1. Allele-specific tumor spectrum in Pten knockin mice
- Author
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Shan Naidu, Gustavo Leone, Wolfgang Sadee, Hui-Zi Chen, Paul C. Stromberg, Hui Wang, Matt Karikomi, Maysoon Rawahneh, Thomas J. Rosol, Charis Eng, Danxin Wang, Ravi Rajmohan, Julie A. Stephens, Michael Weinstein, Michael C. Ostrowski, Enrico Caserta, Krista M. D. La Perle, Julie Moffitt, and Soledad Fernandez
- Subjects
Tumor suppressor gene ,DNA Mutational Analysis ,Molecular Sequence Data ,Embryonic Development ,Biology ,Mice ,Germline mutation ,Neoplasms ,medicine ,Animals ,Point Mutation ,Tensin ,Missense mutation ,PTEN ,Genetic Predisposition to Disease ,Gene Knock-In Techniques ,Gene Silencing ,Alleles ,Cell Proliferation ,Genetics ,Multidisciplinary ,Base Sequence ,Protein Stability ,Tumor Suppressor Proteins ,Point mutation ,PTEN Phosphohydrolase ,Cowden syndrome ,Biological Sciences ,medicine.disease ,Organ Specificity ,Lipid phosphatase activity ,Gene Targeting ,Disease Progression ,Embryo Loss ,biology.protein ,Mutant Proteins ,Precancerous Conditions ,Proto-Oncogene Proteins c-akt - Abstract
Germline mutations in the tumor suppressor gene PTEN (phosphatase and tensin homology deleted on chromosome 10) cause Cowden and Bannayan–Riley–Ruvalcaba (BRR) syndromes, two dominantly inherited disorders characterized by mental retardation, multiple hamartomas, and variable cancer risk. Here, we modeled three sentinel mutant alleles of PTEN identified in patients with Cowden syndrome and show that the nonsense Pten ∆4–5 and missense Pten C124R and Pten G129E alleles lacking lipid phosphatase activity cause similar developmental abnormalities but distinct tumor spectra with varying severity and age of onset. Allele-specific differences may be accounted for by loss of function for Pten ∆4–5 , hypomorphic function for Pten C124R , and gain of function for Pten G129E . These data demonstrate that the variable tumor phenotypes observed in patients with Cowden and BRR syndromes can be attributed to specific mutations in PTEN that alter protein function through distinct mechanisms.
- Published
- 2010