Serrated adenomas and mixed polyposis caused by a splice acceptor deletion in the mouse Smad4 gene.
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.
Hohenstein
Peter
P
Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Molenaar
Lia
L
Elsinga
Joyce
J
Morreau
Hans
H
van der Klift
Heleen
H
Struijk
Ada
A
Jagmohan-Changur
Shantie
S
Smits
Ron
R
van Kranen
Henk
H
van Ommen
Gert-Jan B
GJ
Cornelisse
Cees
C
Devilee
Peter
P
Fodde
Riccardo
R
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
D004268:DNA-Binding Proteins; D022821:RNA Splice Sites; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta