GABRB3 – Developmental and Epileptic Encephalopathy

GABRB3 encodes the β3 subunit of the GABAA receptor, a pentameric chloride channel critical for inhibitory neurotransmission in the central nervous system. Developmental and epileptic encephalopathy (DEE) presents in early infancy with refractory seizures and global developmental delay, often implicating de novo variants in neurotransmitter receptor genes. Genetic studies have identified heterozygous GABRB3 variants in multiple DEE cohorts, supporting a primary role for GABRB3 in DEE pathogenesis.

Autosomal dominant inheritance is typical, with most missense, nonsense, frameshift, and splice-site mutations arising de novo in affected individuals. In a multicenter study of 416 patients with epileptic encephalopathies, 22 unrelated probands harbored heterozygous GABRB3 variants, including three from multiplex families, encompassing loss-of-function (LoF) and hypomorphic alleles (22 probands, 3 families) (PMID:28053010).

Segregation analyses revealed three additional affected relatives with co-segregating GABRB3 variants in multiplex families, reinforcing pathogenicity through familial transmission. Variant spectrum includes multiple protein-truncating alleles (e.g., c.499A>T (p.Arg167Ter)), missense changes in transmembrane and extracellular domains, and canonical splice-site disruptions.

Functional assays in Xenopus laevis oocytes and mammalian cell lines demonstrated that LoF variants reduce GABA-evoked current amplitudes and GABA sensitivity, consistent with haploinsufficiency and neuronal disinhibition (PMID:28053010). Structural mapping of GABRB3 variants further revealed genotype–phenotype correlations: pore-lining and coupling loop variants alter receptor gating and desensitization, correlating with seizure severity and early onset (PMID:34906499).

An animal model carrying the de novo N328D variant (c.982A>G (p.Asn328Asp)) recapitulates key DEE features, including spontaneous seizures, cognitive impairment, and reduced β3 subunit expression in hippocampus and thalamus, mirroring human Lennox–Gastaut syndrome and DEE phenotypes (PMID:37176165).

Collectively, robust genetic and experimental evidence establishes a strong GABRB3–DEE association mediated by loss-of-function mechanisms. GABRB3 variant screening informs molecular diagnosis and guides therapeutic strategies targeting GABAergic signaling. Key Take-home: GABRB3 heterozygous LoF variants cause DEE by impairing inhibitory neurotransmission, supporting their use in genetic testing and precision medicine.

References

• Neurology • 2017 • Mutations in GABRB3: From febrile seizures to epileptic encephalopathies. PMID:28053010
• International journal of molecular sciences • 2023 • GABAA Receptor β3 Subunit Mutation N328D Heterozygous Knock-in Mice Have Lennox-Gastaut Syndrome PMID:37176165
• Genetics in medicine : official journal of the American College of Medical Genetics • 2022 • Structural mapping of GABRB3 variants reveals genotype-phenotype correlations. PMID:34906499

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