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A common variant located in the 3′UTR of the RET gene is associated with protection from Hirschsprung disease
Author(s) -
Griseri Paola,
Lantieri Francesca,
Puppo Francesca,
Bachetti Tiziana,
Di Duca Marco,
Ravazzolo Roberto,
Ceccherini Isabella
Publication year - 2007
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20397
Subject(s) - biology , haplotype , genetics , gene , mendelian inheritance , untranslated region , inheritance (genetic algorithm) , pathogenesis , single nucleotide polymorphism , disease , allele , messenger rna , genotype , immunology , medicine , pathology
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 underrepresentation of the whole haplotype and its role as a modifying factor in HSCR pathogenesis. Hum Mutat 28(2), 168–176, 2007. © 2006 Wiley‐Liss, Inc.