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


CONCLUSIONS
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.
Department of Neurology, Medical University of Vienna, Vienna, Austria.
Eva M
EM
Reinthaler
Institute of Biochemistry, Department of Chemistry, University of Cologne, Cologne, Germany.
Borislav
B
Dejanovic
Department of Neuropediatrics, University Medical Center Giessen and Marburg, Giessen, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.|Cologne Center for Genomics, University of Cologne, Cologne, Germany.
Dennis
D
Lal
RNA Editing and Hyperexcitability Disorders Helmholtz Group, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Marcus
M
Semtner
Institute of Biochemistry, Department of Chemistry, University of Cologne, Cologne, Germany.
Yvonne
Y
Merkler
RNA Editing and Hyperexcitability Disorders Helmholtz Group, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Annika
A
Reinhold
Department of Neurology, Medical University of Vienna, Vienna, Austria.
Dorothea A
DA
Pittrich
Department of Neurology, Medical University of Vienna, Vienna, Austria.
Christoph
C
Hotzy
Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
Martha
M
Feucht
Private Practice of Pediatrics, Vienna, Austria.
Hannelore
H
Steinböck
Department of Pediatrics, Medical University of Graz, Graz, Austria.
Ursula
U
Gruber-Sedlmayr
Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
Gabriel M
GM
Ronen
Department of Neuropediatrics, St Anna Children's Hospital, Vienna, Austria.
Birgit
B
Neophytou
Department of Pediatrics, SMZ Süd - Kaiser-Franz-Josef-Hospital, Vienna, Austria.
Julia
J
Geldner
Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria.
Edda
E
Haberlandt
Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian Albrechts University, Kiel, Germany.
Hiltrud
H
Muhle
Departments of Epidemiology, Neurology, and Radiology, Erasmus Medical Center, Rotterdam, the Netherlands.
M Arfan
MA
Ikram
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
Cornelia M
CM
van Duijn
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
Andre G
AG
Uitterlinden
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
Albert
A
Hofman
Cologne Center for Genomics, University of Cologne, Cologne, Germany.|Institute of Human Genetics, University of Cologne, Cologne, Germany.
Janine
J
Altmüller
Cologne Center for Genomics, University of Cologne, Cologne, Germany.
Amit
A
Kawalia
Cologne Center for Genomics, University of Cologne, Cologne, Germany.
Mohammad R
MR
Toliat
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.|Cologne Center for Genomics, University of Cologne, Cologne, Germany.
Peter
P
Nürnberg
Department of Neurology and Epileptology, Hertie Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Holger
H
Lerche
Cologne Center for Genomics, University of Cologne, Cologne, Germany.
Michael
M
Nothnagel
Cologne Center for Genomics, University of Cologne, Cologne, Germany.
Holger
H
Thiele
Cologne Center for Genomics, University of Cologne, Cologne, Germany.
Thomas
T
Sander
RNA Editing and Hyperexcitability Disorders Helmholtz Group, Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Braunschweig University of Technology, Zoological Institute, Division of Cell Physiology, Braunschweig, Germany.
Jochen C
JC
Meier
Institute of Biochemistry, Department of Chemistry, University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Günter
G
Schwarz
Department of Neuropediatrics, University Medical Center Giessen and Marburg, Giessen, Germany.
Bernd A
BA
Neubauer
Department of Neurology, Medical University of Vienna, Vienna, Austria.
Fritz
F
Zimprich
D019305:Epilepsy, Rolandic / Q000235:genetics*; D059472:Exome; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D018887:Landau-Kleffner Syndrome / Q000235:genetics; D054878:Lipoylation / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011963:Receptors, GABA-A / Q000235:genetics*; D013577:Syndrome; D044465:White People / Q000235:genetics
C546279:GABRG2 protein, human; D011963:Receptors, GABA-A