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THPM1
MCID: THP004
MIFTS: 38

Thiopurines, Poor Metabolism of, 1 (THPM1)

Categories: Blood diseases, Cancer diseases, Genetic diseases, Immune diseases, Metabolic diseases
Genes Variations Tissues Related diseases Publications Pathways Symptoms & Phenotypes
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Aliases & Classifications for Thiopurines, Poor Metabolism of, 1

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MalaCards integrated aliases for Thiopurines, Poor Metabolism of, 1:

Name: Thiopurines, Poor Metabolism of, 1 58
Thiopurine S-Methyltransferase Deficiency 58 12 26 38 15 41
Tpmt Deficiency 58 12 26
Thiopurine S-Methyltransferase Deficiency; Tpmtd 58
Thiopurine S Methyltranferase Deficiency 74
Thiopurine Methyltransferase Deficiency 26
Poor Metabolism of Thiopurines-1 12
Poor Metabolism of Thiopurines 26
Thiopurine S-Methyltransferase 13
Poor Thiopurine Metabolism 30
Thpm1 58
Tpmtd 58

Characteristics:

OMIM:

58
Inheritance:
autosomal recessive

Miscellaneous:
increased susceptibility to toxic effects of treatment with 6-mercaptopurine (6mp), 6-thioguanine (6tg), and azathioprine (aza)
heterozygotes may also show increased susceptibility to toxic effects of thiopurine treatment


HPO:

33
thiopurines, poor metabolism of, 1:
Inheritance autosomal recessive inheritance


Classifications:

MalaCards categories:
Global: Genetic diseases Metabolic diseases Cancer diseases
Anatomical: Immune diseases Blood diseases
See all MalaCards categories (disease lists)


External Ids:

Disease Ontology 12 DOID:0080172
OMIM 58 610460
KEGG 38 H00964
MedGen 43 C0342801
SNOMED-CT via HPO 70 191124002 258211005 34093004
UMLS 74 C0342801
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Summaries for Thiopurines, Poor Metabolism of, 1

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OMIM : 58 THPM1 is an autosomal recessive trait associated with severe hematopoietic toxicity when patients are treated with standard doses of the antineoplastic agents 6-mercaptopurine (6MP) or 6-thioguanine (6TG), or the immunosuppressant azathioprine (AZA) (Lennard et al., 1989). The thiopurines are prodrugs that require extensive metabolism in order to exert their cytotoxic action. Azathioprine is nonenzymatically reduced to 6MP. 6MP and 6TG are activated by HPRT (308000) and subsequent steps to form cytotoxic thioguanine nucleotides (TGNs) which are incorporated into DNA and/or RNA, causing DNA-protein cross-links, single-strand breaks, interstrand cross-links, and sister chromatid exchange. TPMT functions mainly to inactivate these drugs; thus, a deficiency of TPMT results in increased conversion to toxic TGNs, which can result in myelosuppression (Coulthard and Hogarth, 2005). However, 6MP is unique in that it can also be converted via TPMT into a methyl-thioinosine 5-prime monophosphate (MeTIMP), a metabolite that inhibits de novo purine synthesis and likely contributes to the cytotoxic effect of 6MP (Vogt et al., 1993; Krynetski et al., 1995; Coulthard and Hogarth, 2005). (610460)

MalaCards based summary : Thiopurines, Poor Metabolism of, 1, also known as thiopurine s-methyltransferase deficiency, is related to thiopurine s methyltranferase deficiency and thiopurines, poor metabolism of, 2. An important gene associated with Thiopurines, Poor Metabolism of, 1 is TPMT (Thiopurine S-Methyltransferase), and among its related pathways/superpathways are Drug metabolism - other enzymes and Metabolism. Affiliated tissues include myeloid, t cells and bone marrow, and related phenotypes are abnormality of metabolism/homeostasis and abnormality of blood and blood-forming tissues

Disease Ontology : 12 An inherited metabolic disease that is characterized by significantly reduced activity of an enzyme that helps the body process drugs called thiopurines.

Genetics Home Reference : 26 Thiopurine S-methyltransferase (TPMT) deficiency is a condition characterized by significantly reduced activity of an enzyme that helps the body process drugs called thiopurines. These drugs, which include 6-thioguanine, 6-mercaptopurine, and azathioprine, inhibit (suppress) the body's immune system. Thiopurine drugs are used to treat some autoimmune disorders, including Crohn disease and rheumatoid arthritis, which occur when the immune system malfunctions. These drugs are also used to treat several forms of cancer, particularly cancers of blood-forming tissue (leukemias) and cancers of immune system cells (lymphomas). Additionally, thiopurine drugs are used in organ transplant recipients to help prevent the immune system from attacking the transplanted organ.

