Sensitivity to jerky gene dosage underlies epileptic seizures in mice.
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.
Donovan
G P
GP
Department of Pharmacology, New York Hospital, Cornell University Medical Center, New York, New York 10021, USA.
Harden
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C
Gal
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J
Ho
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L
Sibille
E
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Trifiletti
R
R
Gudas
L J
LJ
Toth
M
M
D000375:Aging / Q000502:physiology; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D004198:Disease Susceptibility; D004827:Epilepsy / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D017353:Gene Deletion; D018628:Gene Dosage; D006624:Hippocampus / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D016900:Neurofilament Proteins / Q000096:biosynthesis; D010433:Pentylenetetrazole; D016133:Polymerase Chain Reaction; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D016601:RNA-Binding Proteins; D012640:Seizures / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012741:Sexual Maturation; D014158:Transcription, Genetic
D017931:DNA Primers; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C095835:jrk protein, mouse; C044882:neurofilament protein L; D010433:Pentylenetetrazole