Galanin pathogenic mutations in temporal lobe epilepsy

Hum Mol Genet. 2015 Jun 1;24(11):3082-91. doi: 10.1093/hmg/ddv060.

Michel Guipponi ¹, Amina Chentouf ², Kristin E B Webling ³, Krista Freimann ⁴, Arielle Crespel ⁵, Carlo Nobile ⁶, Johannes R Lemke ⁷, Jörg Hansen ⁸, Thomas Dorn ⁸, Gaetan Lesca ⁹, Philippe Ryvlin ¹⁰, Edouard Hirsch ¹¹, Gabrielle Rudolf ¹¹, Dominique Sarah Rosenberg ¹², Yvonne Weber ¹³, Felicitas Becker ¹³, Ingo Helbig ¹⁴, Hiltrud Muhle ¹⁵, Annick Salzmann ¹⁶, Malika Chaouch ¹⁷, Mohand Laid Oubaiche ², Serena Ziglio ¹⁸, Corinne Gehrig ¹⁶, Federico Santoni ¹⁶, Massimo Pizzato ¹⁸, Ülo Langel ³, Stylianos E Antonarakis ¹⁹

Affiliations

1 Department of Genetic Medicine and Development, University of Geneva Medical School and University Hospitals of Geneva, Geneva, Switzerland [email protected].
2 Department of Neurology, University Hospital of Oran, Oran 31000, Algeria.
3 Department of Neurochemistry, Arrhenius Laboratories for Natural Science, Stockholm University, Stockholm, Sweden.
4 Department of Neurochemistry, Arrhenius Laboratories for Natural Science, Stockholm University, Stockholm, Sweden Institute of Technology, University of Tartu, Tartu, Estonia.
5 Epilepsy Unit, Montpellier University Hospital, Montpellier, France.
6 CNR-Institute of Neurosciences, Section of Padua, Padova, Italy.
7 Division of Human Genetics, University Children's Hospital Inselspital, Bern, Switzerland Institute of Human Genetics, University of Leipzig, Leipzig, Germany.
8 Swiss Epilepsy Center, Zurich, Switzerland.
9 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.
10 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.
11 IGBMC UMR7104 INSERM U964, University of Strasbourg, Strasbourg, France.
12 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.
13 Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen 72076, Germany.
14 Department of Neuropediatrics, University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
15 Department of Neuropediatrics, University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany.
16 Department of Genetic Medicine and Development, University of Geneva Medical School and University Hospitals of Geneva, Geneva, Switzerland.
17 Department of Neurology, Benaknoun University Hospital, Algiers 16000, Algeria.
18 Centre for Integrative Biology (CIBIO), University of Trenton, Trenton, Italy and.
19 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.

PMID: 25691535 DOI: 10.1093/hmg/ddv060

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.

Name
Email *

	Sorry, but the email address you supplied was invalid.