Hirschsprung disease (HSCR, OMIM 142623) is a developmental disorder 
characterized by the absence of ganglion cells along variable lengths of the 
distal gastrointestinal tract, which results in tonic contraction of the 
aganglionic gut segment and functional intestinal obstruction. The RET 
proto-oncogene is the major gene for HSCR with differential contributions of its 
rare and common, coding and noncoding mutations to the multifactorial nature of 
this pathology. Many other genes have been described to be associated with the 
pathology, as NRG1 gene (8p12), encoding neuregulin 1, which is implicated in 
the development of the enteric nervous system (ENS), and seems to contribute by 
both common and rare variants. Here we present the results of a comprehensive 
analysis of the NRG1 gene in the context of the disease in a series of 207 
Spanish HSCR patients, by both mutational screening of its coding sequence and 
evaluation of 3 common tag SNPs as low penetrance susceptibility factors, 
finding some potentially damaging variants which we have functionally 
characterized. All of them were found to be associated with a significant 
reduction of the normal NRG1 protein levels. The fact that those mutations 
analyzed alter NRG1 protein would suggest that they would be related with HSCR 
disease not only in Chinese but also in a Caucasian population, which reinforces 
the implication of NRG1 gene in this pathology.