Identification of a monogenic locus (jams1) causing juvenile audiogenic seizures in mice

Abstract

Epilepsy is a debilitating disease with a strong genetic component. Positional cloning has identified a few genes for rare monogenic epilepsy syndromes; however, the genetics of common human epilepsies are too complex to be analyzed easily by current techniques. Mouse models of epilepsy can further this analysis by eliminating genetic background heterogeneity and enabling the production of sufficient numbers of offspring. Here, we report that Black Swiss mice have a heretofore unrecognized specific susceptibility to audiogenic seizures. These seizures are characterized by wild running, loss of righting reflex, and tonic flexion and extension, and are followed by a postictal period. The susceptibility to these seizures is developmentally regulated, peaking at 21 d of age and nearly disappearing by adulthood. Interestingly, both the susceptibility to seizures and their developmental regulation appear unrelated to hearing thresholds in the Black Swiss strain and backcrossed progeny. Genetic mapping and linkage analysis of hybrid mice localize the seizure gene, jams1 (juvenile audiogenic monogenic seizures), to a 1.6 +/- 0.5 centimorgan (cM) region on mouse chromosome 10, delimited by the gene basigin (Bsg) and marker D10Mit140. Interestingly, the majority of the critical region is syntenic to a region on human chromosome 19p13.3 implicated in a familial form of juvenile febrile convulsions. Cloning the gene for audiogenic seizures in these mice may provide important insight into the fundamental mechanisms for developmentally regulated human epilepsy syndromes.

Fig. 1.

Defining a 1.6 cM jams1 locus. The segregation pattern of the microsatellite markers most closely linked to audiogenic seizures is shown. Black squares indicate markers homozygous for BS alleles. White squaresindicate homozygous alleles from the seizure-resistant strain in the cross (CAST/Ei or 129) or for heterozygous alleles. For seizure frequency, the denominator is total mice with given genotype; the numerator is the number seized. A, jams1cosegregates with marker D10Mit228 in an intraspecific F₂ cross between Black Swiss and 129 (n= 114). B, In F₂ and N₂ crosses between Black Swiss and CAST/Ei, jams1 did not segregate from marker D10Mit22 (n = 794). *We have listed data for D10Mit139 in this figure; however, we have not observed recombination between this marker andD10Mit260 or D10Mit175 in these crosses (data not shown).

Fig. 2.

Black Swiss mice display an age-dependent susceptibility to seizures. Mice were exposed to an auditory stimulus (see Materials and Methods). The percentage of mice that seized and time to onset of seizure [30 sec (▪) or 90 sec ( )] are noted.

Fig. 3.

Seizure susceptibility of backcrossed Black Swiss mice is independent of hearing thresholds. A, Auditory brainstem response thresholds were measured from BALB/c, CAST/Ei, Black Swiss, and various BS × CAST/Ei progeny (F₂ and N₂). F₂ and N₂ mice were tested twice for seizure susceptibility, at 21 d and 4 months of age. Those that seized at both ages are designated Y/Y, and those that seized at 21 d but not at 4 months are designated Y/N. These results suggest that adult onset hearing loss does not correlate with loss of seizure susceptibility.

Fig. 4.

ABR tracings of Black Swiss, CAST/Ei, and N₂ progeny. Shown are representative tracings of auditory brainstem responses to clicks of different sound intensities for the parental strains and N₂ progeny. A, A 3-week-old Black Swiss mouse. B, An adult CAST/Ei mouse.C, An N₂ mouse that seized both as a 21-d-old juvenile and as a 150-d-old adult (Sz/Sz).D, An N₂ mouse that did not seize as an adult (Sz/ØSz).