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Heterozygous mutations of the voltage-gated sodium channel SCN8A are associated with spike-wave discharges and absence epilepsy in mice.

Papale LA, Beyer B, Jones JM, Sharkey LM, Tufik S, Epstein M, Letts VA, Meisler MH, Frankel WN, Escayg A - Hum. Mol. Genet. (2009)

Bottom Line: The missense mutation V929F in this allele alters an evolutionarily conserved residue in the pore loop of domain 2 of Na(v)1.6.Electroencephalography (EEG) revealed well-defined spike-wave discharges (SWD), the hallmark of absence epilepsy, in Scn8a(8J) heterozygotes and in heterozygotes for two classical Scn8a alleles, Scn8a(med) () and Scn8a(med-jo) (missense).The abnormal EEG patterns in heterozygous mutant mice and the influence of genetic background on SWD make SCN8A an attractive candidate gene for common human absence epilepsy, a genetically complex disorder.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.

ABSTRACT
In a chemical mutagenesis screen, we identified the novel Scn8a(8J) allele of the gene encoding the neuronal voltage-gated sodium channel Na(v)1.6. The missense mutation V929F in this allele alters an evolutionarily conserved residue in the pore loop of domain 2 of Na(v)1.6. Electroencephalography (EEG) revealed well-defined spike-wave discharges (SWD), the hallmark of absence epilepsy, in Scn8a(8J) heterozygotes and in heterozygotes for two classical Scn8a alleles, Scn8a(med) () and Scn8a(med-jo) (missense). Mouse strain background had a significant effect on SWD, with mutants on the C3HeB/FeJ strain showing a higher incidence than on C57BL/6J. The abnormal EEG patterns in heterozygous mutant mice and the influence of genetic background on SWD make SCN8A an attractive candidate gene for common human absence epilepsy, a genetically complex disorder.

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Effect of genetic background on incidence of SWD in heterozygous Scn8a8Jmice. Each point shows the number of SWD per hour for an individual mouse, in different genetic backgrounds. Heterozygous (het) genotypes are shown in filled symbols, wild-type (wt) in open symbols. The inset shows a plot of the average seizure frequency (±SE) in the four Scn8a8J genotypes. The average seizure frequency per hour (±SE) are: G3× C3HeB/FeJ: 132.1 ± 15.4 (het), 22.3 ± 4.3 (wt); G3N2 and G3N3: 104.6 ± 14.3 (het); (G3N3 X C57BL/6J)F1: 80.2 ± 12 (het), 0.8 ± .5 (wt); F1 X C57BL/6J: 60.6 ± 7.8 (het); C3HeB/FeJ–Scn8amed/+ 67.9 ± 2.5.
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DDP081F3: Effect of genetic background on incidence of SWD in heterozygous Scn8a8Jmice. Each point shows the number of SWD per hour for an individual mouse, in different genetic backgrounds. Heterozygous (het) genotypes are shown in filled symbols, wild-type (wt) in open symbols. The inset shows a plot of the average seizure frequency (±SE) in the four Scn8a8J genotypes. The average seizure frequency per hour (±SE) are: G3× C3HeB/FeJ: 132.1 ± 15.4 (het), 22.3 ± 4.3 (wt); G3N2 and G3N3: 104.6 ± 14.3 (het); (G3N3 X C57BL/6J)F1: 80.2 ± 12 (het), 0.8 ± .5 (wt); F1 X C57BL/6J: 60.6 ± 7.8 (het); C3HeB/FeJ–Scn8amed/+ 67.9 ± 2.5.

Mentions: SWD were initially observed in two affected homozygous Scn8a8J mice from the G3 generation. Each had a very high incidence of SWD, with a burst frequency of 4–5 Hz (Supplementary Material, Fig. S1). Scn8a8J heterozygotes also exhibited prevalent SWD, with a burst frequency of 7–9 Hz, which is more typical of rodent models of absence epilepsy. The SWD were robust, with high amplitude, significant duration and high frequency, and were observed in most or all recording channels (Fig. 2A). SWD usually occurred between periods of locomotor activity. During episodes of SWD mice were immobile except for occasional whisker twitching, as ascertained in real-time and by video-EEG. Although the C3HeB/FeJ strain has a low incidence of SWD (18,31), in the present crosses there was a highly significant difference in the incidence of SWD between Scn8a8J heterozygotes and their wild-type littermates, indicating a major gene effect of Scn8a8J (Fig. 3, G3× C3HeB/FeJ; P = 7.0 × 10−5). The high incidence of SWD was retained after heterozygotes were backcrossed to strain C3HeB/FeJ for two more generations (Fig. 3, G3N2 and G3N3).


