Alternative titles; symbols
HGNC Approved Gene Symbol: ITPA
SNOMEDCT: 1208747005, 238011005;
Cytogenetic location: 20p13 Genomic coordinates (GRCh38): 20:3,204,065-3,227,449 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20p13 | [Inosine triphosphatase deficiency] | 613850 | 3 | |
| Developmental and epileptic encephalopathy 35 | 616647 | Autosomal recessive | 3 |
Inosine triphosphate pyrophosphohydrolase (ITPase; EC 3.6.1.19) catalyzes the pyrophosphohydrolysis of inosine triphosphate (ITP) to inosine monophosphate (IMP) (Sumi et al., 2002).
Lin et al. (2001) isolated and expressed a full-length cDNA clone encoding human ITPase. The 1,085-basepair cDNA contained an open reading frame of 585 nucleotides encoding a protein of 194 amino acids. Lin et al. (2001) showed that ITPase is present not only in red blood cells, but also in many tissues.
Sumi et al. (2002) showed that the ITPA gene contains 8 exons.
From cell hybrid studies, the ITPA structural gene was shown to be on chromosome 20 (Meera Khan et al., 1976; Hopkinson et al., 1976). Gene dosage studies of adenosine deaminase (ADA; 608958) and ITPA provided corroboration of partial trisomy 20 diagnosed cytogenetically (Rudd et al., 1979).
The human ITPA gene is on 20p; the gene for ADA, a functionally related enzyme, is on 20q (Mohandas et al., 1980). Using linkage methods, Taylor et al. (1987) assigned the mouse Itp locus to chromosome 2.
Stumpf (2020) mapped the ITPA gene to chromosome 20p13 based on an alignment of the ITPA sequence (GenBank BC010138) with the genomic sequence (GRCh38).
Sumi et al. (2002) stated that the putative role of ITPase is to recycle purines trapped in the form of ITP and to protect the cell from the accumulation of 'rogue' nucleotides such as ITP, dITP, or xanthosine triphosphate (XTP) that may be incorporated into RNA and DNA.
Harris et al. (1974) found no genetic variants at the inosine triphosphatase locus by electrophoretic means.
ITPA Deficiency
Sumi et al. (2002) identified 2 mutations in the ITPA gene (147520.0001, 147520.0002) associated with deficient ITPase enzyme activity (613850). Sumi et al. (2002) suggested that the possibility of thiopurine drug toxicity consequent to ITPase deficiency warrants further investigation.
Response to Ribavirin Treatment in Hepatitis C
Chronic hepatitis C virus infection is treated with a combination of pegylated interferon-alpha (147660) and ribavirin. One of the most important side effects is ribavirin-induced hemolytic anemia, which affects most patients and is severe enough to require dose modification in up to 15% of patients (see 609532). Fellay et al. (2010) showed that genetic variants leading to inosine triphosphatase deficiency, a condition not thought to be clinically important, protect against hemolytic anemia in hepatitis C-infected patients receiving ribavirin. The association between the ITPA gene variants with protection against anemia was identified by an association between the SNP rs6051702 with a genomewide P value of 1.1 x 10(-45) among European Americans. This SNP was in linkage disequilibrium with 2 less common alleles within ITPA, a P32T mutation (rs1127354, 147520.0001) and a splice site variant (rs7270101, 147520.0002).
Among 304 patients with hepatitis C who were treated with ribavirin, Thompson et al. (2010) found that the minor allele of ITPA SNPs rs1127354 and rs7270101 were significantly associated with protection against hemoglobin (Hb) reduction at week 4 (p = 3.1 x 10(-13) and p = 1.3 x 10(-3), respectively). Combining the variants into the ITPase deficiency variable according to the severity of enzyme deficiency strengthened the association (p = 2.4 x 10(-18)). The ITPase deficiency variable was associated with lower rates of anemia over the entire treatment period (48 weeks); however, no association with sustained virologic response was observed. The findings replicated those of Fellay et al. (2010) in an independent cohort.
