NUDT15: Difference between revisions

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This gene encodes an enzyme that belongs to the Nudix hydrolase superfamily. Members of this superfamily catalyze the hydrolysis of nucleoside diphosphates, including substrates like 8-oxo-dGTP, which are a result of oxidative damage, and can induce base mispairing during DNA replication, causing transversions. The encoded enzyme is a negative regulator of thiopurine activation and toxicity. Mutations in this gene result in poor metabolism of thiopurines, and are associated with thiopurine-induced early leukopenia. Multiple pseudogenes of this gene have been identified.
This gene encodes an enzyme that belongs to the Nudix hydrolase superfamily. Members of this superfamily catalyze the hydrolysis of nucleoside diphosphates, including substrates like 8-oxo-dGTP, which are a result of oxidative damage, and can induce base mispairing during DNA replication, causing transversions. The encoded enzyme is a negative regulator of thiopurine activation and toxicity. Mutations in this gene result in poor metabolism of thiopurines, and are associated with thiopurine-induced early leukopenia. Multiple pseudogenes of this gene have been identified.


NUDT15 germline variants (e.g., a missense SNP:rs116855232, inducing R139C) have been linked to clinical usage of thiopurines (e.g., mercaptopurine) in [[acute lymphoblastic leukemia]]<ref>{{cite journal | vauthors = Moriyama T, Nishii R, Perez-Andreu V, Yang W, Klussmann FA, Zhao X, Lin TN, Hoshitsuki K, Nersting J, Kihira K, Hofmann U, Komada Y, Kato M, McCorkle R, Li L, Koh K, Najera CR, Kham SK, Isobe T, Chen Z, Chiew EK, Bhojwani D, Jeffries C, Lu Y, Schwab M, Inaba H, Pui CH, Relling MV, Manabe A, Hori H, Schmiegelow K, Yeoh AE, Evans WE, Yang JJ | display-authors = 6 | title = NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity | journal = Nature Genetics | volume = 48 | issue = 4 | pages = 367–73 | date = April 2016 | pmid = 26878724 | doi = 10.1038/ng.3508 }}</ref><ref>{{cite journal | vauthors = Yang JJ, Landier W, Yang W, Liu C, Hageman L, Cheng C, Pei D, Chen Y, Crews KR, Kornegay N, Wong FL, Evans WE, Pui CH, Bhatia S, Relling MV | display-authors = 6 | title = Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia | journal = Journal of Clinical Oncology | volume = 33 | issue = 11 | pages = 1235–42 | date = April 2015 | pmid = 25624441 | doi = 10.1200/JCO.2014.59.4671 }}</ref> as well as inflammatory bowel diseases to avoid thiopurine-induced leukopenia.<ref>{{cite journal | vauthors = Yang SK, Hong M, Baek J, Choi H, Zhao W, Jung Y, Haritunians T, Ye BD, Kim KJ, Park SH, Park SK, Yang DH, Dubinsky M, Lee I, McGovern DP, Liu J, Song K | display-authors = 6 | title = A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia | journal = Nature Genetics | volume = 46 | issue = 9 | pages = 1017–20 | date = September 2014 | pmid = 25108385 | doi = 10.1038/ng.3060 }}</ref><ref>{{cite journal | vauthors = Yin D, Xia X, Zhang J, Zhang S, Liao F, Zhang G, Zhang Y, Hou Q, Yang X, Wang H, Ma Z, Wang H, Zhu Y, Zhang W, Wang Y, Liu B, Wang L, Xu H, Shu Y | display-authors = 6 | title = Impact of NUDT15 polymorphisms on thiopurines-induced myelotoxicity and thiopurines tolerance dose | journal = Oncotarget | volume = 8 | issue = 8 | pages = 13575–13585 | date = February 2017 | pmid = 28088792 | doi = 10.18632/oncotarget.14594 }}</ref> These variants also exhibit ethnicity-specific (e.g.,variant allele of rs116855232 is high is East Asians and Hispanics but low in Caucasians and Africans). Rare functional variants even singletons in this gene have also been identified to be related to thiopurine-induced myelotoxicity,<ref>{{cite journal|last1=Moriyama|first1=T|last2=Yang|first2=YL|last3=Nishii|first3=R|last4=Ariffin|first4=H|last5=Liu|first5=C|last6=Lin|first6=TN|last7=Yang|first7=W|last8=Lin|first8=DT|last9=Yu|first9=CH|last10=Kham|first10=S|last11=Pui|first11=CH|last12=Evans|first12=WE|last13=Jeha|first13=S|last14=Relling|first14=MV|last15=Yeoh|first15=AE|last16=Yang|first16=JJ|title=Novel variants in ''NUDT15'' and thiopurine intolerance in children with acute lymphoblastic leukemia from diverse ancestry.|journal=Blood|date=28 June 2017|doi=10.1182/blood-2017-05-782383|pmid=28659275}}</ref> suggesting the whole gene screening should be taken to determine the initial dosage using of thiopurine.
NUDT15 germline variants (e.g., a missense SNP:rs116855232, inducing R139C) have been linked to clinical usage of thiopurines (e.g., mercaptopurine) in [[acute lymphoblastic leukemia]]<ref>{{cite journal | vauthors = Moriyama T, Nishii R, Perez-Andreu V, Yang W, Klussmann FA, Zhao X, Lin TN, Hoshitsuki K, Nersting J, Kihira K, Hofmann U, Komada Y, Kato M, McCorkle R, Li L, Koh K, Najera CR, Kham SK, Isobe T, Chen Z, Chiew EK, Bhojwani D, Jeffries C, Lu Y, Schwab M, Inaba H, Pui CH, Relling MV, Manabe A, Hori H, Schmiegelow K, Yeoh AE, Evans WE, Yang JJ | display-authors = 6 | title = NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity | journal = Nature Genetics | volume = 48 | issue = 4 | pages = 367–73 | date = April 2016 | pmid = 26878724 | doi = 10.1038/ng.3508 | pmc=5029084}}</ref><ref>{{cite journal | vauthors = Yang JJ, Landier W, Yang W, Liu C, Hageman L, Cheng C, Pei D, Chen Y, Crews KR, Kornegay N, Wong FL, Evans WE, Pui CH, Bhatia S, Relling MV | display-authors = 6 | title = Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia | journal = Journal of Clinical Oncology | volume = 33 | issue = 11 | pages = 1235–42 | date = April 2015 | pmid = 25624441 | doi = 10.1200/JCO.2014.59.4671 | pmc=4375304}}</ref> as well as inflammatory bowel diseases to avoid thiopurine-induced leukopenia.<ref>{{cite journal | vauthors = Yang SK, Hong M, Baek J, Choi H, Zhao W, Jung Y, Haritunians T, Ye BD, Kim KJ, Park SH, Park SK, Yang DH, Dubinsky M, Lee I, McGovern DP, Liu J, Song K | display-authors = 6 | title = A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia | journal = Nature Genetics | volume = 46 | issue = 9 | pages = 1017–20 | date = September 2014 | pmid = 25108385 | doi = 10.1038/ng.3060 | pmc=4999337}}</ref><ref>{{cite journal | vauthors = Yin D, Xia X, Zhang J, Zhang S, Liao F, Zhang G, Zhang Y, Hou Q, Yang X, Wang H, Ma Z, Wang H, Zhu Y, Zhang W, Wang Y, Liu B, Wang L, Xu H, Shu Y | display-authors = 6 | title = Impact of NUDT15 polymorphisms on thiopurines-induced myelotoxicity and thiopurines tolerance dose | journal = Oncotarget | volume = 8 | issue = 8 | pages = 13575–13585 | date = February 2017 | pmid = 28088792 | doi = 10.18632/oncotarget.14594 | pmc=5355121}}</ref> These variants also exhibit ethnicity-specific (e.g.,variant allele of rs116855232 is high is East Asians and Hispanics but low in Caucasians and Africans). Rare functional variants even singletons in this gene have also been identified to be related to thiopurine-induced myelotoxicity,<ref>{{cite journal|last1=Moriyama|first1=T|last2=Yang|first2=YL|last3=Nishii|first3=R|last4=Ariffin|first4=H|last5=Liu|first5=C|last6=Lin|first6=TN|last7=Yang|first7=W|last8=Lin|first8=DT|last9=Yu|first9=CH|last10=Kham|first10=S|last11=Pui|first11=CH|last12=Evans|first12=WE|last13=Jeha|first13=S|last14=Relling|first14=MV|last15=Yeoh|first15=AE|last16=Yang|first16=JJ|title=Novel variants in ''NUDT15'' and thiopurine intolerance in children with acute lymphoblastic leukemia from diverse ancestry.|journal=Blood|date=28 June 2017|doi=10.1182/blood-2017-05-782383|pmid=28659275|volume=130|pmc=5606007|pages=1209–1212}}</ref> suggesting the whole gene screening should be taken to determine the initial dosage using of thiopurine.


== References ==
== References ==

Revision as of 11:05, 2 March 2018

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
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Wikidata
View/Edit Human

Nudix hydrolase 15 is a protein that in humans is encoded by the NUDT15 gene.[1]

Function

This gene encodes an enzyme that belongs to the Nudix hydrolase superfamily. Members of this superfamily catalyze the hydrolysis of nucleoside diphosphates, including substrates like 8-oxo-dGTP, which are a result of oxidative damage, and can induce base mispairing during DNA replication, causing transversions. The encoded enzyme is a negative regulator of thiopurine activation and toxicity. Mutations in this gene result in poor metabolism of thiopurines, and are associated with thiopurine-induced early leukopenia. Multiple pseudogenes of this gene have been identified.

NUDT15 germline variants (e.g., a missense SNP:rs116855232, inducing R139C) have been linked to clinical usage of thiopurines (e.g., mercaptopurine) in acute lymphoblastic leukemia[2][3] as well as inflammatory bowel diseases to avoid thiopurine-induced leukopenia.[4][5] These variants also exhibit ethnicity-specific (e.g.,variant allele of rs116855232 is high is East Asians and Hispanics but low in Caucasians and Africans). Rare functional variants even singletons in this gene have also been identified to be related to thiopurine-induced myelotoxicity,[6] suggesting the whole gene screening should be taken to determine the initial dosage using of thiopurine.

References

  1. ↑ "Entrez Gene: Nudix hydrolase 15".
  2. ↑ Moriyama T, Nishii R, Perez-Andreu V, Yang W, Klussmann FA, Zhao X, et al. (April 2016). "NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity". Nature Genetics. 48 (4): 367–73. doi:10.1038/ng.3508. PMC 5029084. PMID 26878724.
  3. ↑ Yang JJ, Landier W, Yang W, Liu C, Hageman L, Cheng C, et al. (April 2015). "Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia". Journal of Clinical Oncology. 33 (11): 1235–42. doi:10.1200/JCO.2014.59.4671. PMC 4375304. PMID 25624441.
  4. ↑ Yang SK, Hong M, Baek J, Choi H, Zhao W, Jung Y, et al. (September 2014). "A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia". Nature Genetics. 46 (9): 1017–20. doi:10.1038/ng.3060. PMC 4999337. PMID 25108385.
  5. ↑ Yin D, Xia X, Zhang J, Zhang S, Liao F, Zhang G, et al. (February 2017). "Impact of NUDT15 polymorphisms on thiopurines-induced myelotoxicity and thiopurines tolerance dose". Oncotarget. 8 (8): 13575–13585. doi:10.18632/oncotarget.14594. PMC 5355121. PMID 28088792.
  6. ↑ Moriyama, T; Yang, YL; Nishii, R; Ariffin, H; Liu, C; Lin, TN; Yang, W; Lin, DT; Yu, CH; Kham, S; Pui, CH; Evans, WE; Jeha, S; Relling, MV; Yeoh, AE; Yang, JJ (28 June 2017). "Novel variants in NUDT15 and thiopurine intolerance in children with acute lymphoblastic leukemia from diverse ancestry". Blood. 130: 1209–1212. doi:10.1182/blood-2017-05-782383. PMC 5606007. PMID 28659275.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.


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