title: Hirschsprung's disease as a model of complex genetic etiology.
abstract: Hirschsprung disease (HSCR), or aganglionic megacolon, is a developmental disorder characterised by the absence of ganglion cells along variable length of the distal gastrointestinal tract, leading to the most common form of functional intestinal obstruction in neonates and children. Aganglionosis is attributed to a failure of neural crest cells to migrate, proliferate, differentiate or survive during enteric nervous system (ENS) development in the embryonic stage. The incidence of HSCR is estimated at 1/5000 live births and most commonly presents sporadically with reduced penetrance and male predominance, although it can be familial and may be inherited as autosomal dominant or autosomal recessive. In 70% of cases, HSCR occurs as an isolated trait and in the other 30% HSCR is associated with other congenital malformation syndromes. HSCR has a complex genetic etiology with several genes and loci being described as associated with either isolated or syndromic forms. These genes encode for receptors, ligands (especially those participating in the RET and EDNRB signaling transduction pathways), transcriptional factors or other cell elements that are usually involved in the neural crest cell development and migration that give rise to ENS. Nevertheless, the RET proto-oncogene is considered the major disease causing gene in HSCR. A common RET variant within the conserved transcriptional enhancer sequence in intron 1 has been shown to be associated with a great proportion of sporadic cases and could act as a modifier by modulating the penetrance of mutations in other genes and possibly of those mutations in the RET proto-oncogene itself.
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain. salud.borrego.sspa@juntadeandalucia.es
authors.forename: Salud
authors.initials: S
authors.lastname: Borrego
authors.forename: Macarena
authors.initials: M
authors.lastname: Ruiz-Ferrer
authors.forename: Raquel M
authors.initials: RM
authors.lastname: Fernández
authors.forename: Guillermo
authors.initials: G
authors.lastname: Antiñolo
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D016232:Endothelins / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D006627:Hirschsprung Disease / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007438:Introns; D008024:Ligands; D008297:Male; D051379:Mice; D009154:Mutation; D010641:Phenotype; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism; D012737:Sex Factors; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived / Q000235:genetics
chemical_list: D016232:Endothelins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D008024:Ligands; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D014157:Transcription Factors; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human