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Article: Evaluation of the thyroid transcription factor-1 gene (TITF1) as a Hirschsprung's disease locus

TitleEvaluation of the thyroid transcription factor-1 gene (TITF1) as a Hirschsprung's disease locus
Authors
KeywordsHirschsprung's disease
RET
Thyroid transcription factor-1
Issue Date2007
PublisherBlackwell Publishing Ltd. The Journal's web site is located at http://www.blackwellpublishing.com/journals/AHG
Citation
Annals Of Human Genetics, 2007, v. 71 n. 6, p. 746-754 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 TITF1 binding site by two HSCR-associated RET promoter single nucleotide polymorphisms (SNPs). This prompted us to investigate whether DNA alterations in TITF1 could play a role in HSCR by affecting the RET - regulatory properties of the TITF1 protein. Our initial study on 86 Chinese HSCR patients revealed a Gly322Ser amino acid substitution in the TITF1protein. In this study we have examined an additional 102 Chinese and 70 Caucasian patients, and 194 Chinese and 60 Caucasian unselected, unrelated, subjects as controls. The relevance of the DNA changes detected in TITF1 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 patients and 1 Chinese patient, 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 TITF1 mutated protein was not decreased. The Met3Leu mutation may affect the interaction of TITF1 with its protein partners. The absence of Titf1 expression in mouse gut but not in human gut suggests that the role of TITF1 in gut development differs between the two species. TITF1 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/10722/92027
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, DKCen_HK
dc.contributor.authorNgan, ESWen_HK
dc.contributor.authorLeon, TYYen_HK
dc.contributor.authorLiu, TTen_HK
dc.contributor.authorSo, MTen_HK
dc.contributor.authorMiao, XPen_HK
dc.contributor.authorLui, VCCen_HK
dc.contributor.authorWong, KKYen_HK
dc.contributor.authorGanster, RWen_HK
dc.contributor.authorCass, DTen_HK
dc.contributor.authorCroaker, GDHen_HK
dc.contributor.authorTam, PKHen_HK
dc.date.accessioned2010-09-17T10:33:55Z-
dc.date.available2010-09-17T10:33:55Z-
dc.date.issued2007en_HK
dc.identifier.citationAnnals Of Human Genetics, 2007, v. 71 n. 6, p. 746-754en_HK
dc.identifier.issn0003-4800en_HK
dc.identifier.urihttp://hdl.handle.net/10722/92027-
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 TITF1 binding site by two HSCR-associated RET promoter single nucleotide polymorphisms (SNPs). This prompted us to investigate whether DNA alterations in TITF1 could play a role in HSCR by affecting the RET - regulatory properties of the TITF1 protein. Our initial study on 86 Chinese HSCR patients revealed a Gly322Ser amino acid substitution in the TITF1protein. In this study we have examined an additional 102 Chinese and 70 Caucasian patients, and 194 Chinese and 60 Caucasian unselected, unrelated, subjects as controls. The relevance of the DNA changes detected in TITF1 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 patients and 1 Chinese patient, 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 TITF1 mutated protein was not decreased. The Met3Leu mutation may affect the interaction of TITF1 with its protein partners. The absence of Titf1 expression in mouse gut but not in human gut suggests that the role of TITF1 in gut development differs between the two species. TITF1 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.-
dc.subjectHirschsprung's diseaseen_HK
dc.subjectRETen_HK
dc.subjectThyroid transcription factor-1en_HK
dc.titleEvaluation of the thyroid transcription factor-1 gene (TITF1) as a Hirschsprung's disease locusen_HK
dc.typeArticleen_HK
dc.identifier.emailGarciaBarceló, MM: mmgarcia@hkucc.hku.hken_HK
dc.identifier.emailNgan, ESW: engan@hkucc.hku.hken_HK
dc.identifier.emailLui, VCC: vchlui@hkucc.hku.hken_HK
dc.identifier.emailWong, KKY: kkywong@hkucc.hku.hken_HK
dc.identifier.emailTam, PKH: paultam@hkucc.hku.hken_HK
dc.identifier.authorityGarciaBarceló, MM=rp00445en_HK
dc.identifier.authorityNgan, ESW=rp00422en_HK
dc.identifier.authorityLui, VCC=rp00363en_HK
dc.identifier.authorityWong, KKY=rp01392en_HK
dc.identifier.authorityTam, PKH=rp00060en_HK
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1111/j.1469-1809.2007.00384.xen_HK
dc.identifier.pmid17640327-
dc.identifier.scopuseid_2-s2.0-34948862161en_HK
dc.identifier.hkuros135486-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-34948862161&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume71en_HK
dc.identifier.issue6en_HK
dc.identifier.spage746en_HK
dc.identifier.epage754en_HK
dc.identifier.eissn1469-1809-
dc.identifier.isiWOS:000249923200006-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridGarciaBarceló, MM=6701767303en_HK
dc.identifier.scopusauthoridLau, DKC=10642145100en_HK
dc.identifier.scopusauthoridNgan, ESW=22234827500en_HK
dc.identifier.scopusauthoridLeon, TYY=10641704600en_HK
dc.identifier.scopusauthoridLiu, TT=9273613400en_HK
dc.identifier.scopusauthoridSo, MT=8748542200en_HK
dc.identifier.scopusauthoridMiao, XP=7102585391en_HK
dc.identifier.scopusauthoridLui, VCC=7004231344en_HK
dc.identifier.scopusauthoridWong, KKY=24438686400en_HK
dc.identifier.scopusauthoridGanster, RW=6602083865en_HK
dc.identifier.scopusauthoridCass, DT=7005094831en_HK
dc.identifier.scopusauthoridCroaker, GDH=6603013499en_HK
dc.identifier.scopusauthoridTam, PKH=7202539421en_HK
dc.identifier.citeulike1794153-

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