Abstract
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.
Highlights
Hirschsprung disease (HSCR, OMIM 142623), a developmental disorder occurring in 1 of 5,000 live births, is 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
Analysis of NRG1 Variants and Haplotypes We conducted a case-control association study to discern whether any of the variants were directly related to the HSCR phenotype in our population
We did not find any significant difference after comparing allelic and genotypic frequencies of the NRG1 polymorphisms analysed in HSCR vs controls
Summary
Hirschsprung disease (HSCR, OMIM 142623), a developmental disorder occurring in 1 of 5,000 live births, is 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 Such aganglionosis is attributed to a failure of neural crest cells to migrate, proliferate, and/or differentiate during enteric nervous system (ENS) development in the embryonic stage [1,2]. HSCR is regarded as a complex and multifactorial disorder, in which the contribution of several different loci acting in an additive or multiplicative manner is usually required to cause the disease [3] Because of this evidence, many different techniques have emerged to identify new HSCR susceptibility loci, such as genome wide linkage and genome wide association studies (GWLS and GWAS respectively) [10,11]. The genetic and functional evidence for a role of NRG1 in ENS and in HSCR [8,29,35], led us to perform a complete evaluation of this gene in the context of this disease in a series of Spanish patients
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