Chapter

<i>GABRB3</i>, Epilepsy, and Neurodevelopment

Miyabi Tanaka, Timothy M. DeLorey, Antonio V. Delgado-Escueta and Richard W. Olsen

in Jasper's Basic Mechanisms of the Epilepsies

Fourth edition

Published on behalf of ©Jeffrey L. Noebels, Massimo Avoli, Michael A. Rogawski, Richard W. Olsen, and Antonio V. Delgado-Escueta

Published in print July 2012 | ISBN: 9780199746545
Published online April 2013 | e-ISBN: 9780199322817 | DOI: http://dx.doi.org/10.1093/med/9780199746545.003.0070

Series: Contemporary Neurology Series

GABRB3, Epilepsy, and Neurodevelopment

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Three neurodevelopmental disorders—Angelman syndrome (AS), Rett syndrome (RS), and autism spectrum disorders (ASD)—share several clinical features, most notably neurodevelopmental delay and epilepsy. Here, we ask: what common mechanisms do these three neurodevelopmental disorders share that lead to a decline in cognitive development and epilepsy? Based on our observations concerning the genetic regulation of GABRB3 in childhood absence epilepsy (CAE), we posit that the genetic mutations in these three neurodevelopmental disorders converge on a common disease mechanism involving genetic and epigenetic regulation of GABRB3. We first explain the data on human CAE supporting this hypothesis and show that three different point mutations in an alternative signal sequence (exon 1A) and N terminus (exon 2) in GABRB3 result in hyperglycosylation and decreased gamma-aminobutyric acid (GABA) currents, all of which segregate with CAE. One of the variants of exon 1A, P11S, which is maternally transmitted, links GABRB3 dysfunction with ASD and provides a possible cause of the seizures in this syndrome. In AS, GABRB3 deletion contributes to the severe seizure phenotype. Rett syndrome is caused by mutations in MeCp2. Because MeCp2 epigenetically regulates GABRB3, reduced expression of GABRB3 and epilepsy are considered consequences of MeCp2 mutations. We then review the significance of GABRB3 in embryonic and adult neurogenesis and neuronal development in mammalian brain. We point to a master regulator of neurogenesis, RE1 silencing transcription factor (REST), which binds to repressor element 1 (RE1) in intron 3 and the 5′ region of GABRB3. REST epigenetically regulates tissue and developmental expression of GABRB3. Finally, we chart the future challenges and experiments that could prove or disprove our hypothesis that REST and epigenetic regulation are involved in neurogenesis and epileptogenesis of absence seizures.

Chapter.  7182 words.  Illustrated.

Subjects: Neurology

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