Rare variants in -aminobutyric acid type A receptor genes in rolandic epilepsy and related syndromes

EM Reinthaler, B Dejanovic, D Lal, M Semtner, Y Merkler, A Reinhold, DA Pittrich, C Hotzy, M Feucht, H Steinbock, U Gruber-Sedlmayr, GM Ronen, B Neophytou, J Geldner, E Haberlandt, H Muhle, Arfan Ikram, Cornelia Duijn, André Uitterlinden, Bert HofmanJ Altmuller, A Kawalia, MR Toliat, P Nurnberg, H Lerche, M Nothnagel, H Thiele, T Sander, JC Meier, G Schwarz, BA Neubauer, F Zimprich

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ObjectiveTo test whether mutations in -aminobutyric acid type A receptor (GABA(A)-R) subunit genes contribute to the etiology of rolandic epilepsy (RE) or its atypical variants (ARE). MethodsWe 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. ResultsOf 18 screened GABA(A)-R genes, we detected an enrichment of rare variants in the GABRG2 gene in RE/ARE patients (5 of 204, 2.45%) in comparison to controls (1 of 723, 0.14%; odds ratio=18.07, 95% confidence interval=2.01-855.07, p=0.0024, p(corr)=0.043). We identified a GABRG2 splice variant (c.549-3T>G) in 2 unrelated patients as well as 3 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 post-translational modification crucial for trafficking of proteins to the cell membrane. Enzymatically raised palmitoylation levels restored the surface expression of the p.G257R variant 2 subunit. InterpretationThe 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. Ann Neurol 2015;77:972-986
Original languageUndefined/Unknown
Pages (from-to)972-986
Number of pages15
JournalAnnals of Neurology
Issue number6
Publication statusPublished - 2015

Research programs

  • EMC COEUR-09
  • EMC MM-01-39-09-A
  • EMC NIHES-01-64-01
  • EMC NIHES-03-30-02

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