Allele-specific tumor spectrum in pten knockin mice.
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.
Wang
Hui
H
Department of Molecular Genetics, College of Biological Sciences, Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA.
Karikomi
Matt
M
Naidu
Shan
S
Rajmohan
Ravi
R
Caserta
Enrico
E
Chen
Hui-Zi
HZ
Rawahneh
Maysoon
M
Moffitt
Julie
J
Stephens
Julie A
JA
Fernandez
Soledad A
SA
Weinstein
Michael
M
Wang
Danxin
D
Sadee
Wolfgang
W
La Perle
Krista
K
Stromberg
Paul
P
Rosol
Thomas J
TJ
Eng
Charis
C
Ostrowski
Michael C
MC
Leone
Gustavo
G
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
D050505:Mutant Proteins; D025521:Tumor Suppressor Proteins; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse