On this page
NGLY1
N-glycanase 1
The NGLY1 gene provides instructions for N-glycanase 1, an enzyme critical for removing sugar chains from misfolded proteins, a process known as deglycosylation. NGLY1 codes for N-glycanase 1, an enzyme essential in the cellular process of deglycosylation, where it removes N-glycans from specific proteins.
NGLY1 is located on the short (p) arm of chromosome 3, at band 3p24.2. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 3 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The NGLY1 gene is responsible for producing an enzyme called N-glycanase 1. This enzyme plays a key role in a cellular process known as deglycosylation. Specifically, it removes N-glycan sugar chains from proteins, a function important for maintaining cellular health and protein quality control.
Disruptions in the NGLY1 gene's function are associated with a range of health issues, particularly NGLY1-congenital disorder of deglycosylation (NGLY1-CDDG).
What the gene does
The primary function of the NGLY1 gene product, N-glycanase 1, is to facilitate deglycosylation, a process where chains of sugar molecules (glycans) are removed from proteins. More specifically, N-glycanase 1 targets and removes N-glycans from proteins that have become misfolded. This enzymatic action is considered fundamental for the efficient breakdown and degradation of these abnormal proteins within the cell. By ensuring the proper disposal of misfolded proteins, NGLY1 contributes to cellular proteostasis and overall cellular function.
Video: Genetics 101
Chromosome location
The NGLY1 gene is situated on the short arm of chromosome 3. Its specific location is designated as 3p24.2. This genomic address helps researchers and clinicians pinpoint the gene's exact position within the human genome.
Protein structure
The N-glycanase 1 protein comprises 654 amino acids. It features several distinct regions and domains crucial for its function. These include a PUB domain located from amino acids 30-91, a Disordered region spanning amino acids 112-163, and a PAW domain found at amino acids 454-654. Each of these structural elements contributes to the protein's overall shape and enzymatic activity.
Key variants
Genetic variations within the NGLY1 gene can alter the function or production of the N-glycanase 1 enzyme. These changes can range from single nucleotide alterations to larger deletions or insertions, potentially impacting the protein's ability to perform its crucial deglycosylation role.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1107G>A | p.Trp369Ter | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.1168C>T | p.Arg390Ter | Pathogenic | ★★☆☆ | Congenital disorder of deglycosylation 1 |
c.1192del | p.Glu397_Val398insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital disorder of deglycosylation |
c.1722_1723insCA | p.Thr575fs | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital disorder of deglycosylation 1 |
c.1756C>T | p.Arg586Ter | Pathogenic | ★★☆☆ | Congenital disorder of deglycosylation |
c.1764_1785del | p.Asp588fs | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital disorder of deglycosylation 1 |
c.177del | p.Ala60fs | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital disorder of deglycosylation |
c.571C>T | p.Gln191Ter | Pathogenic | ★★☆☆ | Congenital disorder of deglycosylation 1 |
c.841del | p.His281fs | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital disorder of deglycosylation 1 |
c.904_905del | p.Leu302fs | Pathogenic | ★★☆☆ | Congenital disorder of deglycosylation |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the NGLY1 gene are known to cause NGLY1-congenital disorder of deglycosylation (NGLY1-CDDG). This condition can manifest with diverse symptoms affecting multiple bodily systems, including developmental delay, movement abnormalities, liver dysfunction, and issues with eye health, such as reduced or absent tear production.
No disease links recorded for this gene in our reference set.
UK clinical status
The NGLY1 gene is included in several panels within the NHS Genomic Medicine Service's PanelApp. It is covered under 'Congenital disorders of glycosylation', 'DDG2P', 'Dystonia, chorea or related movement disorder, childhood onset' (R57), 'Early onset or syndromic epilepsy', 'Intellectual disability', and 'Likely inborn error of metabolism' (R98) and 'Undiagnosed metabolic disorders', all categorised as green, indicating strong evidence for gene-disease association.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the NGLY1 gene do?
The NGLY1 gene provides instructions for making the N-glycanase 1 enzyme. This enzyme is vital for deglycosylation, the process of removing sugar chains from misfolded proteins to help in their degradation.
What is NGLY1-CDDG?
NGLY1-CDDG, or NGLY1-congenital disorder of deglycosylation, is a genetic condition caused by pathogenic variants in the NGLY1 gene. It affects multiple body systems, leading to symptoms like developmental delay, movement disorders, and liver problems.
How is NGLY1-CDDG diagnosed?
Diagnosis of NGLY1-CDDG typically involves genetic testing to identify pathogenic variants in the NGLY1 gene. Clinical evaluation of symptoms and other laboratory tests may also be part of the diagnostic process.
References
- Suzuki T, Huang C, Fujihira H. The cytoplasmic peptide:N-glycanase (NGLY1) - Structure, expression and cellular functions. Gene. 2016. PMID: 26611529
- Huang C, Harada Y, Hosomi A. Endo-β-N-acetylglucosaminidase forms N-GlcNAc protein aggregates during ER-associated degradation in Ngly1-defective cells. Proceedings of the National Academy of Sciences of the United States of America. 2015. PMID: 25605922
- He P, Grotzke JE, Ng BG. A congenital disorder of deglycosylation: Biochemical characterization of N-glycanase 1 deficiency in patient fibroblasts. Glycobiology. 2015. PMID: 25900930
- Enns GM, Shashi V, Bainbridge M. Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway. Genetics in medicine : official journal of the American College of Medical Genetics. 2014. PMID: 24651605