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CTPS1
CTP synthase 1
CTPS1 is located on the short (p) arm of chromosome 1, at band 1p34.2. Arm ratio per GRCh38 - banding schematic.
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Overview
CTPS1 is located on chromosome 1 and encodes CTP synthase 1, a metabolic enzyme central to pyrimidine nucleotide biosynthesis. The enzyme converts UTP and glutamine into CTP, using ATP as an energy source. This reaction is rate-limiting for the synthesis of cytidine-containing nucleotides, which are indispensable for nucleic acid production and cellular replication. Tissues with rapid cell turnover, particularly lymphocytes and other immune cells, require robust CTP synthase activity to support their proliferative demands. Pathogenic variants in CTPS1 can disrupt nucleotide homeostasis, leading to impaired immune function. The gene is inherited in an autosomal recessive pattern, meaning two altered copies are necessary for clinical manifestations to emerge.
What the gene does
CTP synthase 1 catalyses the ATP-dependent conversion of UTP to CTP, incorporating an amide group from glutamine in the process. This enzymatic step is the committed reaction in the de novo pathway for CTP biosynthesis, making CTPS1 essential for maintaining balanced nucleotide pools. The protein functions as a homotetramer, with each subunit contributing to the active site configuration. CTP is required not only for RNA synthesis but also serves as the precursor for deoxycytidine triphosphate (dCTP), a DNA building block generated through ribonucleotide reductase activity. Lymphocytes undergoing clonal expansion during immune responses exhibit particularly high CTPS1 expression, reflecting their need for rapid nucleotide production. The enzyme's activity is tightly regulated through feedback inhibition by CTP itself, preventing excessive accumulation of the product. CTPS1 also assembles into linear filamentous structures called cytoophidia under certain metabolic conditions, though the functional significance of these filaments remains an area of ongoing research.
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Chromosome location
CTPS1 is located on the short arm of chromosome 1 at position 34.2 (1p34.2). The gene spans approximately 36 kilobases of genomic DNA and contains 17 exons. The transcript encodes a protein of 591 amino acids with a molecular weight of approximately 67 kilodaltons. This chromosomal region is not known to harbour other genes directly involved in nucleotide metabolism, making CTPS1 the principal CTP synthase gene expressed in many cell types.
Protein structure
The CTPS1 protein contains a glutamine amidotransferase type-1 domain spanning amino acids 300 to 554, which is responsible for the glutaminase activity that liberates ammonia from glutamine for CTP synthesis. This domain adopts a characteristic fold that positions catalytic residues to cleave the amide bond in glutamine. The C-terminal region from amino acids 562 to 591 is predicted to be disordered, lacking stable secondary structure. Disordered regions often participate in regulatory interactions or post-translational modification events, though the specific role of this segment in CTPS1 function has not been fully characterised. The N-terminal portion of the protein, upstream of the amidotransferase domain, contributes to UTP binding and tetramer assembly, forming the structural framework required for catalytic activity.
Key variants
Pathogenic variants in CTPS1 are rare and typically consist of missense changes that reduce enzymatic activity or destabilise the protein tetramer. Loss-of-function variants impair the cell's ability to generate CTP at physiological rates, creating a bottleneck in nucleotide biosynthesis. Because the gene follows autosomal recessive inheritance, carriers with one altered copy generally remain asymptomatic, while individuals with biallelic pathogenic variants may present with immunodeficiency phenotypes. Variant classification relies on functional assays measuring CTP synthase activity, protein expression levels, and clinical correlation in affected individuals.
Sample of pathogenic variants
1 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.1692-1G>C | - | Pathogenic | ★★☆☆ | CTPS1-related disorder |
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
Biallelic pathogenic variants in CTPS1 have been associated with primary immunodeficiency characterised by recurrent infections, particularly affecting the respiratory and gastrointestinal tracts. Affected individuals may exhibit reduced lymphocyte proliferation in response to mitogenic stimuli, reflecting the inability to meet nucleotide demands during clonal expansion. Some reports describe viral susceptibility, consistent with the role of CTPS1 in supporting T-cell and B-cell responses. The severity of clinical features can vary depending on the residual enzymatic activity retained by the variant protein, with complete loss of function typically producing more pronounced immune dysfunction.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic CTPS1 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
CTPS1 is included on the NHS Genomic Medicine Service PanelApp as a green gene in the Primary immunodeficiency or monogenic inflammatory bowel disease panel (version R15), reflecting its established role in immune system disorders. It also appears on the COVID-19 research panel, where genes influencing immune response and viral susceptibility have been catalogued to support pandemic research efforts. Green classification indicates strong evidence supporting the gene-disease relationship, meaning variants identified through NHS genomic testing are considered reportable when they meet pathogenicity criteria.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
How is CTPS1 deficiency inherited?
CTPS1-related conditions follow autosomal recessive inheritance, meaning an individual must inherit two altered gene copies (one from each parent) to develop clinical features. Carriers with one pathogenic variant are typically unaffected.
What types of infections are most common in CTPS1 deficiency?
Individuals with biallelic CTPS1 variants often experience recurrent bacterial and viral infections, particularly affecting the respiratory system and gastrointestinal tract. The specific infection spectrum reflects impaired lymphocyte function.
Can CTPS1 variants be detected through carrier screening?
Yes, carrier screening panels that include genes associated with autosomal recessive immunodeficiency can identify CTPS1 variants. Identifying carrier status in prospective parents allows for informed reproductive planning and consideration of prenatal or preimplantation genetic testing.