Variant position:  80

Type of variant:  Polymorphism

Residue change:  From Alanine (A) to Proline (P) at position 80 (A80P, p.Ala80Pro).

Physico-chemical properties:  Change from small size and hydrophobic (A) to medium size and hydrophobic (P)

BLOSUM score:  -1

Polymorphism:  Polymorphic variations define TPMT activity levels that are variable among ethnic groups. 90% of Caucasians have high TPMT activity, 10% have intermediate activity, and 1 in 300 individuals has low activity (PubMed:10208641). These differences influence the clinical use and therapeutic efficacy of thiopurine drugs, generally used as immunosuppressants or cytotoxic drugs in conditions including leukemia, autoimmune disease and organ transplantation. Intermediate or low TPMT activity is associated with thiopurine intolerance and patients are at risk of toxicity after receiving standard doses of thiopurine drugs [MIM:610460] (PubMed:10751626, PubMed:15819814, PubMed:16220112, PubMed:16476125, PubMed:16789994, PubMed:7862671, PubMed:8561894, PubMed:8644731, PubMed:9246020, PubMed:9336428, PubMed:9711875, PubMed:9931345, PubMed:9931346). The most prevalent TPMT alleles associated with TPMT deficiency are TPMT*2 and TPMT*3A. The proteins encoded by TPMT*2 and TPMT*3A mutant are degraded more rapidly by an ATP-dependent proteasome-mediated pathway (PubMed:9177237, PubMed:8644731).TPMT*3A is the most common allele in the Caucasians and American Caucasians; it is the only mutant allele found in the South West Asians; it is not found in the Chinese. TPMT*3C is common in African-Americans and is the only allele in Chinese, Japanese and Taiwanese individuals. This allele is found at a low frequency in the Caucasians. This suggests that TPMT*3C is the oldest mutation, with TPMT*3B being acquired later to form the TPMT*3A allele in the Caucasian and South West Asian populations. TPMT*2 appears to be a more recent allele, which has only been detected in Caucasians to date. -

Variant description:  Polymorphism; allele TPMT*2; TPMT*2 allele frequency is 0.5%; seems to be restricted to the Caucasian population; 100-fold reduction in activity; protein shows enhanced degradation.

Other resources:  

• Variant rs1800462 [ dbSNP | Ensembl ]

Variant position:  80

Protein sequence length:  245

Location on the sequence:   KSGLRVFFPLCGKAVEMKWF  A DRGHSVVGVEISELGIQEFF

Residue conservation: 

Human                         KSGLRVFFPLCGKAVEMKWFADRGHSVVGVEISELGIQEFF

Gorilla                       KSGLRVFFPLCGKAVEMKWFADRGHSVVGVEISELGIQEFF

                              ENGLRVFFPLCGKAVEMKWFADRGHSVVGVEISELGIREFF

Chimpanzee                    KSGLRVFFPLCGKAVEMKWFADRGHSVVGVEISELGIREFF

Mouse                         QSGLRVFFPLCGKAIEMKWFADRGHTVVGVEISEIGIREFF

Rat                           QSGLRVFFPLCGKAIEMKWFADRGHTVVGVEISEIGIREFF

Bovine                        EKALRVFFPLCGKAVEMKWFADRGHSVVGVEISELGIRDFF

Rabbit                        ESGLRVFFPLCGKAVEMKWFADRGHSVVGVEISELGIREFF

Cat                           ENVLRVFFPLCGKAVEMKWFADRGHCVVGVEISELGIREFF

Horse                         ESGLKVFFPLCGKAVEMKWFADRGHSVVGVEISELGIREFF

Zebrafish                     RREVRFFFPLCGKAVDMKWLADMGHTVVGVEFSEKGIKEFS

Sequence annotation in neighborhood:  

A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase.
Krynetski E.Y.; Schuetz J.D.; Galpin A.J.; Pui C.-H.; Relling M.V.; Evans W.E.;
Proc. Natl. Acad. Sci. U.S.A. 92:949-953(1995)
Cited for: VARIANT PRO-80;

Enhanced proteolysis of thiopurine S-methyltransferase (TPMT) encoded by mutant alleles in humans (TPMT*3A, TPMT*2): mechanisms for the genetic polymorphism of TPMT activity.
Tai H.-L.; Krynetski E.Y.; Schuetz E.G.; Yanishevski Y.; Evans W.E.;
Proc. Natl. Acad. Sci. U.S.A. 94:6444-6449(1997)
Cited for: CHARACTERIZATION OF VARIANTS PRO-80 AND THR-154; MECHANISM FOR THE GENETIC POLYMORPHISM OF TPMT ACTIVITY;

Thiopurine methyltransferase alleles in British and Ghanaian populations.
Ameyaw M.-M.; Collie-Duguid E.S.R.; Powrie R.H.; Ofori-Adjei D.; McLeod H.L.;
Hum. Mol. Genet. 8:367-370(1999)
Cited for: VARIANTS PRO-80; THR-154 AND CYS-240;

The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations.
Collie-Duguid E.S.R.; Pritchard S.C.; Powrie R.H.; Sludden J.; Collier D.A.; Li T.; McLeod H.L.;
Pharmacogenetics 9:37-42(1999)
Cited for: VARIANTS PRO-80; THR-154 AND CYS-240; FREQUENCY AND DISTRIBUTION OF ALLELES;

Genetic analysis of thiopurine methyltransferase polymorphism in a Japanese population.
Hiratsuka M.; Inoue T.; Omori F.; Agatsuma Y.; Mizugaki M.;
Mutat. Res. 448:91-95(2000)
Cited for: VARIANTS PRO-80; THR-154 AND CYS-240; FREQUENCY AND DISTRIBUTION OF ALLELES;

Thiopurine S-methyltransferase pharmacogenetics: variant allele functional and comparative genomics.
Salavaggione O.E.; Wang L.; Wiepert M.; Yee V.C.; Weinshilboum R.M.;
Pharmacogenet. Genomics 15:801-815(2005)
Cited for: VARIANTS SER-49; PRO-80; THR-154; PHE-180; HIS-215; GLN-227 AND CYS-240; CHARACTERIZATION OF VARIANTS SER-49; PRO-80; THR-154; PHE-180; HIS-215; GLN-227 AND CYS-240;

Molecular analysis of thiopurine S-methyltransferase alleles in Taiwan aborigines and Taiwanese.
Lu H.-F.; Shih M.-C.; Chang Y.-S.; Chang J.-Y.; Ko Y.-C.; Chang S.-J.; Chang J.-G.;
J. Clin. Pharm. Ther. 31:93-98(2006)
Cited for: VARIANTS PRO-80; THR-154 AND CYS-240; FREQUENCY AND DISTRIBUTION OF ALLELES;

Frequency of the thiopurine S-methyltransferase alleles in the ancient genetic population isolate of Sardinia.
Rossino R.; Vincis C.; Alves S.; Prata M.J.; Macis M.D.; Nucaro A.L.; Schirru E.; Congia M.;
J. Clin. Pharm. Ther. 31:283-287(2006)
Cited for: VARIANTS PRO-80; THR-154 AND CYS-240; FREQUENCY AND DISTRIBUTION OF ALLELES;