HGNC Approved Gene Symbol: TPMT
Cytogenetic location: 6p22.3 Genomic coordinates (GRCh38): 6:18,128,311-18,155,169 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p22.3 | {Thiopurines, poor metabolism of, 1} | 610460 | Autosomal recessive | 3 |
Thiopurine S-methyltransferase (TPMT; S-adenosyl-L-methionine:thiopurine S-methyltransferase; EC 2.1.1.67) catalyzes the S-methylation of aromatic and heterocyclic sulfhydryl compounds, including the antineoplastic agents 6-mercaptopurine (6MP) and 6-thioguanine (6TG), and the immunosuppressant azathioprine (AZA) (Tai et al., 1996).
Honchel et al. (1993) isolated a cDNA corresponding to the TPMT gene from a T84 human colon carcinoma cell cDNA library. The deduced 245-amino acid protein has a molecular mass of 35 kD. COS-1 cells transfected with the cDNA expressed a high level of TPMT enzyme activity.
Szumlanski et al. (1996) determined that the TPMT gene is 34 kb long and contains 10 exons.
By screening of a phage artificial chromosome library, Krynetski et al. (1997) isolated clones corresponding to human TPMT, which they determined spanned 25 kb and contained 9 exons. Differences from the previously reported gene structure included 17 additional nucleotides upstream from the transcription start site and a shorter intron 8.
Seki et al. (2000) determined that the TPMT gene spans 27 kb and contains 9 exons; they did not identify intron 2 reported by Szumlanski et al. (1996).
Szumlanski et al. (1996) mapped the TPMT gene to chromosome 6 by analysis of human/rodent somatic cell hybrids and sublocalized it to 6p22.3 by fluorescence in situ hybridization.
Pseudogene
Lee et al. (1995) identified a processed TPMT pseudogene located on chromosome 18q21.1.
TPMT activity exhibits genetic heterogeneity due to polymorphisms in the TPMT gene. Weinshilboum and Sladek (1980) found trimodality for red cell TPMT activity among 298 randomly selected 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 in families ascertained through probands with undetectable activity was consistent with this hypothesis.
Klemetsdal et al. (1993) found that red blood cell TPMT activity was 8.3% higher in healthy males compared to females.
Cheng et al. (2005) used polymorphisms in the genes encoding TPMT, gamma-glutamyl hydrolase (GGH; 601509) and the reduced folate carrier (SLC19A1; 600424) to assess the nature of chromosomal acquisition and its influence on genotype-phenotype concordance in cancer cells. TPMT and GGH activities in somatic cells were concordant with germline genotypes, whereas activities in leukemia cells were determined by chromosomal number and whether the acquired chromosomes contained a wildtype or variant allele. Leukemia cells that had acquired an additional chromosome containing a wildtype TPMT or GGH allele had significantly lower accumulation of thioguanine nucleotides or methotrexate polyglutamates, respectively. Among these genes, there was a considerable number of acquired chromosomes with wildtype and variant alleles. Cheng et al. (2005) concluded that chromosomal gain can alter the concordance of germline genotype and cancer cell phenotypes, indicating that allele-specific quantitative genotyping may be required to define cancer pharmacogenomics unequivocally.
Relation of TPMT Activity to Thiopurine Drug Metabolism
The thiopurines are pro-drugs that require extensive metabolism in order to exert their cytotoxic action. Azathioprine is nonenzymatically reduced to 6MP. 6MP and 6TG are activated by HPRT (308000) and subsequent steps to form cytotoxic thioguanine nucleotides (TGNs) which are incorporated into DNA and/or RNA, causing DNA-protein cross-links, single-strand breaks, interstrand cross-links, and sister chromatid exchange. TPMT functions mainly to inactivate these drugs; thus, a deficiency of TPMT results in increased conversion to toxic TGNs (Coulthard and Hogarth, 2005). In addition, 6MP is unique in that it can also be converted via TPMT into a methyl-thioinosine 5-prime monophosphate (MeTIMP), a metabolite that inhibits de novo purine synthesis and likely contributes to the cytotoxic effect of 6MP (Vogt et al., 1993; Krynetski et al., 1995; Coulthard and Hogarth, 2005).
