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A novel Akt3 mutation associated with enhanced kinase activity and seizure susceptibility in mice.

Human molecular genetics | Mar 1, 2011

In a phenotype-driven mutagenesis screen, a novel, dominant mouse mutation, Nmf350, caused low seizure threshold, sporadic tonic-clonic seizures, brain enlargement and ectopic neurons in the dentate hilus and molecular layer of the hippocampus. Genetic mapping implicated Akt3, one of four candidates within the critical interval. Sequencing analysis revealed that mutants have a missense mutation in Akt3 (encoding one of three AKT/protein kinase B molecules), leading to a non-synonymous amino acid substitution in the highly conserved protein kinase domain. Previous knockout studies showed that Akt3 is pivotal in postnatal brain development, including a smaller brain, although seizures were not observed. In contrast to Akt3(Nmf350), we find that Akt3 null mice exhibit an elevated seizure threshold. An in vitro kinase assay revealed that Akt3(Nmf350) confers higher enzymatic activity, suggesting that Akt3(Nmf350) might enhance AKT signaling in the brain. In the dentate gyrus of Akt3(Nmf350) homozygotes, we also observed a modest increase in immunoreactivity of phosphorylated ribosomal protein S6, an AKT pathway downstream target. Together these findings suggest that Akt3(Nmf350) confers an increase of AKT3 activity in specific neuronal populations in the brain, and a unique dominant phenotype. Akt3(Nmf350) mice provide a new tool for studying physiological roles of AKT signaling in the brain, and potentially novel mechanisms for epilepsy.

Pubmed ID: 21159799 RIS Download

Mesh terms: Amino Acid Sequence | Animals | Cell Line | Disease Susceptibility | Female | Humans | Male | Mice | Mice, Inbred BALB C | Mice, Inbred C57BL | Mice, Knockout | Molecular Sequence Data | Mutation, Missense | Phosphorylation | Proto-Oncogene Proteins c-akt | Ribosomal Protein S6 Kinases | Seizures | Sequence Alignment | Signal Transduction

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Associated grants

  • Agency: NINDS NIH HHS, Id: NS031348
  • Agency: NINDS NIH HHS, Id: NS041215
  • Agency: NINDS NIH HHS, Id: R01 NS031348
  • Agency: NINDS NIH HHS, Id: U01 NS41215
  • Agency: NIDDK NIH HHS, Id: R01 DK056886
  • Agency: NCI NIH HHS, Id: CA034196
  • Agency: NIDDK NIH HHS, Id: DK56886
  • Agency: NINDS NIH HHS, Id: NS-065020

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