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

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

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

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Item Type:	Article
Title:	Rare variants in γ-aminobutyric acid type A receptor genes in rolandic epilepsy and related syndromes
Creators:	Reinthaler, E.M., Dejanovic, B., Lal, D., Semtner, M. ORCID: https://orcid.org/0000-0001-9379-9023, Merkler, Y., Reinhold, A., Pittrich, D.A., Hotzy, C., Feucht, M., Steinböck, H., Gruber-Sedlmayr, U., Ronen, G.M., Neophytou, B., Geldner, J., Haberlandt, E., Muhle, H., Ikram, M.A., van Duijn, C.M., Uitterlinden, A.G., Hofman, A., Altmüller, J. ORCID: https://orcid.org/0000-0003-4372-1521, Kawalia, A., Toliat, M.R., Nürnberg, P., Lerche, H., Nothnagel, M., Thiele, H., Sander, T., Meier, J.C. ORCID: https://orcid.org/0000-0002-2041-8872, Schwarz, G., Neubauer, B.A. and Zimprich, F.
Abstract:	OBJECTIVE: To test whether mutations in γ-aminobutyric acid type A receptor (GABAA-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 GABAA-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: Of 18 screened GABAA-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, pcorr = 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 γ2 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:	Exome, GABA-A Receptors, HEK293 Cells, Landau-Kleffner Syndrome, Lipoylation, Mutation, Pedigree, Rolandic Epilepsy, Syndrome, White People
Source:	Annals of Neurology
ISSN:	0364-5134
Publisher:	Wiley
Volume:	77
Number:	6
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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