A Role of SCN9A in Human Epilepsies, As a Cause of Febrile Seizures and As a Potential Modifier of Dravet Syndrome
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{"title"=>"A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome", "type"=>"journal", "authors"=>[{"first_name"=>"Nanda A.", "last_name"=>"Singh", "scopus_author_id"=>"7404363649"}, {"first_name"=>"Chris", "last_name"=>"Pappas", "scopus_author_id"=>"7102223035"}, {"first_name"=>"E. Jill", "last_name"=>"Dahle", "scopus_author_id"=>"6602857540"}, {"first_name"=>"Lieve R.F.", "last_name"=>"Claes", "scopus_author_id"=>"7103179546"}, {"first_name"=>"Timothy H.", "last_name"=>"Pruess", "scopus_author_id"=>"25930538500"}, {"first_name"=>"Peter", "last_name"=>"De Jonghe", "scopus_author_id"=>"20435787800"}, {"first_name"=>"Joel", "last_name"=>"Thompson", "scopus_author_id"=>"35376893200"}, {"first_name"=>"Missy", "last_name"=>"Dixon", "scopus_author_id"=>"8652457700"}, {"first_name"=>"Christina", "last_name"=>"Gurnett", "scopus_author_id"=>"6701464580"}, {"first_name"=>"Andy", "last_name"=>"Peiffer", "scopus_author_id"=>"6701400915"}, {"first_name"=>"H. Steve", "last_name"=>"White", "scopus_author_id"=>"35585142000"}, {"first_name"=>"Francis", "last_name"=>"Filloux", "scopus_author_id"=>"7003566969"}, {"first_name"=>"Mark F.", "last_name"=>"Leppert", "scopus_author_id"=>"35351313000"}], "year"=>2009, "source"=>"PLoS Genetics", "identifiers"=>{"issn"=>"15537390", "scopus"=>"2-s2.0-70349668995", "sgr"=>"70349668995", "pui"=>"355378085", "isbn"=>"1553-7404 (Electronic)\\r1553-7390 (Linking)", "pmid"=>"19763161", "doi"=>"10.1371/journal.pgen.1000649"}, "id"=>"c358df81-1de1-3a47-bf43-6e2fb4bceb20", "abstract"=>"A follow-up study of a large Utah family with significant linkage to chromosome 2q24 led us to identify a new febrile seizure (FS) gene, SCN9A encoding Na(v)1.7. In 21 affected members, we uncovered a potential mutation in a highly conserved amino acid, p.N641Y, in the large cytoplasmic loop between transmembrane domains I and II that was absent from 586 ethnically matched population control chromosomes. To establish a functional role for this mutation in seizure susceptibility, we introduced the orthologous mutation into the murine Scn9a ortholog using targeted homologous recombination. Compared to wild-type mice, homozygous Scn9a(N641Y/N641Y) knockin mice exhibit significantly reduced thresholds to electrically induced clonic and tonic-clonic seizures, and increased corneal kindling acquisition rates. Together, these data strongly support the SCN9A p.N641Y mutation as disease-causing in this family. To confirm the role of SCN9A in FS, we analyzed a collection of 92 unrelated FS patients and identified additional highly conserved Na(v)1.7 missense variants in 5% of the patients. After one of these children with FS later developed Dravet syndrome (severe myoclonic epilepsy of infancy), we sequenced the SCN1A gene, a gene known to be associated with Dravet syndrome, and identified a heterozygous frameshift mutation. Subsequent analysis of 109 Dravet syndrome patients yielded nine Na(v)1.7 missense variants (8% of the patients), all in highly conserved amino acids. Six of these Dravet syndrome patients with SCN9A missense variants also harbored either missense or splice site SCN1A mutations and three had no SCN1A mutations. This study provides evidence for a role of SCN9A in human epilepsies, both as a cause of FS and as a partner with SCN1A mutations.", "link"=>"http://www.mendeley.com/research/role-scn9a-human-epilepsies-cause-febrile-seizures-potential-modifier-dravet-syndrome", "reader_count"=>96, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Professor > Associate Professor"=>7, "Researcher"=>24, "Student > Doctoral Student"=>2, "Student > Ph. D. 