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

Abstract

Summary 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 due to 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.

Potentiating α2 subunit containing perisomatic GABAA receptors protects against seizures in a mouse model of Dravet syndrome

“…These strain-dependent phenotypes have led to the suggestion that modifier genes strongly contribute to the phenotype severity (Mullen & Scheffer, 2009;Miller et al 2014;Mistry et al 2014;Rubinstein et al 2015). Genetic mapping studies have discovered several candidate genes contributing to the strain-dependent phenotype in mice Calhoun et al 2017).…”

Potentiating α2 subunit containing perisomatic GABAA receptors protects against seizures in a mouse model of Dravet Syndrome

“…These strain-dependent phenotypes have led to the suggestion that modifier genes strongly contribute to the phenotype severity (Mullen and Scheffer, 2009;Miller et al, 2014;Mistry et al, 2014;Rubinstein et al, 2015). Genetic mapping studies have discovered several candidate genes contributing to the strain-dependent phenotype in mice Calhoun et al, 2017).…”

Modifier genes in SCN1A‐related epilepsy syndromes

“…SCN8A has previously been implicated to ameliorate SCN1A phenotypes by restoring normal seizure thresholds (Hawkins et al, ; Martin et al, ). Furthermore, several severe patients carried variants in genes that were previously described to worsen phenotypes (POLG , SCN2A , CACNA1A , and CACNA1G), strengthening those associations (Calhoun et al, ; Gaily et al, ; Hawkins et al, ; Ohmori et al, ). GPR98 , a gene implicated in myoclonic epilepsy (Myers et al, ), showed the highest overrepresentation of variants in severe patients in three categories of variants, and SCN10A , another sodium channel alpha‐subunit gene, was most often implicated in mild patients.…”