Journal Article

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

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

in Human Molecular Genetics

Volume 12, issue 24, pages 3207-3214
Published in print December 2003 | ISSN: 0964-6906
Published online December 2003 | e-ISSN: 1460-2083 | DOI:
Functional haplotypes of the RET proto-oncogene promoter are associated with Hirschsprung disease (HSCR)

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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.

Journal Article.  5776 words.  Illustrated.

Subjects: Genetics and Genomics

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