Thiopurine S-methyltransferase deficiency

Two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians

Hung Liang Tai, Eugene Y. Krynetski, Charles Yates, Thrina Loennechen, Michael Y. Fessing, Natalia F. Krynetskaia, William E. Evans

Research output: Contribution to journalArticle

311 Citations (Scopus)

Abstract

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 460→A and A 719→G) producing amino acid changes at codons 154 (Ala→Thr) and 240 (Tyr→Cys), differing from the rare mutant TPMT allele we previously identified (i.e., TPMT*2 with only G 238→C). Site-directed mutagenesis and heterologous expression established that either TPMT*3 mutation alone leads to a reduction in catalytic activity (G 460→A, ninefold reduction; A 719→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 ≃75% of unrelated white subjects with heterozygous phenotypes, indicating that TPMT*3 is the most prevalent mutant allele associated with TPMT-deficiency in Caucasians.

Original languageEnglish (US)
Pages (from-to)694-702
Number of pages9
JournalAmerican Journal of Human Genetics
Volume58
Issue number4
StatePublished - 1996
Externally publishedYes

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thiopurine methyltransferase
Nucleotides
Alleles
Mutation
Thioguanine
6-Mercaptopurine
Azathioprine
Genetic Polymorphisms
Site-Directed Mutagenesis
Thiopurine S methyltranferase deficiency
Codon
Restriction Fragment Length Polymorphisms
Molecular Biology
Complementary DNA

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Thiopurine S-methyltransferase deficiency : Two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. / Tai, Hung Liang; Krynetski, Eugene Y.; Yates, Charles; Loennechen, Thrina; Fessing, Michael Y.; Krynetskaia, Natalia F.; Evans, William E.

In: American Journal of Human Genetics, Vol. 58, No. 4, 1996, p. 694-702.

Research output: Contribution to journalArticle

Tai, Hung Liang ; Krynetski, Eugene Y. ; Yates, Charles ; Loennechen, Thrina ; Fessing, Michael Y. ; Krynetskaia, Natalia F. ; Evans, William E. / Thiopurine S-methyltransferase deficiency : Two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. In: American Journal of Human Genetics. 1996 ; Vol. 58, No. 4. pp. 694-702.
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