Loss of Circadian Genes Results in Epilepsy

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A meticulous series of experiments - and the fortuitous use of a vacuum

cleaner - lead to breakthrough new insight on the genetic basis of epilepsy.

Circadian rhythms -- the normal ups and downs of body rhythms - help

organize physiological processes into a 24 hour cycle, affecting everything

from body temperature, hormone levels and heart rate, to pain thresholds.

Scientists have now discovered that the combined deletion of three circadian

genes, encoding the PAR bZip transcription factor protein family, results in

accelerated aging and severe epilepsy in mice. Owing to the roughly 95%

identity of PAR bZip proteins between mice and humans, it is anticipated

that PAR bZip mutations may also underlie some forms of human epilepsy.

A copy of this important new study is being released in advance of its June

15th publication date by the journal Genes & Development

(http://www.genesdev.org). ...

The potential role for Pdxk misregulation in human epilepsy is even more

intriguing, given the close proximity of Pdxk to the CSTB gene, which is

thought to be responsible for the hereditary form of human epilepsy known as

" Unverricht-Lundborg Disease. " ...

As Dr. Schibler explains, " It now becomes important to examine whether

promoter mutations in CSTB (expansion of a GC-rich dodecamer) can also

influence the expression of the gene next door, namely PDXK. Clearly, with

the limited resolution obtained in human haplotype mapping, it cannot be

excluded that underexpression of PDXK contributes to the Unverricht-Lundborg

disease. "

While the scientific community considers this novel role for PAR bZip

transcription factors and Pdxk in epilepsy, Dr. Schibler's group is already

at work on the premature aging phenotype displayed by the triple knockout

mice. " We already have some ideas on what these circadian transcription

factors do in the liver, and we also have some clues (speculations) on why

their elimination might provoke premature aging. But we would like to finish

our experiments before spilling the beans. "

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