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ASL
argininosuccinate lyase
The *ASL* gene provides instructions for producing the argininosuccinate lyase enzyme, which plays a critical role in the body's urea cycle to process excess nitrogen. The *ASL* gene encodes the argininosuccinate lyase enzyme, essential for the urea cycle, which converts excess nitrogen into urea for excretion.
ASL is located on the long (q) arm of chromosome 7, at band 7q11.21. Arm ratio per GRCh38 - banding schematic.
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Overview
The *ASL* gene, or argininosuccinate lyase, is crucial for human metabolism, specifically within the urea cycle. This cycle is a series of biochemical reactions that occur primarily in the liver, responsible for converting harmful excess nitrogen, generated from protein breakdown, into urea for safe removal from the body via the kidneys.
Disruptions in the function of the enzyme produced by the *ASL* gene can lead to the accumulation of toxic nitrogenous compounds, impacting overall health and contributing to conditions such as argininosuccinic aciduria.
What the gene does
The argininosuccinate lyase enzyme, encoded by the *ASL* gene, is a key component of the urea cycle. Its primary role involves converting argininosuccinate into arginine and fumarate. Arginine is an amino acid that is subsequently broken down into urea for excretion and ornithine, which helps to restart the urea cycle.
This process is vital for preventing the build-up of ammonia, a toxic waste product of nitrogen metabolism. Beyond its central role in the urea cycle, the argininosuccinate lyase enzyme also facilitates the transport of arginine into cells throughout the body. Once inside cells, arginine is used to produce nitric oxide, a molecule important for regulating blood flow and blood pressure.
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Chromosome location
The *ASL* gene is located on chromosome 7, specifically at position 7q11.21. This chromosomal location indicates where the gene is situated within the human genome.
Protein structure
The argininosuccinate lyase protein consists of 464 amino acids. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the *ASL* gene can alter the function of the argininosuccinate lyase enzyme. Over 130 such variants have been identified, including deletions of short DNA sequences and substitutions of single amino acids within the protein. These genetic changes can impair the enzyme's ability to perform its metabolic role effectively.
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.104G>A | p.Trp35Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Argininosuccinate lyase deficiency |
c.1143+1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Argininosuccinate lyase deficiency |
c.348+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Argininosuccinate lyase deficiency |
c.425_426insAGCTCCCAGCT | p.Met143fs | Pathogenic/Likely pathogenic | ★★☆☆ | ASL-related disorder |
c.447-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Argininosuccinate lyase deficiency |
c.617G>T | p.Gly206Val | Pathogenic/Likely pathogenic | ★★☆☆ | Argininosuccinate lyase deficiency |
c.656-1G>A | - | Pathogenic | ★★☆☆ | Argininosuccinate lyase deficiency |
c.834-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Argininosuccinate lyase deficiency |
c.963C>A | p.Tyr321Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Argininosuccinate lyase deficiency |
c.974T>G | p.Leu325Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Argininosuccinate lyase deficiency |
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 *ASL* gene are known to cause argininosuccinic aciduria, an inherited metabolic disorder. This condition is characterised by the impaired function of the argininosuccinate lyase enzyme, leading to the accumulation of argininosuccinate and ammonia in the body. It is inherited in an autosomal recessive manner, meaning an individual must inherit two copies of a pathogenic variant (one from each parent) to be affected.
Inheritance pattern
Conditions caused by pathogenic ASL 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 *ASL* gene is part of several NHS England National Genomic Test Directory panels, indicating its clinical relevance within the UK healthcare system. It is included in panels for hyperammonaemia, intellectual disability, and early onset or syndromic epilepsy. It is also covered by panels for conditions such as ataxia and cerebellar anomalies (childhood onset), and likely inborn errors of metabolism, which collectively highlight its importance in diagnosing a range of paediatric and metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the function of the ASL gene?
The *ASL* gene provides instructions for the argininosuccinate lyase enzyme, which is a crucial part of the urea cycle. This cycle helps convert excess nitrogen from protein breakdown into urea for excretion from the body.
What condition is associated with ASL gene variants?
Pathogenic variants in the *ASL* gene are associated with argininosuccinic aciduria. This is an inherited metabolic disorder where the body cannot properly process nitrogenous waste, leading to its accumulation.
How is argininosuccinic aciduria inherited?
Argininosuccinic aciduria follows an autosomal recessive inheritance pattern. This means an individual must inherit two copies of a pathogenic *ASL* gene variant, one from each parent, to develop the condition.
References
- Erez A, Nagamani SC, Shchelochkov OA. Requirement of argininosuccinate lyase for systemic nitric oxide production. Nature medicine. 2011. PMID: 22081021
- Christodoulou J, Craig HJ, Walker DC. Deletion hotspot in the argininosuccinate lyase gene: association with topoisomerase II and DNA polymerase alpha sites. Human mutation. 2006. PMID: 16941645
- Al-Sayed M, Alahmed S, Alsmadi O. Identification of a common novel mutation in Saudi patients with argininosuccinic aciduria. Journal of inherited metabolic disease. 2005. PMID: 16435180
- Reid Sutton V, Pan Y, Davis EC. A mouse model of argininosuccinic aciduria: biochemical characterization. Molecular genetics and metabolism. 2003. PMID: 12559843
- Linnebank M, Tschiedel E, Häberle J. Argininosuccinate lyase (ASL) deficiency: mutation analysis in 27 patients and a completed structure of the human ASL gene. Human genetics. 2002. PMID: 12384776
- Tanaka T, Nagao M, Mori T. A novel stop codon mutation (X465Y) in the argininosuccinate lyase gene in a patient with argininosuccinic aciduria. The Tohoku journal of experimental medicine. 2002. PMID: 12512996
- Yu B, Thompson GD, Yip P. Mechanisms for intragenic complementation at the human argininosuccinate lyase locus. Biochemistry. 2001. PMID: 11747433
- Yu B, Howell PL. Intragenic complementation and the structure and function of argininosuccinate lyase. Cellular and molecular life sciences : CMLS. 2000. PMID: 11092456
- Turner MA, Simpson A, McInnes RR. Human argininosuccinate lyase: a structural basis for intragenic complementation. Proceedings of the National Academy of Sciences of the United States of America. 1997. PMID: 9256435
- Adam MP, Bick S, Mirzaa GM. Argininosuccinate Lyase Deficiency. 1993. PMID: 21290785