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CPS1
carbamoyl-phosphate synthase 1
The CPS1 gene provides instructions for producing carbamoyl-phosphate synthase 1, an enzyme critical for the first step of the urea cycle in the body's nitrogen waste removal pathway. CPS1 is central to metabolising excess nitrogen, converting it into urea for excretion and preventing toxic ammonia build-up.
CPS1 is located on the long (q) arm of chromosome 2, at band 2q34. Arm ratio per GRCh38 - banding schematic.
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Overview
The CPS1 gene encodes carbamoyl-phosphate synthase 1, an enzyme that plays a crucial role in the urea cycle. This metabolic pathway primarily functions in the liver to process and eliminate excess nitrogen, which is generated when proteins are broken down and used by the body. Without proper function, toxic levels of ammonia can accumulate.
The urea cycle converts nitrogen into urea, a less toxic compound that the kidneys can excrete. CPS1 initiates this process, making it an essential component for maintaining metabolic balance and preventing harmful ammonia build-up.
What the gene does
Carbamoyl-phosphate synthase 1, encoded by the CPS1 gene, is responsible for catalysing the first committed step of the urea cycle. This enzyme combines ammonia, bicarbonate, and two molecules of ATP to form carbamoyl phosphate. This reaction is vital for incorporating surplus nitrogen compounds into the urea cycle.
Within the cell, this enzyme localises to the mitochondria, the cell's powerhouses, where the initial stages of the urea cycle take place. The efficient functioning of carbamoyl-phosphate synthase 1 is directly linked to the body's capacity to detoxify ammonia, highlighting its significance in overall metabolic health.
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Chromosome location
The CPS1 gene is situated on chromosome 2, specifically at position 2q34. This genomic location refers to the long (q) arm of chromosome 2, within band 34. The precise localisation on the chromosome is significant for understanding its inheritance patterns and potential genetic linkages.
Protein structure
The carbamoyl-phosphate synthase 1 protein comprises 1500 amino acids and features several distinct domains. These include an Anthranilate phosphoribosyltransferase homolog region (amino acids 39-218), a Glutamine amidotransferase type-1 domain (amino acids 219-404), and two ATP-grasp domains (ATP-grasp 1 at amino acids 551-743 and ATP-grasp 2 at amino acids 1093-1284). Additionally, a MGS-like domain is present towards the C-terminus (amino acids 1355-1500), contributing to the enzyme's overall structure and function.
Key variants
Variants within the CPS1 gene can alter the function or production of the carbamoyl-phosphate synthase 1 enzyme. These genetic changes may lead to an enzyme that is shorter than normal, has an incorrect shape, or is not produced at all. The specific impact of a variant can vary, influencing the efficiency of the urea cycle and the body's ability to manage nitrogen waste.
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.1363_1364del | p.Glu455fs | Pathogenic | ★★☆☆ | Congenital hyperammonemia, type I |
c.1759C>T | p.Arg587Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital hyperammonemia, type I |
c.2499G>A | p.Trp833Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Pulmonary hypertension, neonatal, susceptibility to |
c.2720del | p.Ala907fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pulmonary hypertension, neonatal, susceptibility to |
c.2820G>A | p.Trp940Ter | Pathogenic | ★★☆☆ | Congenital hyperammonemia, type I |
c.2920del | p.His974fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pulmonary hypertension, neonatal, susceptibility to |
c.3136C>T | p.Gln1046Ter | Pathogenic | ★★☆☆ | Pulmonary hypertension, neonatal, susceptibility to |
c.3910_3913del | p.Asp1304fs | Pathogenic | ★★☆☆ | Congenital hyperammonemia, type I |
c.4404+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital hyperammonemia, type I |
c.622-24A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital hyperammonemia, 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 CPS1 gene are primarily associated with Carbamoyl phosphate synthetase I deficiency. This inherited metabolic disorder is characterised by the body's impaired ability to remove ammonia, leading to its accumulation. Elevated ammonia levels can be toxic, particularly to the brain, and can result in severe health complications. Furthermore, a common alteration in the CPS1 gene has been linked to an increased risk of circulatory problems in neonates and individuals who have undergone bone marrow transplants.
Inheritance pattern
Conditions caused by pathogenic CPS1 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 CPS1 gene is included in several NHS Genomic Medicine Service national test panels. It is listed as 'green' on the DDG2P panel and is relevant for conditions such as Hyperammonaemia and Intellectual disability. It is also found on panels for Likely inborn error of metabolism (R98) and Undiagnosed metabolic disorders, indicating its established clinical significance within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the CPS1 gene?
The CPS1 gene provides instructions for carbamoyl-phosphate synthase 1, an enzyme that initiates the urea cycle. This cycle is essential for processing excess nitrogen and converting it into urea for excretion, preventing the build-up of toxic ammonia.
What health conditions are associated with variants in the CPS1 gene?
Variants in the CPS1 gene are mainly associated with Carbamoyl phosphate synthetase I deficiency, a condition where the body struggles to eliminate ammonia. An altered CPS1 gene has also been linked to an increased risk of circulatory issues in newborns and bone marrow transplant recipients.
How does CPS1 deficiency affect the body?
CPS1 deficiency impairs the urea cycle's ability to process nitrogen, leading to elevated and potentially dangerous levels of ammonia in the blood. This hyperammonaemia can be particularly harmful to the brain and can cause significant health problems.
References
- Summar ML, Gainer JV, Pretorius M. Relationship between carbamoyl-phosphate synthetase genotype and systemic vascular function. Hypertension (Dallas, Tex. : 1979). 2004. PMID: 14718356
- Wakutani Y, Nakayasu H, Takeshima T. Mutational analysis of carbamoylphosphate synthetase I deficiency in three Japanese patients. Journal of inherited metabolic disease. 2004. PMID: 15617192
- Häberle J, Schmidt E, Pauli S. Gene structure of human carbamylphosphate synthetase 1 and novel mutations in patients with neonatal onset. Human mutation. 2003. PMID: 12655559
- Summar ML, Hall LD, Eeds AM. Characterization of genomic structure and polymorphisms in the human carbamyl phosphate synthetase I gene. Gene. 2003. PMID: 12853138
- Funghini S, Donati MA, Pasquini E. Structural organization of the human carbamyl phosphate synthetase I gene (CPS1) and identification of two novel genetic lesions. Human mutation. 2003. PMID: 12955727
- Rapp B, Häberle J, Linnebank M. Genetic analysis of carbamoylphosphate synthetase I and ornithine transcarbamylase deficiency using fibroblasts. European journal of pediatrics. 2001. PMID: 11388595
- Pearson DL, Dawling S, Walsh WF. Neonatal pulmonary hypertension--urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function. The New England journal of medicine. 2001. PMID: 11407344
- Aoshima T, Kajita M, Sekido Y. Carbamoyl phosphate synthetase I deficiency: molecular genetic findings and prenatal diagnosis. Prenatal diagnosis. 2001. PMID: 11536261
- Finckh U, Kohlschütter A, Schäfer H. Prenatal diagnosis of carbamoyl phosphate synthetase I deficiency by identification of a missense mutation in CPS1. Human mutation. 1998. PMID: 9711878