Abstract
Human ITPase (encoded by the ITPA gene) is a protective enzyme which acts to exclude noncanonical (deoxy)nucleoside triphosphates ((d)NTPs) such as (deoxy)inosine 5′-triphosphate ((d)ITP), from (d)NTP pools. Until the last few years, the importance of ITPase in human health and disease has been enigmatic. In 2009, an article was published demonstrating that ITPase deficiency in mice is lethal. All homozygous null offspring died before weaning as a result of cardiomyopathy due to a defect in the maintenance of quality ATP pools. More recently, a whole exome sequencing project revealed that very rare, severe human ITPA mutation results in early infantile encephalopathy and death. It has been estimated that nearly one third of the human population has an ITPA status which is associated with decreased ITPase activity. ITPA status has been linked to altered outcomes for patients undergoing thiopurine or ribavirin therapy. Thiopurine therapy can be toxic for patients with ITPA polymorphism, however, ITPA polymorphism is associated with improved outcomes for patients undergoing ribavirin treatment. ITPA polymorphism has also been linked to early-onset tuberculosis susceptibility. These data suggest a spectrum of ITPA-related disease exists in human populations. Potentially, ITPA status may affect a large number of patient outcomes, suggesting that modulation of ITPase activity is an important emerging avenue for reducing the number of negative outcomes for ITPA-related disease. Recent biochemical studies have aimed to provide rationale for clinical observations, better understand substrate selectivity and provide a platform for modulation of ITPase activity.
Highlights
Inosine triphosphate pyrophosphatase (ITPase) has a critical role in sanitizing nucleotide pools by removingnucleoside triphosphates ((d)NTPs) containing noncanonical purines [1,2,3,4,5,6,7]
The goal of this review is to: (1) strengthen the connection between basic science and clinical studies; (2) summarize the many disparate clinical outcomes that have recently been linked to ITPA polymorphism/mutation; (3) argue in favor of viewing ITPA variation as a disease spectrum; and (4) suggest rationale for modulation of ITPase activity in an effort to reduce the number of negative outcomes for ITPA-related disease
With two examples of lethality due to severe homozygous ITPA defects (Itpa knockout mouse data [6] and infantile encephalopathy data [32]), along with an example of increased fitness due to potential ITPA overexpression (TB susceptibility data [44]), it seems more likely that there is a spectrum of ITPA-related disease as Kevelam et al suggested [32]
Summary
Inosine triphosphate pyrophosphatase (ITPase) has a critical role in sanitizing nucleotide pools by removing (deoxy)nucleoside triphosphates ((d)NTPs) containing noncanonical purines [1,2,3,4,5,6,7]. ITPase is a pyrophosphohydrolase and converts noncanonical purine (d)NTPs, such as (deoxy)inosine 5′-triphosphate ((d)ITP), into their corresponding nucleoside monophosphate ((d)NMP); releasing pyrophosphate (PPi) [8] (Fig. 1). Noncanonical purine (d)NTPs spontaneously arise in cells. Yeast and murine systems has demonstrated that ITPase deficiency and/ or polymorphism can result in sensitivity to noncanonical purines, increased mutation rates, delayed cell cycle progression, DNA damage and chromosomal abnormalities such as double-strand breaks [17,18,19,20,21]
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