Galanin pathogenic mutations in temporal lobe epilepsy.

Détails

Ressource 1Télécharger: serval:BIB_8679EB1FCBD3.P001 (621.11 [Ko])
Etat: Public
Version: de l'auteur
Licence: Non spécifiée
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ID Serval
serval:BIB_8679EB1FCBD3
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Galanin pathogenic mutations in temporal lobe epilepsy.
Périodique
Human Molecular Genetics
Auteur(s)
Guipponi M., Chentouf A., Webling K.E., Freimann K., Crespel A., Nobile C., Lemke J.R., Hansen J., Dorn T., Lesca G., Ryvlin P., Hirsch E., Rudolf G., Rosenberg D.S., Weber Y., Becker F., Helbig I., Muhle H., Salzmann A., Chaouch M., Oubaiche M.L., Ziglio S., Gehrig C., Santoni F., Pizzato M., Langel Ü., Antonarakis S.E.
ISSN
1460-2083 (Electronic)
ISSN-L
0964-6906
Statut éditorial
Publié
Date de publication
2015
Peer-reviewed
Oui
Volume
24
Numéro
11
Pages
3082-3091
Langue
anglais
Résumé
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.
Pubmed
Web of science
Open Access
Oui
Création de la notice
06/07/2015 13:56
Dernière modification de la notice
28/02/2020 11:46
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