HGNC Approved Gene Symbol: CPS1
SNOMEDCT: 765329008;
Cytogenetic location: 2q34 Genomic coordinates (GRCh38): 2:210,477,685-210,679,107 (from NCBI)
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
---|---|---|---|---|
2q34 | {Pulmonary hypertension, neonatal, susceptibility to} | 615371 | 3 | |
Carbamoylphosphate synthetase I deficiency | 237300 | Autosomal recessive | 3 |
Carbamoyl phosphate synthetase I (EC 6.3.4.16) is the rate-limiting enzyme that catalyzes the first committed step of the hepatic urea cycle by synthesizing carbamoyl phosphate from ammonia, bicarbonate, and 2 molecules of ATP (summary by Haberle et al., 2011).
The mitochondrial isozyme is designated CPS I and the cytoplasmic enzyme CPS II. CPS II is part of a multifunctional enzyme, called the CAD trifunctional protein of pyrimidine biosynthesis (CAD; 114010), which has been mapped to 2p21.
Lusty (1978) purified the carbamyl phosphate synthetase I enzyme from rat liver mitochondria, and Pierson and Brien (1980) purified it from human liver.
Haraguchi et al. (1991) cloned and sequenced a cDNA for CPS1 from a human liver cDNA library. The full-length sequence encodes a 1,500-amino acid precursor polypeptide with a deduced molecular mass of 165 kD that shows 94.4% amino acid homology to the rat enzyme precursor. Hoshide et al. (1993) corrected the cDNA nucleotide sequence for CPS1 reported by Haraguchi et al. (1991). The 165-kD proenzyme is produced in the cytoplasm and transported into the mitochondria where it is cleaved into its mature 160-kD form. CPS1 is expressed in the liver and in epithelial cells of the intestinal mucosa.
Nyunoya et al. (1985) characterized the rat Cps1 gene.
Summar et al. (2003) determined that the CPS1 gene contains 38 exons. Haberle et al. (2003) also reported the complete sequencing and structure of the CPS1 gene.
The structural gene for carbamoyl phosphate synthetase was assigned to the short arm of chromosome 2 using a cDNA gene probe in human-rodent somatic cell hybrids (Adcock et al., 1984). Adcock and O'Brien (1984) assigned CPS1 to 2p by somatic cell hybrid analysis using a 1.6-kb cDNA fragment.
Summar et al. (1995) used fluorescence in situ hybridization for physical mapping and CEPH families for linkage mapping of the CPS1 gene to 2q34-q35. By fluorescence in situ hybridization, Hoshide et al. (1995) mapped the CPS1 gene to 2q35.
Helou et al. (1997) mapped the mouse homolog to chromosome 1.
CPS I catalyzes the conversion of ammonia and bicarbonate to carbamyl phosphate. The reaction requires a cofactor, N-acetylglutamate (NAG; see 608300).
Mitochondrial nucleoids are large complexes containing, on average, 5 to 7 mitochondrial DNA (mtDNA) genomes and several proteins involved in mtDNA replication and transcription, as well as related processes. Bogenhagen et al. (2008) had previously shown that CPS1 was associated with native purified HeLa cell nucleoids. Using a formaldehyde crosslinking technique, they found that CPS1 copurified with mtDNA and was a core nucleoid protein.
Kim et al. (2017) showed that human non-small cell lung cancer (NSCLC) cells with both oncogenic KRAS (190070) and loss of LKB1 (STK11; 602216), which they called KL cells, and tumors share metabolomic signatures of perturbed nitrogen handling. KL cells express the urea cycle enzyme CPS1, which produces carbamoyl phosphate in the mitochondria from ammonia and bicarbonate, initiating nitrogen disposal. Transcription of CPS1 is suppressed by LKB1 through AMPK, and CPS1 expression correlates inversely with LKB1 in NSCLC. Silencing CPS1 in KL cells induced cell death and reduced tumor growth. Notably, cell death resulted from pyrimidine depletion rather than ammonia toxicity, as CPS1 enables an unconventional pathway of nitrogen flow from ammonia into pyrimidines. CPS1 loss reduced the pyrimidine to purine ratio, compromised S-phase progression, and induced DNA polymerase stalling and DNA damage. Exogenous pyrimidines reversed DNA damage and rescued growth. Kim et al. (2017) concluded that the KL oncologic genotype imposes a metabolic vulnerability related to a dependence on a cross-compartmental pathway of pyrimidine metabolism in an aggressive subset of NSCLC. The authors published a correction stating that the signal reported in Extended Data Fig. 1c of their report was attributed to phosphorylethanolamine, not carbamoyl phosphate, and that another method revealed that the level of carbamoyl phosphate in these NSCLC extracts was below the detection threshold. They further stated that these findings did not alter the overall conclusions of their report.
