GABRB3 – Lennox-Gastaut syndrome

GABRB3 encodes the β3 subunit of the GABA
type-A receptor critical for inhibitory neurotransmission. Heterozygous de novo variants in GABRB3 have been implicated in severe early-onset epileptic encephalopathies, including Lennox-Gastaut syndrome (LGS), characterized by multiple seizure types, cognitive impairment, and behavioral abnormalities.

1. Clinical Validity

Based on genetic and functional concordance across independent cohorts, the association between GABRB3 and LGS is classified as Strong. Four de novo missense variants were identified in 115 LGS probands by trio exome sequencing (PMID:23934111), with three additional de novo mutations observed in unrelated LGS cases (PMID:32467926; PMID:31435640). Robust animal models further support pathogenicity.

2. Genetic Evidence

Inheritance is autosomal dominant with heterozygous de novo missense variants. No multigenerational segregation has been observed (0 affected relatives). In exome screens of 115 LGS trios, four de novo variants in GABRB3 reached exome-wide significance, including c.358G>A (p.Asp120Asn) (PMID:23934111). Independent case reports describe the same c.358G>A (p.Asp120Asn) in a patient with atypical absence and tonic seizures (PMID:32467926). Additional variants N328D and E357K have been reported in severe and moderate epileptic phenotypes, respectively (PMID:31435640).

3. Functional Evidence

Missense variants cluster in the extracellular domain and pore-lining transmembrane helices, impairing GABA-evoked currents by reducing open probability or altering desensitization. Heterozygous Gabrb3+/D120N knock-in mice exhibit spontaneous atypical absence, tonic and myoclonic seizures, hyperactivity, and learning deficits, mirroring LGS phenotype (PMID:32467926). Gabrb3+/N328D mice display spontaneous seizures, cognitive impairment, and reduced β3 expression in thalamus and hippocampus (PMID:37176165).

4. Therapeutic Insights

Pharmacological rescue in a Y302C model with vinpocetine led to a sustained, dose-dependent reduction in spike-wave discharges and behavioral improvement, demonstrating potential for precision therapy (PMID:31755996).

5. Integration & Conclusion

Collectively, these data establish that heterozygous de novo GABRB3 variants disrupt GABAergic inhibition via dominant-negative or haploinsufficiency mechanisms, leading to LGS. Both human genetic studies and multiple knock-in mouse models provide concordant evidence for pathogenicity and therapeutic targeting. Additional in vitro assays and animal models continue to refine genotype-phenotype correlations.

Key Take-home: Genetic testing for de novo GABRB3 variants informs diagnosis of Lennox-Gastaut syndrome and enables precision treatment strategies.

References

• Nature • 2013 • De novo mutations in epileptic encephalopathies PMID:23934111
• Brain communications • 2020 • GABAA receptor β3 subunit mutation D120N causes Lennox-Gastaut syndrome in knock-in mice PMID:32467926
• Brain : a journal of neurology • 2019 • Synaptic clustering differences due to different GABRB3 mutations cause variable epilepsy syndromes PMID:31435640
• International journal of molecular sciences • 2023 • GABAA Receptor β3 Subunit Mutation N328D Heterozygous Knock-in Mice Have Lennox-Gastaut Syndrome PMID:37176165
• Epilepsia • 2019 • Personalized medicine: Vinpocetine to reverse effects of GABRB3 mutation PMID:31755996

Evidence Based Scoring (AI generated)