Epilepsy Caused by an Abnormal Alternative Splicing with Dosage Effect of the SV2A Gene in a Chicken Model
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{"title"=>"Epilepsy caused by an abnormal alternative splicing with dosage effect of the sv2a gene in a chicken model", "type"=>"journal", "authors"=>[{"first_name"=>"Marine", "last_name"=>"Douaud", "scopus_author_id"=>"23988751300"}, {"first_name"=>"Katia", "last_name"=>"Feve", "scopus_author_id"=>"8859228300"}, {"first_name"=>"Fabienne", "last_name"=>"Pituello", "scopus_author_id"=>"6602581736"}, {"first_name"=>"David", "last_name"=>"Gourichon", "scopus_author_id"=>"23570767400"}, {"first_name"=>"Simon", "last_name"=>"Boitard", "scopus_author_id"=>"14524394100"}, {"first_name"=>"Eric", "last_name"=>"Leguern", "scopus_author_id"=>"7006086128"}, {"first_name"=>"Gérard", "last_name"=>"Coquerelle", "scopus_author_id"=>"6604052685"}, {"first_name"=>"Agathe", "last_name"=>"Vieaud", "scopus_author_id"=>"28867456700"}, {"first_name"=>"Cesira", "last_name"=>"Batini", "scopus_author_id"=>"7006303548"}, {"first_name"=>"Robert", "last_name"=>"Naquet", "scopus_author_id"=>"7102207578"}, {"first_name"=>"Alain", "last_name"=>"Vignal", "scopus_author_id"=>"7003783909"}, {"first_name"=>"Michèle", "last_name"=>"Tixier-Boichard", "scopus_author_id"=>"7004728208"}, {"first_name"=>"Frédérique", "last_name"=>"Pitel", "scopus_author_id"=>"7004028717"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"80055092808", "pmid"=>"22046416", "pui"=>"362830180", "isbn"=>"1932-6203", "scopus"=>"2-s2.0-80055092808", "doi"=>"10.1371/journal.pone.0026932", "issn"=>"19326203"}, "id"=>"24d346f0-926a-3924-9a51-3aff3a070428", "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.", "link"=>"http://www.mendeley.com/research/epilepsy-caused-abnormal-alternative-splicing-dosage-effect-sv2a-gene-chicken-model", "reader_count"=>32, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>2, "Researcher"=>12, "Student > Ph. D. Student"=>6, "Student > Master"=>4, "Other"=>4, "Student > Bachelor"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>2, "Researcher"=>12, "Student > Ph. D. Student"=>6, "Student > Master"=>4, "Other"=>4, "Student > Bachelor"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>1, "Medicine and Dentistry"=>8, "Agricultural and Biological Sciences"=>12, "Neuroscience"=>5, "Psychology"=>2}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>8}, "Neuroscience"=>{"Neuroscience"=>5}, "Psychology"=>{"Psychology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>12}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Unspecified"=>{"Unspecified"=>3}}, "reader_count_by_country"=>{"United States"=>1, "Brazil"=>1, "Germany"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/720727"], "description"=>"<p>(a) RT-PCR of <i>SV2A</i> in wild-type, carriers and epi/epi individuals using primers GCT1964U and GCT2146L showed the presence of an additional, smaller band in individuals homozygous for the epi mutation. (b) Direct sequencing of the PCR products (using primers GCT1964Lrev and GCT2044L) from animals of the three genotypes showed identical sequences up to the end of exon 2. Thereafter, a mixture of sequences was observed only in the homozygous <i>epi/epi</i> individuals. (c) Separate sequencing of the two bands confirmed that both corresponded to the <i>SV2A</i> cDNA, but the shorter fragment had a 106-bp deletion starting at the beginning of exon 3. The presence of an (AG) dinucleotide (red highlight) at the 3′ end of the deleted fragment suggested the possibility of a mis-splicing event.</p>", "links"=>[], "tags"=>["abnormal", "splicing", "cdna", "fepi"], "article_id"=>391073, "categories"=>["Genetics", "Neuroscience"], "users"=>["Marine Douaud", "Katia Fève", "Fabienne Pituello", "David Gourichon", "Simon Boitard", "Eric Leguern", "Gérard Coquerelle", "Agathe Vieaud", "Cesira Batini", "Robert Naquet", "Alain Vignal", "Michele Tixier-Boichard", "Frédérique Pitel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0026932.g002", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Identification_of_an_abnormal_splicing_event_in_the_SV2A_cDNA_of_the_Fepi_chicken_/391073", "title"=>"Identification of an abnormal splicing event in the <i>SV2A</i> cDNA of the Fepi chicken.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-27 00:17:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/364134", "https://ndownloader.figshare.com/files/364192", "https://ndownloader.figshare.com/files/364243", "https://ndownloader.figshare.com/files/364312", "https://ndownloader.figshare.com/files/364376", "https://ndownloader.figshare.com/files/364416"], "description"=>"<div><p>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 <em>SV2A</em> (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 <em>SV2A</em> mRNA in homozygous carriers. Levetiracetam, a second generation antiepileptic drug, is known to bind SV2A, and <em>SV2A</em> 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 <em>SV2A</em> 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, <em>SV2A</em> is a very attractive candidate gene for analysis in the context of both mono- and polygenic generalized epilepsies in humans.</p> </div>", "links"=>[], "tags"=>["epilepsy", "caused", "abnormal", "splicing", "dosage", "sv2a"], "article_id"=>131978, "categories"=>["Genetics", "Neuroscience"], "users"=>["Marine Douaud", "Katia Fève", "Fabienne Pituello", "David Gourichon", "Simon Boitard", "Eric Leguern", "Gérard Coquerelle", "Agathe Vieaud", "Cesira Batini", "Robert Naquet", "Alain Vignal", "Michele Tixier-Boichard", "Frédérique Pitel"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0026932.s001", "https://dx.doi.org/10.1371/journal.pone.0026932.s002", "https://dx.doi.org/10.1371/journal.pone.0026932.s003", "https://dx.doi.org/10.1371/journal.pone.0026932.s004", "https://dx.doi.org/10.1371/journal.pone.0026932.s005", "https://dx.doi.org/10.1371/journal.pone.0026932.s006"], "stats"=>{"downloads"=>34, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Epilepsy_Caused_by_an_Abnormal_Alternative_Splicing_with_Dosage_Effect_of_the_SV2A_Gene_in_a_Chicken_Model/131978", "title"=>"Epilepsy Caused by an Abnormal Alternative Splicing with Dosage Effect of the SV2A Gene in a Chicken Model", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-10-27 00:32:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/720870"], "description"=>"<p>(a) Sequencing electropherograms of the <i>SV2A</i> intron 2 fragment showing the candidate dinucleotide mutation (green and black arrows). Abbreviations: wild-type, CC; heterozygous, CC/TG; epileptic, TG. (b) Multalin <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0026932#pone.0026932-Corpet1\" target=\"_blank\">[59]</a> sequence comparison between mammals, wild-type chickens and epileptic chickens in the candidate mutation region. Colors: high degree of consensus (red), low degree of consensus (blue) and single change (black). The second C nucleotide (black arrow) is highly conserved across the various species, whereas the first C nucleotide (green arrow) was found to be replaced by a T (in dog and cow) or a G (in cat, mouse and megabat), suggesting that the former is more likely to be responsible for the epileptic phenotype.</p>", "links"=>[], "tags"=>["dinucleotide", "mutation", "causes", "reflex", "epilepsy", "fepi"], "article_id"=>391211, "categories"=>["Genetics", "Neuroscience"], "users"=>["Marine Douaud", "Katia Fève", "Fabienne Pituello", "David Gourichon", "Simon Boitard", "Eric Leguern", "Gérard Coquerelle", "Agathe Vieaud", "Cesira Batini", "Robert Naquet", "Alain Vignal", "Michele Tixier-Boichard", "Frédérique Pitel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0026932.g003", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Identification_of_a_dinucleotide_mutation_that_causes_reflex_epilepsy_in_the_Fepi_chicken_strain_/391211", "title"=>"Identification of a dinucleotide mutation that causes reflex epilepsy in the Fepi chicken strain.