Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - TTF-1 and RET promoter SNPs
T2 - regulation of RET transcription in Hirschsprung's disease
AU - Garcia-Barcelo, Mercè
AU - Ganster, Raymond W.
AU - Lui, Vincent C. H.
AU - Leon, Thomas Y. Y.
AU - So, Man-Ting
AU - Lau, Anson M. F.
AU - Fu, Ming
AU - Sham, Mai-Har
AU - Knight, Joanne
AU - Zannini, Maria Stella
AU - Sham, Pak C.
AU - Tam, Paul K. H.
PY - 2005/1/15
Y1 - 2005/1/15
N2 - 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.
AB - 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.
KW - Alleles
KW - Gene Expression Regulation
KW - Hirschsprung Disease
KW - Humans
KW - Nuclear Proteins
KW - Oncogene Proteins
KW - Polymorphism, Single Nucleotide
KW - Promoter Regions, Genetic
KW - Proto-Oncogene Proteins c-ret
KW - Receptor Protein-Tyrosine Kinases
KW - Sequence Analysis, DNA
KW - Transcription Factors
U2 - 10.1093/hmg/ddi015
DO - 10.1093/hmg/ddi015
M3 - Journal article
C2 - 15548547
VL - 14
SP - 191
EP - 204
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 2
ER -