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Gain-of-function mutation in Gnao1: a murine model of epileptiform encephalopathy (EIEE17)?

Abstract
G protein-coupled receptors strongly modulate neuronal excitability but there has been little evidence for G protein mechanisms in genetic epilepsies. Recently, four patients with epileptic encephalopathy (EIEE17) were found to have mutations in GNAO1, the most abundant G protein in brain, but the mechanism of this effect is not known. The GNAO1 gene product, Gαo, negatively regulates neurotransmitter release. Here, we report a dominant murine model of Gnao1-related seizures and sudden death. We introduced a genomic gain-of-function knock-in mutation (Gnao1 (+/G184S)) that prevents Go turnoff by Regulators of G protein signaling proteins. This results in rare seizures, strain-dependent death between 15 and 40 weeks of age, and a markedly increased frequency of interictal epileptiform discharges. Mutants on a C57BL/6J background also have faster sensitization to pentylenetetrazol (PTZ) kindling. Both premature lethality and PTZ kindling effects are suppressed in the 129SvJ mouse strain. We have mapped a 129S-derived modifier locus on Chromosome 17 (within the region 41-70 MB) as a Modifer of G protein Seizures (Mogs1). Our mouse model suggests a novel gain-of-function mechanism for the newly defined subset of epileptic encephalopathy (EIEE17). Furthermore, it reveals a new epilepsy susceptibility modifier Mogs1 with implications for the complex genetics of human epilepsy as well as sudden death in epilepsy.
AuthorsJason M Kehrl, Kinshuk Sahaya, Hans M Dalton, Raelene A Charbeneau, Kevin T Kohut, Kristen Gilbert, Madeline C Pelz, Jack Parent, Richard R Neubig
JournalMammalian genome : official journal of the International Mammalian Genome Society (Mamm Genome) Vol. 25 Issue 5-6 Pg. 202-10 (Jun 2014) ISSN: 1432-1777 [Electronic] United States
PMID24700286 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • GNAO1 protein, mouse
  • GTP-Binding Protein alpha Subunits, Gi-Go
Topics
  • Animals
  • Brain (metabolism, pathology)
  • Disease Models, Animal
  • Epilepsy (genetics, metabolism, mortality, pathology)
  • Female
  • GTP-Binding Protein alpha Subunits, Gi-Go (genetics, metabolism)
  • Gene Knock-In Techniques
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation

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