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Article: Evaluation of the NK2 homeobox 1 gene (NKX2-1) as a hirschsprung's disease locus

TitleEvaluation of the NK2 homeobox 1 gene (NKX2-1) as a hirschsprung's disease locus
Authors
KeywordsHirschsprung's disease
NK2homeobox 1
RET
Issue Date2008
PublisherBlackwell Publishing Ltd. The Journal's web site is located at http://www.blackwellpublishing.com/journals/AHG
Citation
Annals Of Human Genetics, 2008, v. 72 n. 2, p. 170-177 How to Cite?
AbstractHirschsprung's disease (HSCR, colonic aganglionosis) is an oligogenic entity that usually requires mutations in RET and other interacting loci. Decreased levels of RET expression may lead to the manifestation of HSCR. We previously showed that RET transcription was decreased due to alteration of the NKX2-1 binding site by two HSCR-associated RET promoter single nucleotide polymorphisms (SNPs). This prompted us to investigate whether DNA alterations in NKX2-1 could play a role in HSCR by affecting the RET-regulatory properties of the NKX2-1 protein. Our initial study on 86 Chinese HSCR patients revealed a Gly322Ser amino acid substitution in the NKX2-1 protein. In this study, we have examined 102 additional Chinese and 70 Caucasian patients and 194 Chinese and 60 Caucasian unselected, unrelated, subjects as controls. The relevance of the DNA changes detected in NKX2-1 by direct sequencing were evaluated using bioinformatics, reporter and binding-assays, mouse neurosphere culture, immunohistochemistry and immunofluorescence techniques. Met3Leu and Pro48Pro were identified in 2 Caucasian and 1 Chinese patients respectively. In vitro analysis showed that Met3Leu reduced the activity of the RET promoter by 100% in the presence of the wild-type or HSCR-associated RET promoter SNP alleles. The apparent binding affinity of the NKX2-1 mutated protein was not decreased. The Met3Leu mutation may affect the interaction of NKX2-1 with its protein partners. The absence of NKX2-1 expression in mouse but not in human gut suggests that the role of NKX2-1 in gut development differs between the two species. NKX2-1 mutations could contribute to HSCR by affecting RET expression through defective interactions with other transcription factors. © 2007 The Authors Journal compilation © 2007 University College London.
Persistent Identifierhttp://hdl.handle.net/10722/83262
ISSN
2015 Impact Factor: 1.889
2015 SCImago Journal Rankings: 1.191
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorGarciabarceló, MMen_HK
dc.contributor.authorLau, DKen_HK
dc.contributor.authorNgan, ESen_HK
dc.contributor.authorLeon, TYen_HK
dc.contributor.authorLiu, Ten_HK
dc.contributor.authorSo, Men_HK
dc.contributor.authorMiao, Xen_HK
dc.contributor.authorLui, VCen_HK
dc.contributor.authorWong, KKen_HK
dc.contributor.authorGanster, RWen_HK
dc.contributor.authorCass, DTen_HK
dc.contributor.authorCroaker, GDHen_HK
dc.contributor.authorTam, PKen_HK
dc.date.accessioned2010-09-06T08:38:56Z-
dc.date.available2010-09-06T08:38:56Z-
dc.date.issued2008en_HK
dc.identifier.citationAnnals Of Human Genetics, 2008, v. 72 n. 2, p. 170-177en_HK
dc.identifier.issn0003-4800en_HK
dc.identifier.urihttp://hdl.handle.net/10722/83262-
