Alternative titles; symbols
HGNC Approved Gene Symbol: ATIC
SNOMEDCT: 725289009;
Cytogenetic location: 2q35 Genomic coordinates (GRCh38): 2:215,312,059-215,368,592 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q35 | AICA-ribosiduria due to ATIC deficiency | 608688 | Autosomal recessive | 3 |
AICARFT (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase; EC 2.1.2.3) and IMPCHase (IMP cyclohydrolase; EC 3.5.4.10) catalyze the penultimate and final steps, respectively, of the de novo purine biosynthetic pathway (summary by Rayl et al., 1996).
Rayl et al. (1996) cloned a cDNA for human AICARFT/IMPCHase from a hepatoma cDNA library. Both enzymatic activities are present in the same protein, designated ATIC, in all species of prokaryotes and eukaryotes studied by Rayl et al. (1996). The human ATIC cDNA encodes a deduced 591-amino acid protein that is 81% identical to the chicken sequence (Ni et al., 1991). Rayl et al. (1996) created truncation mutants of the cDNA and measured their enzymatic properties. In this way they were able to localize the AICARFT activity within the amino-terminal 223 amino acids and the IMPCHase activity to the carboxyl-terminal 406 residues.
The International Radiation Hybrid Mapping Consortium mapped the ATIC gene to chromosome 2 (RH11837).
An et al. (2008) described the purinosome, a transient multienzyme complex composed of the 6 enzymes active in de novo purine synthesis (DNPS) that assembles and disassembles by need and availability of purines: these enzymes are PPAT (172450), GART (138440), FGAMS (PFAS; 602133), PAICS (172439), ADSL (608222), and ATIC. Using immunolabeling and confocal microscopy of these enzymes to examine several human cancer and normal cells lines, Baresova et al. (2012) detected shared compartmentalization and spatial overlapping suggestive of purinosome formation in 5% of carcinoma cells and embryonic cells and in 20% of human skin fibroblasts and keratinocytes during purine depletion. Purinosome structures were observed only in cells cultured in purine-depleted media, suggesting that this process is inherent in most cell types that are in actual need of purines. In particular, there was colocalization of the 2 most functionally distinct proteins, PPAT (step 1 of synthesis) and ATIC (steps 9 and 10).
In a 4-year-old girl who presented with dysmorphic features, severe neurologic defects, and congenital blindness and who was found to have AICA-ribosiduria (608688), Marie et al. (2004) found compound heterozygosity for mutations in the ATIC gene. Sequencing of ATIC showed a K426R mutation in the transformylase region in 1 allele (601731.0001) inherited from the father, and a frameshift mutation caused by a duplication/deletion event in the other allele (601731.0002), inherited from the mother. The missense mutation was located within a conserved region implicated in the binding of a potassium ion in the avian protein (Greasley et al., 2001). This potassium ion has been proposed to play a key role in stabilization of the tertiary structure of the protein. In expression studies, recombinant protein carrying mutation K426R completely lacked AICAR-TF activity but still showed IMP-CH activity. The presence of massive amounts of AICA-riboside in the patient's urine and the accumulation of AICAR (also referred to as ZMP) and its derivatives in her erythrocytes and fibroblasts were taken by Marie et al. (2004) to be a clear indication of deficiency in the enzyme that utilizes this intermediate de novo purine biosynthesis, the bifunctional enzyme AICAR transformylase/IMP cyclohydrolase.
In skin fibroblasts derived from the patient reported by Marie et al. (2004), Baresova et al. (2012) found that immunostaining for ATIC was almost undetectable and that there was no signal overlap with other enzymes of the de novo purine synthesis pathway in a purine-depleted medium compared to controls, suggesting impaired assembly of the purinosome. Baresova et al. (2012) suggested that ATIC deficiency and altered purinosome formation could explain the accumulation of AICA-riboside and other cytotoxic intermediates of the DNPS pathway in patient tissues.
In a 4-year-old girl with AICA-ribosiduria caused by deficiency of AICAR-TF/IMP-CH (ATICD; 608688), Marie et al. (2004) found compound heterozygosity for 2 mutations in the ATIC gene. The allele inherited from the father carried a 1277A-G transition in exon 13 causing a lys426-to-arg (K426R) amino acid substitution; the other allele, inherited from the mother, showed a frameshift in exon 2, caused by a duplication/deletion event (125_129dupGGGAT; 130_132delGCT; 601731.0002).
