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          TPMT allele nomenclature

          The table defines all the single-nucleotide polymorphisms (SNPs) in TPMT as of May 2017

Allele

dbSNP rsID and corresponding nucleotides on the positive chromosomal strand (for standardization)

Nucleotide changes in the TPMT gene (given on the negative chromosomal strand, NCBI reference sequence NM_000367.2)

Gene

location

Amino acid

Change (NCBI reference sequence NP_000358.1)

References

TPMT*1

 

rs2842934 allele A1

Wild type

474T1

 

 

 

TPMT*1A

ND, G>A

-178C>T

Exon I

 

[1]

TPMT*1S

A>G at rs2842934

474T>C

Exon VII

Ile158Ile

[2]

TPMT*2

C>G at rs1800462

 

238G>C

Exon V

Ala80Pro

[3, 4, 5, 6, 7]

TPMT*3A

C>T at rs1800460 

T>C at rs1142345 

460G>A

719A>G

Exon VII

Exon X

Ala154Thr

Tyr240Cys

[4, 5, 6, 7, 8]

TPMT*3B

C>T at rs1800460 

460G>A

Exon VII

Ala154Thr

[4, 6, 7, 8]

TPMT*3C

T>C at rs1142345 

719A>G

Exon X

Tyr240Cys

[4, 6, 7, 8]

TPMT*3D

C>A at s72552739 

C>T at rs1800460

T>C at rs1142345

292G>T

460G>A

719A>G

Exon V

Exon VII

Exon X

Glu98Stop

Ala154Thr

Tyr240Cys

[9]

TPMT*3E

A>T at rs3931660

T>A at rs12529220

A>G at rs2518463

C>T at rs1800460

A>G at rs2842934

T>C at rs1142345

140+114T>A

141-101A>T

366+58T>C

460G>A

474T>C

719A>G

Intron III

Intron III

Intron IV

Exon VII

Exon VII

Exon X

 

 

 

Ala154Thr

Ile158Ile

Tyr240Cys

[10]

TPMT*4

C >T at rs1800584 

626-1G>A

Intron IX/

exon X in splice junction

 

[9, 11]

TPMT*5

A>G at rs72552740

146T>C

Exon IV

Leu49Ser

[4, 6, 9]

TPMT*6

T>A at rs75543815

539A>T

Exon VIII

Tyr180Phe

[4, 6, 9]

TPMT*7

A>C at rs72552736

681T>G

Exon X

His227Gln

[1, 4, 6, 9]

TPMT*8

C>T at rs56161402

644G>A

Exon X

Arg215His

[4, 6, 12]

TPMT*9

T>G  at rs151149760

356A>C

Exon V

Lys119Thr

[4, 6, 13]

TPMT*10

C>G at rs72552737

430G>C

Exon VII

Gly144Arg

[4, 6, 14, 15]

TPMT*11

C>T at rs72552738

395G>A

Exon VI

Cys132Tyr

[4, 6, 16]

TPMT*12

G>A at rs200220210

374C>T

Exon VI

Ser125Leu

[4, 6, 15]

TPMT*13

T>A at rs72552742

83A>T

Exon III

Glu28Val

[4, 6, 15]

TPMT*14

T>C at rs9333569

1A>G

Exon III

Met1Val

[6, 17]

TPMT*15

C>T  at rs9333570

495-1G>A

Intron VII/

exon VIII in splice junction

 

[17]

TPMT*16

C>T at rs144041067

488G>A

Exon VII

Arg163His

[6, 13, 18]

TPMT*17

ND, G>C

124C>G

Exon III

Gln42Glu

[6, 13]

TPMT*18

C>T at rs777686348

211G>A

Exon IV

Gly71Arg

[6, 13]

TPMT*19

ND, T>G

365A>C

Exon V

Lys122Thr

[6, 18]

TPMT*20

T>C at rs150900439

712A>G

Exon X

Lys238Glu

[6, 19]

TPMT*21

G>C at rs200591577

205C>G

Exon IV

Leu69Val

[6, 19]

TPMT*22

ND, C>G

488G>C

Exon VII

Arg163Pro

[6, 19]

TPMT*23

G>C at rs74423290

500C>G

Exon VIII

Ala167Gly

[20]

TPMT*24

C>A at rs6921269

537G>T

Exon VIII

Gln179His

[21]

TPMT*25

A>G at rs377085266

634T>C

Exon X

Cys212Arg

[21]

TPMT*26

A>G at rs72556347

622T>C

Exon IX

Phe208Leu

[22]

TPMT*27

ND, A>C

319T>G

Exon V

Tyr107Asp

[23]

TPMT*28

ND, C>G

349G>C2

Exon V

Gly117Arg

[24]

TPMT*29

A>G at rs267607275

2T>C

Exon III

Met1Thr

[25]

