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ITPA
inosine triphosphatase
ITPA is located on the short (p) arm of chromosome 20, at band 20p13. Arm ratio per GRCh38 - banding schematic.
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Overview
The ITPA gene encodes inosine triphosphatase, a metabolic enzyme responsible for maintaining the purity of the cellular nucleotide pool. This protein catalyses the hydrolysis of inosine triphosphate (ITP) and deoxyinosine triphosphate (dITP) to their respective monophosphate forms, preventing the misincorporation of these non-canonical nucleotides into RNA and DNA.
Variation in ITPA has gained clinical attention primarily through pharmacogenomics research. Reduced enzyme activity resulting from certain genetic variants has been associated with altered responses to thiopurine drugs, a class of medications used to treat inflammatory bowel disease, autoimmune conditions, and certain malignancies. Understanding an individual's ITPA genotype may inform treatment decisions in specific clinical contexts.
What the gene does
Inosine triphosphatase functions as a nucleotide pool sanitising enzyme, removing inosine triphosphate and deoxyinosine triphosphate from the cell. These molecules can arise through spontaneous deamination of adenine nucleotides or through enzymatic pathways, and their accumulation poses a threat to genomic integrity and cellular function.
The enzyme catalyses the hydrolysis of the triphosphate group, converting ITP to inosine monophosphate (IMP) and releasing pyrophosphate. This reaction is essential because DNA and RNA polymerases can mistakenly incorporate ITP and dITP in place of guanosine triphosphate during nucleic acid synthesis, potentially causing mutations or interfering with normal gene expression.
By maintaining low concentrations of these non-canonical nucleotides, ITPA helps preserve the fidelity of DNA replication and RNA transcription. The enzyme operates constitutively in most cell types, reflecting the ongoing need to counteract spontaneous nucleotide damage and maintain cellular nucleotide homeostasis.
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Chromosome location
ITPA is located on the short arm of chromosome 20 at position 20p13. The gene spans approximately 18 kilobases of genomic DNA and contains six exons that encode the 194-amino-acid protein. The chromosomal region surrounding ITPA contains several other genes involved in metabolic processes, though ITPA itself functions as an independent housekeeping gene expressed across most tissues.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Genetic variants in ITPA occur with appreciable frequency in human populations, with two polymorphisms-c.94C>A (p.Pro32Thr) and c.124+21A>C (an intronic variant affecting splicing)-being particularly well studied. These variants reduce enzyme activity to varying degrees, with homozygous or compound heterozygous carriers often showing substantially decreased ITPA function. The functional consequences of reduced enzyme activity have been most extensively investigated in the context of thiopurine drug metabolism, where variant carriers may experience different treatment outcomes.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.124+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Inosine triphosphatase deficiency |
c.124+2T>C | - | Pathogenic | ★★☆☆ | Inosine triphosphatase deficiency |
c.264-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Developmental and epileptic encephalopathy, 35 |
c.270G>A | p.Trp90Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Infantile epileptic dyskinetic encephalopathy |
c.359_366dup | p.Gly123fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hypodontia |
c.452G>A | p.Trp151Ter | Pathogenic | ★★☆☆ | Inosine triphosphatase deficiency |
c.466C>T | p.Gln156Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Inosine triphosphatase deficiency |
c.519del | p.Asn173fs | Pathogenic | ★★☆☆ | Infantile epileptic dyskinetic encephalopathy |
c.189+1G>A | - | Pathogenic | ★☆☆☆ | Developmental and epileptic encephalopathy, 35 |
c.359_365del | p.Leu120fs | Pathogenic | ★☆☆☆ | Developmental and epileptic encephalopathy, 35 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
ITPA variation does not cause a recognised Mendelian disease, and reduced enzyme activity appears to be well tolerated under normal circumstances. The clinical relevance of ITPA variants emerges primarily in pharmacogenomic contexts, particularly regarding thiopurine drugs such as azathioprine and mercaptopurine.
Research has explored whether ITPA genotype influences the likelihood of developing certain adverse effects during thiopurine treatment, with some studies suggesting that reduced ITPA activity may be associated with altered toxicity profiles. However, the relationship between genotype and clinical outcomes remains an area of ongoing investigation, and the utility of routine ITPA testing before thiopurine therapy initiation continues to be evaluated.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic ITPA variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
ITPA appears on several NHS Genomic Medicine Service gene panels, reflecting its potential relevance in specific diagnostic contexts. The gene is included as a green gene (high evidence) on the Early Onset or Syndromic Epilepsy panel (R59), the Intellectual Disability panel (R29), the Likely Inborn Error of Metabolism panel (R98), and the Undiagnosed Metabolic Disorders panel. These inclusions primarily relate to the enzyme's role in nucleotide metabolism and the theoretical potential for severe deficiency to affect neurological function, though ITPA-related conditions remain rare in clinical practice.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the ITPA enzyme do in the body?
ITPA removes inosine triphosphate and deoxyinosine triphosphate from cells, preventing these non-standard nucleotides from being mistakenly incorporated into DNA and RNA during replication and transcription.
Are ITPA variants associated with any health conditions?
ITPA variants do not typically cause disease on their own but have been studied in relation to how individuals respond to certain medications, particularly thiopurine drugs used to treat inflammatory bowel disease and some cancers.
Is ITPA deficiency inherited?
Reduced ITPA enzyme activity follows an autosomal recessive pattern, meaning two copies of a variant (one from each parent) are generally needed for substantially decreased enzyme function. Carriers with one variant copy typically have intermediate enzyme activity.