摘要：GABAA receptors are brain inhibitory chloride ion channels. Here we show functional analyses and structural simulations for three de novo missense mutations in the GABAA receptor β3 subunit gene (GABRB3) identified in patients with early-onset epileptic encephalopathy (EOEE) and profound developmental delay. We sought to obtain insights into the molecular mechanisms that might link defects in GABAA receptor biophysics and biogenesis to patients with EOEE. The mutant residues are part of conserved structural domains such as the Cys-loop (L170R) and M2-M3 loop (A305V) that form the GABA binding/channel gating coupling junction and the channel pore (T288N), which are functionally coupled during receptor activation. The mutant coupling junction residues caused rearrangements and formation of new hydrogen bonds in the open state, while the mutant pore residue reshaped the pore cavity. Whereas mutant coupling junction residues uncoupled during activation and caused gain of function, the mutant pore residue favoured low conductance receptors and differential sensitivity to diazepam and loss of function. These data reveal novel molecular mechanisms by which EOEE-linked mutations affect GABAA receptor function.
