Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B
Febrile seizures affect approximately 3% of all children under six years of age and are by far the most common seizure disorder. A small proportion of children with febrile seizures later develop ongoing epilepsy with afebrile seizures. Segregation analysis suggests the majority of cases have comple...
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Veröffentlicht in: | Nature genetics 1998-08, Vol.19 (4), p.366-370 |
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creator | Wallace, R H Wang, D W Singh, R Scheffer, I E George, Jr, A L Phillips, H A Saar, K Reis, A Johnson, E W Sutherland, G R Berkovic, S F Mulley, J C |
description | Febrile seizures affect approximately 3% of all children under six years of age and are by far the most common seizure disorder. A small proportion of children with febrile seizures later develop ongoing epilepsy with afebrile seizures. Segregation analysis suggests the majority of cases have complex inheritance but rare families show apparent autosomal dominant inheritance. Two putative loci have been mapped (FEB1 and FEB2), but specific genes have not yet been identified. We recently described a clinical subset, termed generalized epilepsy with febrile seizures plus (GEFS+), in which many family members have seizures with fever that may persist beyond six years of age or be associated with afebrile generalized seizures. We now report linkage, in another large GEFS+ family, to chromosome region 19q13.1 and identification of a mutation in the voltage-gated sodium (Na+)-channel beta1 subunit gene (SCN1B). The mutation changes a conserved cysteine residue disrupting a putative disulfide bridge which normally maintains an extracellular immunoglobulin-like fold. Co-expression of the mutant beta1 subunit with a brain Na+-channel alpha subunit in Xenopus laevis oocytes demonstrates that the mutation interferes with the ability of the subunit to modulate channel-gating kinetics consistent with a loss-of-function allele. This observation develops the theme that idiopathic epilepsies are a family of channelopathies and raises the possibility of involvement of other Na+-channel subunit genes in febrile seizures and generalized epilepsies with complex inheritance patterns. |
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A small proportion of children with febrile seizures later develop ongoing epilepsy with afebrile seizures. Segregation analysis suggests the majority of cases have complex inheritance but rare families show apparent autosomal dominant inheritance. Two putative loci have been mapped (FEB1 and FEB2), but specific genes have not yet been identified. We recently described a clinical subset, termed generalized epilepsy with febrile seizures plus (GEFS+), in which many family members have seizures with fever that may persist beyond six years of age or be associated with afebrile generalized seizures. We now report linkage, in another large GEFS+ family, to chromosome region 19q13.1 and identification of a mutation in the voltage-gated sodium (Na+)-channel beta1 subunit gene (SCN1B). The mutation changes a conserved cysteine residue disrupting a putative disulfide bridge which normally maintains an extracellular immunoglobulin-like fold. Co-expression of the mutant beta1 subunit with a brain Na+-channel alpha subunit in Xenopus laevis oocytes demonstrates that the mutation interferes with the ability of the subunit to modulate channel-gating kinetics consistent with a loss-of-function allele. This observation develops the theme that idiopathic epilepsies are a family of channelopathies and raises the possibility of involvement of other Na+-channel subunit genes in febrile seizures and generalized epilepsies with complex inheritance patterns.</description><identifier>ISSN: 1061-4036</identifier><identifier>PMID: 9697698</identifier><language>eng</language><publisher>United States</publisher><subject>Amino Acid Sequence ; Animals ; Chromosomes, Human, Pair 19 - genetics ; DNA Mutational Analysis ; Epilepsy, Generalized - genetics ; Female ; Genetic Linkage ; Humans ; Male ; Molecular Sequence Data ; Oocytes ; Patch-Clamp Techniques ; Pedigree ; Point Mutation - genetics ; Seizures, Febrile - genetics ; Sodium Channels - genetics ; Sodium Channels - physiology ; Tasmania ; Xenopus laevis</subject><ispartof>Nature genetics, 1998-08, Vol.19 (4), p.366-370</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9697698$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wallace, R H</creatorcontrib><creatorcontrib>Wang, D W</creatorcontrib><creatorcontrib>Singh, R</creatorcontrib><creatorcontrib>Scheffer, I E</creatorcontrib><creatorcontrib>George, Jr, A L</creatorcontrib><creatorcontrib>Phillips, H A</creatorcontrib><creatorcontrib>Saar, K</creatorcontrib><creatorcontrib>Reis, A</creatorcontrib><creatorcontrib>Johnson, E W</creatorcontrib><creatorcontrib>Sutherland, G R</creatorcontrib><creatorcontrib>Berkovic, S F</creatorcontrib><creatorcontrib>Mulley, J C</creatorcontrib><title>Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B</title><title>Nature genetics</title><addtitle>Nat Genet</addtitle><description>Febrile