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Autosomal dominant cortical myoclonus and epilepsy (ADCME) is characterized by distal, fairly rhythmic myoclonus and epilepsy with variable severity. We have previously mapped the disease locus on chromosome 2p11.1-q12.2 by genome-wide linkage analysis. Additional pedigrees affected by similar forms of epilepsy have been associated with chromosomes 8q, 5p, and 3q, but none of the causing genes has been identified. We aim to identify the mutant gene responsible for this form of epilepsy.Genes included in the ADCME critical region were directly sequenced. Coimmunoprecipitation, immunofluorescent, and electrophysiologic approaches to transfected human cells have been utilized for testing the functional significance of the identified mutation.Here we show that mutation in the α2 -adrenergic receptor subtype B (α2B -AR) is associated with ADCME by identifying a novel in-frame insertion/deletion in 2 Italian families. The mutation alters several conserved residues of the third intracellular loop, hampering neither the α2B -AR plasma membrane localization nor the arrestin-mediated internalization capacity, but altering the binding with the scaffolding protein spinophilin upon neurotransmitter activation. Spinophilin, in turn, regulates interaction of G protein coupled receptors with regulator of G protein signaling proteins. Accordingly, the mutant α2B -AR increases the epinephrine-stimulated calcium signaling.The identified mutation is responsible for ADCME, as the loss of α2B -AR/spinophilin interaction causes a gain of function effect. This work implicates for the first time the α-adrenergic system in human epilepsy and opens new ways of understanding the molecular pathway of epileptogenesis, widening the spectrum of possible therapeutic targets.

Familial hemiplegic migraine (FHM) is a rare autosomal dominant disorder characterized by episodes of transient hemiparesis followed by headache. Two chromosomal loci are associated to FHM: FHM1 on chromosome 19 and FHM2 on chromosome 1q21-23. Mutations of the alpha-1A subunit of the voltage gated calcium channel (CACNA1A) are responsible for FHM1. FHM2 critical region spans 28 cM, hence hampering the identification of the responsible gene. Here, we report the FHM2 locus refining by linkage analysis on two large Italian families affected by pure FHM. The new critical region covers a small area of 0.9Mb in 1q23 and renders feasible a positional candidate approach. By mutation analysis, we excluded the calsequestrin and two potassium channel genes mapping within the narrowed FHM2 locus.