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

Item Type:Article
Title:Rare variants in GABA(A) receptor genes in Rolandic epilepsy and related syndromes
Creators Name:Reinthaler, E.M. and Dejanovic, B. and Lal, D. and Semtner, M. and Merkler, Y. and Reinhold, A. and Pittrich, D.A. and Hotzy, C. and Feucht, M. and Steinboeck, H. and Gruber-Sedlmayr, U. and Ronen, G. and Neophytou, B. and Geldner, J. and Haberlandt, E. and Muhle, H. and Ikram, M.A. and van Duijn, CM. and Uitterlinden, A.G. and Hofman, A. and Altmüller, J. and Kawalia, A. and Toliat, M.R. and Nuernberg, P. and Lerche, H. and Nothnagel, M. and Thiele, H. and Sander, T. and Meier, J.C. and Schwarz, G. and Neubauer, B.A. and Zimprich, F.
Abstract: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.
Keywords:Rolandic Epilepsy, Idiopathic Focal Childhood Epilepsy, GABRG2, GABA(A) Receptor, Mutation, Association
Source:Annals of Neurology
Page Range:972-986
Date:June 2015
Official Publication:https://doi.org/10.1002/ana.24395
PubMed:View item in PubMed

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