A common variant located in the 3'UTR of the RET gene is associated with protection from Hirschsprung disease.
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.
Griseri
Paola
P
Laboratory of Molecular Genetics, Institute G. Gaslini, Genova, Italy.
Lantieri
Francesca
F
Puppo
Francesca
F
Bachetti
Tiziana
T
Di Duca
Marco
M
Ravazzolo
Roberto
R
Ceccherini
Isabella
I
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
D020413:3' Untranslated Regions; D020033:Protein Isoforms; D012333:RNA, Messenger; D008156:Luciferases; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human