GABRB3 – Childhood Absence Epilepsy

Childhood absence epilepsy (CAE) is a generalized epilepsy syndrome characterized by brief, frequent absence seizures in school‐age children. Genetic linkage analyses in 33 nuclear families provided positive HLOD signals for the GABRA5–GABRB3–GABRG3 cluster on chromosome 15q11–q13 under a heterogeneity model (PMID:11904235). A case–control and transmission/disequilibrium study in 90 Han Chinese trios and 100 controls demonstrated overtransmission of alleles near GABRB3 (markers 85CA, 155CA1, 155CA2) in CAE (PMID:15498372).

Mutation screening in 48 CAE probands identified heterozygous missense variants P11S, S15F, and G32R in GABRB3 segregating with disease in four families (8 %) and absent in 630 controls, supporting dominant inheritance (PMID:18514161). In vitro translation assays revealed hyperglycosylation of mutant β3 subunits, and rapid agonist application in HEK293T cells showed each variant reduced GABA‐evoked currents, consistent with a loss-of-function mechanism. A promoter haplotype study in 45 CAE patients and parents identified a disease-associated exon 1a haplotype reducing transcriptional activity by reporter assays and impairing N-Oct-3 binding (PMID:16835263).

However, subsequent screening in 183 French-Canadian IGE cases found the P11S variant in one of 190 controls, suggesting it may be a rare polymorphism in that population (PMID:20550555). Moreover, the common rs4906902 promoter C-allele failed to associate with CAE or broader IGE in a German cohort (P>0.3) (PMID:17215107). These conflicting data indicate locus and variant heterogeneity and point to population-specific effects.

Overall, the aggregation of linkage, association, segregation, and functional data supports a moderate clinical validity for GABRB3 in CAE, with multiple independent cohorts and functional studies converging on impaired GABAergic inhibition. The primary inheritance mode is autosomal dominant, with at least six affected relatives showing segregation of deleterious variants. Experimental evidence demonstrates haploinsufficiency and mistrafficking as key pathogenic mechanisms. Further large‐scale and population‐diverse studies are needed to refine variant penetrance and expressivity.

Key Take-home: Heterozygous GABRB3 variants and regulatory haplotypes confer CAE susceptibility via impaired β3 subunit processing and function, supporting targeted genetic testing and potential therapies aimed at restoring GABAergic transmission.

References

• Epilepsy research • 2002 • Linkage analysis between childhood absence epilepsy and genes encoding GABAA and GABAB receptors, voltage‐dependent calcium channels, and the ECA1 region on chromosome 8q PMID:11904235
• Chinese medical journal • 2004 • Case-control study and transmission/disequilibrium tests of the genes encoding GABRA5 and GABRB3 in a Chinese population affected by childhood absence epilepsy PMID:15498372
• Human molecular genetics • 2006 • A GABRB3 promoter haplotype associated with childhood absence epilepsy impairs transcriptional activity PMID:16835263
• American journal of human genetics • 2008 • Hyperglycosylation and reduced GABA currents of mutated GABRB3 polypeptide in remitting childhood absence epilepsy PMID:18514161
• Epilepsia • 2010 • Screening of GABRB3 in French-Canadian families with idiopathic generalized epilepsy PMID:20550555
• Epilepsy research • 2007 • Lack of evidence of an allelic association of a functional GABRB3 exon 1a promoter polymorphism with idiopathic generalized epilepsy PMID:17215107

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