title: Allele-specific tumor spectrum in pten knockin mice.
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.
authors.affiliation: Department of Molecular Genetics, College of Biological Sciences, Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Matt
authors.initials: M
authors.lastname: Karikomi
authors.forename: Shan
authors.initials: S
authors.lastname: Naidu
authors.forename: Ravi
authors.initials: R
authors.lastname: Rajmohan
authors.forename: Enrico
authors.initials: E
authors.lastname: Caserta
authors.forename: Hui-Zi
authors.initials: HZ
authors.lastname: Chen
authors.forename: Maysoon
authors.initials: M
authors.lastname: Rawahneh
authors.forename: Julie
authors.initials: J
authors.lastname: Moffitt
authors.forename: Julie A
authors.initials: JA
authors.lastname: Stephens
authors.forename: Soledad A
authors.initials: SA
authors.lastname: Fernandez
authors.forename: Michael
authors.initials: M
authors.lastname: Weinstein
authors.forename: Danxin
authors.initials: D
authors.lastname: Wang
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sadee
authors.forename: Krista
authors.initials: K
authors.lastname: La Perle
authors.forename: Paul
authors.initials: P
authors.lastname: Stromberg
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rosol
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
authors.forename: Michael C
authors.initials: MC
authors.lastname: Ostrowski
authors.forename: Gustavo
authors.initials: G
authors.lastname: Leone
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation; D004252:DNA Mutational Analysis; D018450:Disease Progression; D020964:Embryo Loss / Q000473:pathology; D047108:Embryonic Development; D055879:Gene Knock-In Techniques; D020868:Gene Silencing; D018390:Gene Targeting; D020022:Genetic Predisposition to Disease; D051379:Mice; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D009928:Organ Specificity; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics; D011230:Precancerous Conditions / Q000473:pathology; D055550:Protein Stability; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; D025521:Tumor Suppressor Proteins; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse