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Clinical Chemistry 50: 2182-2184, 2004; 10.1373/clinchem.2004.039685
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(Clinical Chemistry. 2004;50:2182-2184.)
© 2004 American Association for Clinical Chemistry, Inc.

Technical Briefs

Rapid Detection of ITPA 94C>A and IVS2 + 21A>C Gene Mutations by Real-Time Fluorescence PCR and in Vitro Demonstration of Effect of ITPA IVS2 + 21A>C Polymorphism on Splicing Efficiency

Tanja Heller, Michael Oellerich, Victor William Armstrong and Nicolas von Ahsena

1 Department of Clinical Chemistry, George-August-University, Robert-Koch-Strasse 40, 37099 Göttingen, Germany;

aauthor for correspondence: fax 49-551-39-8551, e-mail nahsen@gwdg.de

The first 300 words of the full text of this article appear below.

Inosine triphosphatase (ITPA; EC 3.6.1.19) catalyzes the hydrolysis of ITP to inosine monophosphate, thereby recycling purines that might otherwise be trapped in the form of ITP (1)(2). Two single-nucleotide polymorphisms associated with ITPA deficiency have been identified in the ITPA gene. Individuals who are homozygous for a 94C>A (P32T) mutation have a total deficiency of enzyme activity and accumulate ITP intracellularly, whereas 94C>A heterozygotes have decreased ITPA activity that is 22.5% of the control mean value (2). A second mutation, IVS2 + 21A>C, was detected in ITPA-deficient families. This intronic mutation has a more subtle effect on ITPA activity, and heterozygotes have activities that are, on average, ~60% of the control mean. It was presumed that the IVS2 + 21A>C mutation alters the relatively conserved adenine of a putative splicing branch site, leading to abnormal mRNA splicing (2).

Although ITPA deficiency is not related to any defined pathology in humans, it was recently demonstrated that polymorphisms in the ITPA gene associated with ITPA deficiency have pharmacogenomic implications for patients treated with thiopurines (3). In a retrospective study involving patients with inflammatory bowel disease receiving azathioprine, Marinaki et al. (3) observed that the 94C>A deficient allele was significantly related to the adverse drug reactions (ADRs) flu-like symptoms, rash, and pancreatitis.

The purine analog 6-mercaptopurine and its prodrug azathioprine (AZA) are widely used in the treatment of leukemia and autoimmune disease, and in transplantation. ADRs to these drugs have been related to a genetic deficiency of thiopurine S-methyltransferase (TPMT; EC 2.1.1.67), which is a key enzyme of thiopurine drug catabolism (4). TPMT deficiency leads to life-threatening myelosuppression by accumulation of active thiopurine metabolites (5). Most ADRs to thiopurines, however, cannot be explained by TPMT deficiency. . . . [Full Text of this Article]




The following articles in journals at HighWire Press have cited this article:


Home page
 Clin. Chem.Home page
M. Shipkova, K. Lorenz, M. Oellerich, E. Wieland, and N. von Ahsen
Measurement of Erythrocyte Inosine Triphosphate Pyrophosphohydrolase (ITPA) Activity by HPLC and Correlation of ITPA Genotype-Phenotype in a Caucasian Population
Clin. Chem., February 1, 2006; 52(2): 240 - 247.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Chem.Home page
N. von Ahsen, V. W. Armstrong, C. Behrens, C. von Tirpitz, A. Stallmach, H. Herfarth, J. Stein, P. Bias, G. Adler, M. Shipkova, et al.
Association of Inosine Triphosphatase 94C>A and Thiopurine S-Methyltransferase Deficiency with Adverse Events and Study Drop-Outs under Azathioprine Therapy in a Prospective Crohn Disease Study
Clin. Chem., December 1, 2005; 51(12): 2282 - 2288.
[Abstract] [Full Text] [PDF]


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