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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/882655"], "description"=>"<p>Schematic representation of the (A) wild-type allele, (B) targeting construct introduced into embryonic stem (ES) cells. Numbered boxes denote exons; *, p.N641Y missense change introduced into exon 11; PCRa and PCRb, primers used to screen ES cell DNA for homologous recombination; S and probe, denotes SspI sites and probe used in genomic Southern blot of ES cells; ACN cassette, Cre-recombinase gene (<i>Cre</i>) driven by the testes-specific promoter from the angiotensin-converting enzyme gene (<i>tACE</i>); <i>Cre</i> is linked to the <i>Neo</i><sup>r</sup> selectable marker driven by the mouse RNA polymerase II large subunit gene (<i>polII</i>); the entire cassette is flanked by 34 bp loxP sites oriented in parallel. TK, HSV-TK gene for negative selection of ES cells. (C) following <i>Cre</i>-mediated self-excision in the chimeric mouse germline, a single loxP site and the point mutation remain. (D) Southern blot of three SspI cut ES cell clones followed by hybridization of probe yields an 8.4 kb endogenous band and a 7.2 kb targeted band (horizontal arrows); vertical arrow denotes clone used to make mouse. (E) LightScanner normalized melting peaks used to genotype <i>SCN9A</i><sup>+/+</sup>, <i>SCN9A</i><sup>N641Y/+</sup>, and <i>SCN9A</i><sup>N641Y/N641Y</sup> mice. (F) PCR used to verify self-excision of the ACN cassette. Amplicons generated by primers flanking remaining 34 bp loxP site in intron 10 yield distinct <i>SCN9A</i><sup>+/+</sup> (left), <i>SCN9A</i><sup>N641Y/+</sup> (center), and <i>SCN9A</i><sup>N641Y/N641Y</sup> (right, denoted by arrow) bands on 2% agarose.</p>", "links"=>[], "tags"=>["knockin"], "article_id"=>553101, "categories"=>["Neuroscience", "Genetics"], "users"=>["Nanda A. Singh", "Chris Pappas", "E. Jill Dahle", "Lieve R. F. Claes", "Timothy H. Pruess", "Peter De Jonghe", "Joel Thompson", "Missy Dixon", "Christina Gurnett", "Andy Peiffer", "H. Steve White", "Francis Filloux", "Mark F. Leppert"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000649.g002", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Generation_of_Scn9a_N641Y_knockin_mice_/553101", "title"=>"Generation of <i>Scn9a</i>-N641Y knockin mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 04:30:22"}
  • {"files"=>["https://ndownloader.figshare.com/files/883288"], "description"=>"*<p>In <0.3% controls. FS, febrile seizures; AFS, afebrile seizures; TLE, temporal lobe epilepsy; GSW, generalized spike wave; IGE, idiopathic generalized epilepsy; SMEB-MA, Dravet syndrome without myoclonic seizures and ataxia.</p><p>Reference sequences used are: SCN9A (NP 002968) and SCN1A (Swiss-Prot P35498).</p><p>AD, autosomal dominant; P, paternal; M, maternal; n.a., parents not available.</p>", "links"=>[], "tags"=>["patients", "variants", "corresponding"], "article_id"=>553734, "categories"=>["Neuroscience", "Genetics"], "users"=>["Nanda A. Singh", "Chris Pappas", "E. Jill Dahle", "Lieve R. F. Claes", "Timothy H. Pruess", "Peter De Jonghe", "Joel Thompson", "Missy Dixon", "Christina Gurnett", "Andy Peiffer", "H. Steve White", "Francis Filloux", "Mark F. Leppert"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000649.t001", "stats"=>{"downloads"=>6, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Overview_of_patients_with_SCN9A_variants_and_their_corresponding_SCN1A_mutation_/553734", "title"=>"Overview of patients with <i>SCN9A</i> variants and their corresponding <i>SCN1A</i> mutation.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-21 04:35:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/882569"], "description"=>"<p>(A) Segregation of the Na<sub>v</sub>1.7 p.N641Y mutation and phenotypic findings of K4425; fs, febrile seizures; afs, afebrile seizures; +, wild-type; m, p.N641Y mutation. (B) Sequence chromatogram of genomic DNA from individual III-1 shows a heterozygous c1921A>T (p.N641Y) mutation in exon 11 of <i>SCN9A</i>.