Thiopurine S-methyltransferase deficiency: Two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in caucasians
- Univ. of Tennessee, Memphis, TN (United States); and others
The autosomal recessive trait of thiopurine S-methyltransferase (TPMT) deficiency is associated with severe hematopoietic toxicity when patients are treated with standard doses of mercaptopurine, azathioprine, or thioguanine. To define the molecular mechanism of this genetic polymorphism, we cloned and characterized the cDNA of a TPMT-deficient patient, which revealed a novel mutant allele (TPMT*3) containing two nucleotide transitions (G{sup 460}{yields}A and A{sup 719}{yields}G) producing amino acid changes at codons 154 (Ala{yields}Thr) and 240 (Tyr{yields}Cys), differing from the rare mutant TPMT allele we previously identified (i.e., TPMT*2 with only G{sup 238}{yields}C). Site-directed mutagenesis and heterologous expression established that either TPMT*3 mutation alone leads to a reduction in catalytic activity (G{sup 460}{yields}A, ninefold reduction; A{sup 179}{yields}G, 1.4-fold reduction), while the presence of both mutations leads to complete loss of activity. Using mutation specific PCR-RFLP analysis, the TPMT*3 allele was detected in genomic DNA from {approx}75% of unrelated white subjects with heterozygous phenotypes, indicating that TPMT*3 is the most prevalent mutant allele associated with TPMT-deficiency in Caucasians. 31 refs., 5 figs., 1 tab.
- OSTI ID:
- 285049
- Journal Information:
- American Journal of Human Genetics, Vol. 58, Issue 4; Other Information: PBD: Apr 1996
- Country of Publication:
- United States
- Language:
- English
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