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 Ca(2+) channelopathy due to a missense mutation in the Cacna1a gene. Conversely, decreasing network excitability by impairing Cacna1a Ca(2+)-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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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2-Amino-5-phosphonovalerate / pharmacology
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Age Factors
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Animals
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Calcium Channel Blockers / pharmacology
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Calcium Channels, N-Type
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Calcium Channels, P-Type / genetics*
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Calcium Channels, Q-Type / genetics*
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Disease Models, Animal
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Electric Stimulation
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Electroencephalography
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Epilepsy / genetics*
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Epilepsy / mortality
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Epilepsy / pathology
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Epilepsy / physiopathology*
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Excitatory Amino Acid Antagonists / pharmacology
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Hippocampus / drug effects
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Hippocampus / radiation effects
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In Vitro Techniques
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Kv1.1 Potassium Channel / deficiency*
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Membrane Potentials / drug effects
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Membrane Potentials / genetics
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Membrane Potentials / radiation effects
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Mutation / physiology
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Nerve Net / drug effects
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Nerve Net / physiology
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Nerve Net / radiation effects
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Potassium Chloride / pharmacology
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omega-Agatoxin IVA / pharmacology
Substances
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Calcium Channel Blockers
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Calcium Channels, N-Type
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Calcium Channels, P-Type
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Calcium Channels, Q-Type
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Excitatory Amino Acid Antagonists
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Kcna1 protein, mouse
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omega-Agatoxin IVA
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voltage-dependent calcium channel (P-Q type)
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Kv1.1 Potassium Channel
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Potassium Chloride
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2-Amino-5-phosphonovalerate