FBXW7 mutations typically found in human cancers are distinct from alleles and disrupt lung development.
Bottom Line: In most cases, these mutations do not inactivate the protein, but are mono-allelic missense changes at specific arginine resides involved in substrate binding.Fbxw7(-/-) animals died of vascular abnormalities at E10.5.Fbxw7(R482Q) alleles are not functionally equivalent to heterozygous or homozygous alleles, and we propose that they are selected in tumourigenesis because they cause a selective or partial loss of FBXW7 function.
Affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Oxford University, Roosevelt Drive, Oxford OX3 7BN, UK.Show MeSH
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Mentions: Figure 2A shows the targeting construct used to generate our Fbxw7-mutant mouse. The targeting construct contained a loxP site upstream of exon 9 and two other loxP sites, flanking a Neo cassette, downstream of exon 11. On the other side of the distal loxP, we inserted a repeated genomic region containing exons 9–11, but with an R482Q allele created by site-directed mutagenesis within exon 9. We anticipated that Cre-mediated recombination would generally remove the genomic sequence between the most proximal and distal loxP sites, removing the NeoR cassette and endogenous exons 9–11 and allowing the transcription of the ‘knock-in’ mutated exon 9; in all the mice subsequently reported in this study, recombination had occurred between these outer loxP sites.
Affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Oxford University, Roosevelt Drive, Oxford OX3 7BN, UK.