Alternative titles; symbols
HGNC Approved Gene Symbol: CTPS1
Cytogenetic location: 1p34.2 Genomic coordinates (GRCh38): 1:40,979,696-41,012,565 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p34.2 | Immunodeficiency 24 | 615897 | Autosomal recessive | 3 |
The catalytic conversion of UTP to CTP is accomplished by the enzyme cytidine-5-prime-triphosphate synthetase (UTP:L-glutamine amido ligase; EC 6.3.4.2). The enzyme, encoded by the CTPS1 gene, is important in the biosynthesis of phospholipids and nucleic acids, and plays a key role in cell growth, development, and tumorigenesis (summary by Thomas et al., 1989).
Thomas et al. (1989) isolated a cDNA clone of the CTP synthetase gene from a rat liver cDNA library. It is a key regulatory enzyme in pyrimidine biosynthesis. These authors isolated both cDNA and genomic gene sequences from the rat and Chinese hamster.
Yamauchi et al. (1990) cloned the CTPS gene and showed that the open reading frame encodes 591 amino acids that have a striking degree of similarity to the structural gene in E. coli.
Martin et al. (2014) found that CTPS1 mRNA was comparable among different normal tissues, except for T cells in which CTPS1 expression was strongly upregulated after cell activation in response to T cell receptor (TCR) CD3 and CD28 costimulation. In lysates from resting nonactivated T cells, CTPS1 protein was almost undetectable.
Yamauchi et al. (1991) determined that the CTPS1 genomic sequence is distributed in 19 exons covering about 35 kb.
Yamauchi et al. (1991) assigned the structural CTPS1 gene to chromosome 1p by study of a panel of human/rodent somatic cell hybrids and the CTPS cDNA. By a method of mapping that combines fluorescence in situ hybridization with replicated prometaphase R-bands (Takahashi et al., 1990), Takahashi et al. (1991) mapped the CTPS1 gene to chromosome 1p34.3-p34.1. By high-resolution banding analysis, they further narrowed the assignment to 1p34.1; see Yamauchi et al. (1991).
Immunodeficiency 24
Martin et al. (2014) identified 5 families with 1 or 2 children who all presented with a severe form of combined deficiency of adaptive immunity (CID). The children had severe chronic viral infections, mostly caused by herpesviruses, as well as recurrent encapsulated bacterial infections (IMD24; 615897). All patients were homozygous for a splice site mutation in CTPS1 (123860.0001). CTPS1-deficient cells from 3 patients failed to sustain proliferative responses in response to activation by antigens, anti-CD3 antibody, or costimulation by anti-CD3 and anti-CD28 antibodies, as measured by 3-H-thymidine uptake and other methods. Uptakes of 3-H-uridine and 3-H-cytidine were also impaired in activated CTPS1-deficient T cells, suggesting that both RNA and DNA synthesis were affected. Defective proliferation of CTPS1-deficient T cells was associated with a lack of cell cycle progression, as most cells were arrested in the G1 phase. CTPS1 deficiency causes a defect in T-cell proliferation in response to TCR CD3 activation. Reconstitution experiments with wildtype CTPS1 or direct addition of CTP or its cytidine precursor fully restored proliferation upon CD3 stimulation and enabled cells to expand selectively. No such effect was detected in CTPS1-deficient cells transduced with an empty vector or in control cells transduced with the CTPS1-containing vector. Martin et al. (2014) also found that proliferation of B cells was dependent on CTPS1; however, CTPS1-deficient B cells preserved an intact capacity to expand upon transformation by EBV, and patients had normal immunoglobulin levels and/or elevated IgG. Martin et al. (2014) showed that in the absence of CTPS1, the de novo pyrimidine synthesis pathway is impaired but not totally abrogated. This residual activity is probably dependent on CTPS2 (300380).
Multidrug Resistance
Mutations eliminating the feedback regulation of CTPS result in multidrug resistance and mutator phenotype in Chinese hamster ovary (CHO) cells. The region to which the CTPS gene has been mapped is the location of breakpoints involved in several tumor types. Yamauchi et al. (1993) found that inactivating mutations clustered in a highly conserved region of the gene make it feasible to assess the role of such mutations in the development of drug resistance encountered in the treatment of malignant disease and not readily explained by altered expression of the multidrug resistance genes (e.g., 171050).
