Objective: To understand the molecular basis and differential penetrance of febrile seizures and absence seizures in patients with the g2(R43Q) GABA A receptor mutation.Methods: Spike-and-wave discharges and thermal seizure susceptibility were measured in heterozygous GABA A g2 knock-out and GABA A g2(R43Q) knock-in mice models crossed to different mouse strains.Results: By comparing the GABA A g2 knock-out with the GABA A g2(R43Q) knock-in mouse model we show that haploinsufficiency underlies the genesis of absence seizures but cannot account for the thermal seizure susceptibility. Additionally, while the expression of the absence seizure phenotype was very sensitive to mouse background genetics, the thermal seizure phenotype was not. Conclusions:Our results show that a single gene mutation can cause distinct seizure phenotypes through independent molecular mechanisms. A lack of effect of genetic background on thermal seizure susceptibility is consistent with the higher penetrance of febrile seizures compared to absence seizures seen in family members with the mutation. These mouse studies help to provide a conceptual framework within which clinical heterogeneity seen in genetic epilepsy can be explained. Neurology Family members harboring the GABA A g2(R43Q) mutation display multiple seizure types, incomplete penetrance, and variable seizure severity, 1,2 a common feature of genetic epilepsies. 3To predict clinical outcomes for patients based on their personal genomes, it is important that we develop a conceptual framework explaining the genetic and molecular basis of heterogeneity. Animal models of epilepsy, based on human mutations, provide a means of investigating this. The knock-in mouse model based on the GABA A g2(R43Q) mutation recapitulates the 2 major phenotypes seen in family members, including febrile seizures and typical absence seizures. 4,5 However, the molecular mechanisms causing epilepsy in this model are unclear. In vitro studies suggest that the deficit could be through haploinsufficiency (loss-of-function) or a dominant impact of the mutated protein. 6 To investigate this, we compared the seizure phenotypes of heterozygous Gabrg2 knock-out mice with those of knock-in mice.Penetrance is relatively low for absence seizures in the GABA A g2(R43Q) family. 1,2 By backcrossing the GABA A g2(R43Q) knock-in mouse to strains with different seizure susceptibility, we have demonstrated that the spike-wave phenotype requires additional susceptibility alleles for full expression, 5,7 potentially explaining the low penetrance of absence in the family. In contrast, febrile seizures segregate as a more highly penetrant autosomal dominant trait, which suggests that background genetics have less impact.1,2 Here we investigate the influence of genetic background on thermal seizure and spike-wave susceptibility in the knock-in mouse model. METHODS Mice. All experiments were approved by the Animal Ethics Committee at the Florey Institute of Neuroscience and Mental Health (09-046). Genotyping of the GABA...

Polymorphisms in NFKB1 that diminish its expression have been linked to human inflammatory diseases and increased risk for epithelial cancers. The underlying mechanisms are unknown, and the link is perplexing given that NF-kB signaling reportedly typically exerts pro-tumorigenic activity. Here we have shown that NF-kB1 deficiency, even loss of a single allele, resulted in spontaneous invasive gastric cancer (GC) in mice that mirrored the histopathological progression of human intestinal-type gastric adenocarcinoma. Bone marrow chimeras revealed that NF-kB1 exerted tumor suppressive functions in both epithelial and hematopoietic cells. RNA-seq analysis showed that NF-kB1 deficiency resulted in aberrant JAK-STAT signaling, which dysregulated expression of effectors of inflammation, antigen presentation, and immune checkpoints. Concomitant loss of STAT1 prevented these immune abnormalities and GC development. These findings provide mechanistic insight into how polymorphisms that attenuate NFKB1 expression predispose humans to epithelial cancers, highlighting the pro-tumorigenic activity of STAT1 and identifying targetable vulnerabilities in GC.