Dataset Information

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

ACCESS DATA

Publications

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]

PMID: 24700286

Similar Datasets

Project description:ObjectiveSH3BP2 is a signaling adapter protein which regulates immune and skeletal systems. Gain-of-function mutations in SH3BP2 cause cherubism, characterized by jawbone destruction. This study was aimed to examine the role of SH3BP2 in inflammatory bone loss using a collagen-induced arthritis (CIA) model.MethodsCIA was induced in wild-type (Sh3bp2(+/+)) and heterozygous P416R SH3BP2 cherubism mutant knock-in (Sh3bp2(KI/+)) mice, an SH3BP2 gain-of-function model. Severity of the arthritis was determined by assessing the paw swelling and histological analyses of the joints. Micro-CT analysis was used to determine the levels of bone loss. Inflammation and osteoclastogenesis in the joints were evaluated by quantitating the gene expression of inflammatory cytokines and osteoclast markers. Furthermore, involvement of the T- and B-cell responses was determined by draining lymph node cell culture and measurement of the serum anti-mouse type II collagen antibody levels, respectively. Finally, roles of the SH3BP2 mutation in macrophage activation and osteoclastogenesis were determined by evaluating the TNF-? production levels and osteoclast formation in bone marrow-derived M-CSF-dependent macrophage (BMM) cultures.ResultsSh3bp2(KI/+) mice exhibited more severe inflammation and bone loss, accompanying an increased number of osteoclasts. The mRNA levels for TNF-? and osteoclast marker genes were higher in the joints of Sh3bp2(KI/+) mice. Lymph node cell culture showed that lymphocyte proliferation and IFN-? and IL-17 production were comparable between Sh3bp2(+/+) and Sh3bp2(KI/+) cells. Serum anti-type II collagen antibody levels were comparable between Sh3bp2(+/+) and Sh3bp2(KI/+) mice. In vitro experiments showed that TNF-? production in Sh3bp2(KI/+) BMMs is elevated compared with Sh3bp2(+/+) BMMs and that RANKL-induced osteoclastogenesis is enhanced in Sh3bp2(KI/+) BMMs associated with increased NFATc1 nuclear localization.ConclusionGain-of-function of SH3BP2 augments inflammation and bone loss in the CIA model through increased macrophage activation and osteoclast formation. Therefore, modulation of the SH3BP2 expression may have therapeutic potential for the treatment of rheumatoid arthritis.

Project description:BackgroundThe GNAO1 gene encodes the α-subunit (Gαo) of the heterotrimeric guanine nucleotide-binding protein (G protein). The aim of this study was to explore the clinical characteristics of patients with GNAO1 pathogenic variations.MethodsTen patients with pathogenic variations in GNAO1 were enrolled from the Shenzhen Children's Hospital. Clinical data from several cases previously reported from China were also included and analyzed.ResultsTwenty-seven patients with variations in GNAO1 were analyzed (10 patients from Shenzhen Children's Hospital, 17 patients from previously published studies) including 12 boys and 15 girls. The median age of onset was 3 months with moderate to severe global developmental delay. Nineteen different GNAO1 heterozygous variants were identified. Epilepsy was observed in 18 patients (67%, 18/27), movement disorder (MD) was observed in 22 patients (81%, 22/27), and both were seen in 13 patients (48%, 13/27). Seizures typically presented as focal seizures in all patients with epilepsy. MD typically presented as dystonia and chorea. Loss-of-function (LOF) or partial loss-of-function (PLOF) mutations were more frequent in patients with developmental and epileptic encephalopathy (p = 0.029). Interictal electroencephalograms showed multifocal or diffuse epileptiform discharges. The most common magnetic resonance imaging finding was widened extracerebral space. In contrast to MD, in which improvements were not common, seizures were easily controlled by anti-seizure medications. Severe dystonia in three patients was effectively treated by deep brain stimulation. Seven (26%, 7/27) patients died of respiratory complications, status dystonicus, choreoathetosis, or sudden unexpected death in epilepsy.ConclusionWe analyzed clinical data of 27 cases of GNAO1-related encephalopathy in China. MD seemed to be the central feature and was most difficult to control. LOF or PLOF variants were significantly associated with developmental and epileptic encephalopathy. The active intervention of severe dystonia may prevent death due to status dystonicus. However, future studies with larger samples are needed to confirm these results.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets