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ASL
argininosuccinate lyase
The ASL gene encodes the argininosuccinate lyase enzyme, a critical component of the urea cycle responsible for processing excess nitrogen, and plays a role in nitric oxide synthesis. The ASL gene provides instructions for creating the argininosuccinate lyase enzyme.
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, also known as argininosuccinate lyase, provides the genetic blueprint for an enzyme with the same name. This enzyme is vital for two key biological processes: the urea cycle and nitric oxide synthesis. Its primary role in the urea cycle involves managing nitrogen waste in the body.
Dysfunction of the ASL gene can lead to conditions such as argininosuccinic aciduria, which is an inherited metabolic disorder. Understanding the ASL gene is crucial for diagnosing and managing related health conditions.
What the gene does
The argininosuccinate lyase enzyme, produced from the ASL gene, is primarily active in the urea cycle within liver cells. The urea cycle is a series of biochemical reactions that process surplus nitrogen, generated from protein breakdown, into urea for excretion by the kidneys. This process prevents the accumulation of toxic ammonia in the body.
Specifically, the argininosuccinate lyase enzyme catalyses a reaction where arginine, an amino acid, is produced from argininosuccinate. Arginine is subsequently broken down into urea, which is excreted, and ornithine, which re-enters the urea cycle. Beyond the urea cycle, this enzyme also facilitates the transport of arginine into cells throughout the body 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 at position 7q11.21. This specific band on the long arm of chromosome 7 is where the gene resides 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
Genetic variations within the ASL gene can impact the function of the argininosuccinate lyase enzyme. Over 130 different variants have been identified that are associated with health conditions. These variants can involve deletions of DNA sequences or substitutions of single amino acids within the enzyme, altering its structure and activity.
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 | ★★☆☆ | Argininosuccinate lyase deficiency |
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 primarily associated with argininosuccinic aciduria. This is an inherited metabolic disorder that results from the body's inability to properly break down and remove excess nitrogen, leading to the build-up of harmful substances. The severity and presentation of argininosuccinic aciduria can vary significantly among affected individuals.
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 included in several UK NHS national genomic testing panels, reflecting its importance in diagnosing a range of conditions. These include panels for ataxia and cerebellar anomalies (childhood onset), early onset or syndromic epilepsy, intellectual disability, and hyperammonaemia. It is also part of panels for likely inborn errors of metabolism and undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the ASL gene?
The ASL gene provides instructions for the argininosuccinate lyase enzyme, which is crucial for the urea cycle to process excess nitrogen and for producing nitric oxide, a molecule that regulates blood flow.
Which condition is most commonly associated with ASL gene variants?
Variants in the ASL gene are most commonly associated with argininosuccinic aciduria, an inherited metabolic disorder characterised by the accumulation of harmful nitrogen-containing compounds in the body.
How does the ASL gene contribute to nitric oxide production?
The argininosuccinate lyase enzyme, encoded by the ASL gene, facilitates the transport of the amino acid arginine into cells. Arginine is then used to synthesise nitric oxide, which is important for vascular health and blood pressure regulation.
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