Identification of a novel thiopurine S-methyltransferase allele (TPMT*37).
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.
aDepartment of Surgical Sciences, Dunedin School of Medicine, University of Otago, Dunedin bDepartment of Medicine, University of Otago Christchurch, Christchurch, New Zealand.
Rebecca L
RL
Roberts
Mary C
MC
Wallace
Jill M
JM
Drake
Lisa K
LK
Stamp
D000368:Aged; D000483:Alleles; D000595:Amino Acid Sequence; D001379:Azathioprine / Q000009:adverse effects / Q000627:therapeutic use; D059472:Exome / Q000235:genetics; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics*; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects / Q000627:therapeutic use; D008780:Methyltransferases / Q000235:genetics* / Q000302:isolation & purification; D009154:Mutation; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA; D044465:White People
D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine