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Am J Hum Genet
2002 Feb 01;702:530-6. doi: 10.1086/338710.
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Truncation of the GABA(A)-receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus.
Harkin LA, Bowser DN, Dibbens LM, Singh R, Phillips F, Wallace RH, Richards MC, Williams DA, Mulley JC, Berkovic SF, Scheffer IE, Petrou S.
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Recent findings from studies of two families have shown that mutations in the GABA(A)-receptor gamma2 subunit are associated with generalized epilepsies and febrile seizures. Here we describe a family that has generalized epilepsy with febrile seizures plus (GEFS(+)), including an individual with severe myoclonic epilepsy of infancy, in whom a third GABA(A)-receptor gamma2-subunit mutation was found. This mutation lies in the intracellular loop between the third and fourth transmembrane domains of the GABA(A)-receptor gamma2 subunit and introduces a premature stop codon at Q351 in the mature protein. GABA sensitivity in Xenopus laevis oocytes expressing the mutant gamma2(Q351X) subunit is completely abolished, and fluorescent-microscopy studies have shown that receptors containing GFP-labeled gamma2(Q351X) protein are retained in the lumen of the endoplasmic reticulum. This finding reinforces the involvement of GABA(A) receptors in epilepsy.
Figure 1. Pedigree of an Australian family with GEFS+. An asterisk (*) indicates members carrying the Q351X mutation in GABRG2, and a minus sign (−) indicates members who were tested and are negative for the Q351X mutation.
Figure 2. Sequencing trace of a portion of exon 9 GABRG2, showing the c.1168C→T transition (arrow). The upper chromatogram shows the mutation, and the lower chromatogram shows the control sequence.
Figure 3. Schematic representation of the GABRG2 protein, with arrows indicating the positions of mutations associated with epilepsy.
Figure 4. Two-electrode voltage-clamp recordings in oocytes, demonstrating that coexpression of the GABRG2Q351X abolishes the response to GABA. For all recordings, n=6. The current and time scale bars apply to all traces. Holding potential was −80 mV. A, Injection of oocytes with wild-type GABRA1:GABRB2:GABRG2 cRNAs (1:1:10 ratio, to favor assembly of γ subunit–containing complexes), resulting in both a robust inward current response to GABA and a low sensitivity to Zn2+ blockade, characteristic of GABRG2 coexpression. B, Expression of GABRA1:GABRB2 only (1:1 ratio). This also produced robust responses to GABA, but with high sensitivity to blockade by Zn2+. C, Expression of GABRA1:GABRB2:GABRG2Q351X subunits (1:1:10 ratio), abolishing GABA-induced currents.
Figure 5. Imaging of GFP-tagged GABRG2 expressed with GABRA1 and GABRB2 subunits, revealing the fate of GABRG2Q351X-containing receptors in HEK293 cells. Images were obtained by confocal fluorescence microscopy (excitation, 488 nm; emission, >515 nm). The scale bar in panel C corresponds to 5 microns and applies to all three panels. A, EGFP-tagged wild-type GABRG2 subunit, found in both the membrane and the intracellular compartment (n=20 individual cells analyzed). B, EGFP-tagged GABRG2Q351X, found only in the intracellular compartment (n=20 individual cells analyzed). C, ER-targeted EYFP expression, demonstrating subcellular distribution of ER that is remarkably similar to that seen in B.
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