Developmental and Epileptic Encephalopathy 35
In 7 patients from 4 unrelated families with developmental and epileptic encephalopathy-35 (DEE35; 616647), Kevelam et al. (2015) identified 4 different homozygous mutations in the ITPA gene (147520.0003-147520.0006). In 3 families, the mutations were found by homozygosity mapping and/or whole-exome sequencing. The erythrocytes of 1 proband showed severely reduced ITPase activity and accumulation of ITP, whereas fibroblasts of the 3 other probands showed severely reduced ITPase activity and no accumulation of ITP. Kevelam et al. (2015) postulated that the abnormal accumulation of ITP could be toxic to neurons and other cells if it is incorporated into DNA and RNA instead of the canonical nucleotides. ITP may also interfere with normal ATP- and GTP-related signal transduction within the cell.
Behmanesh et al. (2009) found that over half of Itpa -/- mice died before birth. Those that survived were growth retarded and died about 14 days after birth. Itpa -/- mice showed ataxia, abnormal breathing, and heart abnormalities. Further examination revealed immature hair follicles, hyperkeratosis of forestomach, decreased extramedullary hematopoiesis in liver and spleen, and germ cell hypoplasia in testis. Itpa -/- mouse heart had thinner ventricular walls compared with wildtype and unsynchronized contraction upon echocardiography. Itpa -/- heart also showed disorganized myocardial fibers, absence of Z-discs, and broken and disorganized sarcomere structure. Itpa -/- heart, but not wildtype heart, showed accumulation of inosine nucleotides in RNA. Behmanesh et al. (2009) noted that ATP is required for actomyosin function in sarcomere, and they hypothesized that ITP may compete with ATP for binding to actomyosin in Itpa -/- heart and that ITPA functions to exclude ITP from the ATP pool.
In patients with ITPase deficiency (613850), Sumi et al. (2002) found a 94C-A transversion in exon 2 of the ITPA gene that resulted in a pro32-to-thr (P32T) substitution. The proline residue is conserved in mouse and Drosophila. All 6 individuals who were homozygous for the 94C-A mutation had completely deficient erythrocyte ITPase activity, accompanied by the abnormal accumulation of ITP and red blood cells. In addition, ITPase activity was decreased in all 13 heterozygotes, providing further evidence of the association between the 94C-A mutation and an ITPase-deficient phenotype. Heterozygotes showed a mean ITPase activity of 22.5% of the control value, consistent with a dimeric structure of ITPase. In heterozygotes, only 1 of the 4 possible dimers would be composed of wildtype subunits.
Cao and Hegele (2002) sequenced genomic DNA for the ITPA gene in a Caucasian subject with complete ITPase deficiency and found homozygosity for the P32T mutation. The authors referred to the transversion as 198C-A because they included 104 bp of untranslated region and 66 bp of translated region. The P32T allele frequency of 0.07 in Caucasians was similar to the estimates derived from earlier biochemical studies (0.05). P32T was found to be present at varying frequency in other ethnic groups. Cao and Hegele (2002) concluded that the P32T allele appears to be more prevalent in subjects of Chinese and East Indian origin. Thus, homozygous ITPase deficiency may be higher in these populations than in Caucasians. They also noted that P32T is evolutionarily conserved in species ranging from human to mouse (Lin et al., 2001), supporting the functionality of this residue.
Using in vitro studies, Stepchenkova et al. (2009) found that the P32T variant, like wildtype, is a dimer in solution and has normal ITPA activity, although its melting point was 5 degrees C lower than that of wildtype. The P32T variant was also able to complement a bacterial and yeast Itpa defect. Human fibroblasts with the P32T variant showed an almost 10-fold decrease in immunoreactive ITPA. Stepchenkova et al. (2009) proposed that the P32T variant exerts its effect in certain human tissues by cumulative effects of destabilization of transcripts, protein stability, and availability.
In patients with ITPase deficiency, Sumi et al. (2002) found a SNP in intron 2, IVS2+21A-C. ITPase activity of heterozygotes was 60% that of the normal control mean; in individuals compound heterozygous for IVS2+21A-C and P32T (147520.0001), activity was 10%.
In 3 sibs (family I), born of consanguineous Moroccan parents, with developmental and epileptic encephalopathy-35 (DEE35; 616647), Kevelam et al. (2015) identified a homozygous 1,874-bp deletion (c.264-607_295+1267del, NM_033453.3) in the ITPA gene. The deletion, which spanned exon 5 and extended into both introns 4 and 5, was predicted to result in an out-of-frame transcript. The mutation, which was found by a combination of SNP array analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP (build 137), 1000 Genomes Project, Exome Variant Server, or in-house control exome databases. Patient fibroblasts showed 0.3% residual ITPA activity without accumulation of ITP. The patients presented between 3 and 5 months of age with microcephaly, severe seizures, and developmental delay. All died in the first years of life.
