Characterization of a novel TPMT mutation associated with azathioprine-induced myelosuppression

Azathioprine (AZA), a prodrug of 6-mercaptopurine, is prescribed in evolving forms of inflammatory bowel disease (IBD), affecting predominantly White adolescents and young adults. Thiopurine S-methyltransferase (TPMT) catabolizes AZA and its genetic polymorphism affects the balance between active 6-thioguanine nucleotides (6-TGN) intracellular concentrations [recommended target 235–400 pmol per 8 × 108 red blood cells (RBC)] and hepatotoxic 6-methylmercaptopurine ribonucleotides (6-MMP) [1]. Three polymorphisms (TPMT*2, *3B, *3C; rs1800462, rs1800460, rs1142345, respectively) account for >95% of variant alleles, but additional rare variants are described (TPMT*1S to TPMT*25) [2]. Approximately 90% of Whites are extensive metabolizers with two wild-type TPMT alleles, 6–11% are intermediate metabolizers and 0.2–0.6% are TPMT-deficient patients, exposed to severe myelotoxicity as they accumulate high 6-TGN concentrations under AZA conventional doses [3]. This case reports a pancytopenia under AZA treatment for IBD. As 6-TGN and 6-MMP concentrations and TPMT genotype based on the three predominant polymorphisms were discordant, we conducted additional genetic analysis and identified a new, never described TPMT mutation affecting TPMT activity.