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The Journal of Neuroscience, June 16, 2004, 24(24):5570-5578; doi:10.1523/JNEUROSCI.1301-04.2004

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Neurobiology of Disease
The Juvenile Myoclonic Epilepsy GABA_A Receptor 1 Subunit Mutation A322D Produces Asymmetrical, Subunit Position-Dependent Reduction of Heterozygous Receptor Currents and 1 Subunit Protein Expression

Martin J. Gallagher,¹ Luyan Song,¹ Fazal Arain,¹ and Robert L. Macdonald^1,2,3

Departments of ¹Neurology, ²Molecular Physiology and Biophysics, and ³Pharmacology, Vanderbilt University, Nashville, Tennessee 37212

Individuals with autosomal dominant juvenile myoclonic epilepsy are heterozygous for a GABA_A receptor 1 subunit mutation (1A322D). GABA_A receptor subunits are arranged around the pore in a ---- sequence (counterclockwise from the synaptic cleft). Therefore, each 1 subunit has different adjacent subunits, and heterozygous expression of 1(A322D), , and subunits could produce receptors with four different subunit arrangements: -1--1- (wild type); -1(A322D)--1- (Het); -1--1(A322D)- (Het);-1(A322D)--1(A322D)- (homozygous). Expression of a 1:1 mixture of wild-type and1(A322D) subunits with 2S and 2S subunits (heterozygous transfection) produced smaller currents than wild type and much larger currents than homozygous mutant transfections. Western blot and biotinylation assays demonstrated that the amount of total and surface 1 subunit from heterozygous transfections was also intermediate between those of wild-type and homozygous mutant transfections. 1(A322D) mutations were then made in covalently tethered triplet (2S-2S-1) and tandem (2S-1) concatamers to target selectively 1(A322D) to each of the asymmetric 1 subunits. Coexpression of mutant and wild-type concatamers resulted in expression of either Het or Het receptors. Het currents were smaller than wild type and much larger than Het and homozygous currents. Furthermore, Het transfections contained less - concatamer than wild type but more than both Het and homozygous mutant transfections. Thus, whole-cell currents and protein expression of heterozygous 1(A322D)2S2S receptors depended on the position of the mutant 1 subunit, and GABA_A receptor currents in heterozygous individuals likely result primarily from wild-type and Het receptors with little contribution from Het and homozygous receptors.

Key words: juvenile myoclonic epilepsy; chloride ion channel; GABA_A receptors; mutant; myoclonus; patch clamp; protein; concatamer

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Received Oct 10, 2003; revised April 30, 2004; accepted May 4, 2004.

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