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-27 00:20:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/720625"], "description"=>"<p>(a) Genetic map of GGA25. (b) Haplotype analysis of animals from generation 1, i.e., the offspring of <i>epi/epi</i> dams crossed with carrier sires. The colors represent the origins of the chromosome haplotypes, as determined by SNP genotyping: red, epileptic line (Fepi); green, other line; gray, unknown origin (non-informative markers). An initial interval of 11.6 cM was defined between markers SEQ1285 (individuals 1 and 2) and 100A3M13 (individuals 3 and 4). Individual 5 alone restricted the interval to a 6.6-cM region having an estimated size of 650 kb based on radiation hybrid mapping data <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0026932#pone.0026932-Douaud1\" target=\"_blank\">[17]</a>. (c) Two recombinant animals obtained in the fourth generation restricted the interval to 0.5 cM (two-point genetic distance calculation based on the pedigree data). (d) This distance corresponded to 13 kb on the sequence assembly; the linked region fell between exons 2 and 9 of the <i>SV2A</i> gene. Exons 12 and 13 and intron 12 (dotted lines) were not sequenced. The vertical double lines indicate introns that were only partially sequenced.</p>", "links"=>[], "tags"=>["mutation", "causes", "epileptic", "seizures", "fepi"], "article_id"=>390965, "categories"=>["Genetics", "Neuroscience"], "users"=>["Marine Douaud", "Katia Fève", "Fabienne Pituello", "David Gourichon", "Simon Boitard", "Eric Leguern", "Gérard Coquerelle", "Agathe Vieaud", "Cesira Batini", "Robert Naquet", "Alain Vignal", "Michele Tixier-Boichard", "Frédérique Pitel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0026932.g001", "stats"=>{"downloads"=>3, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Fine_mapping_of_the_mutation_that_causes_epileptic_seizures_in_the_Fepi_chicken_/390965", "title"=>"Fine mapping of the mutation that causes epileptic seizures in the Fepi chicken.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-27 00:16:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/721003"], "description"=>"<p>(a) Real-time relative RT-PCR analysis showing the expression of <i>SV2A</i> versus that of β-actin in chicken embryos from the three genotypes (wild-type, carriers and <i>epi/epi</i>; n = 5 for each). The average <i>SV2A</i> expression was found to be higher in wild-type chickens compared to carriers and epileptic chickens, and in carriers compared to epileptics (p<0.003, Kruskal-Wallis test). (b) The relative expression in each tested embryo is shown in color by genotype: green, wild-type; orange, carrier; and pink, <i>epi/epi</i>. (c) Northern blot analysis showing that <i>SV2A</i> expression is highest in wild-type embryos and adults. Size estimations are indicated in kb. (d) <i>In situ</i> hybridization analysis of brains cross-sections from wild-type and <i>epi/epi</i> 17 day-old chicken embryos (E17). <i>SV2A</i> is clearly expressed in the mesencephalon of the wild-type embryonic brain (black arrow) but not in <i>epi/epi</i> embryos.</p>", "links"=>[], "tags"=>["fepi"], "article_id"=>391354, "categories"=>["Genetics", "Neuroscience"], "users"=>["Marine Douaud", "Katia Fève", "Fabienne Pituello", "David Gourichon", "Simon Boitard", "Eric Leguern", "Gérard Coquerelle", "Agathe Vieaud", "Cesira Batini", "Robert Naquet", "Alain Vignal", "Michele Tixier-Boichard", "Frédérique Pitel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0026932.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_analysis_of_SV2A_in_the_Fepi_chicken_strain_/391354", "title"=>"Expression analysis of <i>SV2A</i> in the Fepi chicken strain.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-27 00:22:34"}

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Relative Metric

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