title: Haplotypes of the human RET proto-oncogene associated with Hirschsprung disease in the Italian population derive from a single ancestral combination of alleles.
abstract: The RET proto-oncogene is the major gene involved in the complex genetics of Hirschsprung disease (HSCR), or aganglionic megacolon, showing causative loss-of-function mutations in 15-30% of the sporadic cases. Several RET polymorphisms and haplotypes have been described in association with the disease, suggesting a role for this gene in HSCR predisposition, also in the absence of mutations in the coding region. Finally, the presence of a functional variant in intron 1 has repeatedly been proposed to explain such findings. Here we report a case-control study conducted on 97 Italian HSCR sporadic patients and 85 population matched controls, using 13 RET polymorphisms distributed throughout the gene, from the basal promoter to the 3'UTR. Linkage disequilibrium and haplotype analyses have shown increased recombination between the 5' and 3' portions of the gene and an over-representation, in the cases studied, of two haplotypes sharing a common allelic combination that extends from the promoter up to intron 5. We propose that these two disease-associated haplotypes derive from a single founding locus, extending up to intron 19 and successively rearranged in correspondence with a high recombination rate region located between the proximal and distal portions of the gene. Our results suggests the possibility that a common HSCR predisposing variant, in linkage disequilibrium with such haplotypes, is located further downstream than the previously suggested interval encompassing intron 1.
authors.affiliation: Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, Genova, Italy, 16148.
authors.forename: F
authors.initials: F
authors.lastname: Lantieri
authors.forename: P
authors.initials: P
authors.lastname: Griseri
authors.forename: F
authors.initials: F
authors.lastname: Puppo
authors.forename: R
authors.initials: R
authors.lastname: Campus
authors.forename: G
authors.initials: G
authors.lastname: Martucciello
authors.forename: R
authors.initials: R
authors.lastname: Ravazzolo
authors.forename: M
authors.initials: M
authors.lastname: Devoto
authors.forename: I
authors.initials: I
authors.lastname: Ceccherini
mesh_terms: D000483:Alleles; D001483:Base Sequence; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D017931:DNA Primers; D019143:Evolution, Molecular; D040461:Gene Components; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D007558:Italy; D015810:Linkage Disequilibrium; D018895:Microsatellite Repeats / Q000235:genetics; D008969:Molecular Sequence Data; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D011995:Recombination, Genetic / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D017931:DNA Primers; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human