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NAGS gene

N-acetylglutamate synthase

Normal Function

The NAGS gene provides instructions for making the enzyme N-acetylglutamate synthase. This enzyme is needed for the urea cycle, a series of reactions that occurs in liver cells. The urea cycle breaks down excess nitrogen, which is made when protein is used by the body, into a compound called urea. Urea is removed from the body in urine. Removing the excess nitrogen prevents it from accumulating in the form of ammonia, which is toxic at high levels, especially to the brain.

N-acetylglutamate synthase controls the production of a compound called N-acetylglutamate in the mitochondria, the energy-producing centers in cells. N-acetylglutamate is necessary to turn on the enzyme carbamoyl phosphate synthetase I. This enzyme controls the first step of the urea cycle, in which excess nitrogen compounds are incorporated into the cycle to be broken down.

Health Conditions Related to Genetic Changes

N-acetylglutamate synthase deficiency

More than 40 NAGS gene mutations have been identified in people with N-acetylglutamate synthase deficiency, which is characterized by abnormally high levels of ammonia in the blood. This condition can cause extreme tiredness (lethargy), difficulty feeding, problems controlling breathing or body temperature, and seizures in infancy. Affected adults can have episodes of vomiting, confusion, headaches, or other neurological problems.

Most NAGS gene mutations that cause N-acetylglutamate synthase deficiency change single protein building blocks (amino acids) in the N-acetylglutamate synthase enzyme. It is thought that the abnormal enzyme cannot function properly. Other mutations result in production of an abnormally short N-acetylglutamate synthase enzyme or prevent any enzyme from being produced at all.

When the function of the N-acetylglutamate synthase enzyme is reduced or eliminated, N-acetylglutamate is produced in lower-than-normal amounts, or not at all. This shortage of N-acetylglutamate prevents carbamoyl phosphate synthetase I from being turned on, which prevents the urea cycle from starting. As a result, excess nitrogen is not converted to urea for removal, and ammonia accumulates in the blood. The buildup of ammonia damages tissues in the brain and causes the neurological problems and other signs and symptoms of N-acetylglutamate synthase deficiency.

More About This Health Condition

Other Names for This Gene

  • ARGA
  • MGC133025

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases


  • Caldovic L, Morizono H, Gracia Panglao M, Gallegos R, Yu X, Shi D, Malamy MH, Allewell NM, Tuchman M. Cloning and expression of the human N-acetylglutamate synthase gene. Biochem Biophys Res Commun. 2002 Dec 13;299(4):581-6. doi: 10.1016/s0006-291x(02)02696-7. Citation on PubMed
  • Caldovic L, Morizono H, Panglao MG, Cheng SF, Packman S, Tuchman M. Null mutations in the N-acetylglutamate synthase gene associated with acute neonatal disease and hyperammonemia. Hum Genet. 2003 Apr;112(4):364-8. doi: 10.1007/s00439-003-0909-5. Epub 2003 Feb 20. Citation on PubMed
  • Caldovic L, Morizono H, Panglao MG, Lopez GY, Shi D, Summar ML, Tuchman M. Late onset N-acetylglutamate synthase deficiency caused by hypomorphic alleles. Hum Mutat. 2005 Mar;25(3):293-8. doi: 10.1002/humu.20146. Citation on PubMed
  • Caldovic L, Tuchman M. N-acetylglutamate and its changing role through evolution. Biochem J. 2003 Jun 1;372(Pt 2):279-90. doi: 10.1042/BJ20030002. Citation on PubMed or Free article on PubMed Central
  • Cavicchi C, Chilleri C, Fioravanti A, Ferri L, Ripandelli F, Costa C, Calabresi P, Prontera P, Pochiero F, Pasquini E, Funghini S, la Marca G, Donati MA, Morrone A. Late-Onset N-Acetylglutamate Synthase Deficiency: Report of a Paradigmatic Adult Case Presenting with Headaches and Review of the Literature. Int J Mol Sci. 2018 Jan 24;19(2):345. doi: 10.3390/ijms19020345. Citation on PubMed or Free article on PubMed Central
  • Haberle J, Schmidt E, Pauli S, Kreuder JG, Plecko B, Galler A, Wermuth B, Harms E, Koch HG. Mutation analysis in patients with N-acetylglutamate synthase deficiency. Hum Mutat. 2003 Jun;21(6):593-7. doi: 10.1002/humu.10216. Citation on PubMed
  • Morizono H, Caldovic L, Shi D, Tuchman M. Mammalian N-acetylglutamate synthase. Mol Genet Metab. 2004 Apr;81 Suppl 1(Suppl 1):S4-11. doi: 10.1016/j.ymgme.2003.10.017. Citation on PubMed or Free article on PubMed Central
  • Sancho-Vaello E, Marco-Marin C, Gougeard N, Fernandez-Murga L, Rufenacht V, Mustedanagic M, Rubio V, Haberle J. Understanding N-Acetyl-L-Glutamate Synthase Deficiency: Mutational Spectrum, Impact of Clinical Mutations on Enzyme Functionality, and Structural Considerations. Hum Mutat. 2016 Jul;37(7):679-94. doi: 10.1002/humu.22995. Epub 2016 May 6. Citation on PubMed
  • Schmidt E, Nuoffer JM, Haberle J, Pauli S, Guffon N, Vianey-Saban C, Wermuth B, Koch HG. Identification of novel mutations of the human N-acetylglutamate synthase gene and their functional investigation by expression studies. Biochim Biophys Acta. 2005 Apr 15;1740(1):54-9. doi: 10.1016/j.bbadis.2005.02.006. Epub 2005 Feb 24. Citation on PubMed

The information on this site should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health.