Masking epilepsy by combining two epilepsy genes.
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.
Glasscock
Edward
E
Department of Neurology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
Qian
Jing
J
Yoo
Jong W
JW
Noebels
Jeffrey L
JL
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000367:Age Factors; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type / Q000235:genetics*; D020907:Calcium Channels, Q-Type / Q000235:genetics*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004569:Electroencephalography; D004827:Epilepsy / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000528:radiation effects; D066298:In Vitro Techniques; D051662:Kv1.1 Potassium Channel / Q000172:deficiency*; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D011189:Potassium Chloride / Q000494:pharmacology; D020867:omega-Agatoxin IVA / Q000494:pharmacology
D015763:2-Amino-5-phosphonovalerate; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D018691:Excitatory Amino Acid Antagonists; D051662:Kv1.1 Potassium Channel; D011189:Potassium Chloride; D020867:omega-Agatoxin IVA; C496947:Kcna1 protein, mouse