Introduction
- GABRB3 gene is a recently identified gene located in 15q12 chromosome and encodes encodes the β3-subunit of the GABA-A receptor, a ligand-gated chloride channel.
- The gene is believed to share a role in inhibitory GABAergic synapses, GABA iron-gated channel function, and possible cellular response to histamine.
- The β3 subunit is expressed in cerebral grey matter, thalami, hippocampi, and cerebellum, among other structures.
- GABA-A receptors mediate fast inhibitory neurotransmission in the central nervous system (CNS).
- Faulty GABRB3 function is linked to several neurological disorders and clinical syndromes. However, the spectrum of such disorders is not yet well known
- Mutations in GABRB3 are emerging as a significant cause of early infantile epileptic encephalopathy (EIEE), a severe developmental and epileptic encephalopathy.
GABA-A Receptor: Structure and Function
- Composition: Pentameric assembly of subunits (α, β, γ, δ, etc.). Typical GABA-A receptors have:
- 2 α-subunits
- 2 β-subunits (e.g., GABRB3)
- 1 γ-subunit
Clinical Relevance of GABRB3
- Formed by transmembrane domains M1–M4 of each subunit.
- The M2 domain lines the ion channel pore.
GABRB3 Mutations and Epilepsy
- GABA binding leads to chloride influx (hyperpolarization → neuronal inhibition).
- In immature neurons, GABA causes chloride efflux (depolarization → excitation) due to NKCC1 transporter activity
Mutation Age at Onset Seizure Types EEG Findings Other Features p.Asn110Asp 5 months Infantile spasms Hypsarrhythmia None p.Asn120Asp 10 months Infantile spasms Generalized 2 Hz bursts ADHD, impulsivity p.Thr287Ile 3 months Multiple seizure types Generalized fast activity Severe hypotonia, dysmorphia p.Tyr302Cys 10 months Focal dyscognitive Slow, left-temporal focus Behavioral arrest, severe ID Key Point: The p.Thr287Ile mutation, located in the M2 domain, impacts ion pore function and likely reduces chloride flux, causing hyperexcitability
