Rare variants in γ‐aminobutyric acid type A receptor genes in rolandic epilepsy and related syndromes. Issue 6 (28th March 2015)

• Record Type: Journal Article
• Authors: Reinthaler, Eva M.; Dejanovic, Borislav; Lal, Dennis; Semtner, Marcus; Merkler, Yvonne; Reinhold, Annika; Pittrich, Dorothea A.; Hotzy, Christoph; Feucht, Martha; Steinböck, 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; Altmüller, Janine; Kawalia, Amit; Toliat, Mohammad R.; Nürnberg, Peter; Lerche, Holger; Nothnagel, Michael; Thiele, Holger; Sander, Thomas; Meier, Jochen C.; Schwarz, Günter; Neubauer, Bernd A.; Zimprich, Fritz;
• Is Part Of: Annals of neurology. Volume 77:Issue 6(2015:Jun.)
• Page Start: 972
• Page End: 986
• Publication Date: 2015-03-28
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.24395
• Languages: English
• ISSNs: 0364-5134

Abstract

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, 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 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. Ann Neurol 2015;77:972–986