Association of nonsense mutation in GABRG2 with abnormal trafficking of GABAA receptors in severe epilepsy

Epilepsy Res. 2014 Mar;108(3):420-32. doi: 10.1016/j.eplepsyres.2013.12.005. Epub 2014 Jan 3.


Mutations in GABRG2, which encodes the γ2 subunit of GABAA receptors, can cause both genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome. Most GABRG2 truncating mutations associated with Dravet syndrome result in premature termination codons (PTCs) and are stably translated into mutant proteins with potential dominant-negative effects. This study involved search for mutations in candidate genes for Dravet syndrome, namely SCN1A, 2A, 1B, 2B, GABRA1, B2, and G2. A heterozygous nonsense mutation (c.118C>T, p.Q40X) in GABRG2 was identified in dizygotic twin girls with Dravet syndrome and their apparently healthy father. Electrophysiological studies with the reconstituted GABAA receptors in HEK cells showed reduced GABA-induced currents when mutated γ2 DNA was cotransfected with wild-type α1 and β2 subunits. In this case, immunohistochemistry using antibodies to the α1 and γ2 subunits of GABAA receptor showed granular staining in the soma. In addition, microinjection of mutated γ2 subunit cDNA into HEK cells severely inhibited intracellular trafficking of GABAA receptor subunits α1 and β2, and retention of these proteins in the endoplasmic reticulum. The mutated γ2 subunit-expressing neurons also showed impaired axonal transport of the α1 and β2 subunits. Our findings suggested that different phenotypes of epilepsy, e.g., GEFS+ and Dravet syndrome (which share similar abnormalities in causative genes) are likely due to impaired axonal transport associated with the dominant-negative effects of GABRG2.

Keywords: Channelopathy; ER stress; Sorting; Trafficking; Unfolded protein response.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Cells, Cultured
  • Child, Preschool
  • Codon, Nonsense / genetics*
  • Epilepsies, Myoclonic / genetics
  • Epilepsies, Myoclonic / pathology
  • Epilepsy / genetics*
  • Female
  • Gene Expression Regulation
  • HEK293 Cells
  • Hippocampus / cytology
  • Humans
  • Infant
  • Japan
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Mice
  • Models, Molecular
  • Neurons / drug effects
  • Neurons / physiology
  • Protein Subunits / genetics
  • Protein Transport / genetics
  • Receptors, GABA-A / genetics*
  • Receptors, GABA-A / metabolism*
  • Subcellular Fractions / metabolism
  • Subcellular Fractions / ultrastructure
  • Twins, Dizygotic


  • Codon, Nonsense
  • GABRG2 protein, human
  • Protein Subunits
  • Receptors, GABA-A