title: Within-gene interaction between c.135 G/A genotypes and RET proto-oncogene germline mutations in HSCR families.
abstract: Hirschsprung disease (HSCR) is considered a model for a complex inheritance disorder. Several genes, including the major HSCR-susceptibility RET proto-oncogene, play an aetiological role in the development of HSCR. Genetic linkage analysis in familial HSCR with both long- and short-segment phenotypes has demonstrated a tight linkage to the RET locus, while the phenotype within a HSCR family is characterised by an incomplete penetrance or a variable extension of the aganglionosis. Therefore, additional genetic alterations of RET are postulated in the aetiology or modification of the HSCR phenotype. In this study, the coding region of all 21 exons of the RET proto-oncogene, including the flanking intronic sequences, were investigated by direct DNA sequencing in a HSCR population. We genotyped the c.135 G/A polymorphism and resolved haplotypes comprising the mutation locus and the c.135 G/A polymorphism. Twenty different mutations were detected in 18 of 76 HSCR patients. In ten families the mutations were inherited from the parents, while only four patients had a positive family history for the disease. Moreover, in all ten families an incomplete penetrance of the HSCR phenotype was observed. We have investigated the effect of the non-mutated wild-type allele as well as the c.135 G/A polymorphism on the phenotype within the HSCR families. Our findings support the notion that both RET alleles are involved in the pathogenesis of a subgroup of HSCR patients in a dose-dependent fashion. Additionally, we have shown a modifying effect of the c.135 G/A polymorphism on the HSCR phenotype within HSCR families.
authors.affiliation: Department of Paediatric Surgery, University of Technology Dresden, Fetscherstrasse 74, 01307 Dresden, Germany. Guido.Fitze@mailbox.tu-dresden.de
authors.forename: G
authors.initials: G
authors.lastname: Fitze
authors.forename: J
authors.initials: J
authors.lastname: Cramer
authors.forename: A
authors.initials: A
authors.lastname: Serra
authors.forename: M
authors.initials: M
authors.lastname: Schreiber
authors.forename: D
authors.initials: D
authors.lastname: Roesner
authors.forename: H K
authors.initials: HK
authors.lastname: Schackert
mesh_terms: D000483:Alleles; D005091:Exons; D005260:Female; D018628:Gene Dosage; D005838:Genotype; D018095:Germ-Line Mutation; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D017422:Sequence Analysis, DNA
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