GABRG2 – Epilepsy

GABRG2 encodes the γ2 subunit of the GABA_A receptor, a critical mediator of inhibitory neurotransmission in the central nervous system. Pathogenic variants in GABRG2 are associated with a spectrum of epilepsy phenotypes ranging from simple febrile seizures to developmental and epileptic encephalopathies (DEE) (PMID:37703949).

Inheritance is autosomal dominant with both familial and recurrent de novo occurrences. A microdeletion encompassing GABRG2 and GABRA1 presented with intractable epilepsy and optic atrophy in one patient (PMID:37703949). Segregation in a French Canadian family carrying c.247C>T (p.Pro83Ser) demonstrated high penetrance across four affected relatives (PMID:21714819).

Over 20 unrelated probands harbor GABRG2 variants. A recurrent de novo missense, c.316G>A (p.Ala106Thr), was identified in five individuals with severe early‐onset seizures and neurodevelopmental delay (PMID:28460589). Eight additional de novo variants (including p.Ile107Thr and p.Pro282Ser) were reported in epileptic encephalopathy cohorts (PMID:27864268). Four probands were identified in a Chinese cohort by whole exome sequencing (PMID:40665309). A single missense, c.236A>G (p.Asn79Ser), emerged from a Japanese study of generalized tonic–clonic seizures (PMID:20485450).

Variant spectrum is dominated by missense substitutions affecting transmembrane and extracellular domains. Recurrent p.Ala106Thr (5 probands) and p.Pro282Ser (3 probands) underline critical structural roles. Truncating alleles (e.g., c.118C>T (p.Gln40Ter)) and frameshifts produce loss‐of‐function receptors via nonsense‐mediated decay or defective assembly. No common variants in GABRG2 confer significant epilepsy risk (PMID:16806831; PMID:16256272).

Functional assays across multiple models confirm predominantly loss‐of‐function and dominant‐negative mechanisms. Patch‐clamp studies in HEK293T cells show accelerated deactivation and reduced GABA sensitivity for p.Arg82Gln and p.Lys289Met (PMID:12097483), while mouse and zebrafish models of p.Q390X and p.F343L reveal seizure phenotypes ameliorated by phenobarbital or dexamethasone (PMID:32944937; PMID:36738682). Gentamicin read‐through partially rescues p.Gln40Ter surface expression (PMID:22750526).

Despite robust evidence, two association studies using tagging SNPs and familial focal epilepsy screens found no enrichment of common GABRG2 variants (PMID:16806831; PMID:16256272).

GABRG2 demonstrates a Strong gene–disease relationship with concordant experimental data. Clinical testing for GABRG2 variants supports diagnosis, guides therapy (e.g., phenobarbital sensitivity), and informs prognosis. Key take-home: Heterozygous GABRG2 variants cause autosomal dominant epilepsies via loss‐of‐function or dominant‐negative effects, and targeted genetic testing is clinically actionable.

References

• Experimental Neurology • 2023 • Epilepsy plus blindness in microdeletion of GABRA1 and GABRG2 in mouse and human. PMID:37703949
• Journal of human genetics • 2010 • Mutational analysis of GABRG2 in a Japanese cohort with childhood epilepsies. PMID:20485450
• Journal of neurogenetics • 2017 • Expanding the phenotypic spectrum of GABRG2 variants: a recurrent GABRG2 missense variant associated with a severe phenotype. PMID:28460589
• Brain • 2017 • De novo GABRG2 mutations associated with epileptic encephalopathies. PMID:27864268
• Seizure • 2019 • Novel variants and phenotypes widen the phenotypic spectrum of GABRG2-related disorders. PMID:31004928
• Epilepsy research • 2006 • Examining the role of common genetic variation in the gamma2 subunit of the GABA(A) receptor in epilepsy using tagging SNPs. PMID:16806831
• The Journal of neuroscience • 2002 • Two different mechanisms of disinhibition produced by GABAA receptor mutations linked to epilepsy in humans. PMID:12097483
• Epilepsia • 2020 • Endoplasmic reticulum stress increases inflammatory cytokines in an epilepsy mouse model Gabrg2+/Q390X knockin: A link between genetic and acquired epilepsy? PMID:32944937

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