Annotated PGx Gene Information for TPMT
Submitted by: Liewei Wang, Linda Pelleymounter, Richard Weinshilboum and Julie A. Johnson(PPII)
Reviewed by: Reviewed
Submitted date: January 19, 2007
| Gene HGNC Name: | TPMT |
|---|---|
| Introductory Information: | Thiopurine S-methyltransferase (TPMT; S-adenosyl-L-methionine:thiopurine S-methyltransferase; EC 2.1.1.67) catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine (6-MP) and azathioprine as well as other aromatic and heterocyclic sulfhydryl compounds [PMID:13981612, 6838629]. Weinshilboum and Sladek (1980) [PMID: 7191632 ] reported trimodality for level of red cell TPMT among 298 randomly selected Caucasian subjects: 88.6% had high enzyme activity; 11.1% had intermediate activity and 0.3% had undetectable activity. This distribution conformed to Hardy-Weinberg expectations for a pair of autosomal codominant alleles for low and high activity, TPMT-L and TPMT-H, with frequencies of 0.059 and 0.941, respectively. Segregation analysis was consistent with this hypothesis. This genetic polymorphism has been shown to be an important factor in individual variations in response to thiopurine drug therapy. 6-MP is inactivated, in part, by S-methylation, catalyzed by TPMT. An alternative "metabolic activation" process leads to the formation of cytotoxic 6-thioguanine nucleotides (6-TGN). In addition, 6-MP is metabolized to methyl-thioinosine monophosphate which inhibits de novo purine synthesis adding another mechanism of cytotoxicity [PMID: 4328325, 14576848]. Lennard et al. (1987, 1990) [PMID: 3467886, 1973780 ] showed that, in the children with acute lymphoblastic leukemia (ALL) who were treated with 6-MP, red cell 6-TGN correlated inversely with RBC TPMT activity, i.e., the lower the level of S-methylation the more drug would be available for metabolism to form the cytotoxic 6-TGNs. It was also demonstrated that subjects with very low RBC TPMT ( i.e., those homozygous for that trait) were at greatly increased risk for life-threatening myelosuppression when they were treated with "standard" doses of thiopurine drugs [PMID: 2758725, 1960624]. Conversely, patients with ALL who had 6-TGN concentrations below the group mean had higher TPMT activities and a higher subsequent relapse rate. Individuals heterozygous for functional variants tolerate 6-MP intermediate between homozygous deficient and homozygous wildtype patients [PMID: 11304783 ]. RBC TPMT levels have been found to correlate with levels in other tissues such as liver, kidney, and lymphocytes [PMID: 7138494, 1306116]. Therefore, the TPMT genetic polymorphism is a significant factor responsible for serious adverse drug reactions (myelosuppression) in patients treated with thiopurines and may also contribute to individual variation in therapeutic efficacy [PMID: 15784872]. TPMT has become one of a small number of examples in pharmacogenomics to be "translated" into routine clinical care. The human TPMT gene is 34 kb in length, consists of 10 exons, maps to chromosome 6p22.3 [PMID: 8561894] and has a pseudogene located on chromosome 18 [PMID: 7628307]. Twenty-one variant alleles had been identified up to 2006 which are, or might be, associated with decreased activity. Eighteen included nonsynonymous SNPs [PMID: 16220112]. Among those, TPMT*2,*3A,*3B, and *3C have been intensively studied both with regard to their clinical implications and/or molecular mechanisms. Szumlanski et al. (1996) [PMID: 8561894] and Tai et al. (1996) [PMID: 8644731] described TPMT*3A (187680.0002), the most common variant allele associated with low TPMT activity in Caucasians (frequency approximately 5%). TPMT*3A contains two nonsynonymous cSNPs, one in exon 7 and another in exon 10 that result in Ala154Thr and Try240Cys alterations in encoded amino acids. TPMT*3B occurs rarely and contains only the exon 7 SNP while TPMT*3C contains the exon 10 SNP and is the most common variant allele in East Asian and African American populations (frequency approximately 2%). TPMT*2 was the first variant allele described, resulting in an Ala80Pro amino acid substitution (*2; 187680.0001) [PMID: 7862671], but this allele is much less common than either TPMT*3A or *3C. It was also shown that expression of TPMT*2 and *3A were comparable in wild-type and mutant cDNA s, but wild-type had an ~100 fold higher enzymatic activity than mutant TPMT [PMID: 9177237]. Gene expression did not correlate with protein activity in TPMT*2 and *3 [PMID: 7862671, 9177237]. Tai et al. (1997)[PMID: 9177237] showed that enhanced degradation of TPMT allozymes encoded by the TPMT*2 and TPMT*3A alleles is the mechanism for decreased levels of TPMT protein and catalytic activity inherited as a result of these alleles. Subsequent studies performed by Wang et al. (2003, 2005) [PMID: 12972954, 15967990] demonstrated that the rapid degradation of TPMT *3A involves molecular chaperones such as the heat shock proteins hsp70 and hsp90, and that TPMT*3A can also form intracellular aggresomes, both processes that contribute to the low levels of protein and activity observed in the tissues of subjects with this allele. TPMT*4 and *15 involve alterations in canonical mRNA splice site sequences [PMID: 15083071, 9486974], resulting in alternative TPMT mRNA splicing and decreased enzyme expression. All of these SNPs associated with low TPMT activity have different allele frequencies among various ethnic groups. *3A is the most common allele in Caucasians, with a frequency about 5%. However, *3C is the most common allele in African American and East Asian populations [PMID: 9931346, 9931345, 10634140, 10208641]. |
| Key PubMed IDs: | 13981612, 6838629, 7191632, 8561894, 9177237, 8644731, 7862671, 1973780, 2758725, 9931346, 10634140, 9931345, 9486974, 15967990, 12972954, 8561894, 15784872, 11304783, 7628307, 14576848, 4328325, 7138494, 1306116 , 3467886, 1960624, 15083071, 10208641 |
| Key Pathways: | Thiopurine metabolism pathway |
| Drugs/Substrates: | 6-mercaptopurine, azathioprine (a "prodrug" that is converted to 6-MP in vivo ), 6-thioguanine [PMID: 1451710] |
| Phenotypes/Diseases: | The variant alleles ( *3A, *3B, *3C and *2) result in significant decreases in levels of TPMT protein and, therefore, enzyme activity [PMID: 8561894, 8644731, 7862671, 9177237, 11304783 ]. *4 results in a truncated protein and is associated with decreased enzyme activity [PMID: 9486974] . *3A, *3B, *3C and *2 are associated with thiopurine drug-related toxicity (myelosuppression), which is associated with increased RBC 6-TGN levels and bone marrow suppression after treatment with standard doses of thiopurine drugs [PMID: 2758725 , 1960624]. Thiopurine therapy plays a role in the treatment of autoimmune diseases, inflammatory bowel diseases, lupus, and transplantation [PMID: 1451710]. |
| Important Variants: | *2, *3B, *3C, *4 |
| Important Haplotypes: | *3A Haplotype publication references include [PMID: 8561894] and [ PMID: 8644731] . |