Key result
Gain-of-function GABRB3 variants that reduced desensitization at equilibrium correlated with more severe clinical outcomes, including younger seizure onset (median 0.5 months), than those accelerating decay.
Why the study?
It was unclear how receptor desensitization contributes to the greater clinical severity observed with gain-of-function GABRB3 variants.
Observational (n=20)
Gain-of-function GABRB3 variants can increase or decrease receptor desensitization properties, which correlates with the degree of clinical severity in developmental and epileptic encephalopathies.
May guide variant classification in encephalopathies; leaves open whether desensitization-targeted therapies alter clinical outcomes.
Genetic variants associated with developmental and epileptic encephalopathies have been identified in the GABRB3 gene that encodes the β3 subunit of GABAA receptors. Typically, variants alter receptor sensitivity to GABA resulting in either gain- or loss-of-function, which correlates with patient phenotypes. However, it is unclear how another important receptor property, desensitization, contributes to the greater clinical severity of gain-of-function variants. Desensitization properties of 20 gain-of-function GABRB3 variant receptors were evaluated using two-electrode voltage-clamp electrophysiology. The parameters measured included current decay rates and steady-state currents. Selected variants with increased or reduced desensitization were also evaluated using whole-cell electrophysiology in transfected mammalian cell lines. Of the 20 gain-of-function variants assessed, 13 were found to alter receptor desensitization properties. Seven variants reduced desensitization at equilibrium, which acts to worsen gain-of-function traits. Six variants accelerated current decay kinetics, which limits gain-of-function traits. All affected patients displayed severe clinical phenotypes with intellectual disability and difficult-to-treat epilepsy. Nevertheless, variants that reduced desensitization at equilibrium were associated with more severe clinical outcomes. This included younger age of first seizure onset (median 0.5 months), movement disorders (dystonia and dyskinesia), epilepsy of infancy with migrating focal seizures (EIMFS) and risk of early mortality. Variants that accelerated current decay kinetics were associated with slightly milder phenotypes with later seizure onset (median 4 months), unclassifiable developmental and epileptic encephalopathies or Lennox-Gastaut syndrome and no movement disorders. Our study reveals that gain-of-function GABRB3 variants can increase or decrease receptor desensitization properties and that there is a correlation with the degree of disease severity. Variants that reduced the desensitization at equilibrium were clustered in the transmembrane regions that constitute the channel pore and correlated with greater disease severity, while variants that accelerated current decay were clustered in the coupling loops responsible for receptor activation and correlated with lesser severity.
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Lin et al. (2023) conducted an observational in Developmental and epileptic encephalopathies (n=20). Gain-of-function GABRB3 variants was evaluated on Clinical severity (including age of seizure onset, movement disorders, and mortality risk). Gain-of-function GABRB3 variants that reduced desensitization at equilibrium correlated with more severe clinical outcomes, including younger seizure onset (median 0.5 months), than those accelerating decay.
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