A genetic study of a family of transcription factors has thrown up a surprising link between circadian genes and epilepsy, thanks to some knockout transgenic mice and the fortuitous involvement of a vacuum cleaner.

The PAR bZip protein family consists of three transcription factors — DBP, HLF and TEF — that fluctuate in expression according to a daily rhythm. To assign a physiological role to this small protein family in mice, Ueli Schibler and colleagues knocked out the three corresponding genes one at a time and in combination. Single, double and triple knockout animals were normal and fertile, although the triple knockout animals died prematurely. The reasons for the low survival rates were unclear until the researchers noticed that more animals died on Mondays and Thursdays — the two days on which the animal facility was routinely cleaned out. The vacuum cleaners used in this process provoked strong and often lethal epileptic seizures specifically in the triple knockout animals. Continuous electroencephalography (EEG) recordings confirmed what was seen when the noisy cleaner was switched on — that triple knockouts had abnormal EEG activity that developed into epileptic seizures.

The causal link between the PAR bZIP family and epilepsy might be explained by the involvement of pyridoxal kinase ( Pdxk ), which is normally regulated by the PAR bZIP proteins and, the authors found, is expressed at very low levels in the brains of the triple knockout animals. The PDXK enzyme is involved in converting vitamin B6 into a form that is required as a cofactor in the metabolism of several neurotransmitters. The connection between Pdxk misregulation and epilepsy is interesting for two reasons. First, vitamin B6 deficiency can cause epilepsy in humans and laboratory rodents. Second, the human PDXK gene lies close to cystatin B ( CSTB ), a gene that is involved in Myoclonic epilepsy of Unverricht and Lundborg, a hereditary form of epilepsy.

The PAR bZIP family has come along way since Schibler's group first discovered it 15 years ago. The remarkable sequence conservation of these proteins between mice and humans (92–98%) makes them appealing targets for understanding their common physiological functions. The authors suspect that the triple knockout mice have a low survival rate for reasons that are unrelated to epilepsy but, for the moment, this story is being kept tightly under wraps.