In an 8-year-old girl with TPMT deficiency (THPM1; 610460) who developed severe hematopoietic toxicity with conventional oral doses of 6MP for treatment of acute lymphoblastic leukemia (ALL) (Evans et al., 1991), Krynetski et al. (1995) identified a mutation in the TPMT gene, referred to as variant TPMT*2 (A80P; 187680.0001). The mutation was heterozygous in both the proposita and her mother and absent in the father. The authors concluded that the patient had a second inactivating mutation. Krynetski et al. (1995) commented that a reliable method to determine TPMT genotype is important, given the potentially fatal nature of hematopoietic toxicity when full doses of mercaptopurine or azathioprine are given to TPMT-deficient patients.
In 4 individuals with decreased TPMT activity, Szumlanski et al. (1996) identified homozygosity for a complex TPMT allele, referred to as TPMT*3A (A154T and Y240C; 187680.0002). TPMT*3A is the most common mutant TPMT allele among Caucasians (Tai et al., 1996). Tai et al. (1997) showed that enhanced degradation of TPMT proteins encoded by the TPMT*2 (187680.0001) and TPMT*3A alleles is the mechanism for lower TPMT protein and catalytic activity conferred by these mutants.
In a 14-year-old girl who developed severe pancytopenia after starting AZA for HLA-B27-associated juvenile spondyloarthritis (106300), Leipold et al. (1997) identified homozygosity for the TPMT*3A allele. Family studies showed that the mother was also homozygous for the deficiency while other family members were heterozygous. In a patient with AZA-induced myelosuppression after renal transplant, Kurzawski et al. (2005) identified compound heterozygosity for 2 variants in the TPMT gene (TPMT*3A and TPMT*3C; 187680.0005).
Stanulla et al. (2005) stated that 20 TPMT variant alleles, TPMT*2-TPMT*18, associated with decreased enzyme activity had been identified. More than 95% of decreased TPMT activity can be explained by the most frequent mutant alleles TPMT*2 and TPMT*3(A-D).
Otterness et al. (1997) described 8 variant alleles for TPMT and their ethnic differences in frequency.
Among 248 African Americans and 282 Caucasian Americans, Hon et al. (1999) found that the overall TPMT mutant allele frequencies were similar, 4.6% and 3.7%, respectively. TPMT*3C was the most prevalent mutant allele in African Americans (52.2% of mutant alleles), but represented only 4.8% of mutant alleles in Caucasians. TPMT*3A was the most prevalent mutant allele in Caucasians (85.7% of mutant alleles), but represented only 17.4% of mutant alleles in African Americans. Hon et al. (1999) found a novel allele, designated TPMT*8 (R215H; 187680.0006), in an African American who had intermediate activity.
Ameyaw et al. (1999) identified mutant TPMT alleles in 32 (14.8%) of 217 Ghanaian individuals and 18 (10%) of 199 British Caucasians. All of the Ghanaian individuals with a mutant allele had TPMT*3C (allele frequency of 7.6%), whereas only 1 British Caucasian individual had the TPMT*3C allele (frequency of 0.3%). The other 3 variant alleles were not detected in any of the Ghanaian samples analyzed. Seventeen of the British subjects had TPMT*3A (frequency of 4.5%). Phylogenetic analyses estimate the divergence of Africans and non-Africans to have occurred at least 100,000 years ago. From gene evolution studies, it is considered that the most common allele in all populations is usually the ancestral allele. Mutation and recombination then give rise to the other genotypes. Ameyaw et al. (1999) concluded that the TPMT*3C mutation may be the ancestral TPMT mutant allele, as it was present in both Caucasian and African subjects and had been described in Southwest Asian and Chinese populations (Collie-Duguid et al., 1999). The TPMT*3B allele was then acquired and added to form TPMT*3A. Since the TPMT*2 allele appears to be confined to Caucasians, it may be a more recent allele of this polymorphic enzyme.
Collie-Duguid et al. (1999) found that the frequency of individuals with a TPMT variant was 10% (20 of 199) in Caucasians, 2% (2 of 99) in Southwest Asians, and 4.7% (9 of 192) in Chinese. TPMT*3A was the only mutant allele found in Southwest Asians (2 heterozygotes) and was the most common allele in Caucasians (16 heterozygotes and 1 homozygote), but was not found in Chinese. All mutant alleles in the Chinese were TPMT*3C (9 heterozygotes). The findings further suggested that TPMT*3C is the oldest mutation, with TPMT*3B being acquired later to form TPMT*3A in the Caucasian and Southwest Asian populations.
