his mother, and a nonsense mutation in exon 8 inherited from his father. The frameshift mutation resulted from a 1-bp deletion (c.1891delC) and the nonsense mutation (R401X; 610661.0002) resulted from a 1201A-T transversion (Shashi, 2013).
For discussion of the arg401-to-ter (R401X) mutation in the NGLY1 gene that was found in compound heterozygous state in a patient with congenital disorder of deglycosylation (CDDG1; 615273) by Need et al. (2012), see 610661.0001.
In 5 patients from 3 families with CDDG1, Enns et al. (2014) identified a homozygous c.1201A-T transversion in exon 8 of the NGLY1 gene, resulting in an arg401-to-ter (R401X) substitution. All of the patients were Caucasian and of European descent, suggesting the possibility of a founder mutation. The R401X mutation was found in 2 of 8,598 chromosomes of European ancestry and once among African American chromosomes in the Exome Variant Server database.
The R401X mutation was the most common among the 12 individuals studied by Lam et al. (2017), accounting for 7 alleles.
In 3 unrelated patients with CDDG1, Panneman et al. (2020) identified the R401X mutation in the NGLY1 gene: patient 2 was homozygous for the mutation, whereas patient 1 also had a c.849T-G transversion, resulting in a cys283-to-trp (C283W; 610661.0006) substitution, and patient 3 had a c.1067A-G transition, resulting in a glu356-to-gly (E356G; 610661.0007) substitution. The mutations were identified by whole-exome sequencing, and the parents in all families were confirmed to be carriers. Western blot analysis in patient muscle tissue and fibroblasts showed absence of NGLY1 protein expression.
In an Italian girl with congenital disorder of deglycosylation (CDDG1; 615273), Enns et al. (2014) identified a homozygous 1-bp duplication (c.1370dupG) in exon 9 of the NGLY1 gene, resulting in a frameshift and premature termination (Arg458fsTer). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the Exome Variant Server database.
In a 4-year-old Caucasian girl of European descent with congenital disorder of deglycosylation (CDDG1; 615273), Enns et al. (2014) identified compound heterozygosity for 2 mutations in the NGLY1 gene: a 3-bp deletion (c.1205_1207delTTC), resulting in the deletion of 1 residue (402del), and a c.1570C-T transition, resulting in an arg542-to-ter (R542X; 610661.0005) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.
For discussion of the arg542-to-ter (R542X) mutation in the NGLY1 gene that was found in compound heterozygous state in a patient with congenital disorder of deglycosylation (CDDG1; 615273) by Enns et al. (2014), see 610661.0004.
For discussion of the c.849T-G transversion in the NGLY1 gene, resulting in a cys283-to-trp (C283W) substitution, that was found in compound heterozygous state in a patient with congenital disorder of deglycosylation (CDDG1; 615273) by Panneman et al. (2020), see 610661.0002.
For discussion of the c.1067A-G transition in the NGLY1 gene, resulting in a glu356-to-gly (E356G) substitution, that was found in compound heterozygous state in a patient with congenital disorder of deglycosylation (CDDG1; 615273) by Panneman et al. (2020), see 610661.0002.
In a North African patient with congenital disorder of deglycosylation (CDDG1; 615273), Panneman et al. (2020) identified homozygosity for a 1-bp deletion (c.1837del) in the NGLY1 gene, predicted to result in a frameshift and premature termination (Ile613PhefsTer6). The mutation was identified by whole-exome sequencing, and the parents were confirmed to be carriers. Western blot analysis in patient muscle and fibroblasts showed absence of NGLY1 protein expression. (In the article by Panneman et al. (2020), the frameshift is designated Gln613fs in table 1, but as Ile613Phefs*6 in the text. Rodenburg (2020) confirmed that Ile613Phefs*6 is correct.)
Enns, G. M., Shashi, V., Bainbridge, M., Gambello, M. J., Zahir, F. R., Bast, T., Crimian, R., Schoch, K., Platt, J., Cox, R., Bernstein, J. A., Scavina, M., and 22 others. Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway. Genet. Med. 16: 751-758, 2014. Note: Erratum: Genet. Med. 16: 568 only, 2014. [PubMed: 24651605] [Full Text: https://doi.org/10.1038/gim.2014.22]
Lam, C., Ferreira, C., Krasnewich, D., Toro, C., Latham, L., Zein, W. M., Lehky, T., Brewer, C., Baker, E. H., Thurm, A., Farmer, C. A., Rosenzweig, S. D., and 12 others. Prospective phenotyping of NGLY1-CDDG, the first congenital disorder of deglycosylation. Genet. Med. 19: 160-168, 2017. [PubMed: 27388694] [Full Text: https://doi.org/10.1038/gim.2016.75]
Lehrbach, N. J., Breen, P. C., Ruvkun, G. Protein sequence editing of SKN-1A/Nrf1 by peptide:N-glycanase controls proteasome gene expression. Cell 177: 737-750, 2019. [PubMed: 31002798] [Full Text: https://doi.org/10.1016/j.cell.2019.03.035]
Need, A. C., Shashi, V., Hitomi, Y., Schoch, K., Shianna, K. V., McDonald, M. T., Meisler, M. H., Goldstein, D. B. Clinical application of exome sequencing in undiagnosed genetic conditions. J. Med. Genet. 49: 353-361, 2012. [PubMed: 22581936] [Full Text: https://doi.org/10.1136/jmedgenet-2012-100819]
Panneman, D. M., Wortmann, S. B., Haaxma, C. A., van Hasselt, P. M., Wolf, N. I., Hendriks, Y., Kusters, B., van Emst-deVries, S., van de Westerlo, E., Koopman, W. J. H., Wintjes, L., van den Brandt, F., de Vries, M., Lefeber, D. J., Smeitink, J. A. M., Rodenburg, R. J. Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction. Clin. Genet. 97: 556-566, 2020. [PubMed: 31957011] [Full Text: https://doi.org/10.1111/cge.13706]
Rodenburg, R. Personal Communication. Nijmegen, The Netherlands 12/2/2020.
Shashi, V. Personal Communication. Durham, N.C. 6/11/2013.
Suzuki, T., Kwofie, M. A., Lennarz, W. J. Ngly1, a mouse gene encoding a deglycosylating enzyme implicated in proteasomal degradation: expression, genomic organization, and chromosomal mapping. Biochem. Biophys. Res. Commun. 304: 326-332, 2003. [PubMed: 12711318] [Full Text: https://doi.org/10.1016/s0006-291x(03)00600-4]
Suzuki, T., Park, H., Hollingsworth, N. M., Sternglanz, R., Lennarz, W. J. PNG1, a yeast gene encoding a highly conserved peptide:N-glycanase. J. Cell Biol. 149: 1039-1051, 2000. [PubMed: 10831608] [Full Text: https://doi.org/10.1083/jcb.149.5.1039]
Zhou, X., Zhao, G., Truglio, J. J., Wang, L., Li, G., Lennarz, W. J., Schindelin, H. Structural and biochemical studies of the C-terminal domain of mouse peptide-N-glycanase identify it as a mannose-binding module. Proc. Nat. Acad. Sci. 103: 17214-17219, 2006. [PubMed: 17088551] [Full Text: https://doi.org/10.1073/pnas.0602954103]