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ASS1
argininosuccinate synthase 1
The ASS1 gene provides instructions for making argininosuccinate synthase 1, an enzyme vital for the urea cycle, which helps remove waste nitrogen from the body. The ASS1 gene encodes an enzyme called argininosuccinate synthase 1.
ASS1 is located on the long (q) arm of chromosome 9, at band 9q34.11. Arm ratio per GRCh38 - banding schematic.
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Overview
The ASS1 gene codes for the enzyme argininosuccinate synthase 1, which is a critical component of the urea cycle. This cycle is a series of biochemical reactions that primarily occur in liver cells, responsible for converting ammonia, a toxic waste product of protein metabolism, into urea, which can then be safely excreted from the body in urine. Maintaining a functional urea cycle is essential for preventing the accumulation of harmful nitrogenous compounds.
Variations within the ASS1 gene can affect the enzyme's function, potentially disrupting the urea cycle. Such disruptions can lead to the build-up of ammonia and other related compounds in the bloodstream, which can have significant health consequences.
What the gene does
The argininosuccinate synthase 1 enzyme, produced from the ASS1 gene, is instrumental in the third step of the urea cycle. This metabolic pathway is essential for the detoxification and removal of excess nitrogen generated from protein catabolism. Specifically, argininosuccinate synthase 1 catalyses the condensation reaction between citrulline and aspartate.
This reaction produces argininosuccinic acid, a crucial intermediate molecule in the urea cycle. Subsequent steps further process argininosuccinic acid to eventually form urea. By facilitating this key reaction, the ASS1 enzyme ensures the efficient conversion of ammonia into urea, preventing its accumulation to toxic levels in the body.
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Chromosome location
The ASS1 gene is located on chromosome 9, specifically at position 9q34.11. This means it is found on the long arm (q) of chromosome 9, within region 34, band 11. The precise location on the chromosome helps in mapping and understanding the genetic context of the gene.
Protein structure
The argininosuccinate synthase 1 protein consists of 412 amino acids. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the ASS1 gene can alter the production or function of the argininosuccinate synthase 1 enzyme. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions, and their impact depends on how they affect the enzyme's structure and activity. Pathogenic variants typically lead to a reduction or complete loss of enzyme function, impairing the urea cycle.
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.102T>G | p.Tyr34Ter | Pathogenic | ★★☆☆ | Citrullinemia type I |
c.1168G>C | p.Gly390Arg | Pathogenic | ★★☆☆ | Citrullinemia |
c.271A>C | p.Thr91Pro | Pathogenic | ★★☆☆ | Citrullinemia |
c.364-2A>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Citrullinemia type I |
c.537G>A | p.Trp179Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Citrullinemia type I |
c.571G>C | p.Glu191Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Citrullinemia |
c.631C>T | p.Gln211Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Citrullinemia |
c.773+1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Citrullinemia |
c.815G>A | p.Arg272His | Pathogenic | ★★☆☆ | Citrullinemia type I |
c.848del | p.Glu283fs | Pathogenic | ★★☆☆ | Citrullinemia type I |
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 ASS1 gene are known to cause Citrullinaemia type I. This is an autosomal recessive inherited disorder, meaning an individual must inherit two copies of a pathogenic variant (one from each parent) to develop the condition. Citrullinaemia type I is characterised by the impaired function of the argininosuccinate synthase 1 enzyme, leading to an accumulation of ammonia and citrulline in the blood.
Inheritance pattern
Conditions caused by pathogenic ASS1 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 ASS1 gene is recognised within several NHS Genomic Medicine Service national panels. It is listed with a 'green' status on panels including DDG2P, Foetal anomalies (R21), Hyperammonaemia, Intellectual disability, Likely inborn error of metabolism (R98), and Undiagnosed metabolic disorders. This indicates that there is strong evidence for the gene's association with these conditions and it is routinely considered in diagnostic testing.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the urea cycle?
The urea cycle is a series of biochemical reactions that occur primarily in the liver. Its main function is to convert toxic ammonia, a waste product of protein breakdown, into urea, which is then safely excreted from the body through urine.
How does the ASS1 gene relate to Citrullinaemia type I?
Pathogenic variants in the ASS1 gene lead to a deficiency in the argininosuccinate synthase 1 enzyme. This enzyme is crucial for a step in the urea cycle, and its impaired function causes the build-up of ammonia and citrulline, which characterises Citrullinaemia type I.
Is Citrullinaemia type I an inherited condition?
Yes, Citrullinaemia type I is an autosomal recessive inherited disorder. This means that a child must inherit two copies of a pathogenic variant in the ASS1 gene, one from each parent, to be affected by the condition.
References
- Diez-Fernandez C, Rüfenacht V, Häberle J. Mutations in the Human Argininosuccinate Synthetase (ASS1) Gene, Impact on Patients, Common Changes, and Structural Considerations. Human mutation. 2017. PMID: 28111830
- Kose E, Unal O, Bulbul S. Identification of three novel mutations in fourteen patients with citrullinemia type 1. Clinical biochemistry. 2017. PMID: 28132756
- Husson A, Brasse-Lagnel C, Fairand A. Argininosuccinate synthetase from the urea cycle to the citrulline-NO cycle. European journal of biochemistry. 2003. PMID: 12709047
- Gao HZ, Kobayashi K, Tabata A. Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients. Human mutation. 2003. PMID: 12815590
- Häberle J, Pauli S, Linnebank M. Structure of the human argininosuccinate synthetase gene and an improved system for molecular diagnostics in patients with classical and mild citrullinemia. Human genetics. 2002. PMID: 11941481
- Adam MP, Bick S, Mirzaa GM. Urea Cycle Disorders Overview. 1993. PMID: 20301396
- Adam MP, Bick S, Mirzaa GM. Citrullinemia Type I. 1993. PMID: 20301631