TPMT*26 (208F→L), a novel mutation detected in a Chinese

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • More than 27 mutations in the TPMT gene causing decreased TPMT activity have been reported in various races. • Decreased TPMT activity is associated with increased myelosuppression from azathioprine or thioguanine treatment. • TPMT*3C is the most common genetic variant found in Asian populations. WHAT THIS STUDY ADDS • TPMT*26 (208F→L) is a novel mutation, previously not reported, which is associated with reduced TPMT activity in three siblings in an Asian Chinese family. • This mutation is associated with increased sensitivity to azathioprine clinically. AIMS Azathioprine, mercaptopurine and thioguanine are commonly used to treat autoimmune disorders, leukaemia and solid organ transplantation. However, azathiopurine and its metabolites can also cause adverse reactions such as myelosuppression. These manifestations may be attributed to polymorphisms or mutations in the thiopurine methyltransferase (TPMT) gene that might result in low TPMT enzyme activity. Our aim was to investigate if azathioprine‐related myelosuppression is associated with TPMT polymorphism, which in turn affects its enzyme activity. METHODS A 61‐year‐old Chinese man with severe atopic eczema developed moderate myelosuppression with standard doses of azathioprine. His TPMT activity was measured using radiochemical assay. Genotyping of TPMT *3C, *3A and *6 were screened using polymerase chain reaction‐restriction fragment length polymorphism. Novel mutation was detected by sequencing. Family studies of his three other siblings were performed. RESULTS After 4 weeks of azathioprine treatment, the patient's white blood cells and absolute neutrophil count dropped by 40–45%. He was then taken off azathioprine, and blood counts returned to normal. TPMT activity test showed intermediate levels of 9.1 nmol h −1  ml −1 peripheral red blood cells (pRBC). Resequencing of the TPMT gene revealed a missense mutation Phe→Leu at 208 aa position in exon 9 (ss105107120). Two of his three siblings were heterozygous for 208F→L, which accounts for the decreased enzyme activity (brother 8.9 nmol h −1  ml −1 pRBC, sister 8.8 nmol h −1  ml −1 pRBC). The remaining sibling had wild‐type allele with normal enzyme activity. Screening of 100 normal healthy Chinese subjects did not reveal any individual with this mutation. CONCLUSION We report a novel mutation TPMT*26 (208F→L) associated with a decrease in TPMT enzyme activity.