Severe epilepsy resulting from genetic interaction between Scn2a and Kcnq2

Jennifer A. Kearney*, Yan Yang, Barbara Beyer, Sarah K. Bergren, Lieve Claes, Peter DeJonghe, Wayne N. Frankel

*Corresponding author for this work

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

A mutation in the voltage-gated sodium-channel Scn2aQ54 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 (IKM) 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 Scn2aQ54 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 Scn2aQ54 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 Kcnq2demonstrates 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.

Original languageEnglish (US)
Pages (from-to)1043-1048
Number of pages6
JournalHuman molecular genetics
Volume15
Issue number6
DOIs
StatePublished - Mar 1 2006

Fingerprint

Epilepsy
Seizures
Mutation
Sodium Channels
Missense Mutation
Alleles
Genetic Crosses
Voltage-Gated Sodium Channels
Phenotype
Voltage-Gated Potassium Channels
Neurons
Transgenes
Genes
Hippocampus
Animal Models
Sodium

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Kearney, J. A., Yang, Y., Beyer, B., Bergren, S. K., Claes, L., DeJonghe, P., & Frankel, W. N. (2006). Severe epilepsy resulting from genetic interaction between Scn2a and Kcnq2. Human molecular genetics, 15(6), 1043-1048. https://doi.org/10.1093/hmg/ddl019
Kearney, Jennifer A. ; Yang, Yan ; Beyer, Barbara ; Bergren, Sarah K. ; Claes, Lieve ; DeJonghe, Peter ; Frankel, Wayne N. / Severe epilepsy resulting from genetic interaction between Scn2a and Kcnq2. In: Human molecular genetics. 2006 ; Vol. 15, No. 6. pp. 1043-1048.
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Kearney, JA, Yang, Y, Beyer, B, Bergren, SK, Claes, L, DeJonghe, P & Frankel, WN 2006, 'Severe epilepsy resulting from genetic interaction between Scn2a and Kcnq2', Human molecular genetics, vol. 15, no. 6, pp. 1043-1048. https://doi.org/10.1093/hmg/ddl019

Severe epilepsy resulting from genetic interaction between Scn2a and Kcnq2. / Kearney, Jennifer A.; Yang, Yan; Beyer, Barbara; Bergren, Sarah K.; Claes, Lieve; DeJonghe, Peter; Frankel, Wayne N.

In: Human molecular genetics, Vol. 15, No. 6, 01.03.2006, p. 1043-1048.

Research output: Contribution to journalArticle

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AU - Kearney, Jennifer A.

AU - Yang, Yan

AU - Beyer, Barbara

AU - Bergren, Sarah K.

AU - Claes, Lieve

AU - DeJonghe, Peter

AU - Frankel, Wayne N.

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N2 - A mutation in the voltage-gated sodium-channel Scn2aQ54 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 (IKM) 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 Scn2aQ54 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 Scn2aQ54 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 Kcnq2demonstrates 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.

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