This TPMT variant is referred to as the TPMT*2 allele (Tai et al., 1996).
In an 8-year-old girl with thiopurine S-methyltransferase deficiency (THPM1; 610460) originally reported by Evans et al. (1991), Krynetski et al. (1995) identified a 238G-C transversion in the TPMT gene, resulting in an ala80-to-pro (A80P) substitution. The patient developed severe hematologic toxicity after conventional therapy for acute lymphoblastic leukemia with oral mercaptopurine. Functional expression studies in a yeast heterologous expression system showed that the A80P mutant enzyme had a 100-fold reduction in TPMT catalytic activity compared to the wildtype enzyme, despite a comparable level of mRNA expression. A mutation-specific PCR amplification method was developed and used to detect the same mutation in genomic DNA of the proposita and her mother. Krynetski et al. (1995) concluded that the patient had a second inactivating mutation.
Tai et al. (1997) showed that the TPMT*2 and TPMT*3A (187680.0002) mutant proteins showed enhanced degradation, thus resulting in decreased TPMT protein and catalytic activity.
Ameyaw et al. (1999) identified the TPMT*2 allele in 2 of 199 British Caucasian individuals (allele frequency of 0.5%) and none of 217 Ghanaian individuals, suggesting that it is restricted to the Caucasian population.
