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

Guido Fitze*, Hella Appelt, Inke R. König, Ulrike Stein, Wolfgang Walther, Manfred Gossen, Matthias Schreiber, Andreas Ziegler, Dietmar Roesner, Hans K. Schackert

*Corresponding author for this work
66 Citations (Scopus)


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.

Original languageEnglish
JournalHuman Molecular Genetics
Issue number24
Pages (from-to)3207-3214
Number of pages8
Publication statusPublished - 15.12.2003


Dive into the research topics of 'Functional haplotypes of the RET proto-oncogene promoter are associated with Hirschsprung disease (HSCR)'. Together they form a unique fingerprint.

Cite this