Thiopurines, Poor Metabolism of, 1 disease: Malacards - Research Articles, Drugs, Genes, Clinical Trials

MCID: THP004 MIFTS: 34	Thiopurines, Poor Metabolism of, 1 Categories: Genetic diseases, Metabolic diseases
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Aliases & Classifications for Thiopurines, Poor Metabolism of, 1

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

Name: Thiopurines, Poor Metabolism of, 1 ⁵⁷

Thiopurine S-Methyltransferase Deficiency ⁵⁷ ¹² ²⁵ ³⁷ ¹⁵ ⁴⁰

Tpmt Deficiency ⁵⁷ ¹² ²⁵

Thiopurine S-Methyltransferase Deficiency; Tpmtd ⁵⁷

Thiopurine S Methyltranferase Deficiency ⁷³

Thiopurine Methyltransferase Deficiency ²⁵

Poor Metabolism of Thiopurines-1 ¹²

Poor Metabolism of Thiopurines ²⁵

Thiopurine S-Methyltransferase ¹³

Poor Thiopurine Metabolism ²⁹

Thpm1 ⁵⁷

Tpmtd ⁵⁷

Characteristics:

OMIM:

⁵⁷

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:

³²

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

Classifications:

MalaCards categories:
Global: Genetic diseases Metabolic diseases

See all MalaCards categories (disease lists)

External Ids:

OMIM ⁵⁷ 610460

Disease Ontology ¹² DOID:0080172

MedGen ⁴² C0342801

KEGG ³⁷ H00964

SNOMED-CT via HPO ⁶⁹ 258211005 191124002 34093004

UMLS ⁷³ C0342801

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Summaries for Thiopurines, Poor Metabolism of, 1

OMIM : ⁵⁷ 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 and kidney, and related phenotypes are abnormality of blood and blood-forming tissues and abnormality of metabolism/homeostasis

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 : ²⁵ 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

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 14)

#	Related Disease	Score	Top Affiliating Genes
1	thiopurine s methyltranferase deficiency	11.5
2	thiopurines, poor metabolism of, 2	10.9
3	crohn's disease	10.1
4	leukemia	10.1
5	leukemia, acute myeloid	10.0
6	leukemia, acute lymphoblastic	10.0
7	ulcerative colitis	10.0
8	inflammatory bowel disease	10.0
9	colitis	10.0
10	lymphoblastic leukemia	10.0
11	myeloid leukemia	10.0
12	azathioprine or 6-mercatopurine toxicity or dose selection	9.9	NUDT15 TPMT
13	nodular regenerative hyperplasia	9.7	ITPA TPMT
14	adenosine deaminase deficiency	9.2	ITPA PNP

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

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Symptoms & Phenotypes for Thiopurines, Poor Metabolism of, 1

Symptoms via clinical synopsis from OMIM:

⁵⁷

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

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

³²

#	Description	HPO Frequency	HPO Source Accession
1	abnormality of blood and blood-forming tissues ³²		HP:0001871
2	abnormality of metabolism/homeostasis ³²		HP:0001939

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Drugs & Therapeutics for Thiopurines, Poor Metabolism of, 1

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

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Genetic Tests for Thiopurines, Poor Metabolism of, 1

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

#	Genetic test	Affiliating Genes
1	Poor Thiopurine Metabolism ²⁹

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Anatomical Context for Thiopurines, Poor Metabolism of, 1

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

⁴¹

Myeloid, Kidney

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Publications for Thiopurines, Poor Metabolism of, 1

Articles related to Thiopurines, Poor Metabolism of, 1:

(show all 12)

#	Title	Authors	Year
1	Analysis of Thiopurine S-Methyltransferase Deficient Alleles in Acute Lymphoblastic Leukemia Patients in Mexican Patients. ( 28476189 )	JimAcnez-Morales S....Hidalgo-Miranda A.	2016
2	Thiopurine S-methyltransferase deficiency associated with a novel mutation. ( 20186941 )	Torres J....Broly F.	2010
3	Azathioprine-associated acute myeloid leukemia in a patient with Crohn's disease and thiopurine S-methyltransferase deficiency. ( 17696202 )	Yenson P.R....Dalal B.I.	2008
4	Dosing azathioprine in thiopurine S-methyltransferase deficient inflammatory bowel disease patients. ( 18477684 )	Derijks L.J....Stokkers P.C.	2008
5	Association of inosine triphosphatase 94C&gt;A and thiopurine S-methyltransferase deficiency with adverse events and study drop-outs under azathioprine therapy in a prospective Crohn disease study. ( 16214825 )	von Ahsen N....SchA1tz E.	2005
6	Severe azathioprine-induced myelotoxicity in a kidney transplant patient with thiopurine S-methyltransferase-deficient genotype (TPMT3A/3C). ( 15819814 )	Kurzawski M....Drozdzik M.	2005
7	Safe treatment of thiopurine S-methyltransferase deficient Crohn's disease patients with azathioprine. ( 12477776 )	Kaskas B.A....Schwab M.	2003
8	Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. ( 11304783 )	Evans W.E....Relling M.V.	2001
9	Allelic variants of the thiopurine S-methyltransferase deficiency in patients with ulcerative colitis and in healthy controls. ( 11007234 )	Corominas H....Baiget M.	2000
10	Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. ( 9103127 )	Yates C.R....Evans W.E.	1997
11	Molecular diagnosis of thiopurine S-methyltransferase deficiency. ( 9412292 )	Blank R.D.	1997
12	Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. ( 8644731 )	Tai H.-L....Evans W.E.	1996

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Genes for Thiopurines, Poor Metabolism of, 1

Genes related to Thiopurines, Poor Metabolism of, 1 (1 elite genes):

- Elite gene

- Cancer Census gene in COSMIC

#	Symbol	Description	Category	Score	Evidence	PubmedIds
1	TPMT	Thiopurine S-Methyltransferase	Protein Coding	593.04	Molecular basis known ⁵⁷ Susceptibility factor ⁵⁷ Drug response ⁶ DISEASES inferred ¹⁵ GeneCards inferred via : DISEASES inferred (show sections)	8644731 1960624 7862671 (more) 9177237 9931345 8561894 9931346 10208641 9336428 15819814 15967990 9486974 10751626 16476125 17885628
2	NUDT15	Nudix Hydrolase 15	Protein Coding	17.06	DISEASES inferred ¹⁵ GeneCards inferred via : DISEASES inferred (show sections)
3	ITPA	Inosine Triphosphatase	Protein Coding	16.78	DISEASES inferred ¹⁵ GeneCards inferred via : DISEASES inferred (show sections)
4	PNP	Purine Nucleoside Phosphorylase	Protein Coding	14.96	DISEASES inferred ¹⁵ GeneCards inferred via : DISEASES inferred (show sections)
5	RAB3D	RAB3D, Member RAS Oncogene Family	Protein Coding	5.51	DISEASES inferred ¹⁵
6	PRSS3	Serine Protease 3	Protein Coding	5.17	DISEASES inferred ¹⁵

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Variations for Thiopurines, Poor Metabolism of, 1

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

⁶

(show top 50) (show all 94)

