Luzón-Toro, BertaTorroglosa, AnaNúñez-Torres, RocíoEnguix-Riego, María ValleFernández, Raquel Maríade Agustín, Juan CarlosAntiñolo, GuillermoBorrego, Salud2013-03-182013-03-182012-05-04Luzón-Toro B, Torroglosa A, Núñez-Torres R, Enguix-Riego MV, Fernández RM, de Agustín JC, et al. Comprehensive analysis of NRG1 common and rare variants in Hirschsprung patients. PLoS ONE; 7(5):e36524http://hdl.handle.net/10668/841Journal Article; Research Support, Non-U.S. Gov't;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.enEnfermedad de HirschsprungNeurregulina-1Sistema Nervioso EntéricoVariación GenéticaMedical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Transformed::COS CellsMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Cercopithecidae::Cercopithecinae::Cercopithecus::Cercopithecus aethiopsMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Sequence Analysis::Sequence Analysis, DNA::DNA Mutational AnalysisMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Sequence Analysis::Sequence Analysis, DNA::DNA Mutational AnalysisMedical Subject Headings::Check Tags::FemaleMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Gene FrequencyMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic VariationMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genotype::HaplotypesMedical Subject Headings::Diseases::Digestive System Diseases::Digestive System Abnormalities::Hirschsprung DiseaseMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Nerve Growth Factors::Neuregulins::Neuregulin-1Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Polymorphism, Single NucleotideMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Check Tags::Maleresearch article22574178open access10.1371/journal.pone.00365241932-6203PMC3344894