Circadian rhythms are endogenous oscillationsof physiological and behavioral phenomenawith period length of _24 hr. A mutation in humanPeriod 2 (hPER2), a gene crucial for resettingthe central clock in response to light, isassociated with familial advanced sleep phasesyndrome (FASPS), an autosomal dominantcondition with early morning awakening andearly sleep times. The FASPS hPER2 S662Gmutation resulted in PER2 being hypophosphorylatedby casein kinase I (CKI) in vitro. Wegenerated transgenic mice carrying the FASPShPER2 S662G mutation and faithfully recapitulatethe human phenotype. We show that phosphorylationat S662 leads to increased PER2transcription and suggest that phosphorylationat another site leads to PER2 degradation.Altering CKId dosage modulates the S662 phenotypedemonstrating that CKId can regulateperiod through PER2 in vivo. Modeling a naturallyoccurring human variant in mice hasyielded novel insights into PER2 regulation.

Paroxysmal non-kinesigenic dyskinesia (PNKD) is characterized by spontaneous hyperkinetic attacks thatare precipitated by alcohol, coffee, stress and fatigue. We report mutations in the myofibrillogenesis regulator1 (MR-1) gene causing PNKD in 50 individuals from eight families. The mutations cause changes (Alato Val) in the N-terminal region of two MR-1 isoforms. The MR-1L isoform is specifically expressed in brainand is localized to the cell membrane while the MR-1S isoform is ubiquitously expressed and shows diffusecytoplasmic and nuclear localization. Bioinformatic analysis reveals that the MR-1 gene is homologous to thehydroxyacylglutathione hydrolase (HAGH) gene. HAGH functions in a pathway to detoxify methylglyoxal, acompound present in coffee and alcoholic beverages and produced as a by-product of oxidative stress.Our results suggest a mechanism whereby alcohol, coffee and stress may act as precipitants of attacks inPNKD. Stress response pathways will be important areas for elucidation of episodic disease geneticswhere stress is a common precipitant of many common disorders like epilepsy, migraine and cardiacarrhythmias.

KIFC3, a microtubule (MT) minus end–directed kinesin superfamily protein, is expressed abundantly and is associated with the Golgi apparatus in adrenocortical cells. We report here that disruption of the kifC3 gene induced fragmentation of the Golgi apparatus when cholesterol was depleted. Analysis of the reassembly process of the Golgi apparatus revealed bidirectional movement of the Golgi fragments in both wild-type and kifC3-/-cells. However, we observed a markedly reduced inwardly directed motility of the Golgi fragments in cholesterol-depleted kifC3-/-cells compared with either cholesterol-depleted wild-type cells or cholesterol-replenished kifC3-/-cells. These results suggest that (a) under the cholesterol-depleted condition, reduced inwardly directed motility of the Golgi apparatus results in the observed Golgi scattering phenotype in kifC3-/-cells, and (b) cholesterol is necessary for the Golgi fragments to attain sufficient inwardly directed motility by MT minus end–directed motors other than KIFC3, such as dynein, in kifC3-/-cells. Furthermore, we showed that Golgi scattering was much more drastic in kifC3-/-cells than in wild-type cells to the exogenous dynamitin expression even in the presence of cholesterol. These results collectively demonstrate that KIFC3 plays a complementary role in Golgi positioning and integration with cytoplasmic dynein.

Paroxysmal