Genetics of the GABA-A Receptor in Epilepsy

GABA. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system. The main function of GABA is to reduce the excitability of neurons, which is the opposite of the excitatory glutamate that we described more extensively on our blog when talking about GRIN– and GRIA-related disorders. Many variants in GABA receptors are linked to epilepsy. Here, we will dive specifically into the genetics of the GABAA receptor.

Figure 1. GABR genes encode the subunits of the GABAA receptor. After GABA binds to it, chloride ions are able to flow into the neuron. Created with BioRender.

GABAA receptor. GABA receptors come in two main flavors: ionotropic (GABAA) and metabotropic (GABAB). The GABAA receptor acts like an ion channel: upon GABA binding, it opens and lets chloride ions flow into the post-synaptic neuron, hyperpolarizing it. The GABAA receptor consists of five subunits (Figure 1), each encoded by different genes. GABRA1-6 encode the α subunits (including GABRA1), GABRB1-3 encode the β subunits (including GABRB3), GABRG1-3 encode the γ subunits, GABRD encodes the δ subunit, GABRE encodes the ε subunit, GABRP encodes the π subunit, and GABRQ encodes the θ subunit. This high number of genes whose protein products come together to form the heteropentameric GABAA receptor points towards the complexity of the genetic architecture underlying it.

Genetics and mechanism. GABR- variants causative of epilepsy predominantly exert their effects through the loss-of-function mechanism. The variant subunit genes are located across the genome, with several clustering in chromosomes 4, 5, 15, and X. Different combinations of subunits are differentially expressed in different tissues. α1β3γ2 and α2β3γ2 for example are both widely expressed, while α3β3γ2 is mainly expressed in the reticular thalamic nucleus. GABAA-related disorders typically have an autosomal dominant inheritance pattern, though variants can be loss of function or gain of function, including dominant negative. As seen in other genes, the gain of function variants (including dominant negative variants) are typically more severe (as evidenced by GABRB3 variants in Absalom et al. 2022). The dominant negative effects are a consequence of the heteropentameric nature of the GABAA receptor, where non-functional missense variants lead to a loss of more than 50% of functional receptors.

Phenotypes. Rare variants in genes encoding the GABAA receptor underly a variety of epilepsy phenotypes. The primary phenotypic categories include epilepsy with fever sensitivity, developmental and epileptic encephalopathy (DEE), and generalized genetic epilepsy (GGE). Within the fever-sensitive epilepsies, these disorders share characteristics of other genetic epilepsy with febrile seizures + (GEFS+) epilepsies such as those caused by SCN1A, SCN1B, STX1B, and HCN1. This phenotype is the most mild of the three primary categories. The DEE phenotypes are the most severe, and can include with features such as migrating focal seizures, and typically involve a gain of function (including dominant negative) mechanism. In GGE cases, myoclonic-atonic seizures, juvenile myoclonic epilepsy, and atypical absence seizures can occur.

Future. Undoubtedly, more research will provide additional insights into genotype-phenotype correlations of the GABAA receptor disorders. Its complex genetics are both a challenge and an opportunity to define the phenotypic landscape of GABR-related conditions. The presence of different functional mechanisms, such as loss of function, dominant negative, and other gain of function creates a challenge especially when functional testing of individual variants is limited. And, although care must be taken with genes that are expressed differently across tissues, the presence of many closely related genes can increase sample sizes and resources for studying these disorders. It is promising to note that a relatively new family foundation for these genes, Cure GABA-A, has been founded, and will help to bring together family and researchers towards a better understanding and eventual treatments for these disorders.


Written by Jan Magielski and Laina Lusk.

Jan Magielski

Jan is a student researcher in the Helbig lab.