TPMT*30

Old TPMT*20/*24, C>T at

rs750424422

106G>A

Exon III

Gly36Ser

[6, 26]

TPMT*31

Old TPMT*28  A>G at rs79901429

611T>C

Exon IX

Ile204Thr

[27]

TPMT*32

C>T at rs115106679

340G>A

Exon V

Glu114Lys

[28]

TPMT*33

G>A at rs112339338

487C>T

Exon VII

Arg163Cys

[28]

TPMT*34

G>A at rs111901354

244C>T

Exon V

Arg82Trp

[28]

TPMT*35 ND 200T>C3 Exon III Phe67Ser [29]
TPMT*36 ND 595G>A3 Exon VIII Val199Ile [29]
TPMT*37   A>T at rs398122996 648T>A Exon X Cys216Ter [30]
TPMT*38 G>A at rs772832951 514T>C Exon VIII Ser172Pro [31]
TPMT*39    A>G at rs281874771      218C>T       Exon VI Ala73Val [32]
TPMT*40        T>C at rs139392616     677G>A   Exon X   Arg226Q [33]
TPMT*41 T>G at rs1142345  719A>C Exon X Tyr240Ser [34]

ND – Not reported to dbSNP, 1dbSNP reports G>A at this position: however the TPMT nomenclature committee has defined wildtype as having allele A at this position (positive chromosomal strand) and the *1S allele as having allele G at this position (positive chromosomal strand): 2 incorrect nucleotide substitutions given in reference 24: the corrected nucleotide substitution is included in the table (personal communication T. Marinaki).3 These alleles was numbered differently in the original publication [29].

 

1. Spire-Vayron de la Moureyre C, Debuysere H, Sabbagh N, Marez D, Vinner E, Chevalier ED, et al. Detection of known and new mutations in the thiopurine S-methyltransferase gene by single-strand conformation polymorphism analysis. Hum Mutat 1998; 12: 177-185.

2. Yates CR, Krynetski EY, Loennechen T, Fessing MY, Tai HL, Pui CH, et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 1997; 126: 608-614.

3. Krynetski EY, Schuetz JD, Galpin AJ, Pui CH, Relling MV, Evans WE. A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase. Proc Natl Acad Sci USA 1995; 92: 949-953.

4. Salavaggione OE, Wang L, Wiepert M, Yee VC, Weinshilboum RM. Thiopurine S-methyltransferase pharmacogenetics: variant allele functional and comparative genomics. Pharmacogenet Genomics 2005; 15: 801-815.

5. Tai HL, Krynetski EY, Schuetz EG, Yanishevski Y, Evans WE. 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 Natl Acad Sci U S A 1997; 94: 6444-6449.

6. Ujiie S, Sasaki T, Mizugaki M, Ishikawa M, Hiratsuka M. Functional characterization of 23 allelic variants of thiopurine S-methyltransferase gene (TPMT*2 - *24). Pharmacogenet Genomics 2008; 18: 887-893.

7. Tai HL, Krynetski EY, Yates CR, Loennechen T, Fessing MY, Krynetskaia NF, 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.

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

9. Otterness D, Szumlanski C, Lennard L, Klemetsdal B, Aarbakke J, Park-Hah JO, et al. Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms. Clin Pharmacol Ther 1997; 62: 60-73.

10. Colleoni L, Kapetis D, Maggi L, Camera G, Canioni E, Cavalcante P, et al. A New Thiopurine S-Methyltransferase Haplotype Associated With Intolerance to Azathioprine. J Clin Pharmacol 2013; 53: 67-74.

11. Otterness D, Szumlanski C, Weinshilboum R. Human thiopurine methyltransferase pharmacogenetics: identification of a novel variant allele. J Invest Med 1996; 44: 248A.

12. Hon YY, Fessing MY, Pui CH, Relling MV, Krynetski EY, Evans WE. Polymorphism of the thiopurine S-methyltransferase gene in African-Americans. Hum Mol Genet 1999; 8: 371-376.

13. Schaeffeler E, Fischer C, Brockmeier D, Wernet D, Moerike K, Eichelbaum M, et al. Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants. Pharmacogenetics 2004; 14: 407-417.

14. Colombel JF, Ferrari N, Debuysere H, Marteau P, Gendre JP, Bonaz B, et al. Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy. Gastroenterology 2000; 118: 1025-1030.

15. Hamdan-Khalil R, Allorge D, Lo-Guidice JM, Cauffiez C, Chevalier D, Spire C, et al. In vitro characterization of four novel non-functional variants of the thiopurine S-methyltransferase. Biochem Biophys Res Commun 2003; 309: 1005-1010.

16. Schaeffeler E, Stanulla M, Greil J, Schrappe M, Eichelbaum M, Zanger UM, et al. A novel TPMT missense mutation associated with TPMT deficiency in a 5-year-old boy with ALL. Leukemia 2003; 17: 1422-1424.

