Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency

Abstract

Inosine triphosphate pyrophosphohydrolase (ITPase) deficiency is a common inherited condition characterized by the abnormal accumulation of inosine triphosphate (ITP) in erythrocytes. The genetic basis and pathological consequences of ITPase deficiency are unknown. We have characterized the genomic structure of the ITPA gene, showing that it has eight exons. Five single nucleotide polymorphisms were identified, three silent (138G-->A, 561G-->A, 708G-->A) and two associated with ITPase deficiency (94C-->A, IVS2+21A-->C). Homozygotes for the 94C-->A missense mutation (Pro32 to Thr) had zero erythrocyte ITPase activity, whereas 94C-->A heterozygotes averaged 22.5% of the control mean, a level of activity consistent with impaired subunit association of a dimeric enzyme. ITPase activity of IVS2+21A-->C homozygotes averaged 60% of the control mean. In order to explore further the relationship between mutations and enzyme activity, we examined the association between genotype and ITPase activity in 100 healthy controls. Ten subjects were heterozygous for 94C-->A (allele frequency: 0.06), 24 were heterozygotes for IVS2+21A-->C (allele frequency: 0.13) and two were compound heterozygous for these mutations. The activities of IVS2+21A-->C heterozygotes and 94C-->A/IVS2+21A-->C compound heterozygotes were 60% and 10%, respectively, of the normal control mean, suggesting that the intron mutation affects enzyme activity. In all cases when ITPase activity was below the normal range, one or both mutations were found. The ITPA genotype did not correspond to any identifiable red cell phenotype. A possible relationship between ITPase deficiency and increased drug toxicity of purine analogue drugs is proposed.

Thiopurines in inflammatory bowel disease: New strategies for optimization of pharmacotherapy?

“…TPMT allele frequencies found in our cohort of IBD patients were very similar to those reported in other Caucasian populations [31,38,39]: 238 (90.8%) patients carried wild-type alleles, 17 (6.5%) and 6 (2.2%) proved heterozygous for TPMT*3A and TPMT*3C respectively and 1 (0.4%) patient was a homozygous TPMT *3A mutant. ITPA allele frequencies in our population however, were higher than reported in other populations [40,41]: 173 (66.0%) patients carried wild-type alleles, 29 (11.1%) and 55 (21.0%) patients were heterozygous mutants for C94A and IVS2+A21C respectively and 1 (0.4%) and 4 (1.5%) homozygous mutants for C94A and IVS2+A21C respectively were identified. Five patients (1.9%) were compound heterozygotes for C94A and IVS2+A21C and 9 patients (3.4%) were compound heterozygotes for ITPA and TPMT mutant alleles [37].…”

“…Although increased frequencies of malignancies are reported in other patient populations on thiopurines, this seems not to be the case in IBD patients [40]. Moreover, in a decision analysis it was recently concluded that the benefits of thiopurines outweigh the potential risk of lymphoma [41]. Also, the use of thiopurines before or during pregnancy appears to be safe as there is no statistical difference in abortions, congenital malformations or neoplasia among IBD patients on thiopurines compared with healthy controls [42].…”

Crystal Structure of Human Inosine Triphosphatase

“…Of these, the mutation P32T abolished ITPase activity and caused accumulation of ITP in erythrocytes (6,7). ITPase activity was lost in individuals homozygous for the P32T mutation, and it was reduced to ϳ 25% in heterozygous subjects (8).…”

Evolving Trends in the Hepatitis C Virus Molecular Epidemiology Studies: From the Viral Sequences to the Human Genome

“…With the aim to detect predictor biomarkers that could evaluate possible risks over benefits from currently available treatment and thus avoid these side effects in patients who will not be helped by the treatment, as well as reduce the substantial cost of the treatment, recent studies indicated that genetic variants leading to inosine triphosphatase (ITPase) deficiency, a benign red cell enzymopathy [125], protect against hemolytic anemia in CHC patients receiving RBV. In an American GWAS, a strong association was shown between hemoglobin reduction after 4 weeks of treatment and SNP rs6051702 [126].…”

“…The association was explained by two known functional variants in the ITPA gene, located on chromosome 20 and encoding for inosine triphosphatase (ITPase). The two variants, a missense polymorphism in exon 2 (g.3141842C>A, P32T; rs1127354) and a splicealtering SNP located in the second intron (g.8838A>C, rs7270101), result in reduced enzyme activity: homozygosity for the P32T mutation leads to undetectable ITPase activity, accumulation of its substrate ITP in erythrocytes, and increased toxicity of purine analogue drugs [125,[127][128][129][130][131]. Conversely, reduced ITPase activity may be protective from RBV-induced hemolysis through the competition of ITP with RBV-TP [127,132].…”