GABRB3, Epilepsy, and Neurodevelopment

Excerpt

GABRB3, in chromosome 15q11.2-q12, an important neurodevelopmental gene, is regulated by non-Mendelian processes, epigenetic modulation, and sex-specific transcription with deviation of parental gene expression. GABRB3 encodes the β3 subunit of GABA_A receptor. It is highly expressed in embryonic brain where repressor-element-1-silencing transcription factor (REST) regulates neuronal genes. GABRB3 is expressed at lower levels in adult brain, except in hippocampus where it remains high. Homozygous disruption of Gabrb3 in mice leads to myoclonic and atypical absence seizures, and impaired cognition, motor coordination, and somatosensory processes. Heterozygous disruption produces increased epileptiform EEG activity and elevated seizure susceptibility. In human, three different point mutations in exon 1A, coding the signal peptide and exon 2 of GABRB3, segregate with childhood absence epilepsy (CAE), and result in decreased neuronal GABA currents, Three neurological disorders, Rett syndrome, (a deficiency of MeCP2), Angelman syndrome, and autism, each exhibit reduced expression of GABRB3 and UBE3A, along with mental retardation and epilepsy. GABRB3 is highly associated with epilepsy and when a deficiency of UBE3A is also present, more severe symptoms result. UBE3A modulation of REST, which controls GABRB3 expression, and MeCP2 modification of UBE3A link Rett, Angelman, and autism syndromes with epilepsy, and invoke epigenetic mechanisms in epileptogenesis.