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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, G?o, 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.

SUBMITTER: Kehrl JM 

PROVIDER: S-EPMC4042023 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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

Kehrl Jason M JM   Sahaya Kinshuk K   Dalton Hans M HM   Charbeneau Raelene A RA   Kohut Kevin T KT   Gilbert Kristen K   Pelz Madeline C MC   Parent Jack J   Neubig Richard R RR  

Mammalian genome : official journal of the International Mammalian Genome Society 20140405 5-6


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  ...[more]

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