GENETIC POLYMORPHISMS OF THIOPURINE METHYLTRANSFERASE (TPMT) ©2011 Pharmacology Weekly, Inc.
Allele	Population	Single Nucleotide Polymorphism	Location	TPMT Activity	Notes
TPMT	General Population	Wild-type; 34kb	6q22.3	normal	None
TPMT*2	Caucasians 0.5%	G238C (A80P)	Exon 5	↓	TPMT activity ↓100- fold due to ↑degradation
TPMT*3A	Caucasians: up to 85% African Americans .8%	G460A (A154T) Y240C (A719G)	Exon 7 Exon 10	↓	Rapid degradation of the enzyme; most common TPMT mutation in whites
TPMT*3C	African Americans 52% Caucasians 4.8%	A874G (Y240C)	Exon 10	↓	Most common TPMT mutations in African Americans
TPMT*4	Only identified in a few cases	G→A transition at final splice acceptor nucleotide	Intron 9	↓	Causes a disruption in the intron9 - exon10 acceptor splice site
TPMT*8	Only identified in a few cases	G644A (R215H)	Exon 10	↓	Intermediate activity
TPMT*23	Only identified in a few cases	C500G (A167G)	Exon 8	↓	TPMT enzyme deficiency

The letters  before and after the numbers represent the single nucleotides that make up the DNA sequence and codons to code for an amino acid (A = adenine, C = cytosine, G = guanine, T = thymine).  Amino acids represented: (A = alanine, C = cysteine, G = glycine, H = histidine, P = proline, R = arginine, T = threonine, Y = tyrosine). 


MEDICATIONS AFFECTED:

Azathioprine, cefazolin, cisplatin, docetaxel, etoposide, mercaptopurine, sulfasalazine, thioguanine


REFERENCES:

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Tai HL, Krynetski EY, Yates CR et al. Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians.  Am J Hum Genet  1996;58:694-702.  PubMed

Krynetski EY, Schuetz JD, Galpin AJ et al. A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase.  Proc Nat Acad Sci  1995;92:949-953.  PubMed

Tai HL, Krynetski EY, Schuetz EG et al. 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.  Proc Nat Acad Sci  1997;94:6444-6449.  PubMed

Szumlanski C, Otterness D, Her C et al.  Thiopurine methyltransferase pharmacogenetics: human gene cloning and characterization of a common polymorphism.  DNA Cell Biol  1996;15:17-30.  PubMed

Otterness DM, Szumlanski CL, Wood TC et al. Human thiopurine methyltransferase pharmacogenetics: kindred with a terminal exon splice junction mutation that results in loss of activity.  J Clin Invest 1998;101:1036-1044.  PubMed

Hon YY, Fessing MY, Pui CH et al. Polymorphism of the thiopurine S-methyltransferase gene in African-Americans.  Hum Molec Genet  1999;8:371-376.  PubMed

Lindqvist M, Skoglund K, Karlgren A et al. Explaining TPMT genotype/phenotype discrepancy by haplotyping of TPMT*3A and identification of a novel sequence variant, TPMT*23.  Pharmacogenet Genomics 2007;17:891-895.  PubMed
 

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