title: A common variant located in the 3'UTR of the RET gene is associated with protection from Hirschsprung disease.
abstract: Complex diseases are common genetic disorders showing familial aggregation but no typical Mendelian inheritance. Hirschsprung disease (HSCR), a developmental disorder characterized by the absence of enteric neurons in distal segments of the gut, shows a complex pattern of inheritance, with the RET protooncogene acting as a major gene and additional susceptibility loci playing minor roles. In the last years, we have identified a "protective" RET haplotype, which is underrepresented in HSCR patients with respect to controls. Here, we demonstrate that the protective effect of this haplotype is due to a variant located in the 3' untranslated region (UTR) of the RET gene, which slows down the physiological mRNA decay of the gene transcripts. Such a functional effect of this common RET variant explains the under-representation of the whole haplotype and its role as a modifying factor in HSCR pathogenesis.
authors.affiliation: Laboratory of Molecular Genetics, Institute G. Gaslini, Genova, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Griseri
authors.forename: Francesca
authors.initials: F
authors.lastname: Lantieri
authors.forename: Francesca
authors.initials: F
authors.lastname: Puppo
authors.forename: Tiziana
authors.initials: T
authors.lastname: Bachetti
authors.forename: Marco
authors.initials: M
authors.lastname: Di Duca
authors.forename: Roberto
authors.initials: R
authors.lastname: Ravazzolo
authors.forename: Isabella
authors.initials: I
authors.lastname: Ceccherini
mesh_terms: D020413:3' Untranslated Regions / Q000737:chemistry*; D001483:Base Sequence; D020295:Brain Stem Neoplasms / Q000235:genetics; D002277:Carcinoma / Q000235:genetics; D004252:DNA Mutational Analysis; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008156:Luciferases / Q000032:analysis; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D013964:Thyroid Neoplasms / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D020033:Protein Isoforms; D012333:RNA, Messenger; D008156:Luciferases; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human