title: Novel mouse model for Gardner syndrome generated by a large-scale N-ethyl-N-nitrosourea mutagenesis program.
abstract: Mutant mouse models are indispensable tools for clarifying the functions of genes and elucidating the underlying pathogenic mechanisms of human diseases. We carried out large-scale mutagenesis using the chemical mutagen N-ethyl-N-nitrosourea. One specific aim of our mutagenesis project was to generate novel cancer models. We screened 7012 animals for dominant traits using a necropsy test and thereby established 17 mutant lines predisposed to cancer. Here, we report on a novel cancer model line that developed osteoma, trichogenic tumor, and breast cancer. Using fine mapping and genomic sequencing, we identified a point mutation in the adenomatous polyposis coli (Apc) gene. The Apc1576 mutants bear a nonsense mutation at codon 1576 in the Apc gene. Although most Apc mutant mice established thus far have multifocal intestinal tumors, mice that are heterozygous for the Apc1576 mutation do not develop intestinal tumors; instead, they develop multifocal breast cancers and trichogenic tumors. Notably, the osteomas that develop in the Apc1576 mutant mice recapitulate the lesion observed in Gardner syndrome, a clinical variant of familial adenomatous polyposis. Our Apc1576 mutant mice will be valuable not only for understanding the function of the Apc gene in detail but also as models of human Gardner syndrome.
authors.affiliation: Team for Advanced Development and Evaluation of Human Disease Models, Riken BioResource Center, Tsukuba, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Toki
authors.forename: Maki
authors.initials: M
authors.lastname: Inoue
authors.forename: Hiromi
authors.initials: H
authors.lastname: Motegi
authors.forename: Osamu
authors.initials: O
authors.lastname: Minowa
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kanda
authors.forename: Noriko
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Ami
authors.initials: A
authors.lastname: Ikeda
authors.forename: Yuko
authors.initials: Y
authors.lastname: Karashima
authors.forename: Junko
authors.initials: J
authors.lastname: Matsui
authors.forename: Hideki
authors.initials: H
authors.lastname: Kaneda
authors.forename: Ikuo
authors.initials: I
authors.lastname: Miura
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Wakana
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Masuya
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Gondo
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Shiroishi
authors.forename: Tetsu
authors.initials: T
authors.lastname: Akiyama
authors.forename: Ryoji
authors.initials: R
authors.lastname: Yao
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
mesh_terms: D000818:Animals; D003062:Codon; D004195:Disease Models, Animal; D005038:Ethylnitrosourea; D005260:Female; D005736:Gardner Syndrome / Q000139:chemically induced* / Q000235:genetics*; D017491:Genes, APC; D016678:Genome; D006579:Heterozygote; D007414:Intestinal Neoplasms / Q000139:chemically induced / Q000235:genetics; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics; D051379:Mice; D016296:Mutagenesis; D009153:Mutagens; D009154:Mutation; D010016:Osteoma / Q000139:chemically induced / Q000235:genetics; D010641:Phenotype
chemical_list: D003062:Codon; D009153:Mutagens; D005038:Ethylnitrosourea
references.citation: Jpn J Clin Oncol. 2000 Feb;30(2):82-8
references.pmid: 10768871
references.citation: Tanpakushitsu Kakusan Koso. 1995 Oct;40(14):2035-44
references.pmid: 8532859
references.citation: Proc Natl Acad Sci U S A. 1985 Oct;82(19):6619-21
references.pmid: 3863118
references.citation: Mamm Genome. 2000 Jul;11(7):478-83
references.pmid: 10886009
references.citation: PLoS Genet. 2009 Jul;5(7):e1000547
references.pmid: 19578404
references.citation: J Neurosci. 2009 Sep 30;29(39):12089-100
references.pmid: 19793967
references.citation: Cell. 1991 Aug 9;66(3):589-600
references.pmid: 1651174
references.citation: Nat Genet. 2000 Aug;25(4):440-3
references.pmid: 10932191
references.citation: Gastroenterology. 2009 Mar;136(3):780-98
references.pmid: 19263594
references.citation: Am J Hum Genet. 1951 Jun;3(2):167-76
references.pmid: 14902760
references.citation: Science. 1997 Oct 3;278(5335):120-3
references.pmid: 9311916
references.citation: Am J Med Genet A. 2006 Feb 1;140(3):200-4
references.pmid: 16411234
references.citation: Lab Invest. 2004 Dec;84(12):1619-30
references.pmid: 15502862
references.citation: J Cell Sci. 2007 Oct 1;120(Pt 19):3327-35
references.pmid: 17881494
references.citation: Cancer Res. 2007 Oct 15;67(20):9721-30
references.pmid: 17942902
references.citation: J Med Genet. 1996 Apr;33(4):274-80
references.pmid: 8730280
references.citation: Orphanet J Rare Dis. 2009 Oct 12;4:22
references.pmid: 19822006
references.citation: PLoS Genet. 2006 Sep 15;2(9):e146
references.pmid: 17002498
references.citation: Pathol Res Pract. 2008;204(7):479-90
references.pmid: 18538487
references.citation: Proc Natl Acad Sci U S A. 1995 May 9;92(10):4482-6
references.pmid: 7753829
references.citation: Science. 1991 Aug 9;253(5020):665-9
references.pmid: 1651563
references.citation: Carcinogenesis. 2010 May;31(5):946-52
references.pmid: 20176656
references.citation: Hum Mol Genet. 2004 Jun 1;13(11):1147-57
references.pmid: 15102714
references.citation: Science. 1990 Jan 19;247(4940):322-4
references.pmid: 2296722
references.citation: Genes Dev. 1999 May 15;13(10):1309-21
references.pmid: 10346819
references.citation: Nat Genet. 2000 Aug;25(4):444-7
references.pmid: 10932192
references.citation: J Cell Biol. 2007 Jan 15;176(2):183-95
references.pmid: 17227893
references.citation: Hum Mol Genet. 1999;8(10):1955-63
references.pmid: 10469849