Heterozygous mutations of the voltage-gated sodium channel SCN8A are associated with spike-wave discharges and absence epilepsy in mice.

Papale LA, Beyer B, Jones JM, Sharkey LM, Tufik S, Epstein M, Letts VA, Meisler MH, Frankel WN, Escayg A - Hum. Mol. Genet. (2009)

Effect of genetic background on incidence of SWD in heterozygous Scn8a8Jmice. Each point shows the number of SWD per hour for an individual mouse, in different genetic backgrounds. Heterozygous (het) genotypes are shown in filled symbols, wild-type (wt) in open symbols. The inset shows a plot of the average seizure frequency (±SE) in the four Scn8a8J genotypes. The average seizure frequency per hour (±SE) are: G3× C3HeB/FeJ: 132.1 ± 15.4 (het), 22.3 ± 4.3 (wt); G3N2 and G3N3: 104.6 ± 14.3 (het); (G3N3 X C57BL/6J)F1: 80.2 ± 12 (het), 0.8 ± .5 (wt); F1 X C57BL/6J: 60.6 ± 7.8 (het); C3HeB/FeJ–Scn8amed/+ 67.9 ± 2.5.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2667290&req=5

DDP081F3: Effect of genetic background on incidence of SWD in heterozygous Scn8a8Jmice. Each point shows the number of SWD per hour for an individual mouse, in different genetic backgrounds. Heterozygous (het) genotypes are shown in filled symbols, wild-type (wt) in open symbols. The inset shows a plot of the average seizure frequency (±SE) in the four Scn8a8J genotypes. The average seizure frequency per hour (±SE) are: G3× C3HeB/FeJ: 132.1 ± 15.4 (het), 22.3 ± 4.3 (wt); G3N2 and G3N3: 104.6 ± 14.3 (het); (G3N3 X C57BL/6J)F1: 80.2 ± 12 (het), 0.8 ± .5 (wt); F1 X C57BL/6J: 60.6 ± 7.8 (het); C3HeB/FeJ–Scn8amed/+ 67.9 ± 2.5.
Mentions: SWD were initially observed in two affected homozygous Scn8a8J mice from the G3 generation. Each had a very high incidence of SWD, with a burst frequency of 4–5 Hz (Supplementary Material, Fig. S1). Scn8a8J heterozygotes also exhibited prevalent SWD, with a burst frequency of 7–9 Hz, which is more typical of rodent models of absence epilepsy. The SWD were robust, with high amplitude, significant duration and high frequency, and were observed in most or all recording channels (Fig. 2A). SWD usually occurred between periods of locomotor activity. During episodes of SWD mice were immobile except for occasional whisker twitching, as ascertained in real-time and by video-EEG. Although the C3HeB/FeJ strain has a low incidence of SWD (18,31), in the present crosses there was a highly significant difference in the incidence of SWD between Scn8a8J heterozygotes and their wild-type littermates, indicating a major gene effect of Scn8a8J (Fig. 3, G3× C3HeB/FeJ; P = 7.0 × 10−5). The high incidence of SWD was retained after heterozygotes were backcrossed to strain C3HeB/FeJ for two more generations (Fig. 3, G3N2 and G3N3).

Bottom Line: The missense mutation V929F in this allele alters an evolutionarily conserved residue in the pore loop of domain 2 of Na(v)1.6.Electroencephalography (EEG) revealed well-defined spike-wave discharges (SWD), the hallmark of absence epilepsy, in Scn8a(8J) heterozygotes and in heterozygotes for two classical Scn8a alleles, Scn8a(med) () and Scn8a(med-jo) (missense).The abnormal EEG patterns in heterozygous mutant mice and the influence of genetic background on SWD make SCN8A an attractive candidate gene for common human absence epilepsy, a genetically complex disorder.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.

ABSTRACT
In a chemical mutagenesis screen, we identified the novel Scn8a(8J) allele of the gene encoding the neuronal voltage-gated sodium channel Na(v)1.6. The missense mutation V929F in this allele alters an evolutionarily conserved residue in the pore loop of domain 2 of Na(v)1.6. Electroencephalography (EEG) revealed well-defined spike-wave discharges (SWD), the hallmark of absence epilepsy, in Scn8a(8J) heterozygotes and in heterozygotes for two classical Scn8a alleles, Scn8a(med) () and Scn8a(med-jo) (missense). Mouse strain background had a significant effect on SWD, with mutants on the C3HeB/FeJ strain showing a higher incidence than on C57BL/6J. The abnormal EEG patterns in heterozygous mutant mice and the influence of genetic background on SWD make SCN8A an attractive candidate gene for common human absence epilepsy, a genetically complex disorder.

Show MeSH
Related in: MedlinePlus