SENSITIVITY TO JERKY GENE DOSAGE UNDERLIES EPILEPTIC SEIZURES IN MICE

Animals with one deleted jerky allele are more susceptible to chemical ly induced seizures than wild-type mice and display recurrent behavior al seizures. The phenotype of these hemizygotes is characterized by no apparent neurological symptoms other than recurrent seizures reminisc ent of human idiopathic epilepsy. The jerky gene encodes a 60 kDa prot ein resembling a number of DNA-binding proteins. Here, we show that th e jerky gene is expressed in all tissues examined, including brain, li ver, lung, spleen, testis, and ovary, and study an apparent paradox of how an allelic deletion of the ubiquitously expressed jerky gene can lead to hyperexcitability and seizures but not to other symptoms. We d emonstrate that jerky has a dosage-sensitive function (haploinsufficie ncy) in brain and that this sensitivity to reduced jerky dosage could explain the occurrence of seizures in hemizygotes. However, jerky has a nondosage-sensitive function as well, because the total absence of j erky in homozygotes results in abnormalities of somatic and sexual dev elopment. A number of idiopathic epilepsies are dominantly inherited, such as benign familial neonatal convulsions, juvenile myoclonic epile psy, as well as benign epilepsy with centrotemporal spikes, and the pa thomechanism of these epilepsies may be based on haploinsufficiency in the brain.