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Related Diseases for Thiopurines, Poor Metabolism of, 1

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Diseases in the Thiopurines, Poor Metabolism of, 1 family:

Thiopurines, Poor Metabolism of, 2

Diseases related to Thiopurines, Poor Metabolism of, 1 via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 45)
# Related Disease Score Top Affiliating Genes
1 thiopurine s methyltranferase deficiency 11.7
2 thiopurines, poor metabolism of, 2 11.1
3 crohn's disease 10.4
4 systemic lupus erythematosus 10.4
5 lupus erythematosus 10.4
6 leukemia 10.3
7 autoimmune hepatitis 10.3
8 hepatitis 10.3
9 autoimmune disease 10.3
10 autoimmune disease 1 10.3
11 alpha/beta t-cell lymphopenia with gamma/delta t-cell expansion, severe cytomegalovirus infection, and autoimmunity 10.3
12 acute leukemia 10.3
13 acute lymphoblastic leukemia, childhood 10.3
14 neuromyelitis optica 10.3
15 irritable bowel syndrome 10.3
16 neuromyelitis optica spectrum disorder 10.3
17 pancytopenia 10.2
18 leukemia, acute myeloid 10.2
19 leukemia, acute lymphoblastic 10.2
20 acute lymphocytic leukemia 10.2
21 ulcerative colitis 10.2
22 inflammatory bowel disease 10.2
23 colitis 10.2
24 crohn's colitis 10.2
25 lymphocytic leukemia 10.2
26 myeloid leukemia 10.2
27 pulmonary fibrosis, idiopathic 10.1
28 rheumatoid arthritis 10.1
29 aplastic anemia 10.1
30 acute promyelocytic leukemia 10.1
31 pulmonary fibrosis and/or bone marrow failure, telomere-related, 2 10.1
32 arthritis 10.1
33 liver disease 10.1
34 neutropenia 10.1
35 pulmonary fibrosis 10.1
36 uremia 10.1
37 beta-thalassemia 10.0
38 thalassemia 10.0
39 sclerosing cholangitis 10.0
40 cholangitis 10.0
41 rheumatic disease 10.0
42 dermatitis 10.0
43 azathioprine or 6-mercatopurine toxicity or dose selection 10.0 NUDT15 TPMT
44 nodular regenerative hyperplasia 9.9 ITPA TPMT
45 adenosine deaminase deficiency 9.6 ITPA PNP

Graphical network of the top 20 diseases related to Thiopurines, Poor Metabolism of, 1:



Diseases related to Thiopurines, Poor Metabolism of, 1
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Symptoms & Phenotypes for Thiopurines, Poor Metabolism of, 1

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Human phenotypes related to Thiopurines, Poor Metabolism of, 1:

33
# Description HPO Frequency HPO Source Accession
1 abnormality of metabolism/homeostasis 33 HP:0001939
2 abnormality of blood and blood-forming tissues 33 HP:0001871

Symptoms via clinical synopsis from OMIM:

58
Hematology:
myelosuppression develops on standard doses of thiopurine drugs
hematopoietic toxicity develops on standard doses of thiopurine drugs

Laboratory Abnormalities:
decreased activity of thiopurine s-methyltransferase
decreased metabolism of thiopurine drugs
increased toxic thioguanine nucleotides (tgns) on standard doses of thiopurine drugs

Clinical features from OMIM:

610460
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Drugs & Therapeutics for Thiopurines, Poor Metabolism of, 1

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Search Clinical Trials , NIH Clinical Center for Thiopurines, Poor Metabolism of, 1

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Genetic Tests for Thiopurines, Poor Metabolism of, 1

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Genetic tests related to Thiopurines, Poor Metabolism of, 1:

# Genetic test Affiliating Genes
1 Poor Thiopurine Metabolism 30
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Anatomical Context for Thiopurines, Poor Metabolism of, 1

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MalaCards organs/tissues related to Thiopurines, Poor Metabolism of, 1:

42
Myeloid, T Cells, Bone Marrow, Kidney
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Publications for Thiopurines, Poor Metabolism of, 1

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Articles related to Thiopurines, Poor Metabolism of, 1:

