The ASS1 gene provides instructions for making an enzyme called argininosuccinate synthase 1. This enzyme participates in the urea cycle, which is a sequence of chemical reactions that takes place in liver cells. The urea cycle processes excess nitrogen that is generated as the body breaks down proteins. The excess nitrogen is used to make a compound called urea, which is excreted from the body in urine.
Argininosuccinate synthase 1 is involved in the third step of the urea cycle. This step combines two protein building blocks (amino acids), citrulline and aspartate, to form a molecule called argininosuccinic acid. A series of additional chemical reactions uses argininosuccinic acid to form urea.
Health Conditions Related to Genetic Changes
At least 118 mutations that cause type I citrullinemia have been identified in the ASS1 gene. Type I citrullinemia is a serious condition that usually appears in the first few days of life. It causes life-threatening health problems, including poor feeding, vomiting, seizures, and loss of consciousness. Most of the mutations involved in type I citrullinemia change single amino acids in the argininosuccinate synthase 1 enzyme. These genetic changes likely alter the structure of the enzyme, impairing its ability to attach to molecules such as citrulline and aspartate. A few mutations lead to the production of an abnormally short version of the enzyme that cannot effectively play its role in the urea cycle.
Defects in argininosuccinate synthase 1 disrupt the third step of the urea cycle, preventing the liver from processing excess nitrogen into urea. As a result, nitrogen (in the form of ammonia) and other byproducts of the urea cycle (such as citrulline) build up in the bloodstream. Ammonia is toxic, particularly to the nervous system. An accumulation of ammonia during the first few days of life leads to poor feeding, vomiting, seizures, and the other signs and symptoms of type I citrullinemia.More About This Health Condition
Other Names for This Gene
- argininosuccinate synthetase 1
- Citrulline-aspartate ligase
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
- Ah Mew N, Simpson KL, Gropman AL, Lanpher BC, Chapman KA, Summar ML. Urea Cycle Disorders Overview. 2003 Apr 29 [updated 2017 Jun 22]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from http://www.ncbi.nlm.nih.gov/books/NBK1217/ Citation on PubMed
- Diez-Fernandez C, Rufenacht V, Haberle J. Mutations in the Human Argininosuccinate Synthetase (ASS1) Gene, Impact on Patients, Common Changes, and Structural Considerations. Hum Mutat. 2017 May;38(5):471-484. doi: 10.1002/humu.23184. Epub 2017 Feb 15. Citation on PubMed
- Gao HZ, Kobayashi K, Tabata A, Tsuge H, Iijima M, Yasuda T, Kalkanoglu HS, Dursun A, Tokatli A, Coskun T, Trefz FK, Skladal D, Mandel H, Seidel J, Kodama S, Shirane S, Ichida T, Makino S, Yoshino M, Kang JH, Mizuguchi M, Barshop BA, Fuchinoue S, Seneca S, Zeesman S, Knerr I, Rodes M, Wasant P, Yoshida I, De Meirleir L, Abdul Jalil M, Begum L, Horiuchi M, Katunuma N, Nakagawa S, Saheki T. Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients. Hum Mutat. 2003 Jul;22(1):24-34. doi: 10.1002/humu.10230. Citation on PubMed
- Haberle J, Pauli S, Linnebank M, Kleijer WJ, Bakker HD, Wanders RJ, Harms E, Koch HG. Structure of the human argininosuccinate synthetase gene and an improved system for molecular diagnostics in patients with classical and mild citrullinemia. Hum Genet. 2002 Apr;110(4):327-33. doi: 10.1007/s00439-002-0686-6. Epub 2002 Mar 1. Citation on PubMed
- Husson A, Brasse-Lagnel C, Fairand A, Renouf S, Lavoinne A. Argininosuccinate synthetase from the urea cycle to the citrulline-NO cycle. Eur J Biochem. 2003 May;270(9):1887-99. doi: 10.1046/j.1432-1033.2003.03559.x. Citation on PubMed
- Kose E, Unal O, Bulbul S, Gunduz M, Haberle J, Arslan N. Identification of three novel mutations in fourteen patients with citrullinemia type 1. Clin Biochem. 2017 Aug;50(12):686-689. doi: 10.1016/j.clinbiochem.2017.01.011. Epub 2017 Jan 27. Citation on PubMed
- Quinonez SC, Lee KN. Citrullinemia Type I. 2004 Jul 7 [updated 2022 Aug 18]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from http://www.ncbi.nlm.nih.gov/books/NBK1458/ Citation on PubMed