‘Relearning’ epilepsy – Functional and phenotypic associations of GABRG2 and GABRB3 variants

Abstract

Epilepsy affects over 60 million people worldwide, making it one of the most common chronic neurological conditions. Epilepsy can range from mild simple febrile seizures to severe developmental and epileptic encephalopathies (DEEs). DEEs are a group of rare, severe neurodevelopmental disorders often starting in childhood. DEEs often results from de novo variants in ion channels, impacting cognitive functions. Variants found in GABAA receptors (GABAAR) are a major cause of DEE.

GABAA receptors are a part of the pentameric ligand-gated ion channel superfamily and are the principal inhibitory receptor within the mammalian brain. Recent whole genome sequencing of patients with epilepsy have identified 11 out of the 19 genes to be associated with epilepsy.

As activation of GABAA receptors has an inhibitory effect on nerve transmission under normal circumstances (with the exception of early development), it has long been assumed that loss-of-function mutations lead to hypoactive GABAA receptors, overexcitation and hence epilepsy. Recent studies indicate that gain-of-function mutations that cause hyperactive receptors can also cause DEEs. These findings are surprising and require further investigation to better our understanding of disease mechanisms.

Therefore, the overarching aims of this doctoral work were to 1) assess the functional changes caused by epilepsy-associated GABRG2 and GABRB3 variants and correlate these changes to the patient’s clinical phenotypes, 2) evaluate variant pathogenicity prediction using currently available knowledge in the literature and in silico prediction tools and 3) characterise the effect of a gain-of-function GABAA receptor variant in a mice model.