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Masking epilepsy by combining two epilepsy genes

Nature Neuroscience volume 10, pages 1554–1558 (2007)Cite this article

Abstract

Inherited errors in ion channel genes comprise the largest subset of monogenic causes of idiopathic epilepsy, and pathogenic variants contribute to genetic risk in the complex inheritance of this common disorder. We generated a digenic mouse model of human idiopathic epilepsy by combining two epilepsy-associated ion channel mutations with mutually opposing excitability defects and overlapping subcellular localization. We found that increasing membrane excitability by removing Shaker-like K+ channels, which are encoded by the Kcna1 gene, masked the absence epilepsy caused by a P/Q-type Ca2+ channelopathy due to a missense mutation in the Cacna1a gene. Conversely, decreasing network excitability by impairing Cacna1a Ca2+-channel function attenuated limbic seizures and sudden death in Kcna1-null mice. We also identified intermediate excitability phenotypes at the network and axonal levels. Protective interactions between pathogenic ion channel variants may markedly alter the clinical expression of epilepsy, highlighting the need for comprehensive profiling of this candidate gene set to improve the accuracy of genetic risk assessment of this complex disease.

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Figure 1: Survival curve for Kcna1−/− mice with different doses of Cacna1atg alleles.
Figure 2: EEG recordings of spontaneous absence (Cacna1atg/tg) and convulsive (Kcna1−/−) seizures in single and double mutant mice.
Figure 3: Quantitative analysis of spike-wave seizures per hour and tonic-clonic seizures per day.
Figure 4: Analysis of network excitability in hippocampal slices exposed to high [K+]o.
Figure 5: Analysis of hippocampal presynaptic fiber volley (FV) facilitation.

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Acknowledgements

We thank I. Cohen for assistance with hippocampal experiments and data analysis, and D. Burgess, C. Davis, F. Deng, S. Ernst, W. Ernst, A. Goldman, M. Price and Y. Zhang for their critical input and guidance. This work was supported by US National Institute of Neurological Disorders and Stroke grants NS43124 (E.G.) and NS29709 (J.L.N.).

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Authors and Affiliations

  1. Departments of Neurology, Baylor College of Medicine, One Baylor Plaza, Houston, 77030, Texas, USA

    Edward Glasscock, Jing Qian, Jong W Yoo & Jeffrey L Noebels

  2. Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, 77030, Texas, USA

    Jeffrey L Noebels

  3. Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, 77030, Texas, USA

    Jeffrey L Noebels

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  1. Edward Glasscock
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  2. Jing Qian
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Contributions

E.G. carried out genetic crosses, genotyping, survival and behavioral analysis and recordings of evoked burst discharges. J.Q. performed the recordings of presynaptic fiber volley facilitation. J.W.Y. performed surgeries and recordings for electroencephalography, as well as drug injections. E.G. wrote the manuscript with assistance from J.L.N.

Corresponding author

Correspondence to Jeffrey L Noebels.

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Supplementary Figures 1–3, Tables 1–3, Discussion and Note (PDF 1522 kb)

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Glasscock, E., Qian, J., Yoo, J. et al. Masking epilepsy by combining two epilepsy genes. Nat Neurosci 10, 1554–1558 (2007). https://doi.org/10.1038/nn1999

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