Rare variants in GABA(A) receptor genes in Rolandic epilepsy and related syndromes


  • E.M. Reinthaler
  • B. Dejanovic
  • D. Lal
  • M. Semtner
  • Y. Merkler
  • A. Reinhold
  • D.A. Pittrich
  • C. Hotzy
  • M. Feucht
  • H. Steinboeck
  • U. Gruber-Sedlmayr
  • G. Ronen
  • B. Neophytou
  • J. Geldner
  • E. Haberlandt
  • H. Muhle
  • M.A. Ikram
  • CM. van Duijn
  • A.G. Uitterlinden
  • A. Hofman
  • J. Altmüller
  • A. Kawalia
  • M.R. Toliat
  • P. Nuernberg
  • H. Lerche
  • M. Nothnagel
  • H. Thiele
  • T. Sander
  • J.C. Meier
  • G. Schwarz
  • B.A. Neubauer
  • F. Zimprich


  • Annals of Neurology


  • Ann Neurol 77 (6): 972-986


  • Objective: To test whether mutations in gamma-aminobutyric acid type A receptor (GABA(A)-R) subunit genes contribute to the etiology of Rolandic epilepsy (RE) or its atypical variants (ARE). Methods: We performed exome sequencing to compare the frequency of variants in 18 GABA(A)-R genes in 204 European patients with RE/ARE versus 728 platform matched controls. Identified GABRG2 variants were functionally assessed for protein stability, trafficking, postsynaptic clustering and receptor function. Results: Out of 18 screened GABA(A)-R genes, we detected an enrichment of rare variants in the GABRG2 gene in RE/ARE patients (5/204, 2.45%) in comparison to controls (1/723, 0.14%) (OR = 18.07, 95% CI = 2.01 - 855.07, p = 0.0024, pcorr = 0.043). We identified a GABRG2 splice variant (c.549-3T>G) in two unrelated patients as well as three nonsynonymous variations in this gene (p.G257R, p.R323Q, p.I389V). Functional assessment showed reduced surface expression of p.G257R and decreased GABA-evoked currents for p.R323Q. The p.G257R mutation displayed diminished levels of palmitoylation, a posttranslational modification crucial for trafficking of proteins to the cell membrane. Enzymatically raised palmitoylation levels restored the surface expression of the p.G257R variant {Gamma}2-subunit. Interpretation: The statistical association and the functional evidence suggest that mutations of the GABRG2 gene may increase the risk of RE/ARE. Restoring the impaired membrane trafficking of some GABRG2 mutations by enhancing palmitoylation might be an interesting therapeutic approach to reverse the pathogenic effect of such mutants.