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The Journal of Neuroscience, February 1, 2006, 26(5):1499-1506; doi:10.1523/JNEUROSCI.2913-05.2006

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Neurobiology of Disease
Subunit Susceptibility Variants E177A and R220H Associated with Complex Epilepsy Alter Channel Gating and Surface Expression of 42 GABA_A Receptors

Hua-Jun Feng,¹ Jing-Qiong Kang,¹ Luyan Song,¹ Leanne Dibbens,^4,5 John Mulley,^4,6 and Robert L. Macdonald^1,2,3

¹Departments of Neurology, ²Molecular Physiology and Biophysics, and ³Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37212, ⁴Department of Genetic Medicine, Women’s and Children’s Hospital, ⁵Department of Pediatrics, and ⁶School of Molecular and Biomedical Sciences, The University of Adelaide, Adelaide, SA 5031, Australia

Correspondence should be addressed to Dr. Robert L. Macdonald, Department of Neurology, Vanderbilt University Medical Center, 6140 Medical Research Building III, 465 21st Avenue South, Nashville, TN 37232-8552. Email: robert.macdonald{at}vanderbilt.edu

Most human idiopathic generalized epilepsies (IGEs) are polygenic, but virtually nothing is known of the molecular basis for any of the complex epilepsies. Recently, two GABA_A receptor subunit variants (E177A, R220H) were proposed as susceptibility alleles for generalized epilepsy with febrile seizures plus and juvenile myoclonic epilepsy. In human embryonic kidney 293T cells, recombinant h12(E177A) and h12(R220H) receptor currents were reduced, but the basis for the current reduction was not determined. We examined the mechanistic basis for the current reduction produced by these variants using the h42 receptor, an isoform more physiologically relevant and linked to epileptogenesis, by characterizing the effects of these variants on receptor cell surface expression and single-channel gating properties. Expression of variant 42(R220H) receptors resulted in a decrease in surface receptor proteins, and a smaller, but significant, reduction was observed for variant 42(E177A) receptors. For both variants, no significant alterations of surface expression were observed for mixed population of wild-type and variant receptors. The mean open durations of 42(E177A) and 42(R220H) receptor single-channel currents were both significantly decreased compared to wild-type receptors. These data suggest that both (E177A) and (R220H) variants may result in disinhibition in IGEs by similar cellular and molecular mechanisms, and in heterozygously affected individuals, a reduction in channel open duration of subunit-containing GABA_A receptors may be the major contributor to the epilepsy phenotypes.

Key words: complex epilepsy; susceptibility gene; GABA_A receptor; ; subunit; single channel; surface receptor

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Received July 14, 2005; revised Dec. 12, 2005; accepted Dec. 15, 2005.

Correspondence should be addressed to Dr. Robert L. Macdonald, Department of Neurology, Vanderbilt University Medical Center, 6140 Medical Research Building III, 465 21st Avenue South, Nashville, TN 37232-8552. Email: robert.macdonald{at}vanderbilt.edu

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