Masking epilepsy by combining two epilepsy genes

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.

Reduction of seizures by transplantation of cortical GABAergic interneuron precursors into Kv1.1 mutant mice

“…To monitor spontaneous tonic-clonic seizures, we performed prolonged video EEG starting around P32, or Ϸ30 DAT (see Materials and Methods for full description of electrographic phenotypes). As expected (14,16,17), the EEG of Kv1.1 Ϫ/Ϫ mice showed generalized electrographic seizures lasting between 10 and 340 seconds and occurring approximately once per hour (Fig. 6A).…”

Seizures and disturbed brain potassium dynamics in the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts

“…Long‐term recordings (48 hours) from mice in their home cage revealed that both MLC lines show a significantly higher occurrence of abnormal discharges than wild‐type mice (Fig 3B–E). These discharges bear resemblance to interictal spikes 32. They did not have a clear behavioral correlate, as assessed from simultaneous video recordings of mouse behavior.…”

Epistasis

“…Common episodic neurologic disorders such as migraine and epilepsy seem good candidates for disease-associated genemasking by epistatic loci. 10 Ion channel variation leading to greater than average inhibitory/excitatory influences may be masked by protective polymorphisms reducing clinical penetrance and expressivity.…”