In 2 sibs (family II), born of consanguineous Pakistani parents, with developmental and epileptic encephalopathy-35 (DEE35; 616647), Kevelam et al. (2015) identified a homozygous c.452G-A transition (c.452G-A, NM_033453.3) in exon 7 of the ITPA gene, resulting in a trp151-to-ter (W151X) substitution at the substrate binding site. The mutation, which was found by a combination of SNP array analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not found in the dbSNP (build 137), 1000 Genomes Project, or in-house control exome databases, but was reported once in a heterozygous individual in the Exome Variant Server database (frequency of 0.009%). Erythrocyte ITPA activity was severely decreased in 1 of the patients tested, corresponding to about 0.4% residual activity, which is similar to that observed in erythrocytes from individuals with a homozygous P32T (147520.0001) ITPA variant. Erythrocytes from the patient reported by Kevelam et al. (2015) also showed accumulation of ITP. The patients presented between 2 and 3 years of age with severe refractory seizures and developmental delay. Both died in early childhood.
In a Canadian patient (family III) with developmental and epileptic encephalopathy-35 (DEE35; 616647), Kevelam et al. (2015) identified a homozygous c.532C-T transition (c.532C-T, NM_033453.3) in exon 8 of the ITPA gene, resulting in an arg178-to-cys (R178C) substitution at a highly conserved residue at the substrate binding site. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 137), 1000 Genomes Project, Exome Variant Server, or in-house control exome databases. Patient fibroblasts showed 5.3% residual ITPA activity without accumulation of ITP. The patient presented with severe seizures at 4.5 months of age.
In a patient of Roma origin (family IV) with developmental and epileptic encephalopathy-35 (DEE35; 616647), Kevelam et al. (2015) identified a homozygous 8-bp duplication (c.359_366dupTCAGCACC, NM_033453.3) in exon 6 of the ITPA gene, resulting in a frameshift (Gly123SerfsTer104), that would result in an extended protein of 225 amino acids instead of 194 amino acids. The mutation segregated with the disorder in the family and was not found in the dbSNP (build 137), 1000 Genomes Project, Exome Variant Server, or in-house control exome databases, but was reported in the heterozygous state in 1 Bulgarian control individual. Patient fibroblasts showed 2.9% residual ITPA activity without accumulation of ITP. The patient presented at birth with hypotonia and irritability. She developed refractory seizures at 5 months of age.
Behmanesh, M., Sakumi, K., Abolhassani, N., Toyokuni, S., Oka, S., Ohnishi, Y. N., Tsuchimoto, D., Nakabeppu, Y. ITPase-deficient mice show growth retardation and die before weaning. Cell Death Differ. 16: 1315-1322, 2009. [PubMed: 19498443] [Full Text: https://doi.org/10.1038/cdd.2009.53]
Cao, H., Hegele, R. A. DNA polymorphisms in ITPA including basis of inosine triphosphatase deficiency. J. Hum. Genet. 47: 620-622, 2002. [PubMed: 12436200] [Full Text: https://doi.org/10.1007/s100380200095]
Fellay, J., Thompson, A. J., Ge, D., Gumbs, C. E., Urban, T. J., Shianna, K. V., Little, L. D., Qiu, P., Bertelsen, A. H., Watson, M., Warner, A., Muir, A. J., Brass, C., Albrecht, J., Sulkowski, M., McHutchison, J. G., Goldstein, D. B. ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C. Nature 464: 405-408, 2010. [PubMed: 20173735] [Full Text: https://doi.org/10.1038/nature08825]
Harris, H., Hopkinson, D. A., Robson, E. B. The incidence of rare alleles determining electrophoretic variants: data on 43 enzyme loci in man. Ann. Hum. Genet. 37: 237-253, 1974. [PubMed: 4812947] [Full Text: https://doi.org/10.1111/j.1469-1809.1974.tb01832.x]
Holmes, S. L., Turner, B. M., Hirschhorn, K. Human inosine triphophatase: catalytic properties and population studies. Clin. Chim. Acta 97: 143-153, 1979. [PubMed: 487601] [Full Text: https://doi.org/10.1016/0009-8981(79)90410-8]
Hopkinson, D. A., Povey, S., Solomon, E., Bobrow, M., Gormley, I. P. Confirmation of the assignment of the locus determining ADA to chromosome 20 in man: data on possible synteny of ADA and ITP in human-Chinese hamster somatic cell hybrids. Birth Defects Orig. Art. Ser. XII(7): 159-160, 1976. Note: Alternate: Cytogenet. Cell Genet. 16: 159-160, 1976.