Using a PCR-SSCP technique to genotype 310 individuals from northern Portugal. Alves et al. (1999) identified 15 heterozygotes for TPMT*3A; the corresponding gene frequency estimate was 0.024. Alves et al. (1999) also identified a silent 474T-C transition (TPMT*1S = 0.215) in this population.
McLeod et al. (1999) found that the frequency of mutant TPMT alleles was similar between the Caucasian (10.1%) and Kenyan (10.9%) populations; however, all mutant alleles in the Kenyan population were TPMT*3C compared with 4.8% in Caucasians. In contrast, TPMT*3A was the most common mutant allele in the Caucasian individuals.
Hiratsuka et al. (2000) identified the TPMT*3C allele in 0.8% of 192 Japanese individuals; there were 3 heterozygotes. The TPMT*2, TPMT*3A, and TPMT*3B alleles were not identified in any of the samples.
Lu et al. (2006) found that the frequency of the TPMT*3C allele was 0.12% and 1.28% in Taiwan aborigines and Taiwanese individuals, respectively. Other variants, TPMT*2 through TPMT*8, were not identified.
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.
This TPMT variant is referred to as TPMT*3A (Tai et al., 1997). See also TPMT*3B (A154T; 187680.0004) and TPMT*3C (Y240C; 187680.0005).
In 4 individuals with decreased TPMT activity (THPM1; 610460), Szumlanski et al. (1996) identified homozygosity for 2 mutations in the TPMT gene: a 460G-A transition in exon 7 resulting in an ala154-to-thr (A154T) substitution, and a 719A-G transition in exon 10 resulting in a tyr240-to-cys (Y240C) substitution. Three liver samples from individuals with intermediate TPMT activity were heterozygous for the 2 mutations. In vitro functional expression studies showed that each mutation independently, as well as both together, resulted in decreased expression of TPMT enzymatic activity and immunoreactive protein.
Independently, Tai et al. (1996) identified homozygosity for a mutant allele carrying the A154T and Y240C substitutions in a TPMT-deficient patient. Site-directed mutagenesis and heterologous expression established that either mutation alone resulted in a reduction in catalytic activity (A154T, 9-fold reduction; Y240C, 1.4-fold reduction), while the presence of both mutations resulted in complete loss of enzyme activity.
With mutation-specific PCR-RFLP analysis, Tai et al. (1996) identified the TPMT*3A mutation in genomic DNA from approximately 75% of unrelated white subjects with heterozygous TPMT phenotypes, indicating that it is the most common mutant allele associated with TPMT deficiency.
Tai et al. (1997) showed that the TPMT*2 (187680.0001) and TPMT*3A mutant proteins showed enhanced degradation, thus resulting in decreased TPMT protein and catalytic activity.
Ameyaw et al. (1999) identified the TPMT*3A allele in 17 of 199 British Caucasian individuals (allele frequency of 4.5%) and none of 217 Guanaian individuals.
Hon et al. (1999) identified the TPMT*3A allele in 4 of 248 African Americans (allele frequency of 0.8%) and 18 of 282 Caucasian Americans (allele frequency of 3.2%).
Collie-Duguid et al. (1999) found that the TPMT*3A allele was the most common mutant variant among 199 Caucasian individuals (16 heterozygotes and 1 homozygote). The mutation was not identified in 192 Chinese individuals. TPMT*3A was the only mutant allele found in Southwest Asians (2 heterozygotes in 99 individuals). The findings suggested that TPMT*3C is the oldest mutation, with TPMT*3B being acquired later to form TPMT*3A in the Caucasian and Southwest Asian populations.
Leipold et al. (1997) reported a 14-year-old girl who developed severe pancytopenia 7 weeks after starting azathioprine for HLA-B27-associated juvenile spondyloarthritis (see 106300). She was found to have toxic levels of 6-thioguanine nucleotides and was TPMT-deficient. Withdrawal of azathioprine allowed recovery 8 weeks later. Molecular analysis identified homozygosity for the TPMT*3A allele. Family studies showed that the mother was also homozygous for the deficiency while other family members were heterozygous.
In a patient with azathioprine-induced myelosuppression after renal transplant, Kurzawski et al. (2005) identified compound heterozygosity for 2 variants in the TPMT gene TPMT*3A and TPMT*3C.
