The RET proto-oncogene is the major gene involved in the pathogenesis of 
Hirschsprung (HSCR), a complex genetic disease characterized by lack of ganglia 
along variable lengths of the gut. Here we present a survey of the different 
molecular mechanisms through which RET mutations lead to the disease 
development. Among these, loss of function, gain of function, apoptosis, 
aberrant splicing and decreased gene expression are exemplified and considered 
with respect to their pathogenetic impact. In particular, RET transcription 
regulation represents a new insight into the outline of HSCR susceptibility, and 
having reached important progress in the last few years, deserves to be 
reviewed. Notably, gene expression impairment seems to be at the basis of the 
association of HSCR disease with several RET polymorphisms, allowing us to 
define a predisposing haplotype spanning from the promoter to exon 2. Putative 
functional variants, in the promoter and in intron 1, and proposed as low 
penetrant predisposing alleles, are presented and discussed. Finally, based on 
the RET mutation effects thus summarized, we attempt to derive conclusions which 
may be useful for HSCR risk prediction and genetic counselling.