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Human Molecular Genetics Advance Access originally published online on November 4, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 24 3207-3214
DOI: 10.1093/hmg/ddg354
© 2003 Oxford University Press

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

Guido Fitze1,*, Hella Appelt2, Inke R. König3, Heike Görgens2, Ulrike Stein4, Wolfgang Walther4, Manfred Gossen4, Matthias Schreiber5, Andreas Ziegler3, Dietmar Roesner1 and Hans K. Schackert2

1Department of Pediatric Surgery, University of Technology Dresden, Fetscherstr. 74, D-01307 Dresden, Germany, 2Department of Surgical Research, University of Technology Dresden, D-01307 Dresden, Germany, 3Institute of Medical Biometry and Statistics, University at Lübeck, D-23538 Lübeck, Germany, 4Max-Delbrück-Center for Molecular Medicine, D-13092 Berlin, Germany and 5Department of Pediatric Surgery, University of Erlangen, D-91054 Erlangen, Germany

Received June 18, 2003; Revised October 7, 2003; Accepted October 15, 2003

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 proto-oncogene 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.

* To whom correspondence should be addressed. Tel: +49 3514583598; Fax: +49 3514585343; Email: guido.fitze{at}mailbox.tu-dresden.de


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