Eva M Reinthaler1, Borislav Dejanovic2, Dennis Lal3,4,5, Marcus Semtner6, Yvonne Merkler2, Annika Reinhold6, Dorothea A Pittrich1, Christoph Hotzy1, Martha Feucht7, Hannelore Steinböck8, Ursula Gruber-Sedlmayr9, Gabriel M Ronen10, Birgit Neophytou11, Julia Geldner12, Edda Haberlandt13, Hiltrud Muhle14, M Arfan Ikram15, Cornelia M van Duijn16, Andre G Uitterlinden17, Albert Hofman16, Janine Altmüller5,18, Amit Kawalia5, Mohammad R Toliat5, Peter Nürnberg4,5, Holger Lerche19, Michael Nothnagel5, Holger Thiele5, Thomas Sander5, Jochen C Meier6,20, Günter Schwarz2,4,21, Bernd A Neubauer3, Fritz Zimprich1. 1. Department of Neurology, Medical University of Vienna, Vienna, Austria. 2. Institute of Biochemistry, Department of Chemistry, University of Cologne, Cologne, Germany. 3. Department of Neuropediatrics, University Medical Center Giessen and Marburg, Giessen, Germany. 4. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. 5. Cologne Center for Genomics, University of Cologne, Cologne, Germany. 6. RNA Editing and Hyperexcitability Disorders Helmholtz Group, Max Delbrück Center for Molecular Medicine, Berlin, Germany. 7. Department of Pediatrics, Medical University of Vienna, Vienna, Austria. 8. Private Practice of Pediatrics, Vienna, Austria. 9. Department of Pediatrics, Medical University of Graz, Graz, Austria. 10. Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada. 11. Department of Neuropediatrics, St Anna Children's Hospital, Vienna, Austria. 12. Department of Pediatrics, SMZ Süd - Kaiser-Franz-Josef-Hospital, Vienna, Austria. 13. Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria. 14. Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian Albrechts University, Kiel, Germany. 15. Departments of Epidemiology, Neurology, and Radiology, Erasmus Medical Center, Rotterdam, the Netherlands. 16. Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands. 17. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands. 18. Institute of Human Genetics, University of Cologne, Cologne, Germany. 19. Department of Neurology and Epileptology, Hertie Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany. 20. Braunschweig University of Technology, Zoological Institute, Division of Cell Physiology, Braunschweig, Germany. 21. Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
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.
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.
Authors: Dheeraj R Bobbili; Dennis Lal; Patrick May; Eva M Reinthaler; Kamel Jabbari; Holger Thiele; Michael Nothnagel; Wiktor Jurkowski; Martha Feucht; Peter Nürnberg; Holger Lerche; Fritz Zimprich; Roland Krause; Bernd A Neubauer; Eva M Reinthaler; Fritz Zimprich; Martha Feucht; Hannelore Steinböck; Birgit Neophytou; Julia Geldner; Ursula Gruber-Sedlmayr; Edda Haberlandt; Gabriel M Ronen; Janine Altmüller; Dennis Lal; Peter Nürnberg; Thomas Sander; Holger Thiele; Roland Krause; Patrick May; Rudi Balling; Holger Lerche; Bernd A Neubauer Journal: Eur J Hum Genet Date: 2018-01-22 Impact factor: 4.246
Authors: Fanggeng Zou; Kirsty McWalter; Lindsay Schmidt; Amy Decker; Jonathan D Picker; Sharyn Lincoln; David A Sweetser; Lauren C Briere; Chellamani Harini; Eric Marsh; Livija Medne; Raymond Y Wang; Karen Leydiker; Andrew Mower; Gepke Visser; Inge Cuppen; Koen L van Gassen; Jasper van der Smagt; Adeel Yousaf; Michael Tennison; Anita Shanmugham; Elizabeth Butler; Gabriele Richard; Dianalee McKnight Journal: J Neurogenet Date: 2017-05-02 Impact factor: 1.250
Authors: Dingding Shen; Ciria C Hernandez; Wangzhen Shen; Ningning Hu; Annapurna Poduri; Beth Shiedley; Alex Rotenberg; Alexandre N Datta; Steffen Leiz; Steffi Patzer; Rainer Boor; Kerri Ramsey; Ethan Goldberg; Ingo Helbig; Xilma R Ortiz-Gonzalez; Johannes R Lemke; Eric D Marsh; Robert L Macdonald Journal: Brain Date: 2016-11-17 Impact factor: 13.501
Authors: Fiona M Baumer; Kristina Pfeifer; Adam Fogarty; Dalia Pena-Solorzano; Camarin E Rolle; Joanna L Wallace; Alexander Rotenberg; Robert S Fisher Journal: J Clin Neurophysiol Date: 2020-03 Impact factor: 2.590