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

EM Reinthaler; B Dejanovic; D Lal; M Semtner; Y Merkler; A Reinhold; DA Pittrich; C Hotzy; M Feucht; H Steinbock; U Gruber-Sedlmayr; GM Ronen; B Neophytou; J Geldner; E Haberlandt; H Muhle; Arfan Ikram; Cornelia Duijn; André Uitterlinden; Bert Hofman; J Altmuller; A Kawalia; MR Toliat; P Nurnberg; H Lerche; M Nothnagel; H Thiele; T Sander; JC Meier; G Schwarz; BA Neubauer; F Zimprich

doi:10.1002/ana.24395

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

EM Reinthaler, B Dejanovic, D Lal, M Semtner, Y Merkler, A Reinhold, DA Pittrich, C Hotzy, M Feucht, H Steinbock, U Gruber-Sedlmayr, GM Ronen, B Neophytou, J Geldner, E Haberlandt, H Muhle, Arfan Ikram, Cornelia Duijn, André Uitterlinden, Bert HofmanJ Altmuller, A Kawalia, MR Toliat, P Nurnberg, H Lerche, M Nothnagel, H Thiele, T Sander, JC Meier, G Schwarz, BA Neubauer, F Zimprich

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Abstract

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

Original language	Undefined/Unknown
Pages (from-to)	972-986
Number of pages	15
Journal	Annals of Neurology
Volume	77
Issue number	6
DOIs	https://doi.org/10.1002/ana.24395
Publication status	Published - 2015

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EMC COEUR-09
EMC MM-01-39-09-A
EMC NIHES-01-64-01
EMC NIHES-03-30-02

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10.1002/ana.24395

Cite this

Reinthaler, EM., Dejanovic, B., Lal, D., Semtner, M., Merkler, Y., Reinhold, A., Pittrich, DA., Hotzy, C., Feucht, M., Steinbock, H., Gruber-Sedlmayr, U., Ronen, GM., Neophytou, B., Geldner, J., Haberlandt, E., Muhle, H., Ikram, A., Duijn, C., Uitterlinden, A., ... Zimprich, F. (2015). Rare variants in -aminobutyric acid type A receptor genes in rolandic epilepsy and related syndromes. Annals of Neurology, 77(6), 972-986. https://doi.org/10.1002/ana.24395

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title = "Rare variants in -aminobutyric acid type A receptor genes in rolandic epilepsy and related syndromes",

abstract = "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",

author = "EM Reinthaler and B Dejanovic and D Lal and M Semtner and Y Merkler and A Reinhold and DA Pittrich and C Hotzy and M Feucht and H Steinbock and U Gruber-Sedlmayr and GM Ronen and B Neophytou and J Geldner and E Haberlandt and H Muhle and Arfan Ikram and Cornelia Duijn and Andr{\'e} Uitterlinden and Bert Hofman and J Altmuller and A Kawalia and MR Toliat and P Nurnberg and H Lerche and M Nothnagel and H Thiele and T Sander and JC Meier and G Schwarz and BA Neubauer and F Zimprich",

year = "2015",

doi = "10.1002/ana.24395",

language = "Undefined/Unknown",

volume = "77",

pages = "972--986",

journal = "Annals of Neurology",

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Reinthaler, EM, Dejanovic, B, Lal, D, Semtner, M, Merkler, Y, Reinhold, A, Pittrich, DA, Hotzy, C, Feucht, M, Steinbock, H, Gruber-Sedlmayr, U, Ronen, GM, Neophytou, B, Geldner, J, Haberlandt, E, Muhle, H, Ikram, A, Duijn, C, Uitterlinden, A , Hofman, B, Altmuller, J, Kawalia, A, Toliat, MR, Nurnberg, P, Lerche, H, Nothnagel, M, Thiele, H, Sander, T, Meier, JC, Schwarz, G, Neubauer, BA & Zimprich, F 2015, 'Rare variants in -aminobutyric acid type A receptor genes in rolandic epilepsy and related syndromes', Annals of Neurology, vol. 77, no. 6, pp. 972-986. https://doi.org/10.1002/ana.24395

TY - JOUR

T1 - Rare variants in -aminobutyric acid type A receptor genes in rolandic epilepsy and related syndromes

AU - Reinthaler, EM

AU - Dejanovic, B

AU - Lal, D

AU - Semtner, M

AU - Merkler, Y

AU - Reinhold, A

AU - Pittrich, DA

AU - Hotzy, C

AU - Feucht, M

AU - Steinbock, H

AU - Gruber-Sedlmayr, U

AU - Ronen, GM

AU - Neophytou, B

AU - Geldner, J

AU - Haberlandt, E

AU - Muhle, H

AU - Ikram, Arfan

AU - Duijn, Cornelia

AU - Uitterlinden, André

AU - Hofman, Bert

AU - Altmuller, J

AU - Kawalia, A

AU - Toliat, MR

AU - Nurnberg, P

AU - Lerche, H

AU - Nothnagel, M

AU - Thiele, H

AU - Sander, T

AU - Meier, JC

AU - Schwarz, G

AU - Neubauer, BA

AU - Zimprich, F

PY - 2015

Y1 - 2015

N2 - 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

AB - 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

U2 - 10.1002/ana.24395

DO - 10.1002/ana.24395

M3 - Article

C2 - 25726841

SN - 0364-5134

VL - 77

SP - 972

EP - 986

JO - Annals of Neurology

JF - Annals of Neurology

IS - 6

ER -