Wang et al. (2005) found that the TPMT*3A protein was ubiquitinated and formed aggresomes in COS-1 cells. Further analysis indicated that the 2 mutations in TPMT*3A disrupted the protein structure, resulting in misfolding and aggregation.
This TPMT variant is referred to as TPMT*4A (Otterness et al., 1998).
In an individual with thiopurine S-methyltransferase deficiency (THPM1; 610460), Otterness et al. (1998) identified compound heterozygosity for 2 mutations in the TPMT gene: TPMT*3A (187680.0002) and a new variant allele, TPMT*4A, caused by a G-to-A transition that disrupted the acceptor splice junction at the final 3-prime nucleotide of intron 9. The new allele was found to cosegregate with reduced TPMT activity within an extended kindred. The mutation was found to lead to generation of at least 2 aberrant mRNA species. The first resulted from use of a novel splice site located 1 nucleotide 3-prime downstream from the original splice junction. This mRNA species contained a single nucleotide deletion and a frameshift in exon 10, the terminal exon of the gene. The second novel mRNA species resulted from activation of a cryptic splice site located within intron 9, leading to inclusion of 330 nucleotides of intron sequence. That sequence contained a premature translation termination codon. TPMT*4 was the first reported allele for low TPMT activity as a result of a mutation within an intron.
This TPMT variant is referred to as the TPMT*3B allele. Together with TPMT*3C (Y240C; 187680.0005), it forms TPMT*3A (187680.0002).
Szumlanski et al. (1996) identified the TPMT*3B polymorphic variant in individuals with decreased TPMT activity (THPM1; 610460). The TPMT*3B polymorphic variant allele results from a 460G-A transition in exon 7 of the TPMT gene, resulting in an ala154-to-thr (A154T) substitution (Szumlanski et al., 1996).
Ameyaw et al. (1999) did not identify the TPMT*3B allele in 217 Ghanaians or 199 British Caucasians, suggesting that it is a rare variant.
This TPMT variant is referred to as TPMT*3C (Ameyaw et al., 1999). Together with TPMT*3B (A154T; 187680.0004), it forms TPMT*3A (187680.0002).
Szumlanski et al. (1996) identified the TPMT*3C polymorphic variant in individuals with decreased TPMT activity (THPM1; 610460). The TPMT*3C polymorphic variant allele results from a 719A-G transition in exon 10 of the TPMT gene, resulting in a tyr240-to-cys (Y240C) substitution (Szumlanski et al., 1996)
Ameyaw et al. (1999) identified the Y240C substitution in all 32 of 217 Ghanaian individuals with a mutant TPMT allele (allele frequency of 7.6%), and in only 1 of 199 British Caucasian individual with a mutant TPMT allele (frequency of 0.3%).
Hon et al. (1999) found that TPMT*3C was the most prevalent mutant allele among 248 African Americans, accounting for 52.2% of mutant alleles. The overall frequency of the TPMT*3C allele in this population was 2.4% compared to 0.17% among 282 Caucasian Americans.
Collie-Duguid et al. (1999) found that the TPMT*3C allele accounted for all variants among a group of Chinese individuals with mutant alleles. Nine (4.7%) of 192 individuals were heterozygous, whereas only 1 of 199 Caucasians was heterozygous for the allele. The findings suggested that TPMT*3C is the oldest mutation, with TPMT*3B being acquired later to form TPMT*3A.
Hiratsuka et al. (2000) and Lu et al. (2006) identified the TPMT*3C allele as the only mutant TPMT variant among Japanese and Taiwanese individuals, respectively.
In a Polish patient with azathioprine-induced myelosuppression after renal transplant caused by TPMT deficiency (610460), Kurzawski et al. (2005) identified compound heterozygosity for 2 variants in the TPMT gene: TPMT*3A and TPMT*3C.
This TPMT variant is referred to as TPMT*8.
In an African American with intermediate TPMT activity (THPM1; 610460), Hon et al. (1999) identified a 644G-A transition in exon 10 of the TPMT gene, resulting in an arg215-to-his (R215H) substitution,
This TPMT variant is referred to as TPMT*23.
In a woman with TPMT deficiency (THPM1; 610460), Lindqvist et al. (2007) identified compound heterozygosity for 2 variant alleles in the TPMT gene: a 500C-G transversion in exon 8, resulting in an ala167-to-gly (A167G) substitution, and the common TPMT*3A allele (187680.0002). The woman's mother and sister had the same genotype; all 3 had extremely low TPMT activity.
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