1. Rare variants in -aminobutyric acid type A receptor genes in rolandic epilepsy and related syndromes
- Author
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Reinthaler, EM, Dejanovic, B, Lal, D, Semtner, M, Merkler, Y, Reinhold, A, Pittrich, DA, Hotzy, C, Feucht, M, Steinbock, H, Gruber-Sedlmayr, U, Ronen, GM, Neophytou, B, Geldner, J, Haberlandt, E, Muhle, H, Ikram, Arfan, Duijn, Cornelia, Uitterlinden, André, Hofman, Bert, Altmuller, J, Kawalia, A, Toliat, MR, Nurnberg, P, Lerche, H, Nothnagel, M, Thiele, H, Sander, T, Meier, JC, Schwarz, G, Neubauer, BA, Zimprich, F, Epidemiology, and Internal Medicine
- Abstract
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
- Published
- 2015