Human Molecular Genetics Advance Access originally published online on November 17, 2004
Human Molecular Genetics 2005 14(2):191-204; doi:10.1093/hmg/ddi015
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Human Molecular Genetics, Vol. 14, No. 2 © Oxford University Press 2005; all rights reserved
TTF-1 and RET promoter SNPs: regulation of RET transcription in Hirschsprung's disease
1Division of Paediatric Surgery, Department of Surgery, 2Genome Research Centre, 3Department of Biochemistry, 4Department of Psychiatry, The University of Hong Kong, Hong Kong SAR, China, 5Department of Surgery, Beijing Children's Hospital, China, 6Institute of Psychiatry, King's College London, UK and 7Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universita degli Studi di Napoli Federico II, Napoli, Italy
* To whom correspondence should be addressed at: Division of Paediatric Surgery, Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, Hong Kong SAR, China. Tel: +852 28554850; Fax: +852 28173155; Email: paultam{at}hkucc.hku.hk
Received June 8, 2004; Revised October 29, 2004; Accepted November 4, 2004
Single nucleotide polymorphisms (SNPs) of the coding regions of receptor tyrosine kinase gene (RET) are associated with Hirschsprung's disease (HSCR, aganglionic megacolon). These SNPs, individually or combined, may act as a low penetrance susceptibility locus and/or 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, 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 an 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, which provides an insight into the higher incidence of the disease in China.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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