Important Variant Information for TPMT
Submitted by: Liewei Wang, Linda Pelleymounter, Richard Weinshilboum and Julie A. Johnson (PPII)
Reviewed by: Reviewed
Submitted date: January 19, 2007
There are Four Important Variants for TPMT.
| Gene HGNC Name: | TPMT |
|---|---|
| Variant Summary: | This variant is known as *2. TPMT cDNA from a TPMT-deficient patient who had developed severe hematopoietic toxicity during mercaptopurine therapy was cloned. Sequencing of the mutant TPMT cDNA revealed a single point mutation (G238->C, where 238 refers to the coding sequence), leading to an amino acid substitution at codon 80 (Ala80->Pro). When assessed in a yeast heterologous expression system, this mutation led to a 100-fold reduction in TPMT catalytic activity relative to the wild-type cDNA, despite a comparable level of mRNA expression. *2 is a relatively rare allele. It is degraded rapidly when transiently expressed in both yeast and mammalian cells. This allele results in low TPMT protein and catalytic activity in blood and cell culture. Therefore, if patients who carry this allele are treated with standard dose of thiopurine drugs, they might have increased 6-TGN level and develop drug-related toxicity such as myelosuppression. |
| Key PubMed IDs: | 7862671, 9177237, 10591545 |
| Genomic Variant & GenBank ID: | 9,002,206 C>G on NT_007592.14 |
| mRNA Variant & GenBank ID: | 393 G>C on NM_000367.2 |
| Protein Variant & GenBank ID: | 80 Ala>Pro on NP_000358.1 |
| dbSNP rs#: | NA |
| GoldenPath Position: | Chr6:18,251,934 (hg18) |
| Key Drugs/Substrates: | Thiopurine drugs |
| Gene HGNC Name: | TPMT |
|---|---|
| Variant Summary: | The TPMT *3B allele is rare and has only the codon 154 SNP. It is usually in tight linkage disequilibrium with another SNP in exon10, resulting in the common allele, *3A. When expressed in the yeast and mammalian cells, *3B is degraded rapidly, resulting in significantly decreased levels of enzyme activity and protein [PMID: 8561894]. This allele is associated with significantly decreased levels of TPMT enzyme activity and protein in cultured mammalian cells such as COS-1 cells. It is also associated with thiopurine drug -related toxicity [PMID: 8561894]. |
| Genomic Variant & GenBank ID: | 8,997,479 C>T on NT_007592.14 |
| mRNA Variant & GenBank ID: |
615 G>A on NM_000367.2 |
| Protein Variant & GenBank ID: |
154 Ala>Thr on NP_000358.1 |
| dbSNP rs#: | rs1800460 |
| GoldenPath Position: | Chr6:18,247,207 (hg18) |
| DNA Source Containing Homozygous Reference Allele(Coriell Lines): |
Coriell NA15324 (PA126721229) |
| DNA Source Containing Heterozygous Reference Allele (Coriell Lines): |
Coriell NA15386 (PA126721230) |
| Key Haplotypes: | *3A |
| Gene HGNC Name: | TPMT |
|---|---|
| Variant Summary: | This SNP results in the TPMT*3C allele. *3C is the most common allele in African American and East Asian populations. It is associated with decreased enzyme activity and protein quantity as a result of accelerated degradation of *3C in mammalian cells. This allele is associated with decreased levels of protein and enzyme activity in blood cells, but less than is the case with TPMT*3A and TPMT*3B [PMID: 16220112]. |
| Genomic Variant & GenBank ID: | 8,989,169 T>C on NT_007592.14 |
| mRNA Variant & GenBank ID: | 874 A>G on NM_000367.2 |
| Protein Variant & GenBank ID: | 240 Tyr>Cys on NP_000358.1 |
| dbSNP rs#: | rs1142345 |
| GoldenPath Position: | Chr6:18,238,897 (hg18) |
| DNA Source Containing Homozygous Reference Allele(Coriell Lines): |
Coriell NA15242 (PA126721227) |
| DNA Source Containing Heterozygous Reference Allele (Coriell Lines): |
Coriell NA15268 (PA126721228) |
| Key Haplotypes: | *3A |
| Gene HGNC Name: | TPMT |
|---|---|
| Variant Summary: | The TPMT*4 allele includes a G to A transition at the final splice acceptor nucleotide in TPMT intron 9 [PMID: 9486974 ]. This mutation disrupts the intron 9-exon 10 acceptor splice site and results in two abnormal transcripts, one that results from the activation of a cryptic splice site in intron 9, leading to the inclusion of 330 nucleotides of intron sequence, and another that uses a novel splice acceptor site located one nucleotide 3' downstream from the original splice junction. The latter situation results in a single nucleotide deletion and a frameshift in the portion of the mRNA encoded by exon 10 [PMID: 9486974 ]. Presence of TPMT*4 in an extended kindred uniformly resulted in very low TPMT activity in subjects carrying this allele [PMID: 9486974 ]. |
| Key PubMed IDs: | 9486974 |
| Genomic Variant & GenBank ID: | 8,989,263 C >T on NT_007592.14 |
| mRNA Variant & GenBank ID: | Not Available |
| Protein Variant & GenBank ID: | Not Available |
| dbSNP rs#: | rs1800584 |
| GoldenPath Position: | Chr6:18,238,991 (hg18) |
| Key Drugs/Substrates: | Thiopurine drugs |