Understanding paralogous epilepsy-associated GABAA receptor variants: Clinical implications, mechanisms, and potential pitfalls

• 成果类型: Article
• 署名作者: Kan, Anthony S. H.; Kusay, Ali S.; Mohammadi, Nazanin A.; Lin, Susan X. N.; Liao, Vivian W. Y.; Lesca, Gaetan; Souci, Sabrine; Milh, Mathieu; Christophersen, Palle; Chebib, Mary; Moller, Rikke S.; Absalom, Nathan L.; Jensen, Anders A.; Ahring, Philip K.
• 署名单位: University of Sydney; Linkoping University; University of Southern Denmark; CHU Lyon; Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Universite Claude Bernard Lyon 1; CHU Lyon; Aix-Marseille Universite; Assistance Publique-Hopitaux de Marseille; Institut National de la Sante et de la Recherche Medicale (Inserm); Aix-Marseille Universite; Western Sydney University; University of Copenhagen
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13407
• DOI: 10.1073/pnas.2413011121
• 发表日期: 2024-12-10
• 关键词: mutations; gabra1; selectivity; activation; seizures; helix

摘要

Recent discoveries have revealed that genetic variants in gamma- aminobutyric acid type A (GABAA) receptor subunits can lead to both gain- of- function (GOF) and loss- of- function (LOF) receptors. GABAA 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 GABRA1, GABRB2, GABRB3, and GABRG2. Seven mutations ( alpha 1 P260L , alpha 1 P260S , beta 2 P252L , beta 3 P253L , beta 3 P253S , gamma 2 P282A , and gamma 2 P282S ) in alpha 1 beta 2/3 gamma 2 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 GABAA 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 GABAAR 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.