</p>", "links"=>[], "tags"=>["k4425"], "article_id"=>553006, "categories"=>["Neuroscience", "Genetics"], "users"=>["Nanda A. Singh", "Chris Pappas", "E. Jill Dahle", "Lieve R. F. Claes", "Timothy H. Pruess", "Peter De Jonghe", "Joel Thompson", "Missy Dixon", "Christina Gurnett", "Andy Peiffer", "H. Steve White", "Francis Filloux", "Mark F. Leppert"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000649.g001", "stats"=>{"downloads"=>2, "page_views"=>50, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Pedigree_of_family_K4425_with_an_SCN9A_mutation_/553006", "title"=>"Pedigree of family K4425 with an <i>SCN9A</i> mutation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 04:29:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/883089"], "description"=>"<p>(A) Phenotypic profile and secondary structure locations of all variants found in <i>SCN9A</i>. Red text, variants in FS patients; blue text, variants in Dravet syndrome patients; black text, variants in both phenotypes; *variants also found in controls. (B) Amino acids from the UCSC genome browser (<a href=\"http://genome.ucsc.edu/\" target=\"_blank\">http://genome.ucsc.edu/</a>) showing conservation across 8 species for FS and Dravet syndrome variants (red) found in <i>SCN9A</i>. The human Na<sub>v</sub>1.7 protein shares identity of 97% to rhesus, 92% to rat, 92% to mouse, 94% to cow, 94% to dog, 93% to rabbit, and 75% to chicken.</p>", "links"=>[], "tags"=>["mutated", "patients", "febrile", "seizures", "dravet"], "article_id"=>553529, "categories"=>["Neuroscience", "Genetics"], "users"=>["Nanda A. Singh", "Chris Pappas", "E. Jill Dahle", "Lieve R. F. Claes", "Timothy H. Pruess", "Peter De Jonghe", "Joel Thompson", "Missy Dixon", "Christina Gurnett", "Andy Peiffer", "H. Steve White", "Francis Filloux", "Mark F. Leppert"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000649.g005", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_SCN9A_is_mutated_in_multiple_patients_with_febrile_seizures_FS_and_Dravet_syndrome_/553529", "title"=>"<i>SCN9A</i> is mutated in multiple patients with febrile seizures (FS) and Dravet syndrome.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 04:32:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/883198"], "description"=>"<p>Sequence chromatograms of wild-type (top panel) and mutant (middle panel) clones of <i>SCN1A</i> exon 15 reveals a frameshift mutation p.N892fsX2 (c.2675delA); sequence chromatogram of genomic DNA shows a heterozygous p.L1123F (c.3369G>T) in exon 17 of <i>SCN9A</i> exon (bottom panel).</p>", "links"=>[], "tags"=>["dravet", "harbors", "mutations"], "article_id"=>553642, "categories"=>["Neuroscience", "Genetics"], "users"=>["Nanda A. Singh", "Chris Pappas", "E. Jill Dahle", "Lieve R. F. Claes", "Timothy H. Pruess", "Peter De Jonghe", "Joel Thompson", "Missy Dixon", "Christina Gurnett", "Andy Peiffer", "H. Steve White", "Francis Filloux", "Mark F. Leppert"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000649.g006", "stats"=>{"downloads"=>2, "page_views"=>32, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Utah_Dravet_syndrome_patient_34302_harbors_mutations_in_both_SCN9A_and_SCN1A_/553642", "title"=>"Utah Dravet syndrome patient #34302 harbors mutations in both <i>SCN9A</i> and <i>SCN1A</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 04:33:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/882810"], "description"=>"<p>Convulsive current curves generated by testing (A) male B6;129-<i>Scn9a</i><sup>N641Y/N641Y</sup>, B6;129-<i>Scn9a</i><sup>N641Y/+</sup>, and B6;129-<i>Scn9a</i><sup>+/+</sup> mice to minimal clonus electroconvulsive seizures (B6;129-<i>Scn9a</i><sup>N641Y/N641Y</sup> vs B6;129-<i>Scn9a</i><sup>N641Y/+</sup><i>p</i> = 0.008; B6;129-<i>Scn9a</i><sup>N641Y/N641Y</sup> vs B6;129-<i>Scn9a</i><sup>+/+</sup><i>p</i> = 0.001; B6;129-<i>Scn9a</i><sup>N641Y/+</sup> vs B6;129-<i>Scn9a</i><sup>+/+</sup><i>p</i> = 0.093) and (B) female B6;129-<i>Scn9a</i><sup>N641Y/N641Y</sup>, B6;129-<i>Scn9a</i><sup>N641Y/+</sup>, and B6;129-<i>Scn9a</i><sup>+/+</sup> mice to minimal tonic hindlimb extension electroconvulsive seizures (B6;129-<i>Scn9a</i><sup>N641Y/N641Y</sup> vs B6;129-<i>Scn9a</i><sup>N641Y/+</sup><i>p</i><0.001; B6;129-<i>Scn9a</i><sup>N641Y/N641Y</sup> vs B6;129-<i>Scn9a</i><sup>+/+</sup><i>p</i><0.001; B6;129-<i>Scn9a</i><sup>N641Y/+</sup> vs B6;129-<i>Scn9a</i><sup>+/+</sup><i>p</i> = 0.227). Convulsive current data are expressed in terms of 1-seizure probability (1-P<sub>seizure</sub>) for a given stimulus (mA). Individual data points shown for homozygote (closed square), heterozygote (x), and wild-type (closed circle) mice are used to construct curves indicated by black solid, red dashed, and blue dotted lines, respectively.