Gamma-aminobutyric acid receptor subunit beta-2
plasma membrane
A <i>de novo</i> missense mutation of <i>GABRB2</i> causes early myoclonic encephalopathy.
<h4>Background</h4>Early myoclonic encephalopathy (EME), a disease with a devastating prognosis, is characterised by neonatal onset of seizures and massive myoclonus accompanied by a continuous suppression-burst EEG pattern. Three genes are associated with EMEs that have metabolic features. Here, we report a pathogenic mutation of an ion channel as a cause of EME for the first time.<h4>Methods</h4>Sequencing was performed for 214 patients with epileptic seizures using a gene panel with 109 genes that are known or suspected to cause epileptic seizures. Functional assessments were demonstrated by using electrophysiological experiments and immunostaining for mutant γ-aminobutyric acid-A (GABA<sub>A</sub>) receptor subunits in HEK293T cells.<h4>Results</h4>We discovered a <i>de novo</i> heterozygous missense mutation (c.859A>C [p.Thr287Pro]) in the <i>GABRB2</i>-encoded β2 subunit of the GABA<sub>A</sub> receptor in an infant with EME. No <i>GABRB2</i> mutations were found in three other EME cases or in 166 patients with infantile spasms. GABA<sub>A</sub> receptors bearing the mutant β2 subunit were poorly trafficked to the cell membrane and prevented γ2 subunits from trafficking to the cell surface. The peak amplitudes of currents from GABA<sub>A</sub> receptors containing only mutant β2 subunits were smaller than that of those from receptors containing only wild-type β2 subunits. The decrease in peak current amplitude (96.4% reduction) associated with the mutant GABA<sub>A</sub> receptor was greater than expected, based on the degree to which cell surface expression was reduced (66% reduction).<h4>Conclusion</h4>This mutation has complex functional effects on GABA<sub>A</sub> receptors, including reduction of cell surface expression and attenuation of channel function, which would significantly perturb GABAergic inhibition in the brain.