#	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.626-1G> A	single nucleotide variant	drug response	rs1800584	GRCh37	Chromosome 6, 18131012: 18131012
4	TPMT	NM_000367.4(TPMT): c.626-1G> A	single nucleotide variant	drug response	rs1800584	GRCh38	Chromosome 6, 18130781: 18130781
5	TPMT	NM_000367.4(TPMT): c.644G> A (p.Arg215His)	single nucleotide variant	drug response	rs56161402	GRCh37	Chromosome 6, 18130993: 18130993
6	TPMT	NM_000367.4(TPMT): c.644G> A (p.Arg215His)	single nucleotide variant	drug response	rs56161402	GRCh38	Chromosome 6, 18130762: 18130762
7	TPMT	NM_000367.4(TPMT): c.500C> G (p.Ala167Gly)	single nucleotide variant	drug response	rs74423290	GRCh37	Chromosome 6, 18134115: 18134115
8	TPMT	NM_000367.4(TPMT): c.500C> G (p.Ala167Gly)	single nucleotide variant	drug response	rs74423290	GRCh38	Chromosome 6, 18133884: 18133884
9	TPMT	NM_000367.4(TPMT): c.*1873G> A	single nucleotide variant	Uncertain significance	rs886061255	GRCh37	Chromosome 6, 18129026: 18129026
10	TPMT	NM_000367.4(TPMT): c.*1873G> A	single nucleotide variant	Uncertain significance	rs886061255	GRCh38	Chromosome 6, 18128795: 18128795
11	TPMT	NM_000367.4(TPMT): c.*1804G> T	single nucleotide variant	Uncertain significance	rs559243767	GRCh37	Chromosome 6, 18129095: 18129095
12	TPMT	NM_000367.4(TPMT): c.*1804G> T	single nucleotide variant	Uncertain significance	rs559243767	GRCh38	Chromosome 6, 18128864: 18128864
13	TPMT	NM_000367.4(TPMT): c.1778_1781dupAAAA	duplication	Uncertain significance	rs886061256	GRCh37	Chromosome 6, 18129118: 18129121
14	TPMT	NM_000367.4(TPMT): c.1778_1781dupAAAA	duplication	Uncertain significance	rs886061256	GRCh38	Chromosome 6, 18128887: 18128890
15	TPMT	NM_000367.4(TPMT): c.*1757delC	deletion	Uncertain significance	rs748123873	GRCh37	Chromosome 6, 18129142: 18129142
16	TPMT	NM_000367.4(TPMT): c.*1757delC	deletion	Uncertain significance	rs748123873	GRCh38	Chromosome 6, 18128911: 18128911
17	TPMT	NM_000367.4(TPMT): c.*1522C> T	single nucleotide variant	Uncertain significance	rs116170115	GRCh37	Chromosome 6, 18129377: 18129377
18	TPMT	NM_000367.4(TPMT): c.*1522C> T	single nucleotide variant	Uncertain significance	rs116170115	GRCh38	Chromosome 6, 18129146: 18129146
19	TPMT	NM_000367.4(TPMT): c.*1204G> A	single nucleotide variant	Uncertain significance	rs886061260	GRCh37	Chromosome 6, 18129695: 18129695
20	TPMT	NM_000367.4(TPMT): c.*1204G> A	single nucleotide variant	Uncertain significance	rs886061260	GRCh38	Chromosome 6, 18129464: 18129464
21	TPMT	NM_000367.4(TPMT): c.*523G> A	single nucleotide variant	Uncertain significance	rs886061261	GRCh37	Chromosome 6, 18130376: 18130376
22	TPMT	NM_000367.4(TPMT): c.*523G> A	single nucleotide variant	Uncertain significance	rs886061261	GRCh38	Chromosome 6, 18130145: 18130145
23	TPMT	NM_000367.4(TPMT): c.*329A> G	single nucleotide variant	Uncertain significance	rs886061263	GRCh37	Chromosome 6, 18130570: 18130570
24	TPMT	NM_000367.4(TPMT): c.*329A> G	single nucleotide variant	Uncertain significance	rs886061263	GRCh38	Chromosome 6, 18130339: 18130339
25	TPMT	NM_000367.4(TPMT): c.375G> A (p.Ser125=)	single nucleotide variant	Uncertain significance	rs760980416	GRCh38	Chromosome 6, 18139709: 18139709
26	TPMT	NM_000367.4(TPMT): c.375G> A (p.Ser125=)	single nucleotide variant	Uncertain significance	rs760980416	GRCh37	Chromosome 6, 18139940: 18139940
27	TPMT	NM_000367.4(TPMT): c.-44-4G> A	single nucleotide variant	Uncertain significance	rs202034437	GRCh37	Chromosome 6, 18149406: 18149406
28	TPMT	NM_000367.4(TPMT): c.-44-4G> A	single nucleotide variant	Uncertain significance	rs202034437	GRCh38	Chromosome 6, 18149175: 18149175
29	TPMT	NM_000367.4(TPMT): c.-66C> T	single nucleotide variant	Uncertain significance	rs141028204	GRCh37	Chromosome 6, 18155285: 18155285
30	TPMT	NM_000367.4(TPMT): c.-66C> T	single nucleotide variant	Uncertain significance	rs141028204	GRCh38	Chromosome 6, 18155054: 18155054
31	TPMT	NM_000367.4(TPMT): c.*1900A> C	single nucleotide variant	Likely benign	rs1142378	GRCh37	Chromosome 6, 18128999: 18128999
32	TPMT	NM_000367.4(TPMT): c.*1900A> C	single nucleotide variant	Likely benign	rs1142378	GRCh38	Chromosome 6, 18128768: 18128768
33	TPMT	NM_000367.4(TPMT): c.*1820A> G	single nucleotide variant	Uncertain significance	rs1142374	GRCh37	Chromosome 6, 18129079: 18129079
34	TPMT	NM_000367.4(TPMT): c.*1820A> G	single nucleotide variant	Uncertain significance	rs1142374	GRCh38	Chromosome 6, 18128848: 18128848
35	TPMT	NM_000367.4(TPMT): c.*1604G> A	single nucleotide variant	Likely benign	rs9465100	GRCh37	Chromosome 6, 18129295: 18129295
36	TPMT	NM_000367.4(TPMT): c.*1604G> A	single nucleotide variant	Likely benign	rs9465100	GRCh38	Chromosome 6, 18129064: 18129064
37	TPMT	NM_000367.4(TPMT): c.*1511G> A	single nucleotide variant	Uncertain significance	rs553500255	GRCh37	Chromosome 6, 18129388: 18129388
38	TPMT	NM_000367.4(TPMT): c.*1511G> A	single nucleotide variant	Uncertain significance	rs553500255	GRCh38	Chromosome 6, 18129157: 18129157
39	TPMT	NM_000367.4(TPMT): c.*1305C> G	single nucleotide variant	Uncertain significance	rs144017186	GRCh37	Chromosome 6, 18129594: 18129594
40	TPMT	NM_000367.4(TPMT): c.*1305C> G	single nucleotide variant	Uncertain significance	rs144017186	GRCh38	Chromosome 6, 18129363: 18129363
41	TPMT	NM_000367.4(TPMT): c.*1218G> A	single nucleotide variant	Uncertain significance	rs186206580	GRCh37	Chromosome 6, 18129681: 18129681
42	TPMT	NM_000367.4(TPMT): c.*1218G> A	single nucleotide variant	Uncertain significance	rs186206580	GRCh38	Chromosome 6, 18129450: 18129450
43	TPMT	NM_000367.4(TPMT): c.*634dupT	duplication	Uncertain significance	rs760084154	GRCh37	Chromosome 6, 18130265: 18130265
44	TPMT	NM_000367.4(TPMT): c.*634dupT	duplication	Uncertain significance	rs760084154	GRCh38	Chromosome 6, 18130034: 18130034
45	TPMT	NM_000367.4(TPMT): c.*515G> A	single nucleotide variant	Uncertain significance	rs145605593	GRCh37	Chromosome 6, 18130384: 18130384
46	TPMT	NM_000367.4(TPMT): c.*515G> A	single nucleotide variant	Uncertain significance	rs145605593	GRCh38	Chromosome 6, 18130153: 18130153
47	TPMT	NM_000367.4(TPMT): c.*60T> C	single nucleotide variant	Uncertain significance	rs886061264	GRCh37	Chromosome 6, 18130839: 18130839
48	TPMT	NM_000367.4(TPMT): c.*60T> C	single nucleotide variant	Uncertain significance	rs886061264	GRCh38	Chromosome 6, 18130608: 18130608
49	TPMT	NM_000367.4(TPMT): c.474T= (p.Ile158=)	single nucleotide variant	Likely benign	rs2842934	GRCh38	Chromosome 6, 18138983: 18138983
50	TPMT	NM_000367.4(TPMT): c.474T= (p.Ile158=)	single nucleotide variant	Likely benign	rs2842934	GRCh37	Chromosome 6, 18139214: 18139214

