Mapping genetic modifiers of survival in a mouse model of Dravet syndrome

Abstract

Epilepsy is a common neurological disorder affecting approximately 1% of the population. Mutations in voltage-gated sodium channels are responsible for several monogenic epilepsy syndromes. More than 800 mutations in the voltage-gated sodium channel SCN1A have been reported in patients with generalized epilepsy with febrile seizures plus and Dravet syndrome. Heterozygous loss-of-function mutations in SCN1A result in Dravet syndrome, a severe infant-onset epileptic encephalopathy characterized by intractable seizures, developmental delays and increased mortality. A common feature of monogenic epilepsies is variable expressivity among individuals with the same mutation, suggesting that genetic modifiers may influence clinical severity. Mice with heterozygous deletion of Scn1a (Scn1a+/−) model a number of Dravet syndrome features, including spontaneous seizures and premature lethality. Phenotype severity in Scn1a+/− mice is strongly dependent on strain background. On the 129S6/SvEvTac strain Scn1a+/− mice exhibit no overt phenotype, while on the (C57BL/6J × 129S6/SvEvTac)F1 strain Scn1a+/− mice exhibit spontaneous seizures and early lethality. To systematically identify loci that influence premature lethality in Scn1a+/− mice, we performed genome scans on reciprocal backcrosses. QTL mapping revealed modifier loci on mouse chromosomes 5, 7, 8 and 11. RNA-seq analysis of strain-dependent gene expression, regulation and coding sequence variation provided a list of potential functional candidate genes at each locus. Identification of modifier genes that influence survival in Scn1a+/− mice will improve our understanding of the pathophysiology of Dravet syndrome and may suggest novel therapeutic strategies for improved treatment of human patients.

Genetic background modulates impaired excitability of inhibitory neurons in a mouse model of Dravet syndrome

“…Similarly DS/B6 mice develop normally until their fourth week of life, when they start to experience frequent spontaneous seizures, and often succumb to premature death (Kalume et al, 2013; Oakley et al, 2009; Yu et al, 2006). In contrast, DS/129 mice survive similarly to WT mice (Miller et al, 2013; Yu et al, 2006), and no signs of behavioral seizures were detected in video recordings from P21-P28.…”

“…While DS mice in 129/SvJ (129) genetic background (DS/129) survive nearly as well as wild-type (WT) animals, eighty percent of DS mice in C57BL/6 (B6) genetic background (DS/B6) die by 12 weeks of age (Yu et al, 2006). Moreover, spontaneous seizures are rare in DS/129, whereas they are frequent in DS/B6 (Miller et al, 2013; Yu et al, 2006). …”

EMX1 regulates NRP1-mediated wiring of the mouse anterior cingulate cortex

“…In humans, different callosal malformations have been observed in patients with similar genetic etiologies, suggesting that modifier genes are likely to influence the severity of this condition (Schaefer et al, 1997;Dastot-Le Moal et al, 2007;Edwards et al, 2014). The effects of genetic background have also been previously described for a number of other genes in the mouse central nervous system, including Scn1a (Miller et al, 2014) and Gnaz (van den Buuse et al, 2007). In these cases, quantitative trait locus mapping, coupled to gene expression and phenotypic analyses have identified the modifier loci and encompassing genes that might mediate these effects.…”

Mutations in GABRB3

“…Possible reasons include the overall genetic background, i.e., a complex combination of different genetic variations, or more specific genetic factors with larger detrimental or protective effects. Both phenomena have been described in mouse models, 22,23 but their role in human epilepsy is not understood.…”