Truncation of the GABAA-Receptor γ2 Subunit in a Family with Generalized Epilepsy with Febrile Seizures Plus Louise A. Harkin, David N. Bowser, Leanne.

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Truncation of the GABAA-Receptor γ2 Subunit in a Family with Generalized Epilepsy with Febrile Seizures Plus Louise A. Harkin, David N. Bowser, Leanne M. Dibbens, Rita Singh, Fiona Phillips, Robyn H. Wallace, Michaella C. Richards, David A. Williams, John C. Mulley, Samuel F. Berkovic, Ingrid E. Scheffer, Steven Petrou The American Journal of Human Genetics Volume 70, Issue 2, Pages 530-536 (February 2002) DOI: 10.1086/338710 Copyright © 2002 The American Society of Human Genetics Terms and Conditions

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. The American Journal of Human Genetics 2002 70, 530-536DOI: (10.1086/338710) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

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. The American Journal of Human Genetics 2002 70, 530-536DOI: (10.1086/338710) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 3 Schematic representation of the GABRG2 protein, with arrows indicating the positions of mutations associated with epilepsy. The American Journal of Human Genetics 2002 70, 530-536DOI: (10.1086/338710) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

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. The American Journal of Human Genetics 2002 70, 530-536DOI: (10.1086/338710) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

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. The American Journal of Human Genetics 2002 70, 530-536DOI: (10.1086/338710) Copyright © 2002 The American Society of Human Genetics Terms and Conditions