dc.description.abstractHirschsprung's disease (HSCR, colonic aganglionosis) is an oligogenic entity that usually requires mutations in RET and other interacting loci. Decreased levels of RET expression may lead to the manifestation of HSCR. We previously showed that RET transcription was decreased due to alteration of the NKX2-1 binding site by two HSCR-associated RET promoter single nucleotide polymorphisms (SNPs). This prompted us to investigate whether DNA alterations in NKX2-1 could play a role in HSCR by affecting the RET-regulatory properties of the NKX2-1 protein. Our initial study on 86 Chinese HSCR patients revealed a Gly322Ser amino acid substitution in the NKX2-1 protein. In this study, we have examined 102 additional Chinese and 70 Caucasian patients and 194 Chinese and 60 Caucasian unselected, unrelated, subjects as controls. The relevance of the DNA changes detected in NKX2-1 by direct sequencing were evaluated using bioinformatics, reporter and binding-assays, mouse neurosphere culture, immunohistochemistry and immunofluorescence techniques. Met3Leu and Pro48Pro were identified in 2 Caucasian and 1 Chinese patients respectively. In vitro analysis showed that Met3Leu reduced the activity of the RET promoter by 100% in the presence of the wild-type or HSCR-associated RET promoter SNP alleles. The apparent binding affinity of the NKX2-1 mutated protein was not decreased. The Met3Leu mutation may affect the interaction of NKX2-1 with its protein partners. The absence of NKX2-1 expression in mouse but not in human gut suggests that the role of NKX2-1 in gut development differs between the two species. NKX2-1 mutations could contribute to HSCR by affecting RET expression through defective interactions with other transcription factors. © 2007 The Authors Journal compilation © 2007 University College London.en_HK
dc.languageengen_HK
dc.publisherBlackwell Publishing Ltd. The Journal's web site is located at http://www.blackwellpublishing.com/journals/AHGen_HK
dc.relation.ispartofAnnals of Human Geneticsen_HK
dc.rightsAnnals of Human Genetics. Copyright © Blackwell Publishing Ltd.en_HK
dc.subjectHirschsprung's diseaseen_HK
dc.subjectNK2homeobox 1en_HK
dc.subjectRETen_HK
dc.titleEvaluation of the NK2 homeobox 1 gene (NKX2-1) as a hirschsprung's disease locusen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0003-4800&volume=72&spage=&epage=&date=2008&atitle=Evaluation+of+the+NK2+Homeobox+1+Gene+(NKX2-1)+as+a+Hirschsprung%27s+Disease+Locusen_HK
dc.identifier.emailGarciabarceló, MM: mmgarcia@hkucc.hku.hken_HK
dc.identifier.emailNgan, ES: engan@hkucc.hku.hken_HK
dc.identifier.emailLui, VC: vchlui@hkucc.hku.hken_HK
dc.identifier.emailWong, KK: kkywong@hkucc.hku.hken_HK
dc.identifier.emailTam, PK: paultam@hkucc.hku.hken_HK
dc.identifier.authorityGarciabarceló, MM=rp00445en_HK
dc.identifier.authorityNgan, ES=rp00422en_HK
dc.identifier.authorityLui, VC=rp00363en_HK
dc.identifier.authorityWong, KK=rp01392en_HK
dc.identifier.authorityTam, PK=rp00060en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1111/j.1469-1809.2007.00403.xen_HK
dc.identifier.pmid18081917-
dc.identifier.scopuseid_2-s2.0-38949216682en_HK
dc.identifier.hkuros160487en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-38949216682&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume72en_HK
dc.identifier.issue2en_HK
dc.identifier.spage170en_HK
dc.identifier.epage177en_HK
dc.identifier.isiWOS:000252928000003-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridGarciabarceló, MM=6701767303en_HK
dc.identifier.scopusauthoridLau, DK=10642145100en_HK
dc.identifier.scopusauthoridNgan, ES=22234827500en_HK
dc.identifier.scopusauthoridLeon, TY=10641704600en_HK
dc.identifier.scopusauthoridLiu, T=9273613400en_HK
dc.identifier.scopusauthoridSo, M=8748542200en_HK
dc.identifier.scopusauthoridMiao, X=7102585391en_HK
dc.identifier.scopusauthoridLui, VC=7004231344en_HK
dc.identifier.scopusauthoridWong, KK=24438686400en_HK
dc.identifier.scopusauthoridGanster, RW=6602083865en_HK
dc.identifier.scopusauthoridCass, DT=7005094831en_HK
dc.identifier.scopusauthoridCroaker, GDH=6603013499en_HK
dc.identifier.scopusauthoridTam, PK=7202539421en_HK
dc.identifier.citeulike2356781-

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