title: Germline alterations in the cyclooxygenase-2 gene are not associated with the development of extracolonic manifestations in a large swiss familial adenomatous polyposis kindred.
abstract: Familial adenomatous polyposis (FAP) is an autosomal dominant condition leading to the development of multiple colorectal polyps and other features. Intrafamilial variation in phenotype is known to occur in FAP; despite carrying the same causing mutation in the APC gene, disease expression may considerably differ in affected individuals, likely due to the existence of modifier genes. Several lines of evidence suggest the cyclooxygenase-2 (COX-2) gene to be a candidate modifier in FAP. Since COX-2 appears to be expressed in tissues prone to be affected in FAP, it might influence the occurrence of extracolonic manifestations in this disorder. Herein, we investigated whether alterations in the COX-2 gene are involved in the development of extracolonic polyps and extragastrointestinal features. Mutational analysis using single-strand conformation polymorphism (SSCP) in 130 members of a FAP family displaying strong phenotype variation revealed 3 polymorphic sites within the coding region of the COX-2 gene. None of these allelic variants, however, segregated with a particular disease phenotype. In addition, expression analysis was performed in 31 family members with representative phenotypes. Neither of the two polymorphisms detected within the COX-2 promoter was associated with a given phenotype nor was there a significant difference in quality or quantity of COX-2 mRNA in lymphocytes as measured by reverse transcription- and real time quantitative reverse transcription PCR (RT-PCR and TaqMan). In conclusion, germline alterations in the COX-2 gene are unlikely to account for the development of extracolonic disease in FAP patients.
authors.affiliation: Research Group Human Genetics, Department of Research, University Hospital, Basel, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Humar
authors.forename: O
authors.initials: O
authors.lastname: Giovanoli
authors.forename: A
authors.initials: A
authors.lastname: Wolf
authors.forename: M
authors.initials: M
authors.lastname: Attenhofer
authors.forename: I
authors.initials: I
authors.lastname: Bendik
authors.forename: R
authors.initials: R
authors.lastname: Meier
authors.forename: H
authors.initials: H
authors.lastname: Müller
authors.forename: Z
authors.initials: Z
authors.lastname: Dobbie
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D051546:Cyclooxygenase 2; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008565:Membrane Proteins; D008875:Middle Aged; D010641:Phenotype; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013557:Switzerland
chemical_list: D007527:Isoenzymes; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases