Lecture Notes

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​

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