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The Journal of Neuroscience, March 4, 2009, 29(9):2833-2844; doi:10.1523/JNEUROSCI.4512-08.2009

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Neurobiology of Disease
Two Molecular Pathways (NMD and ERAD) Contribute to a Genetic Epilepsy Associated with the GABA_A Receptor GABRA1 PTC Mutation, 975delC, S326fs328X

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, Nashville, Tennessee 37212

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

Approximately one-third of human genetic diseases are caused by premature translation-termination codon (PTC)-generating mutations. These mutations in sodium channel and GABA_A receptor genes have been associated with idiopathic generalized epilepsies, but the cellular consequences of the PTCs on the mutant channel subunit biogenesis and function are unknown. The PTCs could result in translation of a truncated subunit, or more likely, trigger mRNA degradation through nonsense-mediated mRNA decay (NMD), thus preventing or reducing production of mutant subunit at the transcriptional level. The GABA_A receptor 1 subunit mutation, 975delC, S326fs328X, is an autosomal dominant mutation associated with childhood absence epilepsy that generates a PTC in exon 8 of the 9 exon GABRA1 gene that is 74 bp upstream of intron 8. Using an intron 8-inclusion minigene that supports NMD, we demonstrated that mutant mRNA was substantially reduced, but not absent. Loss of mutant transcripts was blocked by ribosome inhibition or by silencing the NMD-essential gene hUPF-1. In both neurons and non-neuronal cells, the PTC caused substantial loss of mutant 1(S326fs328X) subunit mRNA through NMD with a minor portion of the mRNA escaping NMD and producing a mutant protein. The translated mutant protein had reduced stability due to endoplasmic reticulum associated degradation (ERAD) and had enhanced association with molecular chaperones. This study suggests that loss of mRNA due to activation of NMD and activation of ERAD by the mutant protein may contribute to epileptogenesis. The molecular mechanisms outlined here delineate a model for the pathogenesis of many PTC-generating mutations.

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Received Sept. 18, 2008; revised Dec. 3, 2008; accepted Dec. 31, 2008.

Correspondence should be addressed to Dr. Jing-Qiong Kang, Department of Neurology, 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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