title: Serrated adenomas and mixed polyposis caused by a splice acceptor deletion in the mouse Smad4 gene.
abstract: Serrated adenomas, hyperplastic polyps, and admixed hyperplastic/adenomatous polyps form a distinct group of colorectal tumors, the molecular genetic basis of which is still poorly understood. We describe a novel mouse model for serrated adenomas and mixed polyposis, here referred to as Sad (serrated adenomas), caused by a spontaneously risen splice site mutation in the murine Smad4 gene. The Sad chromosomal region was identified by genetic linkage and loss of heterozygosity (LOH) analysis. Subsequently, several candidate genes were investigated by expression and mutation analysis. By use of genetic linkage and LOH analysis, we mapped the Sad candidate to mouse chromosome 18, 44-48 cM, syntenic to human chromosome band 18q21. Within this chromosomal interval, the Smad2, Smad4, and Smad7 genes were analyzed for the presence of a disease-causing mutation in affected animals. A single nucleotide (nt) deletion was identified in the intron 5/exon 6 splice acceptor site of the Smad4 gene. The single base deletion results in a frameshift and an early termination codon through activation of a cryptic splice site 4 nt downstream in exon 6. The resulting mRNA is unstable, and the Sad mutation is thus likely to represent a null allele. Identification of a Smad4 mutation in the Sad mouse model provides further support for the involvement of the Smad genes, and thus the TGFB pathway, in the serrated/hyperplastic route to colorectal cancer.
authors.affiliation: Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Hohenstein
authors.forename: Lia
authors.initials: L
authors.lastname: Molenaar
authors.forename: Joyce
authors.initials: J
authors.lastname: Elsinga
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
authors.forename: Heleen
authors.initials: H
authors.lastname: van der Klift
authors.forename: Ada
authors.initials: A
authors.lastname: Struijk
authors.forename: Shantie
authors.initials: S
authors.lastname: Jagmohan-Changur
authors.forename: Ron
authors.initials: R
authors.lastname: Smits
authors.forename: Henk
authors.initials: H
authors.lastname: van Kranen
authors.forename: Gert-Jan B
authors.initials: GJ
authors.lastname: van Ommen
authors.forename: Cees
authors.initials: C
authors.lastname: Cornelisse
authors.forename: Peter
authors.initials: P
authors.lastname: Devilee
authors.forename: Riccardo
authors.initials: R
authors.lastname: Fodde
mesh_terms: D018256:Adenomatous Polyps / Q000235:genetics* / Q000473:pathology; D000818:Animals; D002460:Cell Line; D003111:Colonic Polyps / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005313:Fetal Death / Q000235:genetics; D020869:Gene Expression Profiling; D005804:Genes, Lethal; D006720:Homozygote; D006965:Hyperplasia; D019656:Loss of Heterozygosity / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D022821:RNA Splice Sites / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D051901:Smad4 Protein; D015534:Trans-Activators / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D022821:RNA Splice Sites; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta