title: The pleiotropic phenotype of Apc mutations in the mouse: allele specificity and effects of the genetic background.
abstract: Familial adenomatous polyposis (FAP) is a human cancer syndrome characterized by the development of hundreds to thousands of colonic polyps and extracolonic lesions including desmoid fibromas, osteomas, epidermoid cysts, and congenital hypertrophy of the pigmented retinal epithelium. Afflicted individuals are heterozygous for mutations in the APC gene. Detailed investigations of mice heterozygous for mutations in the ortholog Apc have shown that other genetic factors strongly influence the phenotype. Here we report qualitative and quantitative modifications of the phenotype of Apc mutants as a function of three genetic variables: Apc allele, p53 allele, and genetic background. We have found major differences between the Apc alleles Min and 1638N in multiplicity and regionality of intestinal tumors, as well as in incidence of extracolonic lesions. By contrast, Min mice homozygous for either of two different knockout alleles of p53 show similar phenotypic effects. These studies illustrate the classic principle that functional genetics is enriched by assessing penetrance and expressivity with allelic series. The mouse permits study of an allelic gene series on multiple genetic backgrounds, thereby leading to a better understanding of gene action in a range of biological processes.
authors: McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin 53706, USA.
authors: Richard B
authors: RB
authors: Halberg
authors: Xiaodi
authors: X
authors: Chen
authors: James M
authors: JM
authors: Amos-Landgraf
authors: Alanna
authors: A
authors: White
authors: Kristin
authors: K
authors: Rasmussen
authors: Linda
authors: L
authors: Clipson
authors: Cheri
authors: C
authors: Pasch
authors: Ruth
authors: R
authors: Sullivan
authors: Henry C
authors: HC
authors: Pitot
authors: William F
authors: WF
authors: Dove
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000483:Alleles; D000818:Animals; D003433:Crosses, Genetic; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D006720:Homozygote; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics; D010641:Phenotype
chemical_list: D025601:Adenomatous Polyposis Coli Protein