Understanding paralogous epilepsy-associated GABA<sub>A</sub> receptor variants: Clinical implications, mechanisms, and potential pitfalls.
case_series · Level IV
Where this comes from
- Record sourced from PubMed, PMID 39642202.
- Also identified by DOI 10.1073/pnas.2413011121 and PMC identifier 11648851.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Recent discoveries have revealed that genetic variants in γ-aminobutyric acid type A (GABA<sub>A</sub>) receptor subunits can lead to both gain-of-function (GOF) and loss-of-function (LOF) receptors. GABA<sub>A</sub> receptors, however, have a pseudosymmetrical pentameric assembly, and curiously diverse functional outcomes have been reported for certain homologous variants in paralogous genes (paralogous variants). To investigate this, we assembled a cohort of 11 individuals harboring paralogous M1 proline missense variants in <i>GABRA1</i>, <i>GABRB2</i>, <i>GABRB3,</i> and <i>GABRG2.</i> Seven mutations (α1<sup>P260L</sup>, α1<sup>P260S</sup>, β2<sup>P252L</sup>, β3<sup>P253L</sup>, β3<sup>P253S</sup>, γ2<sup>P282A</sup>, and γ2<sup>P282S</sup>) in α1β2/3γ2 receptors were analyzed using electrophysiological examinations and molecular dynamics simulations. All individuals in the cohort were diagnosed with developmental and epileptic encephalopathy, with a median seizure onset age of 3.5 mo, and all exhibited global developmental delay. The clinical data for this cohort aligned with established GABA<sub>A</sub> receptor GOF but not LOF cohorts. Electrophysiological assessments revealed that all variants caused GOF by increasing GABA sensitivity by 3- to 23-fold. In some cases, this was accompanied by LOF traits such as reduced maximal current amplitude and enhanced receptor desensitization. The specific subunit mutated and whether the mutation occurred in one or two subunits within the pentamer influenced the overall effects. Molecular dynamics simulations confirmed similar structural changes from all mutations, but with position-dependent asymmetry. These findings establish that paralogous variants affecting the 100% conserved proline residue in the M1 transmembrane helix of GABA<sub>A</sub>R subunits all lead to overall GOF traits. The unexpected asymmetric and mixed effects on receptor function have broader implications for interpreting functional analyses for multimeric ion-channel proteins.
Medical subject headings
- Receptors, GABA-A
- Epilepsy