title: Epilepsy caused by an abnormal alternative splicing with dosage effect of the SV2A gene in a chicken model.
abstract: Photosensitive reflex epilepsy is caused by the combination of an individual's enhanced sensitivity with relevant light stimuli, such as stroboscopic lights or video games. This is the most common reflex epilepsy in humans; it is characterized by the photoparoxysmal response, which is an abnormal electroencephalographic reaction, and seizures triggered by intermittent light stimulation. Here, by using genetic mapping, sequencing and functional analyses, we report that a mutation in the acceptor site of the second intron of SV2A (the gene encoding synaptic vesicle glycoprotein 2A) is causing photosensitive reflex epilepsy in a unique vertebrate model, the Fepi chicken strain, a spontaneous model where the neurological disorder is inherited as an autosomal recessive mutation. This mutation causes an aberrant splicing event and significantly reduces the level of SV2A mRNA in homozygous carriers. Levetiracetam, a second generation antiepileptic drug, is known to bind SV2A, and SV2A knock-out mice develop seizures soon after birth and usually die within three weeks. The Fepi chicken survives to adulthood and responds to levetiracetam, suggesting that the low-level expression of SV2A in these animals is sufficient to allow survival, but does not protect against seizures. Thus, the Fepi chicken model shows that the role of the SV2A pathway in the brain is conserved between birds and mammals, in spite of a large phylogenetic distance. The Fepi model appears particularly useful for further studies of physiopathology of reflex epilepsy, in comparison with induced models of epilepsy in rodents. Consequently, SV2A is a very attractive candidate gene for analysis in the context of both mono- and polygenic generalized epilepsies in humans.
authors: INRA-ENVT, Laboratoire de Génétique Cellulaire, Castanet-Tolosan, France.
authors: Marine
authors: M
authors: Douaud
authors: Katia
authors: K
authors: Feve
authors: Fabienne
authors: F
authors: Pituello
authors: David
authors: D
authors: Gourichon
authors: Simon
authors: S
authors: Boitard
authors: Eric
authors: E
authors: Leguern
authors: Gérard
authors: G
authors: Coquerelle
authors: Agathe
authors: A
authors: Vieaud
authors: Cesira
authors: C
authors: Batini
authors: Robert
authors: R
authors: Naquet
authors: Alain
authors: A
authors: Vignal
authors: Michèle
authors: M
authors: Tixier-Boichard
authors: Frédérique
authors: F
authors: Pitel
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D002645:Chickens; D004195:Disease Models, Animal; D004827:Epilepsy / Q000209:etiology / Q000235:genetics*; D018628:Gene Dosage; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010802:Phylogeny; D012640:Seizures / Q000235:genetics
chemical_list: D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C489614:Sv2a protein, mouse