A role for ITPA variants in the clinical course of pulmonary Langerhans' cell histiocytosis?

Bakker, J.; Bierau, Jörgen; Drent, Marjolein

doi:10.1183/09031936.00026610

Cited by 10 publications

(7 citation statements)

References 12 publications

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“…This is in contrast to a reference population which only had 11% ITPA deficiency. Interestingly, the same three patients with ITPA deficiency also had an unfavorable clinical outcome [96]. Although an intriguing result, further work is needed with larger sample sizes to see if this association is genuine.…”

Section: Itpa Deficiency In Humansmentioning

confidence: 99%

ITPA (inosine triphosphate pyrophosphatase): From surveillance of nucleotide pools to human disease and pharmacogenetics

Simone

Pavlov

Borgstahl

2013

Mutation Research/Reviews in Mutation Research

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Cellular nucleotide pools are often contaminated by base analog nucleotides which interfere with a plethora of biological reactions, from DNA and RNA synthesis to cellular signaling. An evolutionarily conserved inosine triphosphate pyrophosphatase (ITPA) removes the non-canonical purine (d)NTPs inosine triphosphate and xanthosine triphosphate by hydrolyzing them into their monophosphate form and pyrophosphate. Mutations in the ITPA orthologs in model organisms lead to genetic instability and, in mice, to severe developmental anomalies. In humans there is genetic polymorphism in ITPA. One allele leads to a proline to threonine substitution at amino acid 32 and causes varying degrees of ITPA deficiency in tissues and plays a role in patients’ response to drugs. Structural analysis of this mutant protein reveals that the protein is destabilized by the formation of a cavity in its hydrophobic core. The Pro32Thr allele is thought to cause the observed dominant negative effect because the resulting active enzyme monomer targets both homo- and heterodimers to degradation.

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Section: Itpa Deficiency In Humansmentioning

confidence: 99%

ITPA (inosine triphosphate pyrophosphatase): From surveillance of nucleotide pools to human disease and pharmacogenetics

Simone

Pavlov

Borgstahl

2013

Mutation Research/Reviews in Mutation Research

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“… 32 In addition, it has been speculated that ITPA has a role in immunity. 33 The variant rs13830 is located in the 3′-UTR of ITPA and polymorphisms in the 3′-UTR of a gene may affect regulation of messenger RNA transcripts and gene expression. 34–36 The eQTL analysis showed that the expression level of ITPA in lymphocyte cell lines differed according to rs13830 genotype, with higher expression in the minor ‘A’ allele.…”

Section: Discussionmentioning

confidence: 99%

Identification of ITPA on chromosome 20 as a susceptibility gene for young-onset tuberculosis

et al. 2016

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Tuberculosis (TB) is a complex disease, and both genetic and environmental factors contribute to disease progression. A previous genome-wide linkage study in Thailand determined that chromosome 20p13-12.3 may contain risk factors for young-onset disease. The present study aimed to identify novel susceptibility genes for young-onset TB within a 1-Mbp target region adjacent to the top-ranking risk marker in Chr.20p13-12.3. We performed next-generation sequencing (NGS) of the region in 13 young patients from multi-case families in Thailand. We then selected the functionally interesting single-nucleotide polymorphisms as candidates for subsequent analyses. The detected candidates rs13830 and rs1127354 in ITPA showed an association with young (<45 years old) TB patients. However, there was no association in old (⩾45 years old) patients. These findings confirm that stratifying patients based on age of TB onset can be important for identifying genetic risk factors for TB susceptibility. In addition, in silico expression quantitative trait loci analyses indicated that ITPA expression was associated with rs13830 genotype. This is the first study to use NGS resequencing to gain insight into host genetic factors associated with TB and to report a significant association for ITPA with host susceptibility in young-onset TB. The study also demonstrated the effectiveness of NGS in identifying susceptibility genes in common diseases.

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“…To this day, no overt causal clinical entity has been associated with deficiency of ITPase [8], [9], [10]. However, ITPA genotype may influence the clinical outcome of certain clinical conditions [11]. Until recently, pharmacogenetic consequences of ITPA have solely been implicated for the thiopurine drugs azathioprine and 6-mercaptopurine [4], [12].…”

Section: Introductionmentioning

confidence: 99%

Erythrocyte Inosine Triphosphatase Activity Is Decreased in HIV-Seropositive Individuals

et al. 2012

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BackgroundInosine triphosphatase (ITPase) is encoded by the polymorphic gene ITPA and maintains low intracellular levels of the inosine nucleotides ITP and dITP. The most frequently reported polymorphisms are ITPA c.94C>A (rs 1127354) and ITPA c. 124+21 A>C (rs7270101). Some nucleoside-analogues used in the treatment of HIV-seropositive (HIV+) patients are potential substrates for ITPase. Therefore, the frequency of ITPA SNPs and ITPase activity were studied in a population of HIV+-patients.MethodsThe study population consisted of 222 patients, predominantly Caucasian males, >95% using HAART. Erythrocyte ITPase activity was determined by measuring the formation of IMP from ITP. ITPA genotype was determined by sequencing genomic DNA. Distribution of ITPase activity, genotype-phenotype correlation and allele frequencies were compared to 198 control subjects. The effect of nucleoside analogues on ITPase activity was studied using lymphoblastic T-cell cultures and human recombinant ITPase. Enzyme kinetic experiments were performed on erythrocyte ITPase from HIV+ patients and controls.ResultsNo difference was observed in the allele frequencies between the HIV+-cohort (± HAART) and the control population. HIV+ carriers of the wild type and ITPA c.94C>A had significantly lower ITPase activities than control subjects with the same genotype (p<0.005). This was not observed in ITPA c. 124+21 A>C carriers. Nucleoside analogues did not affect ITPase activity in cell culture and human recombinant ITPase. Conclusion: ITPA population genetics were identical in HIV+ and control populations. However, the majority of HIV+-patients had decreased erythrocyte ITPase activity compared to controls, probably due to decreased amounts of ITPase protein. It seems unlikely that ITPase activity is decreased due to nucleoside analogues (HAART). Long-term effects of HIV-infection altering ITPase protein expression or stability may explain the phenomenon observed.

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A role for ITPA variants in the clinical course of pulmonary Langerhans' cell histiocytosis?

Cited by 10 publications

References 12 publications

ITPA (inosine triphosphate pyrophosphatase): From surveillance of nucleotide pools to human disease and pharmacogenetics

ITPA (inosine triphosphate pyrophosphatase): From surveillance of nucleotide pools to human disease and pharmacogenetics

Identification of ITPA on chromosome 20 as a susceptibility gene for young-onset tuberculosis

Erythrocyte Inosine Triphosphatase Activity Is Decreased in HIV-Seropositive Individuals

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