Explaining TPMT genotype/phenotype discrepancy by haplotyping of TPMT*3A and identification of a novel sequence variant, TPMT*23.
Thiopurine methyltransferase (TPMT) is a polymorphic enzyme involved in the metabolism of thiopurine drugs. Owing to polymorphisms in the TPMT gene (TPMT*2-*22), the enzyme activity varies interindividually. Patients with reduced TPMT activity may develop adverse reactions when treated with standard doses of thiopurines. This work focuses on a TPMT genotype/phenotype discrepancy found in a patient during routine testing. The patient displayed very low TPMT enzyme activity and she was genotyped by pyrosequencing as being heterozygous for the 460G>A and 719A>G polymorphisms (TPMT*3A). Complete sequencing in combination with haplotyping of the TPMT gene revealed a novel sequence variant, 500C>G, on one allele and TPMT*3A on the other allele, giving rise to the novel genotype TPMT*3A/*23. When investigating the patient's relatives, they too had the TPMT*3A/*23 genotype in combination with low enzyme activity. We conclude that this novel variant allele affects enzyme activity, as the individuals carrying it had almost undetectable TPMT activity.
Lindqvist
Malin
M
Division of Clinical Pharmacology, Department of Medicine and Care, Faculty of Health Sciences, Linköping, Sweden. malin.lindqvist@imv.liu.se
Skoglund
Karin
K
Karlgren
Anna
A
Söderkvist
Peter
P
Peterson
Curt
C
Kidhall
Irene
I
Almer
Sven
S
D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005260:Female; D006239:Haplotypes; D006801:Humans; D008780:Methyltransferases / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D017433:Protein Structure, Secondary
D050505:Mutant Proteins; D008780:Methyltransferases; C022745:thiopurine methyltransferase