NUDT15 deficiency and thiopurine toxicity

Thiopurines are a class of immunosuppressant and antineoplastic agents

• are widely used in the treatment of inflammatory bowel disease, haematological malignancies and autoimmune diseases, but can cause significant toxicity
• toxicity secondary to an inherited loss-of-function mutations in the nudix hydrolase 15 (NUDT15) gene has been reported (1,2)
  • inherited gene mutations in thiopurine-S-methyltransferase (TPMT) and NUDT15 can substantially increase an individual's risk of severe thiopurine toxicity
  • TPMT and NUDT15 encode 2 eponymous enzymes that play essential roles in thiopurine metabolism
  • a review notes that (1) individuals of Hispanic and Asian descent, who are more likely to develop thiopurine toxicity, rarely possess mutations in the TPMT gene
    • `pharmacoepidemiological data suggest that the loss-of-function *3 NUDT15 mutation drives thiopurine intolerance in these patient populations
    • prevalence of NUDT15 alleles differs among ancestral groups with populations of South and East Asian, African and Hispanic descents having the highest prevalence of NUDT15 variant (2)
    • NUDT15 variants are more frequent in Asian and African populations and only present in approximately 2% of individuals of European ethnicity (2)

Reference:

1. Wu AS, Mozessohn L, Kim RB, Zipursky JS. Severe myelosuppression and alopecia after thiopurine initiation in a patient with NUDT15 deficiency. Br J Clin Pharmacol. 2025; 1-5.
2. Afrin S et al. Nudix hydrolase 15 (NUDT15) loss-of-function variants in an Australian inflammatory bowel disease population. Intern Med J. 2022 Nov;52(11):1971-1977.