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

Item Type:	Article
Title:	Functional haplotypes of the RET proto-oncogene promoter are associated with Hirschsprung disease (HSCR)
Creators Name:	Fitze, G. and Appelt, H. and Koenig, I.R. and Goergens, H. and Stein, U. and Walther, W. and Gossen, M. and Schreiber, M. and Ziegler, A. and 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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