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Expression for Thiopurines, Poor Metabolism of, 1

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

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Pathways for Thiopurines, Poor Metabolism of, 1

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

³⁷

#	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 ⁶⁶ Show member pathways Metabolic pathways ³⁷ Metabolism of lipids and lipoproteins ⁶⁶	13.29	ITPA NUDT15 PNP PRSS3 TPMT
2	Purine metabolism (REACTOME) ¹ Show member pathways 5-aminoimidazole ribonucleotide biosynthesis ¹ adenine and adenosine salvage I ¹ adenine and adenosine salvage II ¹ adenosine nucleotides degradation ¹ guanine and guanosine salvage ¹ guanosine nucleotides degradation ¹ inosine-5-phosphate biosynthesis ¹ Metabolism of nucleotides ⁶⁶ oxidized GTP and dGTP detoxification ¹ Phosphate bond hydrolysis by NTPDase proteins ⁶⁶ Phosphate bond hydrolysis by NUDT proteins ⁶⁶ Purine catabolism ⁶⁶ Purine metabolism ⁶⁶ purine nucleotides degradation ¹ Purine ribonucleoside monophosphate biosynthesis ⁶⁶ Purine salvage ⁶⁶ urate biosynthesis/inosine 5-phosphate degradation ¹	11.47	ITPA NUDT15 PNP
3	Pancreatic secretion ³⁷	11.14	PRSS3 RAB3D
4	Thiopurine Pathway, Pharmacokinetics/Pharmacodynamics ⁶¹	10.23	ITPA NUDT15 TPMT

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GO Terms for Thiopurines, Poor Metabolism of, 1

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	nucleotide diphosphatase activity	GO:0004551	9.16	ITPA NUDT15
2	NADH pyrophosphatase activity	GO:0035529	8.96	ITPA NUDT15
3	nucleoside-triphosphate diphosphatase activity	GO:0047429	8.62	ITPA NUDT15

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