{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T22:31:37Z","timestamp":1787524297490,"version":"build-2736575974"},"reference-count":44,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2014,1,2]],"date-time":"2014-01-02T00:00:00Z","timestamp":1388620800000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2014,1]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>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\u2010q12.2 by genome\u2010wide 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Here we show that mutation in the \u03b1<jats:sub>2<\/jats:sub>\u2010adrenergic receptor subtype B (\u03b1<jats:sub>2B<\/jats:sub>\u2010AR) is associated with ADCME by identifying a novel in\u2010frame insertion\/deletion in 2 Italian families. The mutation alters several conserved residues of the third intracellular loop, hampering neither the \u03b1<jats:sub>2B<\/jats:sub>\u2010AR plasma membrane localization nor the arrestin\u2010mediated 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 \u03b1<jats:sub>2B<\/jats:sub>\u2010AR increases the epinephrine\u2010stimulated calcium signaling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>The identified mutation is responsible for ADCME, as the loss of \u03b1<jats:sub>2B<\/jats:sub>\u2010AR\/spinophilin interaction causes a gain of function effect. This work implicates for the first time the \u03b1\u2010adrenergic system in human epilepsy and opens new ways of understanding the molecular pathway of epileptogenesis, widening the spectrum of possible therapeutic targets. ANN NEUROL 2014;75:77\u201387<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.24028","type":"journal-article","created":{"date-parts":[[2013,10,12]],"date-time":"2013-10-12T01:10:40Z","timestamp":1381540240000},"page":"77-87","source":"Crossref","is-referenced-by-count":42,"title":["The \u03b1<sub>2B<\/sub>\u2010adrenergic receptor is mutant in cortical myoclonus and epilepsy"],"prefix":"10.1002","volume":"75","author":[{"given":"Maurizio","family":"De Fusco","sequence":"first","affiliation":[{"name":"Center for Translational Genomics and Bioinformatics San Raffaele Scientific Institute, and Vita\u2010Salute San Raffaele University Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Vago","sequence":"additional","affiliation":[{"name":"Center for Translational Genomics and Bioinformatics San Raffaele Scientific Institute, and Vita\u2010Salute San Raffaele University Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale","family":"Striano","sequence":"additional","affiliation":[{"name":"Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health University of Genoa, G. Gaslini Institute Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Di Bonaventura","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Neurology Unit, La Sapienza University Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Zara","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics, Department of Neurosciences G. 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