Li et al. (2019) reported that the tumor suppressor p53 (191170) regulates ammonia metabolism by repressing the urea cycle. Through transcriptional downregulation of CPS1, OTC (300461), and ARG1 (608313), p53 suppresses ureagenesis and elimination of ammonia in vitro and in vivo, leading to the inhibition of tumor growth. Conversely, downregulation of these genes reciprocally activates p53 by MDM2 (164785)-mediated mechanism(s). Furthermore, the accumulation of ammonia causes a significant decline in mRNA translation of the polyamine biosynthetic rate-limiting enzyme ODC (ODC1; 165640), thereby inhibiting the biosynthesis of polyamine and cell proliferation. Li et al. (2019) conclude that together, their findings linked p53 to ureagenesis and ammonia metabolism, and further revealed a role for ammonia in controlling polyamine biosynthesis and cell proliferation.
Summar et al. (2003) identified 14 polymorphisms in the CPS1 gene.
Carbamoyl Phosphate Synthetase I Deficiency
In a newborn Japanese girl with CPS I deficiency (237300), Hoshide et al. (1993) identified a homozygous missense mutation in the CPS1 gene (608307.0001), causing a splice site alteration that resulted in a 9-bp deletion in the coding region of the mRNA.
In a male infant who died at the age of 11 days from a severe form of CPS I deficiency, Finckh et al. (1998) identified a homozygous mutation in the CPS1 gene (608307.0002). The parents were consanguineous.
In 6 patients with CPS I deficiency, Haberle et al. (2003) identified 9 novel mutations in the CPS1 gene.
In 16 of 18 Japanese patients with a clinical diagnosis of CPS I deficiency, Kurokawa et al. (2007) identified 25 different mutations in the CPS1 gene, including 19 novel mutations (see, e.g., 608307.0007-608307.0009). Two patients with confirmed CPS I deficiency had later onset at ages 13 and 31 years, respectively. Genotype/phenotype correlations were not observed.
By analyzing tissue and DNA samples from 205 individuals with CPS I deficiency spanning 24 years, Haberle et al. (2011) identified 192 different pathogenic mutations in the CPS1 gene, including 130 novel mutations. When combined with previously reported mutations, it was clear that most mutations (90%) were private, occurring in only 1 family each. The few recurrent mutations tended to occur at CpG dinucleotides. Most missense mutations occurred around exon 24, at the boundary between both homologous halves of the region encoding the 120-kD catalytic moiety of the enzyme. Mutations also clustered at the bicarbonate and carbamate phosphorylation domains, at the NAG cofactor binding domain, and at the interface between the large and small subunit-like moieties. Comparative modeling using the E. coli enzyme showed that the location of missense mutations correlated with evolutionary importance and included internal residues, suggesting that they affect protein folding.
Hu et al. (2014) identified a recurrent founder mutation in the CPS1 gene (608307.0013) in the Turkish population.
Neonatal Pulmonary Hypertension, Susceptibility to
Pearson et al. (2001) reported an association between a T1405N polymorphism in the CPS1 gene (608307.0006) and plasma levels of arginine/citrulline with a risk of persistent pulmonary hypertension in newborns (PHN; 615371). The same polymorphism was implicated as a risk factor for venoocclusive disease after bone marrow transplantation (Summar et al., 2004).
In E. coli, carbamoyl phosphate synthetase is a dimer of 2 structurally different polypeptides, alpha and beta (Trotta et al., 1971). Nyunoya et al. (1985) found that the amino acid sequence in the rat CPS1 protein is homologous to the sequences of carbamyl phosphate synthetase of E. coli and yeast, and encompasses the entire sequences of both the small and large subunits of the E. coli and yeast enzymes. The data provided strong evidence that these genes were derived from common ancestral genes, and that the mammalian CPS1 gene arose from fusion of loci from 2 separate ancestral units or duplication (see also Schofield, 1993).
