On this page
NAGS
N-acetylglutamate synthase
The NAGS gene provides instructions for creating N-acetylglutamate synthase, an enzyme critical for the urea cycle, which processes excess nitrogen to prevent toxic ammonia accumulation in the body. N-acetylglutamate synthase plays a vital role in the body's detoxification system, specifically within the urea cycle.
NAGS is located on the long (q) arm of chromosome 17, at band 17q21.31. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 17 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The NAGS gene, or N-acetylglutamate synthase, is fundamental to human metabolism. It provides the genetic blueprint for an enzyme crucial in the urea cycle, a biochemical pathway that converts ammonia, a toxic waste product of protein metabolism, into urea for safe excretion from the body. Deficiencies in this enzyme can lead to serious health implications due to ammonia accumulation.
What the gene does
The NAGS gene encodes the enzyme N-acetylglutamate synthase, which is responsible for producing N-acetylglutamate within the mitochondria, the energy-generating organelles of cells. N-acetylglutamate acts as an essential activator for carbamoyl phosphate synthetase I, the enzyme that initiates the urea cycle. This initial step is crucial for incorporating nitrogen compounds into the cycle, allowing them to be broken down. Without properly functioning N-acetylglutamate synthase, the urea cycle cannot operate effectively, leading to a build-up of ammonia, which is particularly harmful to the brain.
Video: Genetics 101
Chromosome location
The NAGS gene is located on chromosome 17 at position 17q21.31. This specific genomic location houses the instructions for synthesising the N-acetylglutamate synthase protein, which consists of 534 amino acids.
Protein structure
The N-acetylglutamate synthase protein comprises several distinct regions that contribute to its function. It features an Amino-acid kinase domain (AAK) spanning amino acids 19-376, which is crucial for its catalytic activity. A Disordered region is found between amino acids 19-99, and a key N-acetyltransferase domain is located from amino acids 375-526, essential for the synthesis of N-acetylglutamate.
Key variants
Genetic variations within the NAGS gene can alter the function of the N-acetylglutamate synthase enzyme. Over 40 different pathogenic mutations in the NAGS gene have been identified, primarily associated with N-acetylglutamate synthase deficiency. These variants can lead to a range of clinical presentations due to impaired enzyme activity.
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.1097-1G>C | - | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.1097-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperammonemia, type III |
c.1108del | p.Leu370fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperammonemia, type III |
c.1228T>C | p.Ser410Pro | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperammonemia, type III |
c.1272C>G | p.Tyr424Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperammonemia, type III |
c.1292C>T | p.Thr431Ile | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.1313dup | p.Thr439fs | Pathogenic | ★★☆☆ | Hyperammonemia, type III |
c.310del | p.Arg104fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperammonemia, type III |
c.46del | p.Ala16fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperammonemia, type III |
c.654dup | p.Gly219fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperammonemia, type III |
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 NAGS gene are primarily associated with N-acetylglutamate synthase deficiency. This condition is characterised by abnormally high levels of ammonia in the blood, known as hyperammonaemia. Symptoms can vary but often include lethargy, feeding difficulties, and issues with respiratory or temperature control in infants, while adults may experience episodes of vomiting, confusion, and headaches.
Inheritance pattern
Conditions caused by pathogenic NAGS variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The NAGS gene is included in several expert-curated panels within the UK National Health Service (NHS) Genomic Medicine Service. It is listed on the DDG2P panel, the Hyperammonaemia panel, the Likely inborn error of metabolism panel (R98), and the Undiagnosed metabolic disorders panel, all with a 'green' status indicating strong evidence for gene-disease association.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the NAGS gene?
The NAGS gene provides instructions for making the N-acetylglutamate synthase enzyme, which is essential for activating the first step of the urea cycle. This cycle helps convert toxic ammonia into urea for excretion.
What happens if the NAGS gene doesn't work correctly?
If the NAGS gene does not function properly, it can lead to N-acetylglutamate synthase deficiency. This results in the accumulation of high levels of ammonia in the blood, which can be toxic, particularly to the brain.
What are the typical symptoms of N-acetylglutamate synthase deficiency?
Symptoms of N-acetylglutamate synthase deficiency can include extreme tiredness, difficulty feeding, problems controlling breathing or body temperature, and seizures in infants. Adults might experience vomiting, confusion, and headaches.
References
- Cavicchi C, Chilleri C, Fioravanti A. Late-Onset N-Acetylglutamate Synthase Deficiency: Report of a Paradigmatic Adult Case Presenting with Headaches and Review of the Literature. International journal of molecular sciences. 2018. PMID: 29364180
- Sancho-Vaello E, Marco-Marín C, Gougeard N. Understanding N-Acetyl-L-Glutamate Synthase Deficiency: Mutational Spectrum, Impact of Clinical Mutations on Enzyme Functionality, and Structural Considerations. Human mutation. 2016. PMID: 27037498
- Caldovic L, Morizono H, Panglao MG. Late onset N-acetylglutamate synthase deficiency caused by hypomorphic alleles. Human mutation. 2005. PMID: 15714518
- Schmidt E, Nuoffer JM, Häberle J. Identification of novel mutations of the human N-acetylglutamate synthase gene and their functional investigation by expression studies. Biochimica et biophysica acta. 2005. PMID: 15878741
- Morizono H, Caldovic L, Shi D. Mammalian N-acetylglutamate synthase. Molecular genetics and metabolism. 2004. PMID: 15050968
- Caldovic L, Morizono H, Panglao MG. Null mutations in the N-acetylglutamate synthase gene associated with acute neonatal disease and hyperammonemia. Human genetics. 2003. PMID: 12594532
- Caldovic L, Tuchman M. N-acetylglutamate and its changing role through evolution. The Biochemical journal. 2003. PMID: 12633501
- Häberle J, Schmidt E, Pauli S. Mutation analysis in patients with N-acetylglutamate synthase deficiency. Human mutation. 2003. PMID: 12754705
- Caldovic L, Morizono H, Gracia Panglao M. Cloning and expression of the human N-acetylglutamate synthase gene. Biochemical and biophysical research communications. 2002. PMID: 12459178