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 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.

[1]  Hao Wang,et al.  Deletion of the KV1.1 Potassium Channel Causes Epilepsy in Mice , 1998, Neuron.

[2]  H. Brew,et al.  Hyperexcitability and reduced low threshold potassium currents in auditory neurons of mice lacking the channel subunit Kv1.1 , 2003, The Journal of physiology.

[3]  Kazuto Yamazaki,et al.  Single Tottering Mutations Responsible for the Neuropathic Phenotype of the P-type Calcium Channel* , 1998, The Journal of Biological Chemistry.

[4]  O. Jones.  Ca2+ channels and epilepsy. , 2002, European journal of pharmacology.

[5]  N. Katsanis,et al.  Human genetics and disease: Beyond Mendel: an evolving view of human genetic disease transmission , 2002, Nature Reviews Genetics.

[6]  R. Tsien,et al.  Ablation of P/Q-type Ca(2+) channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the alpha(1A)-subunit. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[7]  S Glasauer,et al.  Treatment of episodic ataxia type 2 with the potassium channel blocker 4-aminopyridine , 2004, Neurology.

[8]  P. Rutecki,et al.  Altered hippocampal network excitability in the hypernoradrenergic mutant mousetottering , 1990, Brain Research.

[9]  K. Matsushita.  Reduced voltage sensitivity of activation of P/Q-type Ca2+ channels is associated with the ataxic mouse mutation rolling Nagoya (tg(rol)) , 2000 .

[10]  C. Weisz,et al.  Potassium Channel Blockers Inhibit the Triggers of Attacks in the Calcium Channel Mouse Mutant tottering , 2005, The Journal of Neuroscience.

[11]  J. Noebels,et al.  Presynaptic Ca2+ Influx at a Mouse Central Synapse with Ca2+ Channel Subunit Mutations , 2000, The Journal of Neuroscience.

[12]  R L Sidman,et al.  Inherited epilepsy: spike-wave and focal motor seizures in the mutant mouse tottering. , 1979, Science.

[13]  M. Tanouye,et al.  Abnormal action potentials associated with the Shaker complex locus of Drosophila. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[14]  E. McCabe,et al.  Modifier genes convert "simple" Mendelian disorders to complex traits. , 2000, Molecular genetics and metabolism.

[15]  A. Spauschus,et al.  A novel mutation in the human voltage-gated potassium channel gene (Kv1.1) associates with episodic ataxia type 1 and sometimes with partial epilepsy. , 1999, Brain : a journal of neurology.

[16]  W. Frankel,et al.  Severe epilepsy resulting from genetic interaction between Scn2a and Kcnq2. , 2006, Human molecular genetics.

[17]  A. Bird,et al.  A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome , 2001, Nature Genetics.

[18]  D. Kullmann,et al.  Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia , 2004 .

[19]  F. A. Davis,et al.  Orally administered 4‐aminopyridine improves clinical signs in multiple sclerosis , 1990, Annals of neurology.

[20]  Eric J Topol,et al.  The genetics of health , 2006, Nature Genetics.

[21]  P. Schwartzkroin,et al.  Hyperexcitability of CA3 Pyramidal Cells in Mice Lacking the Potassium Channel Subunit Kv1.1 , 2003, Epilepsia.

[22]  E R McCabe,et al.  Phenotypes of patients with "simple" Mendelian disorders are complex traits: thresholds, modifiers, and systems dynamics. , 2000, American journal of human genetics.

[23]  P. Schwartzkroin,et al.  Localization of Kv1.1 and Kv1.2, two K channel proteins, to synaptic terminals, somata, and dendrites in the mouse brain , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[24]  Richard Hawkes,et al.  Absence Epilepsy in Tottering Mutant Mice Is Associated with Calcium Channel Defects , 1996, Cell.

[25]  S. Chiu,et al.  Specific Alteration of Spontaneous GABAergic Inhibition in Cerebellar Purkinje Cells in Mice Lacking the Potassium Channel Kv1.1 , 1999, The Journal of Neuroscience.

[26]  E. Lander,et al.  Genetic dissection of complex traits science , 1994 .

[27]  M. Baulac,et al.  Monogenic idiopathic epilepsies , 2004, The Lancet Neurology.

[28]  T. Turner,et al.  Enhanced G protein‐dependent modulation of excitatory synaptic transmission in the cerebellum of the Ca2+ channel‐mutant mouse, tottering , 2003, The Journal of physiology.

[29]  P. Genton,et al.  Severe epilepsy, retardation, and dysmorphic features with a 2q deletion including SCN1A and SCN2A , 2004, Neurology.

[30]  P. Saggau,et al.  Activity‐dependent modulation of K+ currents at presynaptic terminals of mammalian central synapses , 1999, The Journal of physiology.

[31]  A. Baruzzi,et al.  Familial continuous motor unit activity and epilepsy , 2001, Muscle & nerve.

[32]  D. Kullmann,et al.  Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia. , 2005, Brain : a journal of neurology.

[33]  Samuel F. Berkovic,et al.  Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel ß1 subunit gene SCN1B , 1998, Nature Genetics.

[34]  I. Forsythe,et al.  Presynaptic K+ channels: electrifying regulators of synaptic terminal excitability , 2004, Trends in Neurosciences.