Gain-of-function mutation in Gnao1: A murine model of epileptiform encephalopathy (EIEE17)?
| Autor: | Raelene A. Charbeneau, Hans Dalton, Madeline C. Pelz, Kinshuk Sahaya, Jason Kehrl, Kristen Gilbert, Kevin Kohut, Jack M. Parent, Richard R. Neubig |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Male
medicine.medical_specialty G protein Encephalopathy Biology GTP-Binding Protein alpha Subunits Gi-Go GNAO1 Sudden death Article 03 medical and health sciences Epilepsy Mice 0302 clinical medicine Internal medicine Genetics medicine Animals Humans Gene Knock-In Techniques Pentylenetetrazol 030304 developmental biology 0303 health sciences Kindling GNAO1 Gene Brain medicine.disease Mice Inbred C57BL Disease Models Animal Endocrinology Mutation Female 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Mammalian Genome |
| ISSN: | 1432-1777 0938-8990 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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