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Article: Evaluation of the thyroid transcription factor-1 gene (TITF1) as a Hirschsprung's disease locus
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TitleEvaluation of the thyroid transcription factor-1 gene (TITF1) as a Hirschsprung's disease locus
 
AuthorsGarciaBarceló, MM
Lau, DKC
Ngan, ESW
Leon, TYY
Liu, TT
So, MT
Miao, XP
Lui, VCC
Wong, KKY
Ganster, RW
Cass, DT3
Croaker, GDH1
Tam, PKH2 2
 
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
 
CitationAnnals Of Human Genetics, 2007, v. 71 n. 6, p. 746-754 [How to Cite?]
DOI: http://dx.doi.org/10.1111/j.1469-1809.2007.00384.x
 
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.
 
ISSN0003-4800
2012 Impact Factor: 2.215
2012 SCImago Journal Rankings: 0.840
 
DOIhttp://dx.doi.org/10.1111/j.1469-1809.2007.00384.x
 
ISI Accession Number IDWOS:000249923200006
 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorGarciaBarceló, MM
 
dc.contributor.authorLau, DKC
 
dc.contributor.authorNgan, ESW
 
dc.contributor.authorLeon, TYY
 
dc.contributor.authorLiu, TT
 
dc.contributor.authorSo, MT
 
dc.contributor.authorMiao, XP
 
dc.contributor.authorLui, VCC
 
dc.contributor.authorWong, KKY
 
dc.contributor.authorGanster, RW
 
dc.contributor.authorCass, DT
 
dc.contributor.authorCroaker, GDH
 
dc.contributor.authorTam, PKH
 
dc.date.accessioned2010-09-17T10:33:55Z
 
dc.date.available2010-09-17T10:33:55Z
 
dc.date.issued2007
 
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.
 
dc.description.naturelink_to_OA_fulltext
 
dc.identifier.citationAnnals Of Human Genetics, 2007, v. 71 n. 6, p. 746-754 [How to Cite?]
DOI: http://dx.doi.org/10.1111/j.1469-1809.2007.00384.x
 
dc.identifier.citeulike1794153
 
dc.identifier.doihttp://dx.doi.org/10.1111/j.1469-1809.2007.00384.x
 
dc.identifier.eissn1469-1809
 
dc.identifier.epage754
 
dc.identifier.hkuros135486
 
dc.identifier.isiWOS:000249923200006
 
dc.identifier.issn0003-4800
2012 Impact Factor: 2.215
2012 SCImago Journal Rankings: 0.840
 
dc.identifier.issue6
 
dc.identifier.pmid17640327
 
dc.identifier.scopuseid_2-s2.0-34948862161
 
dc.identifier.spage746
 
dc.identifier.urihttp://hdl.handle.net/10722/92027
 
dc.identifier.volume71
 
dc.languageeng
 
dc.publisherBlackwell Publishing Ltd. The Journal's web site is located at http://www.blackwellpublishing.com/journals/AHG
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofAnnals of Human Genetics
 
dc.relation.referencesReferences in Scopus
 
dc.rightsAnnals of Human Genetics. Copyright © Blackwell Publishing Ltd.
 
dc.subjectHirschsprung's disease
 
dc.subjectRET
 
dc.subjectThyroid transcription factor-1
 
dc.titleEvaluation of the thyroid transcription factor-1 gene (TITF1) as a Hirschsprung's disease locus
 
dc.typeArticle
 
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Author Affiliations
  1. Canberra Hospital
  2. The University of Hong Kong
  3. Children's Hospital At Westmead