(show all 22)
# Title Authors Year
1
Thiopurine S-methyltransferase deficiency associated with a novel mutation. ( 20186941 )
2010
2
Azathioprine-associated acute myeloid leukemia in a patient with Crohn's disease and thiopurine S-methyltransferase deficiency. ( 17696202 )
2008
3
Explaining TPMT genotype/phenotype discrepancy by haplotyping of TPMT*3A and identification of a novel sequence variant, TPMT*23. ( 17885628 )
2007
4
Molecular analysis of thiopurine S-methyltransferase alleles in Taiwan aborigines and Taiwanese. ( 16476125 )
2006
5
Association of inosine triphosphatase 94C>A and thiopurine S-methyltransferase deficiency with adverse events and study drop-outs under azathioprine therapy in a prospective Crohn disease study. ( 16214825 )
2005
6
Severe azathioprine-induced myelotoxicity in a kidney transplant patient with thiopurine S-methyltransferase-deficient genotype (TPMT*3A/*3C). ( 15819814 )
2005
7
Human thiopurine S-methyltransferase pharmacogenetics: variant allozyme misfolding and aggresome formation. ( 15967990 )
2005
8
Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. ( 11304783 )
2001
9
Allelic variants of the thiopurine S-methyltransferase deficiency in patients with ulcerative colitis and in healthy controls. ( 11007234 )
2000
10
Genetic analysis of thiopurine methyltransferase polymorphism in a Japanese population. ( 10751626 )
2000
11
The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations. ( 10208641 )
1999
12
Thiopurine methyltransferase alleles in British and Ghanaian populations. ( 9931345 )
1999
13
Polymorphism of the thiopurine S-methyltransferase gene in African-Americans. ( 9931346 )
1999
14
Human thiopurine methyltransferase pharmacogenetics. Kindred with a terminal exon splice junction mutation that results in loss of activity. ( 9486974 )
1998
15
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. ( 9336428 )
1997
16
Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. ( 9103127 )
1997
17
Molecular diagnosis of thiopurine S-methyltransferase deficiency. ( 9412292 )
1997
18
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. ( 9177237 )
1997
19
Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. ( 8644731 )
1996
20
Thiopurine methyltransferase pharmacogenetics: human gene cloning and characterization of a common polymorphism. ( 8561894 )
1996
21
A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase. ( 7862671 )
1995
22
Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. ( 1960624 )
1991
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Variations for Thiopurines, Poor Metabolism of, 1

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ClinVar genetic disease variations for Thiopurines, Poor Metabolism of, 1:

