title: A large novel deletion in the APC promoter region causes gene silencing and leads to classical familial adenomatous polyposis in a Manitoba Mennonite kindred.
abstract: Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome caused by the inheritance of germline mutations in the APC tumour suppressor gene. The vast majority of these are nonsense and frameshift mutations resulting in a truncated protein product and abnormal function. While APC promoter hypermethylation has been previously documented, promoter-specific deletion mutations have not been reported. In a large Canadian Mennonite polyposis kindred, we identified a large novel germline deletion in the APC promoter region by linkage analysis and MLPA. By RT-PCR and sequence analysis, this mutation was found to result in transcriptional silencing of the APC allele. A few genetic disorders have been characterized as over-represented in the Manitoba Mennonite population, however, the incidence of cancer has not been recognized as increased in this population as compared to other Manitoba ethnic groups. This study strengthens the likelihood that this novel APC promoter mutation is linked to this unique population as a founder mutation.
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 60 Murray St., Toronto, Box 30, ON, M5T 3L9, Canada. charames@lunenfeld.ca
authors.forename: George S
authors.initials: GS
authors.lastname: Charames
authors.forename: Lily
authors.initials: L
authors.lastname: Ramyar
authors.forename: Angela
authors.initials: A
authors.lastname: Mitri
authors.forename: Terri
authors.initials: T
authors.lastname: Berk
authors.forename: Hong
authors.initials: H
authors.lastname: Cheng
authors.forename: Jack
authors.initials: J
authors.lastname: Jung
authors.forename: Patricia
authors.initials: P
authors.lastname: Bocangel
authors.forename: Bernie
authors.initials: B
authors.lastname: Chodirker
authors.forename: Cheryl
authors.initials: C
authors.lastname: Greenberg
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Spriggs
authors.forename: Bharati
authors.initials: B
authors.lastname: Bapat
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000328:Adult; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D020868:Gene Silencing; D017491:Genes, APC; D008040:Genetic Linkage; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008350:Manitoba; D010375:Pedigree; D011401:Promoter Regions, Genetic; D017384:Sequence Deletion
chemical_list: D017931:DNA Primers