A common variant located in the 3'UTR of the RET gene is associated with protection from Hirschsprung disease

Hum Mutat. 2007 Feb;28(2):168-76. doi: 10.1002/humu.20397.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / chemistry*
  • Base Sequence
  • Brain Stem Neoplasms / genetics
  • Carcinoma / genetics
  • DNA Mutational Analysis
  • Genes, Reporter
  • Genetic Predisposition to Disease
  • Haplotypes
  • Hirschsprung Disease / genetics*
  • Humans
  • Linkage Disequilibrium
  • Luciferases / analysis
  • Molecular Sequence Data
  • Nucleic Acid Conformation
  • Polymorphism, Single Nucleotide*
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Proto-Oncogene Proteins c-ret / chemistry
  • Proto-Oncogene Proteins c-ret / genetics*
  • Proto-Oncogene Proteins c-ret / metabolism
  • RNA Stability / genetics
  • RNA, Messenger / metabolism
  • Sequence Homology, Nucleic Acid
  • Thyroid Neoplasms / genetics


  • 3' Untranslated Regions
  • Protein Isoforms
  • RNA, Messenger
  • Luciferases
  • Proto-Oncogene Proteins c-ret
  • RET protein, human