1 Characterization of allelic variants of the TPMT gene (TPMT) responsible for changes in TPMT activity, and elucidation of the mechanism by which these alleles act, are required because of the clinical importance of this polymorphism for patients receiving thiopurine drugs. 2 We de®ned 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'-¯anking region of the gene. Six mutations were detected throughout the ten exons and seven TPMT alleles were characterized. Four of them, TPMT*2, *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 region, six alleles corresponding to a variable number of tandem repeats (VNTR), were identi®ed. VNTR*V4 and *V5a which harbour four or ®ve repeats of a 17 ± 18 bp unit, were the most frequent (55% and 34%, respectively). The other VNTR alleles, having from ®ve to eight repeats, were rarer. 4 The TPMT phenotype was correctly predicted by genotyping for 87% of individuals. A clear negative correlation between the total number of repeats from both alleles and the TPMT activity level was observed, indicating that VNTRs contribute to interindividual variations of TPMT activity. Therefore, additional analysis of the promoter region of TPMT can improve the phenotype prediction rate by genotyping.

No abstract

No abstract