Functional haplotypes of the RET proto-oncogene promoter are associated with Hirschsprung disease (HSCR)

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Item Type:	Article
Title:	Functional haplotypes of the RET proto-oncogene promoter are associated with Hirschsprung disease (HSCR)
Creators Name:	Fitze, G., Appelt, H., Koenig, I.R., Goergens, H., Stein, U., Walther, W., Gossen, M., Schreiber, M., Ziegler, A., Roesner, D. and Schackert, H.K.
Abstract:	The activation of the RET signaling pathway during embryogenesis is a crucial prerequisite for a directional migration of enteric nervous system progenitor cells. Loss-of-function germline mutations of the RET protooncogene are reported in familial and sporadic cases of Hirschsprung disease (HSCR) with a variable frequency. Furthermore, variants of several RET polymorphisms are over- or under-represented in HSCR populations. Specifically, the c.135A RET variant has been previously shown to be strongly associated with the HSCR phenotype. We have reported an HSCR-phenotype modifying effect of the RET c.135G>A polymorphism due to a within-gene interaction in patients harboring RET germline mutations, yet the function of the c.135G>A variant is unknown. The basic RET promoter region was investigated by DNA sequencing approach in 80 HSCR patients. Identified polymorphisms were genotyped in the HSCR and in a control population and haplotypes were reconstructed. The dual-luciferase assay was used to evaluate the activity of different RET promoter haplotypes. We demonstrate that variants of two RET promoter polymorphisms -5G>A and -1C>A from the transcription start site are associated with HSCR. Furthermore, the -5G>A polymorphism is in strong linkage disequilibrium with the c.135G>A polymorphism. The promoter haplotype -5/-1AC associated with HSCR has a significantly lower activity in an in vitro dual-luciferase expression assay compared with those haplotypes identified in the majority of normal controls. These data suggest a role for RET haplotypes containing the -5A promoter variant in the etiology of HSCR.
Keywords:	Cultured Tumor Cells, Gene Frequency, Genetic Polymorphism, Haplotypes, Hirschsprung Disease, Promoter Regions, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-ret, Receptor Protein-Tyrosine Kinases, Signal Transduction
Source:	Human Molecular Genetics
ISSN:	0964-6906
Publisher:	Oxford University Press
Volume:	12
Number:	24
Page Range:	3207-3214
Date:	1 January 2003
Official Publication:	https://doi.org/10.1093/hmg/ddg354
PubMed:	View item in PubMed

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