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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&gt;A polymorphism due to a within-gene interaction in patients harboring  RET  germline mutations, yet the function of the c.135G&gt;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&gt;A and −1C&gt;A from the transcription start site are associated with HSCR. Furthermore, the −5G&gt;A polymorphism is in strong linkage disequilibrium with the c.135G&gt;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.

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