Cacna1g is a genetic modifier of epilepsy in a mouse model of Dravet syndrome

Jeffrey D. Calhoun, Nicole Alise Hawkins, Nicole J. Zachwieja, Jennifer A Kearney*

*Corresponding author for this work

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Dravet syndrome, an early onset epileptic encephalopathy, is most often caused by de novo mutation of the neuronal voltage-gated sodium channel gene SCN1A. Mouse models with deletion of Scn1a recapitulate Dravet syndrome phenotypes, including spontaneous generalized tonic–clonic seizures, susceptibility to seizures induced by elevated body temperature, and elevated risk of sudden unexpected death in epilepsy. Importantly, the epilepsy phenotype of Dravet mouse models is highly strain-dependent, suggesting a strong influence of genetic modifiers. We previously identified Cacna1g, encoding the Cav3.1 subunit of the T-type calcium channel family, as an epilepsy modifier in the Scn2aQ54 transgenic epilepsy mouse model. In this study, we asked whether transgenic alteration of Cacna1g expression modifies severity of the Scn1a+/− Dravet phenotype. Scn1a+/− mice with decreased Cacna1g expression showed partial amelioration of disease phenotypes with improved survival and reduced spontaneous seizure frequency. However, reduced Cacna1g expression did not alter susceptibility to hyperthermia-induced seizures. Transgenic elevation of Cacna1g expression had no effect on the Scn1a+/− epilepsy phenotype. These results provide support for Cacna1g as a genetic modifier in a mouse model of Dravet syndrome and suggest that Cav3.1 may be a potential molecular target for therapeutic intervention in patients.

Original languageEnglish (US)
Pages (from-to)e111-e115
JournalEpilepsia
Volume58
Issue number8
DOIs
StatePublished - Aug 1 2017

Fingerprint

Myoclonic Epilepsy
Epilepsy
Phenotype
Seizures
T-Type Calcium Channels
Voltage-Gated Sodium Channels
Induced Hyperthermia
Brain Diseases
Sudden Death
Body Temperature
Transgenic Mice
Mutation
Survival
Genes

Keywords

  • Epilepsy
  • Genetics
  • Mouse model
  • Seizures
  • Voltage-gated calcium channels
  • Voltage-gated ion channels

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Calhoun, Jeffrey D. ; Hawkins, Nicole Alise ; Zachwieja, Nicole J. ; Kearney, Jennifer A. / Cacna1g is a genetic modifier of epilepsy in a mouse model of Dravet syndrome. In: Epilepsia. 2017 ; Vol. 58, No. 8. pp. e111-e115.
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Cacna1g is a genetic modifier of epilepsy in a mouse model of Dravet syndrome. / Calhoun, Jeffrey D.; Hawkins, Nicole Alise; Zachwieja, Nicole J.; Kearney, Jennifer A.

In: Epilepsia, Vol. 58, No. 8, 01.08.2017, p. e111-e115.

Research output: Contribution to journalArticle

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T1 - Cacna1g is a genetic modifier of epilepsy in a mouse model of Dravet syndrome

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AU - Hawkins, Nicole Alise

AU - Zachwieja, Nicole J.

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N2 - Dravet syndrome, an early onset epileptic encephalopathy, is most often caused by de novo mutation of the neuronal voltage-gated sodium channel gene SCN1A. Mouse models with deletion of Scn1a recapitulate Dravet syndrome phenotypes, including spontaneous generalized tonic–clonic seizures, susceptibility to seizures induced by elevated body temperature, and elevated risk of sudden unexpected death in epilepsy. Importantly, the epilepsy phenotype of Dravet mouse models is highly strain-dependent, suggesting a strong influence of genetic modifiers. We previously identified Cacna1g, encoding the Cav3.1 subunit of the T-type calcium channel family, as an epilepsy modifier in the Scn2aQ54 transgenic epilepsy mouse model. In this study, we asked whether transgenic alteration of Cacna1g expression modifies severity of the Scn1a+/− Dravet phenotype. Scn1a+/− mice with decreased Cacna1g expression showed partial amelioration of disease phenotypes with improved survival and reduced spontaneous seizure frequency. However, reduced Cacna1g expression did not alter susceptibility to hyperthermia-induced seizures. Transgenic elevation of Cacna1g expression had no effect on the Scn1a+/− epilepsy phenotype. These results provide support for Cacna1g as a genetic modifier in a mouse model of Dravet syndrome and suggest that Cav3.1 may be a potential molecular target for therapeutic intervention in patients.

AB - Dravet syndrome, an early onset epileptic encephalopathy, is most often caused by de novo mutation of the neuronal voltage-gated sodium channel gene SCN1A. Mouse models with deletion of Scn1a recapitulate Dravet syndrome phenotypes, including spontaneous generalized tonic–clonic seizures, susceptibility to seizures induced by elevated body temperature, and elevated risk of sudden unexpected death in epilepsy. Importantly, the epilepsy phenotype of Dravet mouse models is highly strain-dependent, suggesting a strong influence of genetic modifiers. We previously identified Cacna1g, encoding the Cav3.1 subunit of the T-type calcium channel family, as an epilepsy modifier in the Scn2aQ54 transgenic epilepsy mouse model. In this study, we asked whether transgenic alteration of Cacna1g expression modifies severity of the Scn1a+/− Dravet phenotype. Scn1a+/− mice with decreased Cacna1g expression showed partial amelioration of disease phenotypes with improved survival and reduced spontaneous seizure frequency. However, reduced Cacna1g expression did not alter susceptibility to hyperthermia-induced seizures. Transgenic elevation of Cacna1g expression had no effect on the Scn1a+/− epilepsy phenotype. These results provide support for Cacna1g as a genetic modifier in a mouse model of Dravet syndrome and suggest that Cav3.1 may be a potential molecular target for therapeutic intervention in patients.

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