title: TTF-1 and RET promoter SNPs: regulation of RET transcription in Hirschsprung's disease.
abstract: 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.
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Mercè
authors.initials: M
authors.lastname: Garcia-Barcelo
authors.forename: Raymond W
authors.initials: RW
authors.lastname: Ganster
authors.forename: Vincent C H
authors.initials: VC
authors.lastname: Lui
authors.forename: Thomas Y Y
authors.initials: TY
authors.lastname: Leon
authors.forename: Man-Ting
authors.initials: MT
authors.lastname: So
authors.forename: Anson M F
authors.initials: AM
authors.lastname: Lau
authors.forename: Ming
authors.initials: M
authors.lastname: Fu
authors.forename: Mai-Har
authors.initials: MH
authors.lastname: Sham
authors.forename: Joanne
authors.initials: J
authors.lastname: Knight
authors.forename: Maria Stella
authors.initials: MS
authors.lastname: Zannini
authors.forename: Pak C
authors.initials: PC
authors.lastname: Sham
authors.forename: Paul K H
authors.initials: PK
authors.lastname: Tam
mesh_terms: D000483:Alleles; D005786:Gene Expression Regulation / Q000502:physiology*; D006627:Hirschsprung Disease / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C000614412:NKX2-1 protein, human; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D020794:Receptor Protein-Tyrosine Kinases