Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians

A and A719-->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 G238-->C). Site-directed mutagenesis and heterologous expression established that either TPMT*3 mutation alone leads to a reduction in catalytic activity (G460-->A, ninefold reduction; A719-->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 approximately 75 percent of unrelated white subjects with heterozygous phenotypes, indicating that TPMT*3 is the most prevalent mutant allele associated with TPMT-deficiency in Caucasians. -->

Jazyk:	English
Přístupová URL adresa:	https://explore.openaire.eu/search/publication?articleId=pmid_dedup__::f9cd757b846ef70aa6e242c65740c82d https://europepmc.org/articles/PMC1914689/
Rights:	OPEN
Přírůstkové číslo:	edsair.pmid.dedup....f9cd757b846ef70aa6e242c65740c82d
Autor:	Tai, H. -L, Krynetski, E. Y., Yates, C. R., Loennechen, T., Michael Fessing, Krynetskaia, N. F., Evans, W. E.
Jazyk:	angličtina
Rok vydání:	1996
Předmět:	Male S-Adenosylmethionine DNA Complementary Erythrocytes Base Sequence Mercaptopurine Molecular Sequence Data DNA Neoplasm Methyltransferases Precursor Cell Lymphoblastic Leukemia-Lymphoma Methylation Recombinant Proteins White People Kinetics Gene Frequency Child Preschool Yeasts Enzyme Stability Humans Point Mutation Amino Acid Sequence RNA Messenger Cloning Molecular Polymorphism Restriction Fragment Length Research Article
Zdroj:	Scopus-Elsevier
Popis:	The autosomal recessive trait of thiopurine S-methytransferase (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 (G460-->A and A719-->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 G238-->C). Site-directed mutagenesis and heterologous expression established that either TPMT*3 mutation alone leads to a reduction in catalytic activity (G460-->A, ninefold reduction; A719-->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 approximately 75 percent of unrelated white subjects with heterozygous phenotypes, indicating that TPMT*3 is the most prevalent mutant allele associated with TPMT-deficiency in Caucasians.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=pmid_dedup__::f9cd757b846ef70aa6e242c65740c82d https://europepmc.org/articles/PMC1914689/ Zobrazit plný text záznamu