title: Galanin pathogenic mutations in temporal lobe epilepsy.
abstract: Temporal lobe epilepsy (TLE) is a common epilepsy syndrome with a complex etiology. Despite evidence for the participation of genetic factors, the genetic basis of TLE remains largely unknown. A role for the galanin neuropeptide in the regulation of epileptic seizures has been established in animal models more than two decades ago. However, until now there was no report of pathogenic mutations in GAL, the galanin-encoding gene, and therefore its role in human epilepsy was not established. Here, we studied a family with a pair of monozygotic twins affected by TLE and two unaffected siblings born to healthy parents. Exome sequencing revealed that both twins carried a novel de novo mutation (p.A39E) in the GAL gene. Functional analysis revealed that the p.A39E mutant showed antagonistic activity against galanin receptor 1 (GalR1)-mediated response, and decreased binding affinity and reduced agonist properties for GalR2. These findings suggest that the p.A39E mutant could impair galanin signaling in the hippocampus, leading to increased glutamatergic excitation and ultimately to TLE. In a cohort of 582 cases, we did not observe any pathogenic mutations indicating that mutations in GAL are a rare cause of TLE. The identification of a novel de novo mutation in a biologically-relevant candidate gene, coupled with functional evidence that the mutant protein disrupts galanin signaling, strongly supports GAL as the causal gene for the TLE in this family. Given the availability of galanin agonists which inhibit seizures, our findings could potentially have direct implications for the development of anti-epileptic treatment.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School and University Hospitals of Geneva, Geneva, Switzerland michel.guipponi@unige.ch.
authors.forename: Michel
authors.initials: M
authors.lastname: Guipponi
authors.affiliation: Department of Neurology, University Hospital of Oran, Oran 31000, Algeria.
authors.forename: Amina
authors.initials: A
authors.lastname: Chentouf
authors.affiliation: Department of Neurochemistry, Arrhenius Laboratories for Natural Science, Stockholm University, Stockholm, Sweden.
authors.forename: Kristin E B
authors.initials: KE
authors.lastname: Webling
authors.affiliation: Department of Neurochemistry, Arrhenius Laboratories for Natural Science, Stockholm University, Stockholm, Sweden Institute of Technology, University of Tartu, Tartu, Estonia.
authors.forename: Krista
authors.initials: K
authors.lastname: Freimann
authors.affiliation: Epilepsy Unit, Montpellier University Hospital, Montpellier, France.
authors.forename: Arielle
authors.initials: A
authors.lastname: Crespel
authors.affiliation: CNR-Institute of Neurosciences, Section of Padua, Padova, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Nobile
authors.affiliation: Division of Human Genetics, University Children's Hospital Inselspital, Bern, Switzerland Institute of Human Genetics, University of Leipzig, Leipzig, Germany.
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Lemke
authors.affiliation: Swiss Epilepsy Center, Zurich, Switzerland.
authors.forename: Jörg
authors.initials: J
authors.lastname: Hansen
authors.affiliation: Swiss Epilepsy Center, Zurich, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dorn
authors.affiliation: Department of Medical Genetics, Hospices Civils de Lyon, Lyon, France Claude Bernard Lyon I University, Lyon, France CRNL, CNRS UMR 5292, Lyon, France INSERM U1028, Lyon, France.
authors.forename: Gaetan
authors.initials: G
authors.lastname: Lesca
authors.affiliation: Department of Clinical Neurosciences, CHUV, Lausanne, Switzerland Lyon's Neuroscience Research Center, INSERM U1028, CNRS 5292, UCBL, Lyon, France Department of Functional Neurology and Epileptology, HCL, Lyon, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Ryvlin
authors.affiliation: IGBMC UMR7104 INSERM U964, University of Strasbourg, Strasbourg, France.
authors.forename: Edouard
authors.initials: E
authors.lastname: Hirsch
authors.affiliation: IGBMC UMR7104 INSERM U964, University of Strasbourg, Strasbourg, France.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Rudolf
authors.affiliation: Service de Neurologie et Neurophysiologie Clinique, IGCNC - EA 7282, UMR 6284 ISIT, Université d'Auvergne, Clermont Université, CHU Clermont-Ferrand, Hôpital Gabriel Montpied, Clermont-Ferrand, France.
authors.forename: Dominique Sarah
authors.initials: DS
authors.lastname: Rosenberg
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen 72076, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Weber
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen 72076, Germany.
authors.forename: Felicitas
authors.initials: F
authors.lastname: Becker
authors.affiliation: Department of Neuropediatrics, University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Ingo
authors.initials: I
authors.lastname: Helbig
authors.affiliation: Department of Neuropediatrics, University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany.
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Muhle
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School and University Hospitals of Geneva, Geneva, Switzerland.
authors.forename: Annick
authors.initials: A
authors.lastname: Salzmann
authors.affiliation: Department of Neurology, Benaknoun University Hospital, Algiers 16000, Algeria.
authors.forename: Malika
authors.initials: M
authors.lastname: Chaouch
authors.affiliation: Department of Neurology, University Hospital of Oran, Oran 31000, Algeria.
authors.forename: Mohand Laid
authors.initials: ML
authors.lastname: Oubaiche
authors.affiliation: Centre for Integrative Biology (CIBIO), University of Trenton, Trenton, Italy and.
authors.forename: Serena
authors.initials: S
authors.lastname: Ziglio
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School and University Hospitals of Geneva, Geneva, Switzerland.
authors.forename: Corinne
authors.initials: C
authors.lastname: Gehrig
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School and University Hospitals of Geneva, Geneva, Switzerland.
authors.forename: Federico
authors.initials: F
authors.lastname: Santoni
authors.affiliation: Centre for Integrative Biology (CIBIO), University of Trenton, Trenton, Italy and.
authors.forename: Massimo
authors.initials: M
authors.lastname: Pizzato
authors.affiliation: Department of Neurochemistry, Arrhenius Laboratories for Natural Science, Stockholm University, Stockholm, Sweden.
authors.forename: Ülo
authors.initials: Ü
authors.lastname: Langel
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School and University Hospitals of Geneva, Geneva, Switzerland Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland.
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
mesh_terms: D000328:Adult; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004252:DNA Mutational Analysis; D004833:Epilepsy, Temporal Lobe / Q000235:genetics*; D019004:Galanin / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D020125:Mutation, Missense; D010375:Pedigree; D011485:Protein Binding; D015398:Signal Transduction
chemical_list: C056567:GAL protein, human; D019004:Galanin