To validate our findings further, we obtained an in-depth comparison of two novel mutations [GABRB3 (N328D) and GABRB3 (E357K)] associated with epilepsy with different severities of epilepsy phenotype.
Our results indicate that GABRB3 mutations are associated with a broad phenotypic spectrum of epilepsies and that reduced receptor function causing GABAergic disinhibition represents the relevant disease mechanism.
One 15q11-q13 locus encodes the GABA(A) receptor β3 subunit gene (GABRB3), which has been implicated by several studies in both autism and absence epilepsy, and the co-morbidity of epilepsy in autism is well established.
GABAA receptor beta3 subunit gene-deficient heterozygous mice show parent-of-origin and gender-related differences in beta3 subunit levels, EEG, and behavior.
These gabrb3 gene knockout mice provide direct evidence that a reduction of a specific subunit of the GABA(A) receptor system can result in epilepsy and support a GABAergic role in the pathophysiology of Angelman syndrome.