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: Paola Griseri, Francesca Lantieri, Francesca Puppo, Tiziana Bachetti, Marco Di Duca, Roberto Ravazzolo, Isabella Ceccherini
• Journal: Human mutation (Hum Mutat) Vol. 28 Issue 2 Pg. 168-76 (Feb 2007) ISSN: 1098-1004 [Electronic] United States
• PMID: 16986122 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2006 Wiley-Liss, Inc.

Chemical References

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

Topics

• 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, metabolism)
• Proto-Oncogene Proteins c-ret (chemistry, genetics, metabolism)
• RNA Stability (genetics)
• RNA, Messenger (metabolism)
• Sequence Homology, Nucleic Acid
• Thyroid Neoplasms (genetics)