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The α2B-adrenergic receptor is mutant in cortical myoclonus and epilepsy

Authors

  • Maurizio De Fusco BS,

    1. Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, and Vita-Salute San Raffaele University, Milan, Italy
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  • Riccardo Vago PhD,

    1. Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, and Vita-Salute San Raffaele University, Milan, Italy
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  • Pasquale Striano MD,

    1. Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, G. Gaslini Institute, Genoa, Italy
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  • Carlo Di Bonaventura MD,

    1. Department of Neuroscience, Neurology Unit, La Sapienza University, Rome, Italy
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  • Federico Zara PhD,

    1. Laboratory of Neurogenetics, Department of Neurosciences, G. Gaslini Institute, Genoa, Italy
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  • Davide Mei BS,

    1. Pediatric Neurology Unit and Laboratories, Anna Meyer Children's Hospital and University of Florence, Florence, Italy
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  • Min Seuk Kim PhD,

    1. Department of Oral Physiology, School of Dentistry, Wonkwang University, Iksan, Jeonbuk, Republic of Korea
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  • Shmuel Muallem PhD,

    1. Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institute of Health, Bethesda, MD
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  • Yunjia Chen PhD,

    1. Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL
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  • Qin Wang PhD,

    1. Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL
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  • Renzo Guerrini MD,

    1. Pediatric Neurology Unit and Laboratories, Anna Meyer Children's Hospital and University of Florence, Florence, Italy
    2. Stella Maris, Pisa, Italy
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  • Giorgio Casari PhD

    Corresponding author
    1. Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, and Vita-Salute San Raffaele University, Milan, Italy
    • Address correspondence to Dr Casari, Vita-Salute San Raffaele University, School of Medicine and Center for Translational Genomics and Bioinformatics, Neurogenomics Unit, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy. E-mail casari.giorgio@hsr.it

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Abstract

Objective

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.

Methods

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.

Results

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.

Interpretation

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. ANN NEUROL 2014;75:77–87

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