Variant position:  154

Type of variant:  Polymorphism

Residue change:  From Alanine (A) to Threonine (T) at position 154 (A154T, p.Ala154Thr).

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

BLOSUM score:  0

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*3A and allele TPMT*3B; very low activity; protein shows enhanced degradation leading to strongly reduced protein levels.

Other resources:  

• Variant rs1800460 [ dbSNP | Ensembl ]

Variant position:  154

Protein sequence length:  245

Location on the sequence:   SIFDLPRTNIGKFDMIWDRG  A LVAINPGDRKCYADTMFSLL

Residue conservation: 

Human                         SIFDLPRTNIGKFDMIWDRGALVAINPGDRKCYADTMFSLL

Gorilla                       SIFDLPRTNIGKFDMIWDRGALVAINPGDRKCYADTMLSLL

                              SLFDLPRANIGKFDRIWDRGALVAINPGDRERYADIMLSLT

Chimpanzee                    SIFDLPRTNIGKFDMIWDRGALVAINPGDRKCYADTMLSLL

Mouse                         SIFDLPRANIGKFDRIWDRGALVAINPGDHDRYADIILSLL

Rat                           SIFDLPRANIGKFDRIWDRGALVAVNPGDRDRYADIILSLL

Bovine                        NLFDLPRANIGKFDRIWDRGALVAVNPSDRKRYSDVMLSLT

Rabbit                        SIFDLPRVNIGKFDRIWDRGALVAVNPSDRKRYAAVMLSLL

Cat                           NLFDLPRVNIGKFDRIWDRGALVAVNPGDRKCYTDIMLSLT

Horse                         NIFDLPRTNIGKFDRIWDRGALVAVNPGDRKRYVDIMLSLT

Zebrafish                     DLYKFSSAVAGHFGGIWDRGALVAINPCDRQKYASLLVSLM

Sequence annotation in neighborhood:  

Thiopurine methyltransferase pharmacogenetics: human gene cloning and characterization of a common polymorphism.
Szumlanski C.; Otterness D.; Her C.; Lee D.; Brandriff B.; Kelsell D.; Spurr N.; Lennard L.; Wieben E.; Weinshilboum R.M.;
DNA Cell Biol. 15:17-30(1996)
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]; VARIANTS THR-154 AND CYS-240;

Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms.
Otterness D.; Szumlanski C.; Lennard L.; Klemetsdal B.; Aarbakke J.; Park-Hah J.O.; Iven H.; Schmiegelow K.; Branum E.; O'Brien J.; Weinshilboum R.M.;
Clin. Pharmacol. Ther. 62:60-73(1997)
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]; VARIANTS SER-49; THR-154; PHE-180 AND CYS-240;

Structural basis of allele variation of human thiopurine-S-methyltransferase.
Wu H.; Horton J.R.; Battaile K.; Allali-Hassani A.; Martin F.; Zeng H.; Loppnau P.; Vedadi M.; Bochkarev A.; Plotnikov A.N.; Cheng X.;
Proteins 67:198-208(2007)
Cited for: X-RAY CRYSTALLOGRAPHY (1.58 ANGSTROMS) OF 16-245 IN COMPLEX WITH S-ADENOSYL-L-HOMOCYSTEINE; SUBUNIT; CHARACTERIZATION OF VARIANTS THR-154 AND CYS-240;

Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians.
Tai H.-L.; Krynetski E.Y.; Yates C.R.; Loennechen T.; Fessing M.Y.; Krynetskaia N.F.; Evans W.E.;
Am. J. Hum. Genet. 58:694-702(1996)
Cited for: VARIANTS THR-154 AND CYS-240;

Azathioprine-induced severe pancytopenia due to a homozygous two-point mutation of the thiopurine methyltransferase gene in a patient with juvenile HLA-B27-associated spondylarthritis.
Leipold G.; Schuetz E.; Haas J.P.; Oellerich M.;
Arthritis Rheum. 40:1896-1898(1997)
Cited for: VARIANTS THR-154 AND CYS-240;

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;

Severe azathioprine-induced myelotoxicity in a kidney transplant patient with thiopurine S-methyltransferase-deficient genotype (TPMT*3A/*3C).
Kurzawski M.; Dziewanowski K.; Ciechanowski K.; Drozdzik M.;
Transpl. Int. 18:623-625(2005)
Cited for: VARIANTS THR-154 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;