期刊
ANNALS OF NEUROLOGY
卷 77, 期 6, 页码 972-986出版社
WILEY
DOI: 10.1002/ana.24395
关键词
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资金
- EuroEPINOMICS program (DFG) within the EUROCORES [LE1030/11-1, BN416/5-1, NU50/8-1, SA434/5-1]
- EuroEPINOMICS program (FWF) within the EUROCORES [I643-B09]
- Helmholtz Association [VH-NG-246]
- Bundesministerium fur Bildung und Forschung (ERA-Net NEURON II CIPRESS)
- Netherlands Organization of Scientific Research NOW Investments [175.010.2005.011, 911-03-012]
- Netherlands Genomics Initiative/NOW [050-060-810]
- Erasmus Medical Center
- Erasmus University, Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly
- Ministry of Education, Culture, and Science
- Ministry for Health, Welfare, and Sports
- European Commission (DG XII)
- Municipality of Rotterdam
- Austrian Science Fund (FWF) [I 643] Funding Source: researchfish
- Austrian Science Fund (FWF) [I643] Funding Source: Austrian Science Fund (FWF)
ObjectiveTo test whether mutations in -aminobutyric acid type A receptor (GABA(A)-R) subunit genes contribute to the etiology of rolandic epilepsy (RE) or its atypical variants (ARE). MethodsWe performed exome sequencing to compare the frequency of variants in 18 GABA(A)-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. ResultsOf 18 screened GABA(A)-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 2 subunit. InterpretationThe 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
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