title: Novel intronic polymorphisms in the RET proto-oncogene and their association with Hirschsprung disease.
abstract: Germline mutations of the RET proto-oncogene have been found in familial and sporadic forms of Hirschsprung disease (HSCR), but also in the autosomal dominantly inherited multiple endocrine neoplasia type 2 (MEN2) syndromes, which comprise the medullary thyroid carcinoma (MTC) as an obligatory feature. Besides mutations various polymorphisms of the RET proto-oncogene are associated with the HSCR. In this study, we have characterized seven intronic RET polymorphisms (IVS2+9G>A, IVS4+48A>G, IVS12+47C>T, IVS14-24G>A, IVS19+47T>C, IVS20+96C>T, 3'UTR+124A>G) and investigated these variants by DNA sequencing in populations of 76 HSCR patients and 40 sporadic MTC patients as well as in a control population. Variants of four of these seven polymorphisms have a strong association with the HSCR phenotype. In contrast, none of the investigated polymorphisms show a significant difference in the genotype distribution and the allele frequencies in patients with sporadic MTC when compared to controls. These findings support the hypothesis that specific RET haplotypes cause or modify the HSCR phenotype.
authors.affiliation: Department of Pediatric Surgery, University of Technology Dresden, Germany. guido.Fitz@mailbox.tu-dresden.de
authors.forename: Guido
authors.initials: G
authors.lastname: Fitze
authors.forename: Mandy
authors.initials: M
authors.lastname: Schierz
authors.forename: Eberhard
authors.initials: E
authors.lastname: Kuhlisch
authors.forename: Matthias
authors.initials: M
authors.lastname: Schreiber
authors.forename: Andreas
authors.initials: A
authors.lastname: Ziegler
authors.forename: Dietmar
authors.initials: D
authors.lastname: Roesner
authors.forename: Hans K
authors.initials: HK
authors.lastname: Schackert
mesh_terms: D005260:Female; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics*; D008297:Male; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases