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: Michel Guipponi, Amina Chentouf, Kristin E B Webling, Krista Freimann, Arielle Crespel, Carlo Nobile, Johannes R Lemke, Jörg Hansen, Thomas Dorn, Gaetan Lesca, Philippe Ryvlin, Edouard Hirsch, Gabrielle Rudolf, Dominique Sarah Rosenberg, Yvonne Weber, Felicitas Becker, Ingo Helbig, Hiltrud Muhle, Annick Salzmann, Malika Chaouch, Mohand Laid Oubaiche, Serena Ziglio, Corinne Gehrig, Federico Santoni, Massimo Pizzato, Ülo Langel, Stylianos E Antonarakis
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 24 Issue 11 Pg. 3082-91 (Jun 01 2015) ISSN: 1460-2083 [Electronic] England
• PMID: 25691535 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Twin Study)
• Copyright: © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• GAL protein, human
• Galanin

Topics

• Adult
• Animals
• Base Sequence
• CHO Cells
• Cricetinae
• Cricetulus
• DNA Mutational Analysis
• Epilepsy, Temporal Lobe (genetics)
• Galanin (genetics)
• Genetic Association Studies
• Humans
• Mutation, Missense
• Pedigree
• Protein Binding
• Signal Transduction