Khoja et al. (2018) conditionally deleted Cps1 in livers of adult mice. Cps1-knockout mice developed severe weight loss and died within 4 weeks. Deletion of Cps1 in liver resulted in increased plasma ammonia levels and severe hyperammonemia compared with wildtype mice. The hyperammonemic Cps1-knockout mice also exhibited elevated plasma glutamine, with normal orotic acid levels. Moreover, plasma taurine, serine, asparagine, glycine, phenylalanine, tryptophan, and lysine were increased, whereas methionine and serine were decreased, in Cps1-knockout mice. Plasma homoalanine, also known as alpha-amino butyric acid, was markedly increased, and widespread derangement of hepatic amino acids occurred with disruption of hepatic Cps1 activity. Liver-directed expression of mouse Cps1 rescued Cps1-knockout mice from lethality and normalized plasma ammonia and glutamine. Female Cps1-knockout mice required a higher minimum level of hepatic Cps1 expression to survive compared with male Cps1-knockout mice.
Hoshide et al. (1993) determined the molecular basis of CPS I deficiency (237300) in a newborn Japanese girl with consanguineous parents. Northern and Western blots demonstrated a marked decrease in CPS I mRNA and enzyme protein. Genomic DNA sequencing of the CPS1 gene demonstrated an 840G-C transversion at the last nucleotide of an exon in the splice donor site, resulting in a 9-bp deletion of nucleotides 832-840 in the CPS1 mRNA. The patient was homozygous; both parents, a sister, and a brother were heterozygous.
In a male infant who died at the age of 11 days from a severe form of CPS I deficiency (237300), Finckh et al. (1998) identified a homozygous thr544-to-met (T544M) mutation in the CPS1 gene. The parents were consanguineous.
In a patient with CPS I deficiency (237300), Ihara et al. (1999) identified a C-T change in the CPS1 gene, resulting in a nonsense mutation in codon 44 (Q44X).
Kurokawa et al. (2007) identified the Q44X mutation in 2 unrelated Japanese patients with CPS I deficiency.
Aoshima et al. (2001) described compound heterozygosity for 2 mutations in the CPS1 gene in a Japanese girl who at day 9 showed lethargy and grunting with severe hyperammonemia. She was suspected of suffering from CPS I deficiency (237300) because of elevated blood glutamine and glutamic acid concentration, low blood citrulline concentration, and absence of orotic aciduria. At 16 months of age, a diagnosis of CPS I deficiency was established enzymatically. The 2 mutations in this case were a 1010A-G transition resulting in a his337-to-arg (H337R) substitution, and a 4.2-kb deletion (608307.0005) resulting in a 375-bp in-frame deletion of codons 238-362. Three exons were skipped.
For discussion of the 4.2-kb deletion in the CPS1 gene that was found in compound heterozygous state in a Japanese girl with CPS I deficiency (237300) by Aoshima et al. (2001), see 608307.0004.
Pulmonary Hypertension, Neonatal, Susceptibility to
In a study of 31 neonates with persistent pulmonary hypertension (PHN; 615371), 6 cases of which were idiopathic, Pearson et al. (2001) found an association (p = 0.05) between PHN and a 4332C-A transversion in the CPS1 gene, resulting in a thr1405-to-asn substitution.
See 608307.0012 and Solomon et al. (2011). Solomon et al. (2011) stated that the T1405N substitution (rs1047891) results from a c.4217C-A transversion and is sometimes referred to as THR1406ASN based on a different numbering system.
Venoocclusive Disease After Bone Marrow Transplantation, Susceptibility to
Summar et al. (2004) implicated the T1405N polymorphism as a risk factor for venoocclusive disease after bone marrow transplantation. Lanpher et al. (2006) noted that these studies supported the hypothesis that altered flux through the urea cycle can secondarily affect the nitric oxide metabolism in the pathogenesis of distinct, complex phenotypes (Scaglia et al., 2004).
Homocysteine Levels
Increased blood plasma homocysteine (Hcy) levels (see 603174) are a risk factor for cardiovascular disease and may play an etiologic role in vascular damage, a precursor for atherosclerosis. Lange et al. (2010) performed a genomewide association study for Hcy in 1,786 unrelated Filipino women from the Cebu Longitudinal Health and Nutrition Survey (CLHNS). The most strongly associated single-nucleotide polymorphism (SNP), rs7422339 (p = 4.7 x 10(-13)), encodes T1405N in CPS1 and explained 3.0% of variation in the Hcy level. The widely studied MTHFR C677T SNP (rs1801133; 607093.0003) was also highly significant (p = 8.7 x 10(-10)) and explained 1.6% of the trait variation. In a follow-up genotyping of these 2 SNPs in 1,679 CLHNS young adult offspring, the MTHFR C677T SNP was strongly associated (p = 1.9 x 10(-26)) with Hcy and explained 5.1% of the variation in gender-combined offspring. In contrast, the CPS1 variant was significant only in females. Combined analysis of all samples confirmed that the MTHFR variant was more strongly associated with Hcy in the offspring. Although there was evidence for a positive synergistic effect between the CPS1 and MTHFR SNPs in the offspring, there was no significant evidence for an interaction in the mothers. The authors suggested that genetic effects on Hcy may differ across developmental stages.
In 2 unrelated Japanese infants with CPS I deficiency (237300), Kurokawa et al. (2007) identified a heterozygous 2945G-A transition in exon 24 of the CPS1 gene, resulting in a gly982-to-asp (G982D) substitution. The male infant was compound heterozygous for another pathogenic mutation in the CPS1 gene, whereas a second mutation was not identified in the female infant. Both patients died within the first months of life.
In 2 unrelated Japanese patients with CPS I deficiency (237300), Kurokawa et al. (2007) identified a 1-bp deletion (1528delG) in exon 14 of the CPS1 gene, resulting in a frameshift and premature termination at codon 514. The male patient was homozygous for the mutation and died at age 4 days. The female patient was compound heterozygous with another CPS1 mutation, had 17% residual hepatic enzyme activity, and was alive without mental retardation.
In 2 unrelated Japanese patients with CPS I deficiency (237300), Kurokawa et al. (2007) identified a heterozygous 2359C-T transition in exon 19 of the CPS1 gene, resulting in an arg787-to-ter (R787X) substitution. Both patients were compound heterozygous for another pathogenic CPS1 mutation.
In a Lebanese man and his grandson with highly variable manifestations of CPS I deficiency (237300), Klaus et al. (2009) identified compound heterozygosity for 2 splice site mutations in the CPS1 gene: a G-to-C transversion in intron 29 (3558+1G-C), resulting in the loss of exon 29, and a T-to-C transition in intron 34, (4101+2T-C; 608307.0011) resulting in either an in-frame deletion of exon 34 or an in-frame insertion of 42 bp when a cryptic donor splice site within intron 34 is used. Despite the identical genotype, the patients had very different disease manifestations: the grandfather presented at age 45 years with acute confusion associated with increased ammonia that was subsequently managed, whereas the grandson presented at age 2 days with encephalopathy and died at age 3 years during an episode of pneumonia. Cloning experiments in E. coli indicated that the proportioning of the allelic expression was different between the 2 patients: the more severely affected grandson had a skewed 3-fold higher expression of the 4101+2T-C mutation compared to his grandfather, who had equal expression both mutations. Although the mechanism for this skewing of allelic expression was unclear, Klaus et al. (2009) concluded that it contributed to the clinical variability in this family.
For discussion of the T-to-C transition (4101+2T-C) in intron 34 of the CPS1 gene that was found in compound heterozygous state in a Lebanese man and his grandson with highly variable manifestations of CPS I deficiency (237300) by Klaus et al. (2009), see 608307.0010.
This variant is classified as a variant of unknown significance because its contribution to susceptibility to neonatal pulmonary hypertension (615371) has not been confirmed.
In a neonate with VACTERL association (see 192350) who had severe postsurgical neonatal pulmonary hypertension, Solomon et al. (2011) identified heterozygosity for a 1589G-T transversion in the CPS1 gene, resulting in a gly530-to-val (G530V) substitution in a conserved residue in the bicarbonate phosphorylation domain, as well as heterozygosity for the CPS1 T1405N substitution (608307.0006), which had already been associated with susceptibility to PHN. Both mutations were also found in his healthy monozygotic twin and were inherited from their father. The G530V substitution was not found in 100 ethnically matched chromosomes and was predicted to be pathogenic by several programs.
Hu et al. (2014) identified 11 patients of Turkish origin with CPS I deficiency (237300) who were homozygous for a 3-bp deletion in the CPS1 gene at c.3037_3039del (p.Val1013del). All 11 patients (6 female and 5 male) had neonatal onset of disease between day 1 and 6 and died in the neonatal period or infancy. Although some of the families originated from eastern regions of Turkey, there was no apparent relationship between them. All parents for whom DNA was available (5 of 11 families) were carriers of the respective mutation, confirming segregation on each parental allele. Clinical information was available for all 11 patients confirming the severity of CPS I deficiency in all cases (e.g., maximum ammonia levels were between 970 and 2,957 micromol/L).
This variant was not detected in the Exome Aggregation Consortium (ExAC) browser (Hamosh, 2015).
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