Reply

Abstract

We thank Lien and colleagues for their letter in response to our recent publication 1 describing a patient with epileptic encephalopathy harboring a novel de novo GABRB1 mutation, T287I. The phenotypes of this patient are similar to those of the patient with the epileptic encephalopathy infantile spasms, and the GABRB1 (F246S) mutation, that was reported by the Epi4K consortium in 2013. 2 In this article, the GABRB1 mutation was found in only the 1 patient, and GABRB1 had not been previously associated with epilepsy. Thus, it was not considered to be a confirmed cause of epilepsy. Our recent publication, 1 however, reported that the GABRB1 (F246S) mutation disrupted GABA A receptor function, suggesting a likely contribution to epilepsy pathogenesis. The current report by Lien et al extends our findings and further strengthens the involvement of GABRB1 in epilepsy syndromes. The GABRB1 (T287I) mutation alters a highly conserved amino acid residue located in the channel pore forming the transmembrane 2 domain of the b1 subunit, and thus, it is likely to disrupt GABA A receptor function. Moreover, the polyphen-2 score of 0.999 for the GABRB1 (T287I) mutation also suggests that this mutation is likely to be damaging. Mutations in GABRB3 and their contribution to epilepsy syndromes are well documented. 3As b1 and b3 subunits are highly homologous and are ubiquitously expressed in the regions involved with generation of seizures such as cortex, hippocampus, and thalamus, it can be anticipated that future studies will reveal additional mutations in GABRB1 in patients with epilepsy.

Phenols and GABAA receptors: from structure and molecular mechanisms action to neuropsychiatric sequelae

“…Moreover, changes in the physiological and biochemical properties of β3-containing GABA A R assemblies in the brains of patients with epilepsy (Menzikov et al, 2021). Several studies have reported that GABRB3 mutations with juvenile myoclonic epilepsy, childhood absence epilepsy, and/or other syndromes and that reduced GABA A R function causes an E: I imbalance (Gurba et al, 2012;Janve et al, 2016). Animal models of epilepsy have demonstrated obvious alterations in the expression and rearrangement of GABA A R subunits in the hippocampus and the parahippocampal areas, including downregulation of the α5 and δ subunits and upregulation of the α4 subunit (Sperk et al, 2021).…”