6 (show top 50) (show all 100)
# Gene Variation Type Significance SNP ID Assembly Location
1 TPMT NM_000367.2(TPMT): c.238G> C (p.Ala80Pro) single nucleotide variant drug response rs1800462 GRCh37 Chromosome 6, 18143955: 18143955
2 TPMT NM_000367.2(TPMT): c.238G> C (p.Ala80Pro) single nucleotide variant drug response rs1800462 GRCh38 Chromosome 6, 18143724: 18143724
3 TPMT NM_000367.4(TPMT): c.460G> A (p.Ala154Thr) single nucleotide variant other rs1800460 GRCh37 Chromosome 6, 18139228: 18139228
4 TPMT NM_000367.4(TPMT): c.460G> A (p.Ala154Thr) single nucleotide variant other rs1800460 GRCh38 Chromosome 6, 18138997: 18138997
5 TPMT NM_000367.4(TPMT): c.626-1G> A single nucleotide variant drug response rs1800584 GRCh37 Chromosome 6, 18131012: 18131012
6 TPMT NM_000367.4(TPMT): c.626-1G> A single nucleotide variant drug response rs1800584 GRCh38 Chromosome 6, 18130781: 18130781
7 TPMT NM_000367.4(TPMT): c.719A> G (p.Tyr240Cys) single nucleotide variant other rs1142345 GRCh37 Chromosome 6, 18130918: 18130918
8 TPMT NM_000367.4(TPMT): c.719A> G (p.Tyr240Cys) single nucleotide variant other rs1142345 GRCh38 Chromosome 6, 18130687: 18130687
9 TPMT NM_000367.4(TPMT): c.644G> A (p.Arg215His) single nucleotide variant drug response rs56161402 GRCh37 Chromosome 6, 18130993: 18130993
10 TPMT NM_000367.4(TPMT): c.644G> A (p.Arg215His) single nucleotide variant drug response rs56161402 GRCh38 Chromosome 6, 18130762: 18130762
11 TPMT NM_000367.4(TPMT): c.500C> G (p.Ala167Gly) single nucleotide variant drug response rs74423290 GRCh37 Chromosome 6, 18134115: 18134115
12 TPMT NM_000367.4(TPMT): c.500C> G (p.Ala167Gly) single nucleotide variant drug response rs74423290 GRCh38 Chromosome 6, 18133884: 18133884
13 TPMT NM_000367.4(TPMT): c.420-4G> A single nucleotide variant Uncertain significance rs56019966 GRCh37 Chromosome 6, 18139272: 18139272
14 TPMT NM_000367.4(TPMT): c.420-4G> A single nucleotide variant Uncertain significance rs56019966 GRCh38 Chromosome 6, 18139041: 18139041
15 TPMT NM_000367.4(TPMT): c.*1873G> A single nucleotide variant Uncertain significance rs886061255 GRCh37 Chromosome 6, 18129026: 18129026
16 TPMT NM_000367.4(TPMT): c.*1873G> A single nucleotide variant Uncertain significance rs886061255 GRCh38 Chromosome 6, 18128795: 18128795
17 TPMT NM_000367.4(TPMT): c.*1804G> T single nucleotide variant Uncertain significance rs559243767 GRCh37 Chromosome 6, 18129095: 18129095
18 TPMT NM_000367.4(TPMT): c.*1804G> T single nucleotide variant Uncertain significance rs559243767 GRCh38 Chromosome 6, 18128864: 18128864
19 TPMT NM_000367.4(TPMT): c.*1778_*1781dup duplication Uncertain significance rs886061256 GRCh37 Chromosome 6, 18129118: 18129121
20 TPMT NM_000367.4(TPMT): c.*1778_*1781dup duplication Uncertain significance rs886061256 GRCh38 Chromosome 6, 18128887: 18128890
21 TPMT NM_000367.4(TPMT): c.*1757del deletion Uncertain significance rs748123873 GRCh37 Chromosome 6, 18129142: 18129142
22 TPMT NM_000367.4(TPMT): c.*1757del deletion Uncertain significance rs748123873 GRCh38 Chromosome 6, 18128911: 18128911
23 TPMT NM_000367.4(TPMT): c.*1522C> T single nucleotide variant Uncertain significance rs116170115 GRCh37 Chromosome 6, 18129377: 18129377
24 TPMT NM_000367.4(TPMT): c.*1522C> T single nucleotide variant Uncertain significance rs116170115 GRCh38 Chromosome 6, 18129146: 18129146
25 TPMT NM_000367.4(TPMT): c.*1204G> A single nucleotide variant Uncertain significance rs886061260 GRCh38 Chromosome 6, 18129464: 18129464
26 TPMT NM_000367.4(TPMT): c.*1204G> A single nucleotide variant Uncertain significance rs886061260 GRCh37 Chromosome 6, 18129695: 18129695
27 TPMT NM_000367.4(TPMT): c.*523G> A single nucleotide variant Uncertain significance rs886061261 GRCh38 Chromosome 6, 18130145: 18130145
28 TPMT NM_000367.4(TPMT): c.*523G> A single nucleotide variant Uncertain significance rs886061261 GRCh37 Chromosome 6, 18130376: 18130376
29 TPMT NM_000367.4(TPMT): c.*329A> G single nucleotide variant Uncertain significance rs886061263 GRCh38 Chromosome 6, 18130339: 18130339
30 TPMT NM_000367.4(TPMT): c.*329A> G single nucleotide variant Uncertain significance rs886061263 GRCh37 Chromosome 6, 18130570: 18130570
31 TPMT NM_000367.4(TPMT): c.375G> A (p.Ser125=) single nucleotide variant Uncertain significance rs760980416 GRCh38 Chromosome 6, 18139709: 18139709
32 TPMT NM_000367.4(TPMT): c.375G> A (p.Ser125=) single nucleotide variant Uncertain significance rs760980416 GRCh37 Chromosome 6, 18139940: 18139940
33 TPMT NM_000367.4(TPMT): c.-44-4G> A single nucleotide variant Uncertain significance rs202034437 GRCh37 Chromosome 6, 18149406: 18149406
34 TPMT NM_000367.4(TPMT): c.-44-4G> A single nucleotide variant Uncertain significance rs202034437 GRCh38 Chromosome 6, 18149175: 18149175
35 TPMT NM_000367.4(TPMT): c.-66C> T single nucleotide variant Uncertain significance rs141028204 GRCh37 Chromosome 6, 18155285: 18155285
36 TPMT NM_000367.4(TPMT): c.-66C> T single nucleotide variant Uncertain significance rs141028204 GRCh38 Chromosome 6, 18155054: 18155054
37 TPMT NM_000367.4(TPMT): c.*1900A> C single nucleotide variant Likely benign rs1142378 GRCh37 Chromosome 6, 18128999: 18128999
38 TPMT NM_000367.4(TPMT): c.*1900A> C single nucleotide variant Likely benign rs1142378 GRCh38 Chromosome 6, 18128768: 18128768
39 TPMT NM_000367.4(TPMT): c.*1820A> G single nucleotide variant Uncertain significance rs1142374 GRCh37 Chromosome 6, 18129079: 18129079
40 TPMT NM_000367.4(TPMT): c.*1820A> G single nucleotide variant Uncertain significance rs1142374 GRCh38 Chromosome 6, 18128848: 18128848
41 TPMT NM_000367.4(TPMT): c.*1604G> A single nucleotide variant Likely benign rs9465100 GRCh37 Chromosome 6, 18129295: 18129295
42 TPMT NM_000367.4(TPMT): c.*1604G> A single nucleotide variant Likely benign rs9465100 GRCh38 Chromosome 6, 18129064: 18129064
43 TPMT NM_000367.4(TPMT): c.*1511G> A single nucleotide variant Uncertain significance rs553500255 GRCh37 Chromosome 6, 18129388: 18129388
44 TPMT NM_000367.4(TPMT): c.*1511G> A single nucleotide variant Uncertain significance rs553500255 GRCh38 Chromosome 6, 18129157: 18129157
45 TPMT NM_000367.4(TPMT): c.*1305C> G single nucleotide variant Uncertain significance rs144017186 GRCh37 Chromosome 6, 18129594: 18129594
46 TPMT NM_000367.4(TPMT): c.*1305C> G single nucleotide variant Uncertain significance rs144017186 GRCh38 Chromosome 6, 18129363: 18129363
47 TPMT NM_000367.4(TPMT): c.*1218G> A single nucleotide variant Uncertain significance rs186206580 GRCh38 Chromosome 6, 18129450: 18129450
48 TPMT NM_000367.4(TPMT): c.*1218G> A single nucleotide variant Uncertain significance rs186206580 GRCh37 Chromosome 6, 18129681: 18129681
49 TPMT NM_000367.4(TPMT): c.*634dup duplication Uncertain significance rs760084154 GRCh38 Chromosome 6, 18130034: 18130034
50 TPMT NM_000367.4(TPMT): c.*634dup duplication Uncertain significance rs760084154 GRCh37 Chromosome 6, 18130265: 18130265
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Expression for Thiopurines, Poor Metabolism of, 1

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Search GEO for disease gene expression data for Thiopurines, Poor Metabolism of, 1.
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Pathways for Thiopurines, Poor Metabolism of, 1

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Pathways related to Thiopurines, Poor Metabolism of, 1 according to KEGG:

38
# Name Kegg Source Accession
1 Drug metabolism - other enzymes hsa00983

Pathways related to Thiopurines, Poor Metabolism of, 1 according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1
Metabolism 67
Show member pathways
 13.2 ITPA NUDT15 PNP PRSS3 TPMT
2
Pancreatic secretion 38
10.95 PRSS3 RAB3D
3
Thiopurine Pathway, Pharmacokinetics/Pharmacodynamics 62
10.23 ITPA NUDT15 TPMT
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GO Terms for Thiopurines, Poor Metabolism of, 1

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Biological processes related to Thiopurines, Poor Metabolism of, 1 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 neutrophil degranulation GO:0043312 9.33 PNP PRSS3 RAB3D
2 nucleobase-containing compound metabolic process GO:0006139 8.96 PNP TPMT
3 purine nucleotide catabolic process GO:0006195 8.8 ITPA NUDT15 PNP

Molecular functions related to Thiopurines, Poor Metabolism of, 1 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 NADH pyrophosphatase activity GO:0035529 9.16 ITPA NUDT15
2 nucleoside-triphosphate diphosphatase activity GO:0047429 8.96 ITPA NUDT15
3 nucleotide diphosphatase activity GO:0004551 8.62 ITPA NUDT15
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Sources for Thiopurines, Poor Metabolism of, 1

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3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
20 FMA
29 GO
30 GTR
31 HGMD
32 HMDB
33 HPO
34 ICD10
35 ICD10 via Orphanet
36 ICD9CM
37 IUPHAR
38 KEGG
39 LifeMap
41 LOVD
43 MedGen
45 MeSH
46 MESH via Orphanet
47 MGI
50 NCI
51 NCIt
52 NDF-RT
55 NINDS
56 Novoseek
58 OMIM
59 OMIM via Orphanet
63 PubMed
65 QIAGEN
70 SNOMED-CT via HPO
71 SNOMED-CT via Orphanet
72 TGDB
73 Tocris
74 UMLS
75 UMLS via Orphanet
The MalaCards human disease database index: 1-9 A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
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