Severe epilepsy resulting from genetic interaction between Scn2a and Kcnq2.
A mutation in the voltage-gated sodium-channel Scn2a results in moderate epilepsy in transgenic Scn2a(Q54) mice maintained on a C57BL/6J strain background. The onset of progressive epilepsy begins in adults with short-duration partial seizures that originate in the hippocampus. The underlying abnormality is an increase in persistent sodium current in hippocampal neurons. The voltage-gated potassium channel Kcnq2 is responsible for generating M current (I(KM)) that is thought to control excitability and limit repetitive firing of hippocampal neurons. To determine whether impaired M current would exacerbate the seizure phenotype of Scn2a(Q54) mice, we carried out genetic crosses with two mutant alleles of Kcnq2. Szt1 mice carry a spontaneous deletion that removes the C-terminal domain of Kcnq2. A novel Kcnq2 missense mutation V182M was identified by screening the offspring of ENU-treated males for reduced threshold to electrically evoked minimal clonic seizures. Double mutant mice carrying the Scn2a(Q54) transgene together with either of the Kcnq2 mutations exhibited severe epilepsy with early onset, generalized tonic-clonic seizures and juvenile lethality by 3 weeks of age. This dramatic exacerbation of the sodium-channel mutant phenotype indicates that M current plays a critical role in preventing seizure initiation and spreading in this animal model. The genetic interaction between Scn2a and Kcnq2 demonstrates that combinations of mild alleles of monogenic epilepsy genes can result in severe disease and provides a model for complex inheritance of human epilepsy. The data suggest that interaction between these genes might contribute to the variable expressivity observed in human families with sodium-channel mutations. In a screen of 23 SMEI patients with missense mutations of SCN1A, no second-site mutations in KCNQ2 were identified.
Kearney
Jennifer A
JA
Department of Human Genetics, 4909 Buhl Building 0618, 1241 E. Catherine Street, Ann Arbor, MI 48109-0618, USA. jkearney@umich.edu
Yang
Yan
Y
Beyer
Barbara
B
Bergren
Sarah K
SK
Claes
Lieve
L
Dejonghe
Peter
P
Frankel
Wayne N
WN
D000595:Amino Acid Sequence; D000818:Animals; D004827:Epilepsy / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D005038:Ethylnitrosourea / Q000633:toxicity; D005820:Genetic Testing; D006801:Humans; D051658:KCNQ2 Potassium Channel / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism*
D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; C114401:Kcnq2 protein, mouse; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; C568251:SCN2A protein, human; C568249:Scn1a protein, mouse; C000654500:Scn2a protein, mouse; D015222:Sodium Channels; D005038:Ethylnitrosourea