Summary Paroxysmal Kinesigenic Dyskinesia with Infantile Convulsions (PKD/IC) is an episodic movement disorder with autosomal dominant inheritance and high penetrance, but the causative gene is unknown. We have now identified four truncating mutations involving the PRRT2 gene in the vast majority (24/25) of well characterized families with PKD/IC. PRRT2 truncating mutations were also detected in 28 of 78 additional families. The PRRT2 gene encodes a proline-rich transmembrane protein of unknown function that has been reported to interact with the t-SNARE, SNAP25. PRRT2 localizes to axons but not to dendritic processes in primary neuronal culture and mutants associated with PKD/IC lead to dramatically reduced PRRT2 protein levels leading ultimately to neuronal hyperexcitability that manifests in vivo as PKD/IC.

Migraine is a common disabling disorder with a significant genetic component, characterized by severe headache and often accompanied by nausea, vomiting, and light sensitivity. We identified two families, each with a distinct missense mutation in the gene encoding casein kinase Iδ (CKIδ), in which the mutation cosegregated with both the presence of migraine and advanced sleep phase. The resulting alterations (T44A and H46R) occurred in the conserved catalytic domain of CKIδ, where they caused reduced enzyme activity. Mice engineered to carry the CKIδ-T44A allele were more sensitive to pain after treatment with the migraine trigger nitroglycerin. CKIδ-T44A mice also exhibited a reduced threshold for cortical spreading depression (believed to be the physiological analog of migraine aura) and greater arterial dilation during cortical spreading depression. Astrocytes from CKIδ-T44A mice showed increased spontaneous and evoked calcium signaling. These genetic, cellular, physiological, and behavioral analyses suggest that decreases in CKIδ activity can contribute to the pathogenesis of migraine.

Paroxysmal nonkinesigenic dyskinesia (PNKD) is an autosomal dominant episodic movement disorder precipitated by coffee, alcohol, and stress. We previously identified the causative gene but the function of the encoded protein remains unknown. We also generated a PNKD mouse model that revealed dysregulated dopamine signaling in vivo. Here, we show that PNKD interacts with synaptic active zone proteins Rab3-interacting molecule (RIM)1 and RIM2, localizes to synapses, and modulates neurotransmitter release. Overexpressed PNKD protein suppresses release, and mutant PNKD protein is less effective than wild-type at inhibiting exocytosis. In PNKD KO mice, RIM1/2 protein levels are reduced and synaptic strength is impaired. Thus, PNKD is a novel synaptic protein with a regulatory role in neurotransmitter release.paroxysmal dyskinesia | exocytosis | neurological disease P aroxysmal nonkinesigenic dyskinesia (PNKD)* is a rare dominantly inherited episodic movement disorder. First reported in 1940 (1), PNKD is characterized by childhood onset with involuntary movements in the limbs, trunk, and face manifesting as dystonia, chorea, and athetosis (2). PNKD shows nearly complete penetrance and attacks are precipitated by fatigue, stress, hunger, and consumption of coffee or alcohol. Patients are completely normal between attacks.Hereditary forms of many episodic disorders are recognized and include movement disorders, muscle diseases, cardiac arrhythmias, epilepsy, and headache. A majority of the causative genes that have been identified encode ion channels (3). Studies in several spontaneous mouse mutants with a paroxysmal dyskinesia phenotype have provided intriguing insights into these otherwise complicated diseases (4-6). The tottering and lethargic mice display motor abnormalities mimicking paroxysmal dyskinesia and harbor mutations in the genes encoding the α1A and β4 subunits of the P/Q-type voltage-gated Ca 2+ -channel, respectively (7,8). Like PNKD, the dyskinesia phenotype in tottering mice can also be triggered by caffeine and stress. PNKD is interesting in that the gene encodes a novel protein with homology to human glyoxalase II, an enzyme in a stress-response pathway. Although the normal role of PNKD is unknown, we previously identified the causative gene of PNKD (9) and a mouse model of the human mutations recapitulates the phenotype and shows dopamine signaling dysregulation (10).At synapses, vesicle priming, docking, and fusion at synaptic terminals are complex and coordinately regulated by proteins from the active zone, presynaptic membrane, and vesicles (11). Rab3-interacting molecules (RIMs) are a family of active zone proteins encoded by genes, Rims 1 to 4 (12). Through their interactions with vesicle proteins, active zone proteins, and presynaptic membrane proteins, RIMs are centrally involved in basic parameters of neurotransmitter release, and they contribute to both long-term and short-term synaptic plasticity (13-18).Given that PNKD is a novel protein whose function is unknown, we set out to identify ...