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Volume 17, Number 12, Issue of June 15, 1997 pp. 4562-4569
Copyright ©1997 Society for Neuroscience

Sensitivity to Jerky Gene Dosage Underlies Epileptic Seizures in Mice

Received Oct. 4, 1996; revised March 17, 1997; accepted March 31, 1997.

Gerald P. Donovan¹, Cynthia Harden³, Judit Gal¹, Lap Ho¹, Etienne Sibille¹, Rosario Trifiletti², Lorraine J. Gudas¹, and Miklos Toth¹

Departments of ¹ Pharmacology and ² Neurology and Neuroscience, and ³ Comprehensive Epilepsy Center, New York Hospital, Cornell University Medical Center, New York, New York 10021

Animals with one deleted jerky allele are more susceptible to chemically induced seizures than wild-type mice and display recurrent behavioral seizures. The phenotype of these hemizygotes is characterized by no apparent neurological symptoms other than recurrent seizures reminiscent of human idiopathic epilepsy. The jerky gene encodes a 60 kDa protein resembling a number of DNA-binding proteins. Here, we show that the jerky gene is expressed in all tissues examined, including brain, liver, 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 demonstrate that jerky has a dosage-sensitive function (haploinsufficiency) 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 jerky in homozygotes results in abnormalities of somatic and sexual development. A number of idiopathic epilepsies are dominantly inherited, such as benign familial neonatal convulsions, juvenile myoclonic epilepsy, as well as benign epilepsy with centrotemporal spikes, and the pathomechanism of these epilepsies may be based on haploinsufficiency in the brain.

Key words: epilepsy; seizure; haploinsufficiency; gene dosage; jerky gene; c-Fos; in situ hybridization; PTZ

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