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: We analysed E18.5 R482Q embryos for physiological and histological abnormalities to explain the perinatal lethality and noted a striking difference in the histology of the embryonic lungs (Figure 3A). R482Q embryos had thickened alveolar septa in comparison to their wild-type littermates. Wild-type lung septa had a mean width of 16.5 µm (range 2.8–41.7 µm) compared with 32.5 µm (range 8.3–88.9 µm) in R482Q animals (N = 32, p = 1.05 × 10−11, t-test).
Affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Oxford University, Roosevelt Drive, Oxford OX3 7BN, UK.