Alternative titles; symbols
HGNC Approved Gene Symbol: PAICS
SNOMEDCT: 124597000;
Cytogenetic location: 4q12 Genomic coordinates (GRCh38): 4:56,410,507-56,464,578 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q12 | ?Phosphoribosylaminoimidazole carboxylase deficiency | 619859 | Autosomal recessive | 3 |
AIR carboxylase (EC 4.1.1.21)/SAICAR synthetase (EC 6.3.2.6) is a bifunctional enzyme, the activities of which are required for steps 6 and 7, respectively, of purine biosynthesis (summary by Brayton et al., 1994).
Schild et al. (1990) used the functional complementation of mutations in Saccharomyces cerevisiae to isolate a human cDNA clone complementing the ade-2 (phosphoribosylaminoimidazole carboxylase; EC 4.1.1.21) yeast mutation. The same cDNA also complemented ade-1 (phosphoribosylaminoimidazole succinocarboxamide synthetase; EC 6.3.2.6); thus, this is a bifunctional enzyme. Although these enzymes are encoded by genes on different chromosomes in yeast, their enzymatic activities copurify from chicken livers, and the complementation of both activities by this single cDNA clone suggests that the enzyme is bifunctional in humans.
Barton et al. (1991) mapped the PAICS gene to chromosome 4 by fusing Chinese hamster ovary (CHO) cells carrying the Ade(-)D mutation with human lymphocytes using inactivated Sendai virus. Two of the isolated subclones contained only the long arm of human chromosome 4 translocated onto a CHO chromosome, thus providing evidence that the gene in question is on 4q. By subjecting 2 of the subclones containing chromosome 4 to BrdU visible light segregation, Barton et al. (1991) demonstrated that all of the isolated purine auxotrophic cell lines showed a loss of 4q. It is noteworthy that this bifunctional enzyme maps to the same general region as the monofunctional enzyme PPAT (172450), which catalyzes the first step in the biosynthetic pathway for the production of AMP from phosphoribosylpyrophosphate (PRPP) and maps to 4pter-q21.
Brayton et al. (1994) demonstrated that in the human, as in the chicken, the GPAT gene (172450), which catalyzes the first and presumably rate-limiting reaction in purine biosynthesis, is closely linked and divergently transcribed. The intergenic region is approximately 625 bp in the human and 229 bp in the chicken. Although there are several examples for bidirectional transcription in higher eukaryotes, GPAT-AIRC was the first example for bidirectional transcription of tightly coupled genes that are not structurally related but are involved in the same pathway. This may be a eukaryotic equivalent of a prokaryotic operon.
In 2 sibs from the Faroe islands with phosphoribosylaminoimidazole carboxylase deficiency (PAICSD; 619859), Pelet et al. (2019) identified a homozygous mutation in the PAICS gene (K53R; 172439.0001). The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. Testing in patient fibroblasts demonstrated PAICS enzyme activity that was 10% of control levels. Patient fibroblasts grown in purine-depleted media failed to form purinosomes, and purinosome formation was restored with transfection of wildtype PAICS.
In 2 sibs from the Faroe Islands with phosphoribosylaminoimidazole carboxylase deficiency (PAICSD; 619859), who were born to consanguineous parents, Pelet et al. (2019) identified homozygosity for a c.158A-G transition (c.158A-G, NM_001079525.1) in exon 2 of the PAICS gene, resulting in a lys53-to-arg (K53R) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The mutation was present in gnomAD at an allele frequency of 0.001 in non-Finnish Europeans, 0.0002 in Africans, and 0.0007 in Latinos. Molecular modeling predicted that the mutation resulted in destabilization of the PAICS enzyme pocket. PAICS enzyme activity was reduced to 10% in patient fibroblasts and to 50% in fibroblasts from the heterozygous parents and a heterozygous sib compared to controls.
Barton, J. W., Hart, I. M., Patterson, D. Mapping of a locus correcting lack of phosphoribosylaminoimidazole carboxylase activity in Chinese hamster ovary cell Ade(-)D mutants to human chromosome 4. Genomics 9: 314-321, 1991. [PubMed: 2004782] [Full Text: https://doi.org/10.1016/0888-7543(91)90259-h]
Brayton, K. A., Chen, Z., Zhou, G., Nagy, P. L., Gavalas, A., Trent, J. M., Deaven, L. L., Dixon, J. E., Zalkin, H. Two genes for de novo purine nucleotide synthesis on human chromosome 4 are closely linked and divergently transcribed. J. Biol. Chem. 269: 5313-5321, 1994. [PubMed: 8106516] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(17)37689-5]
Pelet, A., Skopova, V., Steuerwald, U., Baresova, V., Zarhrate, M., Plaza, J.-M., Hnizda, A., Krijt, M., Souckova, O., Wibrand, F., Andorsdottir, G., Joensen, F., Sedlak, D., Bleyer, A. J., Kmoch, S., Lyonnet, S., Zikanova, M. PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome. Hum. Molec. Genet. 28: 3805-3814, 2019. [PubMed: 31600779] [Full Text: https://doi.org/10.1093/hmg/ddz237]
Schild, D., Brake, A. J., Kiefer, M. C., Young, D., Barr, P. J. Cloning of three human multifunctional de novo purine biosynthetic genes by functional complementation of yeast mutations. Proc. Nat. Acad. Sci. 87: 2916-2920, 1990. [PubMed: 2183217] [Full Text: https://doi.org/10.1073/pnas.87.8.2916]