GENOTYPIC AND PHENOTYPIC ANALYSIS OF THE POLYMORPHIC THIOPURINE S-METHYLTRANSFERASE GENE (TPMT) IN A EUROPEAN POPULATION

1 Characterization of allelic variants of the TPMT gene (TPMT) respons ible for changes in TPMT activity, and elucidation of the mechanism by which these alleles act, are required because of the clinical importa nce of this polymorphism for patients receiving thiopurine drugs. 2 We defined the mutational and allelic spectrum of TPMT in a group of 191 Europeans. Using PCR SSCP, we screened for mutation the entire coding sequence, the exon-intron boundaries, the promoter region and the 3'- flanking region of the gene. Six mutations were detected throughout th e ten exons and seven TPMT alleles were characterized. Four of them, T PMT2, *3A, *3C and *7, harbouring the known mutations, G238C, G460A, A719G or T681G, were nonfunctional and accounted for 0.5, 5.7, 0.8 and 0.3% of the allele totality, respectively. 3 Within the promoter regi on, six alleles corresponding to a variable number of tandem repeats ( VNTR), were identified. VNTRV4 and *V5a which harbour four or five re peats of a 17-18 bp unit, were the most frequent (55% and 34%, respect ively). The other VNTR alleles, having from five to eight repeats, wer e rarer. 4 The TPMT phenotype was correctly predicted by genotyping fo r 87% of individuals. A clear negative correlation between the total n umber of repeats from both alleles and the TPMT activity level was obs erved, indicating that VNTRs contribute to interindividual variations of TPMT activity. Therefore, additional analysis of the promoter regio n of TPMT can improve the phenotype prediction rate by genotyping.