</p>", "links"=>[], "tags"=>["electroconvulsive", "seizure", "thresholds", "knockin", "mice", "compared", "wild-type", "littermate"], "article_id"=>553240, "categories"=>["Neuroscience", "Genetics"], "users"=>["Nanda A. Singh", "Chris Pappas", "E. Jill Dahle", "Lieve R. F. Claes", "Timothy H. Pruess", "Peter De Jonghe", "Joel Thompson", "Missy Dixon", "Christina Gurnett", "Andy Peiffer", "H. Steve White", "Francis Filloux", "Mark F. Leppert"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000649.g003", "stats"=>{"downloads"=>2, "page_views"=>34, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Reduced_electroconvulsive_seizure_thresholds_of_Scn9a_knockin_mice_compared_to_wild_type_littermate_controls_/553240", "title"=>"Reduced electroconvulsive seizure thresholds of <i>Scn9a</i> knockin mice compared to wild-type littermate controls.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 04:31:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/882939"], "description"=>"<p>Male N5F2 mice separated by genotype (n = 8–15) were stimulated with corneal electrodes twice daily until four consecutive Racine Stage 4 or 5 secondarily generalized seizures were elicited. The effect of <i>Scn9a</i>-N641Y on kindling acquisition is shown in (A) for B6.129-Scn9a<sup>+/+</sup>, B6.129-Scn9a<sup>N641Y/+</sup>, and B6.129-Scn9a<sup>N641Y/N641Y</sup> mice; results are expressed as the average seizure score per genotype observed after each stimulation. (B) The number of stimulations required to reach the first fully generalized Racine Stage 4–5 seizure, regraphed with p-values from the data in (A), is 9.89±0.93 (B6.129-Scn9a<sup>+/+</sup>, clear bar), 5.63±0.92 (B6.129-Scn9a<sup>N641Y/N641Y</sup>, black bar), and 6.93±0.89 (B6.129-Scn9a<sup>N641Y/+</sup>, pink bar), left panel; the number of stimulations required to reach a fully kindled mouse defined as four consecutive Racine Stage 4–5 seizures, regraphed with p-values from the data in (A), is 14.56±0.88 (B6.129-Scn9a<sup>+/+</sup>, clear bar), 11.13±1.2 (B6.129-Scn9a<sup>N641Y/N641Y</sup>, black bar), 12.64±0.86 (B6.129-Scn9a<sup>N641Y/+</sup>, pink bar), right panel.</p>", "links"=>[], "tags"=>["corneal", "kindling", "rates", "knockin", "mice", "compared", "wild-type", "littermate"], "article_id"=>553375, "categories"=>["Neuroscience", "Genetics"], "users"=>["Nanda A. Singh", "Chris Pappas", "E. Jill Dahle", "Lieve R. F. Claes", "Timothy H. Pruess", "Peter De Jonghe", "Joel Thompson", "Missy Dixon", "Christina Gurnett", "Andy Peiffer", "H. Steve White", "Francis Filloux", "Mark F. Leppert"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000649.g004", "stats"=>{"downloads"=>2, "page_views"=>21, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Increased_corneal_kindling_acquisition_rates_of_Scn9a_knockin_mice_compared_to_wild_type_littermate_controls_/553375", "title"=>"Increased corneal kindling acquisition rates of <i>Scn9a</i> knockin mice compared to wild-type littermate controls.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 04:32:03"}

PMC Usage Stats | Further Information

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  • {"unique-ip"=>"40", "full-text"=>"45", "pdf"=>"13", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"7", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"5"}
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Relative Metric

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