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ASS1
argininosuccinate synthase 1
The ASS1 gene provides instructions for producing argininosuccinate synthase 1, an enzyme critical for the urea cycle, which processes nitrogen waste in the body. The ASS1 gene is essential for producing the argininosuccinate synthase 1 enzyme, a key component of the urea cycle.
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, also known as argininosuccinate synthase 1, plays a central role in human metabolism by encoding an enzyme involved in the urea cycle. This biochemical pathway is crucial for detoxification, specifically in processing and removing excess nitrogen generated from the breakdown of proteins in the body.
Disruptions to the normal function of the ASS1 gene can have significant health implications, primarily leading to the accumulation of harmful substances if the urea cycle is impaired. Understanding this gene is important for diagnosing and managing associated metabolic disorders.
What the gene does
The ASS1 gene provides the blueprint for argininosuccinate synthase 1, an enzyme that operates within the urea cycle in liver cells. This cycle is a sequence of biochemical reactions designed to manage excess nitrogen, which is produced when the body metabolises proteins. The ultimate goal of the urea cycle is to convert this nitrogen into urea, a less toxic compound that can be excreted from the body via urine.
Specifically, argininosuccinate synthase 1 facilitates the third step of the urea cycle. In this step, it combines two amino acids, citrulline and aspartate, to form argininosuccinic acid. This intermediate product then undergoes further reactions within the cycle to complete the formation of urea, thereby ensuring the efficient removal of nitrogenous waste from the body.
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Chromosome location
The ASS1 gene is situated on the long arm of chromosome 9, specifically at position 9q34.11. This genomic location indicates its precise address within the human genome, helping researchers and clinicians pinpoint its position for study and diagnosis.
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
Genetic variants in the ASS1 gene can alter the function of the argininosuccinate synthase 1 enzyme, potentially impairing the urea cycle. These variants include changes that may affect the protein's structure or its ability to catalyse the necessary biochemical reaction. The spectrum of variants ranges from benign to pathogenic, with some leading to significant health conditions.
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.1088G>T | p.Arg363Leu | Pathogenic/Likely 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 type I |
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 |
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 within the ASS1 gene are primarily associated with Citrullinaemia type I. This inherited metabolic disorder results from a deficiency in the argininosuccinate synthase 1 enzyme, leading to a build-up of citrulline and ammonia in the blood. The condition typically presents in early life and can cause severe symptoms if not managed appropriately.
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 in the UK by NHS England's Genomic Medicine Service, being included on several PanelApp panels. These include those for Developmental and epileptic encephalopathy (DDG2P), Foetal anomalies, Hyperammonaemia, Intellectual disability, Likely inborn error of metabolism, and Undiagnosed metabolic disorders, indicating its clinical relevance in diagnostic pathways.
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 critical biochemical pathway that occurs primarily in the liver. Its main function is to convert excess nitrogen, produced from protein breakdown, into urea, which is then excreted from the body in urine, thus preventing toxic accumulation of ammonia.
What is Citrullinaemia type I?
Citrullinaemia type I is an inherited metabolic disorder caused by a deficiency in the argininosuccinate synthase 1 enzyme, encoded by the ASS1 gene. This deficiency impairs the urea cycle, leading to high levels of ammonia and citrulline in the blood, which can be toxic.
How is Citrullinaemia type I inherited?
Citrullinaemia type I follows an autosomal recessive inheritance pattern. This means an individual must inherit two copies of the altered ASS1 gene, one from each parent, to develop the condition. Parents who each carry one copy of the altered gene are typically unaffected but are carriers.
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