17. Lindqvist M, Haglund S, Almer S, Peterson C, Taipalensu J, Hertervig E, et al. Identification of two novel sequence variants affecting thiopurine methyltransferase enzyme activity. Pharmacogenetics 2004; 14: 261-265.

18. Hamdan-Khalil R, Gala JL, Allorge D, Lo-Guidice JM, Horsmans Y, Houdret N, et al. Identification and functional analysis of two rare allelic variants of the thiopurine S-methyltransferase gene, TPMT*16 and TPMT*19. Biochem Pharmacol 2005; 69: 525-529.

19. Schaeffeler E, Eichelbaum M, Reinisch W, Zanger UM, Schwab M. Three novel thiopurine S-methyltransferase allelic variants (TPMT*20, *21, *22) - association with decreased enzyme function. Hum Mutat 2006; 27: 976.

20. Lindqvist M, Skoglund K, Karlgren A, Soderkvist P, Peterson C, Kidhall I, 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.

21. Garat A, Cauffiez C, Renault N, Lo-Guidice JM, Allorge D, Chevalier D, et al. Characterisation of novel defective thiopurine S-methyltransferase allelic variants. Biochem Pharmacol 2008; 76: 404-415.

22. Kham SK, Soh CK, Aw DC, Yeoh AE. TPMT*26 (208F-->L), a novel mutation detected in a Chinese. Br J Clin Pharmacol 2009; 68: 120-123.

23. Feng Q, Vannaprasaht S, Peng Y, Angsuthum S, Avihingsanon Y, Yee VC, et al. Thiopurine S-methyltransferase pharmacogenetics: functional characterization of a novel rapidly degraded variant allozyme. Biochem Pharmacol 2010; 79: 1053-1061.

24. Landy J, Bhuva N, Marinaki A, Mawdsley J. Novel thiopurine methyltransferase variant TPMT*28 results in a misdiagnosis of TPMT deficiency. Inflamm Bowel Dis 2010.

25. Lee CK, Loh TP, Wong ST, Lee HK, Huan PT, Chiu LL, et al. Detection of a novel single nucleotide polymorphism of the human thiopurine s-methyltransferase gene in a Chinese individual. Drug Metab Pharmacokinet 2012; 27: 559-561.

26. Sasaki T, Goto E, Konno Y, Hiratsuka M, Mizugaki M. Three novel single nucleotide polymorphisms of the human thiopurine S-methyltransferase gene in Japanese individuals. Drug Metab Pharmacokinet 2006; 21: 332-336.

27. Appell ML, Wennerstrand P, Peterson C, Hertervig E, Martensson LG. Characterization of a novel sequence variant, TPMT*28, in the human thiopurine methyltransferase gene. Pharmacogenet Genomics 2010; 20: 700-707.

28. Lennard L, Cartwright CS, Wade R, Richards SM, Vora A. Thiopurine methyltransferase genotype-phenotype discordance, and thiopurine active metabolite formation, in childhood acute lymphoblastic leukaemia. Br J Clin Pharmacol doi 10.1111/bcp.12066 2012.

29. Skrzypczak-Zielinska M, Borun P, Milanowska K, Jakubowska-Burek L, Zakerska O, Dobrowolska-Zachwieja A, et al. High-resolution melting analysis of the TPMT gene: a study in the Polish population. Genet Test Mol Biomarkers 2013; 17: 153-159.

30. Roberts R, Wallace M, Drake J, Stamp L. Identification of a novel thiopurine methyltransferase allele (TPMT*37). Pharmacogenetics and genomics 2014 DOI: 10.1097/FPC.0000000000000049.

31. Kim HY, Lee SH, Lee MN, Kim JW, Kim YH, Kim MJ, et al. Complete sequence-based screening of TPMT variants in the Korean population. Pharmacogenet Genomics. 2015. DOI 10.1097/FPC.0000000000000117.

32. Coelho, T. et al. Genes implicated in thiopurine-induced toxicity: Comparing TPMT enzyme activity with clinical phenotype and exome data in a paediatric IBD cohort. Scientific reports 6, 34658, doi:10.1038/srep34658 (2016).

33. Liu, C. et al. Genomewide Approach Validates Thiopurine Methyltransferase Activity Is a Monogenic Pharmacogenomic Trait. Clin Pharmacol Ther 101, 373-381, doi:10.1002/cpt.463 (2017).

34. Iu, Y. P. H. et al. One amino acid makes a difference-Characterization of a new TPMT allele and the influence of SAM on TPMT stability. Scientific reports 7, 46428, doi:10.1038/srep46428 (2017).

 

 


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Last updated: Fri Sep 08 08:49:28 CEST 2017