Epilepsy affects more than 0.5% of the population worldwide, and genetic factors play an important role in the idiopathic generalized epilepsy syndromes (IGEs). Many monogenic mutations associated with IGEs are in ion channel genes. GABAA receptors (GABAARs) are the major inhibitory receptors in the brain and mutations in GABAAR subunit genes (GABRs) coding for the y2, ?1 and ?3 subunits are associated with IGEs. We have classified the known monogenic GABR mutations into 6 classes: those that reduce subunit expression due to: 1) impaired transcription;2) impaired translation, 3) misfolding and degradation, 4) truncation and ER retention with or without a dominant negative effect on other subunits or 5) ER retention of functional receptors. A final class of mutations 6) reduces surface receptor function. This classification is useful for developing treatment strategies for severe IGEs. Mutations in GABR?3 (P11S, S15F) and GABR?2 (N79S, R82Q, P83S, R177G) have been associated with IGEs, and P11S has also been associated with autism.
In Specific Aim 1 we continue our strategy of characterizing effects of monogenic GABR mutations associated with IGEs on functional properties and/or biogenesis of GABAARs, focusing on the mutations in ?3 and ?2 subunits. It is important, also, to determine the effects of these mutations in vivo on thalamocortical network function and mouse behavior. In addition and to, characterize the adaptive neuronal plasticity that occurs in response to the loss of inhibition for each mutation. Since the GABR?3 (P11S) mutation has been associated with both epilepsy and autism, it is a particularly important mutation, and in Specific Aim 2 we will study a class 3 ?3+/P11S KI mouse and a ?3+/- mouse for comparison. We will determine if: 1) the KI mice develop a generalized epilepsy and altered "autism-like" behavior due to haploinsufficiency or due also to a dominant negative effect of the mutant subunit, 2) the mutation alters cortical and thalamic inhibition, 3) mut ?3 (P11S) subunits are reduced in mouse brain, and 4) the mutation causes altered transcriptional signatures of cellular plasticity in compensation for the loss of b3 subunits. The basis for most IGEs has not been found since about 98% are polygenic, and thus, likely due to the presence of multiple nsSNPs (nonsynonymous single nucleotide polymorphisms that change aa coding). Thus, new strategies are needed for identification of nsSNPs that contribute to IGEs with complex inheritance. Among GABR genes, monogenic mutations associated with IGEs have been found in the hEP genes, GABR?1, GABR?3 and GABR?2. Exome sequencing of candidate ion channel genes, including GABAR genes, from well characterized IGE cases and controls identified rare nsSNPs in non-hEP genes in cases but not in controls. Also, with the Exome Variant Server, we found rare nsSNPs in the hEP genes.
In Specific Aim 3 we will characterize the effects of the rare nsSNPs found in non hEP genes only in cases or in hEP genes on functional properties and/or biogenesis of GABAARs.

Public Health Relevance

Many forms of epilepsy (recurring, unprovoked brain seizures that impair bodily functions and often cause unconsciousness and/or injury) are inherited. We are studying the basis for genetic epilepsies caused by mutations that impair function of inhibitory GABAA receptors and trying to develop new epilepsy treatments.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Stewart, Randall R
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Vanderbilt University Medical Center
Schools of Medicine
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Janve, Vaishali S; Hernandez, Ciria C; Verdier, Kelienne M et al. (2016) Epileptic encephalopathy de novo GABRB mutations impair GABAA receptor function. Ann Neurol :
Kang, Jing-Qiong; Shen, Wangzhen; Zhou, Chengwen et al. (2015) The human epilepsy mutation GABRG2(Q390X) causes chronic subunit accumulation and neurodegeneration. Nat Neurosci 18:988-96
Huang, Xuan; Hernandez, Ciria C; Hu, Ningning et al. (2014) Three epilepsy-associated GABRG2 missense mutations at the γ+/β- interface disrupt GABAA receptor assembly and trafficking by similar mechanisms but to different extents. Neurobiol Dis 68:167-79
Lo, Wen-Yi; Lagrange, Andre H; Hernandez, Ciria C et al. (2014) Co-expression of γ2 subunits hinders processing of N-linked glycans attached to the N104 glycosylation sites of GABAA receptor β2 subunits. Neurochem Res 39:1088-103
Johnston, Ann J; Kang, Jing-Qiong; Shen, Wangzhen et al. (2014) A novel GABRG2 mutation, p.R136*, in a family with GEFS+ and extended phenotypes. Neurobiol Dis 64:131-41
Tian, Mengnan; Mei, Davide; Freri, Elena et al. (2013) Impaired surface αβγ GABA(A) receptor expression in familial epilepsy due to a GABRG2 frameshift mutation. Neurobiol Dis 50:135-41
Kang, Jing-Qiong; Shen, Wangzhen; Macdonald, Robert L (2013) Trafficking-deficient mutant GABRG2 subunit amount may modify epilepsy phenotype. Ann Neurol 74:547-59
Tian, Mengnan; Macdonald, Robert L (2012) The intronic GABRG2 mutation, IVS6+2T->G, associated with childhood absence epilepsy altered subunit mRNA intron splicing, activated nonsense-mediated decay, and produced a stable truncated γ2 subunit. J Neurosci 32:5937-52
Macdonald, Robert L; Kang, Jing-Qiong (2012) mRNA surveillance and endoplasmic reticulum quality control processes alter biogenesis of mutant GABAA receptor subunits associated with genetic epilepsies. Epilepsia 53 Suppl 9:59-70
Huang, Xuan; Tian, Mengnan; Hernandez, Ciria C et al. (2012) The GABRG2 nonsense mutation, Q40X, associated with Dravet syndrome activated NMD and generated a truncated subunit that was partially rescued by aminoglycoside-induced stop codon read-through. Neurobiol Dis 48:115-23

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