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

• Published in: Annals of neurology Vol. 77; no. 6; p. 972
• Main Authors: Reinthaler, Eva M, Dejanovic, Borislav, Lal, Dennis, Semtner, Marcus, Merkler, Yvonne, Reinhold, Annika, Pittrich, Dorothea A, Hotzy, Christoph, Feucht, Martha, Steinbock, Hannelore, Gruber-Sedlmayr, Ursula, Ronen, Gabriel M, Neophytou, Birgit, Geldner, Julia, Haberlandt, Edda, Muhle, Hiltrud, Ikram, M Arfan, van Duijn, Cornelia M, Uitterlinden, Andre G, Hofman, Albert, Altmuller, Janine, Kawalia, Amit, Toliat, Mohammad R, Nurnberg, Peter, Lerche, Holger, Nothnagel, Michael, Thiele, Holger, Sander, Thomas, Meier, Jochen C, Schwarz, Gunter, Neubauer, Bernd A, Zimprich, Fritz
• Format: Journal Article
• Language: English
• Published: Minneapolis Wiley Subscription Services, Inc 01.06.2015
• Subjects: Confidence intervals; Genes; Mutation
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.24395

Objective To test whether mutations in [gamma]-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 [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. Ann Neurol 2015;77:972-986