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The Journal of Neuroscience, March 4, 2009, 29(9):2845-2856; doi:10.1523/JNEUROSCI.4772-08.2009

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Neurobiology of Disease
The GABRG2 Mutation, Q351X, Associated with Generalized Epilepsy with Febrile Seizures Plus, Has Both Loss of Function and Dominant-Negative Suppression

Jing-Qiong Kang,¹ Wangzhen Shen,¹ and Robert L. Macdonald^1,2,3

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

Correspondence should be addressed to Dr. Jing-Qiong Kang, Vanderbilt University Medical Center, 6140 Medical Research Building III, 465 21st Avenue, South, Nashville, TN 37232-8552. Email: jingqiong.kang{at}vanderbilt.edu

The GABA_A receptor 2 subunit mutation, Q351X, associated with generalized epilepsy with febrile seizures plus (GEFS+), created a loss of function with homozygous expression. However, heterozygous 2(+/–) gene deletion mice are seizure free, suggesting that the loss of one GABRG2 allele alone in heterozygous patients may not be sufficient to produce epilepsy. Here we show that the mutant 2 subunit was immature and retained in the endoplasmic reticulum (ER). With heterozygous coexpression of 2S/2S(Q351X) subunits and 1 and β2 subunits, the trafficking deficient mutant 2 subunit reduced trafficking of wild-type partnering subunits, which was not seen in the hemizygous gene deletion control. Consequently, the function of the heterozygous receptor channel was reduced to less than the hemizygous control and to less than half of the wild-type receptors with a full gene dose. Pulse-chase experiments demonstrated that in the presence of the mutant 2S(Q351X) subunit, wild-type 1 subunits degraded more substantially within 1 h of translation. We showed that the basis for this dominant-negative effect on wild-type receptors was due to an interaction between mutant and wild-type subunits. The mutant subunit oligomerized with wild-type subunits and trapped them in the ER, subjecting them to glycosylation arrest and ER-associated degradation (ERAD) through the ubiquitin proteosome system. Thus, we hypothesize that a likely explanation for the GEFS+ phenotype is a dominant-negative suppression of wild-type receptors by the mutant 2S subunit in combination with loss of mutant 2S subunit protein function.

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Received Oct. 3, 2008; revised Nov. 12, 2008; accepted Dec. 31, 2008.

Correspondence should be addressed to Dr. Jing-Qiong Kang, Vanderbilt University Medical Center, 6140 Medical Research Building III, 465 21st Avenue, South, Nashville, TN 37232-8552. Email: jingqiong.kang{at}vanderbilt.edu

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