Identification of a novel thiopurine S-methyltransferase allele (TPMT*37)

Abstract

Thiopurine S-methyltransferase (TPMT) is a key enzyme in the methylation of the thiopurine drugs azathioprine and 6-mercaptopurine. TPMT is subject to genetic polymorphism that results in a trimodal distribution of enzyme activity. All poor methylators (PMs) and 30-60% of intermediate methylators develop potentially life-threatening myelosuppression on standard doses of azathioprine and 6-mercaptopurine because of excess production of the thioguanine nucleotides (6-TGNs). Over 95% of PMs are explained by the alleles TPMT*2 and TPMT*3, whereas one in 20 intermediate methylators are heterozygous for a novel PM allele. In this brief report, we describe the identification of a novel allele (TPMT*37) in a Caucasian male who had a red blood cell TPMT activity of 8.9 U/ml (reference range: 9.3-17.6 U/ml). TPMT*37 introduces a premature stop codon at position 216, resulting in loss of the last 29 amino acid residues from the C terminal of the TPMT protein.