Kevelam, S. H., Bierau, J., Salvarinova, R., Agrawal, S., Honzik, T., Visser, D., Weiss, M. M., Salomons, G. S., Abbink, T. E. M., Waisfisz, Q., van der Knaap, M. S. Recessive ITPA mutations cause an early infantile encephalopathy. Ann. Neurol. 78: 649-658, 2015. [PubMed: 26224535] [Full Text: https://doi.org/10.1002/ana.24496]
Lin, S., McLennan, A. G., Ying, K., Wang, Z., Gu, S., Jin, H., Wu, C., Liu, W., Yuan, Y., Tang, R., Xie, Y., Mao, Y. Cloning, expression, and characterization of a human inosine triphosphate pyrophosphatase encoded by the ITPA gene. J. Biol. Chem. 276: 18695-18701, 2001. [PubMed: 11278832] [Full Text: https://doi.org/10.1074/jbc.M011084200]
Meera Khan, P., Pearson, P. L., Wijnen, L. L. L., Doppert, B. A., Westerveld, A., Bootsma, D. Assignment of inosine triphosphatase gene to gorilla chromosome 13 and to human chromosome 20 in primate-rodent somatic cell hybrids. Birth Defects Orig. Art. Ser. XII(7): 420-421, 1976. Note: Alternate: Cytogenet. Cell Genet. 16: 420-421, 1976.
Mohandas, T., Sparkes, R. S., Passage, M. B., Sparkes, M. C., Miles, J. H., Kaback, M. M. Regional mapping of ADA and ITP on human chromosome 20: cytogenetic and somatic cell studies in an X/20 translocation. Cytogenet. Cell Genet. 26: 28-35, 1980. [PubMed: 7371431] [Full Text: https://doi.org/10.1159/000131418]
Rudd, N. L., Bain, H. W., Giblett, E., Chen, S.-H., Worton, R. G. Partial trisomy 20 confirmed by gene dosage studies. Am. J. Med. Genet. 4: 357-364, 1979. [PubMed: 231907] [Full Text: https://doi.org/10.1002/ajmg.1320040407]
Stepchenkova, E. I., Tarakhovskaya, E. R., Spitler, K., Frahm, C., Menezes, M. R., Simone, P. D., Kolar, C., Marky, L. A., Borgstahl, G. E. O., Pavlov, Y. I. Functional study of the P32T ITPA variant associated with drug sensitivity in humans. J. Molec. Biol. 392: 602-613, 2009. [PubMed: 19631656] [Full Text: https://doi.org/10.1016/j.jmb.2009.07.051]
Stumpf, A. M. Personal Communication. Baltimore, Md. 10/23/2020.
Sumi, S., Marinaki, A. M., Arenas, M., Fairbanks, L., Shobowale-Bakre, M., Rees, D. C., Thein, S. L., Ansari, A., Sanderson, J., De Abreu, R. A., Simmonds, H. A., Duley, J. A. Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency. Hum. Genet. 111: 360-367, 2002. [PubMed: 12384777] [Full Text: https://doi.org/10.1007/s00439-002-0798-z]
Taylor, B. A., Walls, D. M., Wimsatt, M. J. Localization of inosine triphosphatase locus (Itp) on chromosome 2 of the mouse. Biochem. Genet. 25: 267-274, 1987. [PubMed: 3038074] [Full Text: https://doi.org/10.1007/BF00499320]
Thompson, A. J., Fellay, J., Patel, K., Tillmann, H. L., Naggie, S., Dongliang, G. E., Urban, T. J., Shianna, K. V., Muir, A. J., Fried, M. W., Afdhal, N. H., Goldstein, D. B., McHutchison, J. G. Variants in the ITPA gene protect against ribavirin-induced hemolytic anemia and decrease the need for ribavirin dose reduction. Gastroenterology 139: 1181-1189, 2010. [PubMed: 20547162] [Full Text: https://doi.org/10.1053/j.gastro.2010.06.016]