Human Molecular Genetics Advance Access published online on November 17, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddi015
© 2004 by Oxford University Press
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1 Division of Paediatric Surgery, Department of Surgery, The University of Hong Kong, Hong Kong SAR, China; Genome Research Centre, The University of Hong Kong, Hong Kong SAR, China
* To whom correspondence should be addressed. Single nucleotide polymorphisms (SNPs) of the coding regions of RET are associated with Hirschsprung's disease (HSCR, aganglionic megacolon,). These SNPs, individually or combined, may act as a low penetrance susceptibility locus or/and be in linkage disequilibrium (LD) with another susceptibility locus located in RET regulatory regions. Because two RET promoter SNPs have been found associated with HSCR and in LD with HSCR-associated RET coding region haplotypes, their implication in the transcriptional regulation of RET is of major interest. Analysis of 172 sporadic HSCR patients also revealed the presence of HSCR-associated RET promoter SNPs in LD with the main coding region RET haplotype observed in Chinese patients. By using a weighted logistic regression approach, we determined that of all SNPs tested in our study, the promoter SNPs are the most correlated to the disease. Functional analysis of the RET promoter SNPs in the context of additional 5' regulatory regions demonstrated that the HSCR-associated alleles decrease RET transcription. These SNPs overlap a TTF-1 binding site and TTF-1-activated RET transcription is also decreased by the HSCR-associated SNPs. Moreover, we identified a HSCR patient with a Gly322Ser TTF-1 mutation that compromises activation of transcription from HSCR-associated RET promoter haplotypes. Interestingly, we show that the pattern of RET and TTF-1 expression is coincident in developing human gut. We also present a detailed profile of the RET gene in our population that provides an insight for the higher incidence of the disease in Chinese.
Article
TTF-1 and RET promoter SNPs: regulation of RET transcription in Hirschsprung's disease
2 Division of Paediatric Surgery, Department of Surgery, The University of Hong Kong, Hong Kong SAR, China
3 Division of Paediatric Surgery, Department of Surgery, The University of Hong Kong, Hong Kong SAR, China; Department of Surgery, Beijing Children's Hospital, China
4 Department of Biochemistry, The University of Hong Kong, Hong Kong SAR, China
5 Institute of Psychiatry, King's College London, United Kingdom
6 Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universita degli Studi di Napoli Federico II, Napoli, Italy
7 Genome Research Centre, The University of Hong Kong, Hong Kong SAR, China; Department of Biochemistry, The University of Hong Kong, Hong Kong SAR, China; Institute of Psychiatry, King's College London, United Kingdom; Department of Psychiatry, The University of Hong Kong, Hong Kong SAR, China
8 Division of Paediatric Surgery, Department of Surgery, The University of Hong Kong Medical Centre; Queen Mary Hospital, Hong Kong SAR; P.R. China; Genome Research Centre, The University of Hong Kong, Hong Kong SAR, China
Paul K.H. Tam, E-mail: paultam{at}hkucc.hku.hk
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