In 2 French sisters, aged 19 and 9 years, with AICA-ribosiduria and elevated AICA-riboside, SAICA-riboside, and succinyladenosine in the urine, Ramond et al. (2020) identified heterozygosity for the K426R mutation in the ATIC gene by direct gene sequencing. Parental origin of the variant was not determined. A second mutation in the ATIC gene was not identified, but the K426R mutation was found in homozygous state in transcript studies, which suggested the presence of a noncoding variant causing RNA instability on the second allele. The mutation was reported in the gnomAD database with an allele frequency of 1/38000 in the European population.
For discussion of the duplication/deletion event in the ATIC gene (125_129dup-GGGAT; 130_132delGCT) that was found in compound heterozygous state in a patient with AICA-ribosiduria caused by deficiency of AICAR-TF/IMP-CH (ATICD; 608688) by Marie et al. (2004), see 601731.0001.
In a 7-year-old boy with AICA-ribosiduria (ATICD; 608688) and elevated AICA-riboside, SAICA-riboside, and succinyladenosine in the urine, Ramond et al. (2020) identified compound heterozygous mutations in the ATIC gene: a c.406G-A transition (c.406G-A, NM_004044.7), resulting in an ala136-to-thr (A136T) substitution, and a c.1654A-T transversion, resulting in a lys552-to-ter (K552X; 601731.0004) substitution. The mutations were identified by whole-exome sequencing. Each parent was heterozygous for one of the mutations. The variants were not found in the gnomAD database. Functional studies were not performed.
For discussion of the c.1654A-T transversion (c.1654A-T, NM_004044.7) in the ATIC gene, resulting in a lys552-to-ter (K552X) substitution, that was found in compound heterozygous state in a patient with AICA-ribosiduria (608688) by Ramond et al. (2020), see 601731.0003.
An, S., Kumar, R., Sheets, E. D., Benkovic, S. J. Reversible compartmentalization of de novo purine biosynthetic complexes in living cells. Science 320: 103-106, 2008. [PubMed: 18388293] [Full Text: https://doi.org/10.1126/science.1152241]
Baresova, V., Skopova, V., Sikora, J., Patterson, D., Sovova, J., Zikanova, M., Kmoch, S. Mutations of ATIC and ADSL affect purinosome assembly in cultured skin fibroblasts from patients with AICA-ribosiduria and ADSL deficiency. Hum. Molec. Genet. 21: 1534-1543, 2012. [PubMed: 22180458] [Full Text: https://doi.org/10.1093/hmg/ddr591]
Greasley, S. E., Horton, P., Ramcharan, J., Beardsley, G. P., Benkovic, S. J., Wilson, I. A. Crystal structure of a bifunctional transformylase and cyclohydrolase enzyme in purine biosynthesis. Nature Struct. Biol. 8: 402-406, 2001. [PubMed: 11323713] [Full Text: https://doi.org/10.1038/87555]
Marie, S., Heron, B., Bitoun, P., Timmerman, T., Van den Berghe, G., Vincent, M.-F. AICA-ribosiduria: a novel, neurologically devastating inborn error of purine biosynthesis caused by mutation of ATIC. Am. J. Hum. Genet. 74: 1276-1281, 2004. [PubMed: 15114530] [Full Text: https://doi.org/10.1086/421475]
Ni, L., Guan, K., Zalkin, H., Dixon, J. E. De novo purine nucleotide biosynthesis: cloning, sequencing and expression of a chicken PurH cDNA encoding 5-aminoimidazole-4-carboxamide-ribonucleotide transformylase-IMP cyclohydrolase. Gene 106: 197-205, 1991. [PubMed: 1937050] [Full Text: https://doi.org/10.1016/0378-1119(91)90199-l]
Ramond, F., Rio, M., Heron, B., Imbard, A., Marie, S., Billiemaz, K., Denomme-Pichon, A.-S., Kuentz, P., Ceballos, I., Piraud, M., Vincent, M.-F., Touraine, R. AICA-ribosiduria due to ATIC deficiency: delineation of the phenotype with three novel cases, and long-term update on the first case. J. Inherit. Metab. Dis. 43: 1254-1264, 2020. [PubMed: 32557644] [Full Text: https://doi.org/10.1002/jimd.12274]
Rayl, E. A., Moroson, B. A., Beardsley, G. P. The human purH gene product, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase: cloning, sequencing, expression, purification, kinetic analysis, and domain mapping. J. Biol. Chem. 271: 2225-2233, 1996. [PubMed: 8567683] [Full Text: https://doi.org/10.1074/jbc.271.4.2225]