Human Molecular Genetics Advance Access published online on November 4, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg354
© 2003 by Oxford University Press
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1 Department of Pediatric Surgery, University of Technology Dresden, Fetscherstr. 74, D-01307 Dresden, Germany
* To whom correspondence should be addressed. E-mail: guido.fitze{at}mailbox.tu-dresden.de.
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 as strongly associated with the HSCR phenotype. We have reported a 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 to 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.
Article
Functional haplotypes of the RET proto-oncogene promoter are associated with Hirschsprung disease (HSCR)
2 Department of Surgical Research, University of Technology Dresden, D-01307 Dresden, Germany
3 Institute of Medical Biometry and Statistics, University at Lübeck, D-23538 Lübeck, Germany
4 Max-Delbrück-Center for Molecular Medicine, D-13092 Berlin, Germany
5 Department of Pediatric Surgery, University of Erlangen, D-91054 Erlangen, Germany
6 Department of Pediatric Surgery, University of Technology Dresden, D-01307 Dresden, Germany
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