title: Comprehensive analysis of NRG1 common and rare variants in Hirschsprung patients.
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.
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine. Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.
authors.forename: Berta
authors.initials: B
authors.lastname: Luzón-Toro
authors.forename: Ana
authors.initials: A
authors.lastname: Torroglosa
authors.forename: Rocío
authors.initials: R
authors.lastname: Núñez-Torres
authors.forename: María Valle
authors.initials: MV
authors.lastname: Enguix-Riego
authors.forename: Raquel María
authors.initials: RM
authors.lastname: Fernández
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: de Agustín
authors.forename: Guillermo
authors.initials: G
authors.lastname: Antiñolo
authors.forename: Salud
authors.initials: S
authors.lastname: Borrego
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D017615:Enteric Nervous System / Q000378:metabolism; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D020890:Neuregulin-1 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000090063:Proto-Oncogene Mas
chemical_list: C000715470:MAS1 protein, human; D020890:Neuregulin-1; D000090063:Proto-Oncogene Mas