Whelan et al. (1993) found that dominantly acting mutations that eliminate the allosteric regulation of CTP synthetase confer a form of multidrug resistance and a mutator phenotype on cultured Chinese hamster ovary cells. Mutations responsible for this phenotype were identified in 23 independent strains selected for resistance to arabinosyl cytosine and 5-fluorouracil. All these mutations were due to base substitutions at 7 sites within a highly conserved region of the CTPS gene.
In 8 children from 5 families from the northwest region of England who manifested a combined deficiency of adaptive immunity (IMD24; 615897), Martin et al. (2014) detected a homozygous G-to-C transversion at the -1 position of intron 17 of the CTPS1 gene (rs145092287) using whole-exome and confirmatory Sanger sequencing. The authors referred to the mutation as IVS18-1G-C and noted its genomic location as position 41475832 on chromosome 1. The mutation resulted in expression of an abnormal transcript lacking exon 18. The mutation was considered deleterious since CTPS1 protein expression could not be detected in lysates of EBV-transformed B cells and T-cell blasts from patients. All parents and unaffected sibs tested were heterozygous carriers. Sequencing of a cohort of 752 healthy individuals from the northwest of England gave an estimated frequency of homozygosity of 1 in 560,000. This frequency represented a more than 10-fold increase compared to the frequency estimated from available exome databases. Whole-exome sequencing data and analysis of polymorphic microsatellite markers in all patients revealed a common region of homozygosity of 1.1 Mb surrounding the mutation. These data indicated a founder effect.
Martin, E., Palmic, N., Sanquer, S., Lenoir, C., Hauck, F., Mongellaz, C., Fabrega, S., Nitschke, P., Esposti, M. D., Schwartzentruber, J., Taylor, N., Majewski, J., Jabado, N., Wynn, R. F., Picard, C., Fischer, A., Arkwright, P. D., Latour, S. CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation. Nature 510: 288-292, 2014. Note: Erratum: Nature 511: 370 only, 2014. [PubMed: 24870241] [Full Text: https://doi.org/10.1038/nature13386]
Takahashi, E.-I., Yamauchi, M., Ayusawa, D., Kaneda, S., Seno, T., Meuth, M., Hori, T.-A. Chromosome mappings of the human cytidine-5-prime-triphosphate synthetase (CTPS) gene and the human ubiquitin-activating enzyme UBE1 gene by fluorescence in situ hybridization. (Abstract) Cytogenet. Cell Genet. 58: 1864 only, 1991.
Takahashi, E., Hori, T., O'Connell, P., Leppert, M., White, R. R-banding and nonisotopic in situ hybridization: precise localization of the human type II collagen gene (COL2A1). Hum. Genet. 86: 14-16, 1990. [PubMed: 2253935] [Full Text: https://doi.org/10.1007/BF00205165]
Takahashi, E., Yamauchi, M., Tsuji, H., Hitomi, A., Meuth, M., Hori, T. Chromosome mapping of the human cytidine-5-prime-triphosphate synthetase (CTPS) gene to band 1p34.1-p34.3 by fluorescence in situ hybridization. Hum. Genet. 88: 119-121, 1991. [PubMed: 1959918] [Full Text: https://doi.org/10.1007/BF00204942]
Thomas, P. E., Sen, S., Lamb, B. J., Chu, E. H. Y. Cloning and expression of mammalian CTP synthetase genes. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A11 only, 1989.
Whelan, J., Phear, G., Yamauchi, M., Meuth, M. Clustered base substitutions in CTP synthetase conferring drug resistance in Chinese hamster ovary cells. Nature Genet. 3: 317-322, 1993. [PubMed: 7981751] [Full Text: https://doi.org/10.1038/ng0493-317]
Yamauchi, M., Takahashi, E., Whelan, J., Phear, G., Meuth, M. Mapping and functional analysis of the cytidine triphosphate synthetase (CTPS) gene. (Abstract) Human Genome Mapping Workshop 93, Kobe, Japan 1993. P. 1.
Yamauchi, M., Yamauchi, N., Meuth, M. Molecular cloning of the human CTP synthetase gene by functional complementation with purified human metaphase chromosomes. EMBO J. 9: 2095-2099, 1990. [PubMed: 2113467] [Full Text: https://doi.org/10.1002/j.1460-2075.1990.tb07377.x]
Yamauchi, M., Yamauchi, N., Phear, G., Spurr, N. K., Martinsson, T., Weith, A., Meuth, M. Genomic organization and chromosomal localization of the human CTP synthetase gene (CTPS). Genomics 11: 1088-1096, 1991. [PubMed: 1783378] [Full Text: https://doi.org/10.1016/0888-7543(91)90036-e]