seizures affect approximately 3% of all children under six years of age and are by far the most common seizure disorder. A small proportion of children with febrile seizures later develop ongoing epilepsy with afebrile seizures. Segregation analysis suggests the majority of cases have complex inheritance but rare families show apparent autosomal dominant inheritance. Two putative loci have been mapped (FEB1 and FEB2), but specific genes have not yet been identified. We recently described a clinical subset, termed generalized epilepsy with febrile seizures plus (GEFS+), in which many family members have seizures with fever that may persist beyond six years of age or be associated with afebrile generalized seizures. We now report linkage, in another large GEFS+ family, to chromosome region 19q13.1 and identification of a mutation in the voltage-gated sodium (Na+)-channel beta1 subunit gene (SCN1B). The mutation changes a conserved cysteine residue disrupting a putative disulfide bridge which normally maintains an extracellular immunoglobulin-like fold. Co-expression of the mutant beta1 subunit with a brain Na+-channel alpha subunit in Xenopus laevis oocytes demonstrates that the mutation interferes with the ability of the subunit to modulate channel-gating kinetics consistent with a loss-of-function allele. This observation develops the theme that idiopathic epilepsies are a family of channelopathies and raises the possibility of involvement of other Na+-channel subunit genes in febrile seizures and generalized epilepsies with complex inheritance patterns.</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Chromosomes, Human, Pair 19 - genetics</subject><subject>DNA Mutational Analysis</subject><subject>Epilepsy, Generalized - genetics</subject><subject>Female</subject><subject>Genetic Linkage</subject><subject>Humans</subject><subject>Male</subject><subject>Molecular Sequence Data</subject><subject>Oocytes</subject><subject>Patch-Clamp Techniques</subject><subject>Pedigree</subject><subject>Point Mutation - genetics</subject><subject>Seizures, Febrile - genetics</subject><subject>Sodium Channels - genetics</subject><subject>Sodium Channels - physiology</subject><subject>Tasmania</subject><subject>Xenopus laevis</subject><issn>1061-4036</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNotkD1PwzAURT2ASin8BCRPLCiSHSf-GKGigFSVge7RS_zSGiVOiG2h9tdToNOV7j06w70gc84kzwom5BW5DuGTMV4UTM_IzEijpNFzMq6wnlyHNKA7pgkDBW_pDj1O0LkjWorjaR7DgUIIQ-MgnrpvF_cUaJ8iRDd46jyNe6QbeMiaPXiPHa0xAqch1cm7-CekH8sNf7ohly10AW_PuSDb1fN2-Zqt31_elo_rbKe0zkQtNJdS6dKKptDcliiUaetcK82kZkyWjbE5KKlyhrmwgiNqnre25I1pjViQ-3_tOA1fCUOsehca7DrwOKRQnRRlIdkveHcGU92jrcbJ9TAdqvND4gdChmCY</recordid><startdate>199808</startdate><enddate>199808</enddate><creator>Wallace, R H</creator><creator>Wang, D W</creator><creator>Singh, R</creator><creator>Scheffer, I E</creator><creator>George, Jr, A L</creator><creator>Phillips, H A</creator><creator>Saar, K</creator><creator>Reis, A</creator><creator>Johnson, E W</creator><creator>Sutherland, G R</creator><creator>Berkovic, S F</creator><creator>Mulley, J C</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>199808</creationdate><title>Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B</title><author>Wallace, R H ; Wang, D W ; Singh, R ; Scheffer, I E ; George, Jr, A L ; Phillips, H A ; Saar, K ; Reis, A ; Johnson, E W ; Sutherland, G R ; Berkovic, S F ; Mulley, J C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-g788-3b38166785d3c481d5e379fb28780680065c9d2a76720e23d31ee812fd51c9f93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Chromosomes, Human, Pair 19 - genetics</topic><topic>DNA Mutational Analysis</topic><topic>Epilepsy, Generalized - genetics</topic><topic>Female</topic><topic>Genetic Linkage</topic><topic>Humans</topic><topic>Male</topic><topic>Molecular Sequence Data</topic><topic>Oocytes</topic><topic>Patch-Clamp Techniques</topic><topic>Pedigree</topic><topic>Point Mutation - genetics</topic><topic>Seizures, Febrile - genetics</topic><topic>Sodium Channels - genetics</topic><topic>Sodium Channels - physiology</topic><topic>Tasmania</topic><topic>Xenopus laevis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wallace, R H</creatorcontrib><creatorcontrib>Wang, D W</creatorcontrib><creatorcontrib>Singh, R</creatorcontrib><creatorcontrib>Scheffer, I E</creatorcontrib><creatorcontrib>George, Jr, A L</creatorcontrib><creatorcontrib>Phillips, H A</creatorcontrib><creatorcontrib>Saar, K</creatorcontrib><creatorcontrib>Reis, A</creatorcontrib><creatorcontrib>Johnson, E W</creatorcontrib><creatorcontrib>Sutherland, G R</creatorcontrib><creatorcontrib>Berkovic, S F</creatorcontrib><creatorcontrib>Mulley, J C</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Nature genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wallace, R H</au><au>Wang, D W</au><au>Singh, R</au><au>Scheffer, I E</au><au>George, Jr, A L</au><au>Phillips, H A</au><au>Saar, K</au><au>Reis, A</au><au>Johnson, E W</au><au>Sutherland, G R</au><au>Berkovic, S F</au><au>Mulley, J C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B</atitle><jtitle>Nature genetics</jtitle><addtitle>Nat Genet</addtitle><date>1998-08</date><risdate>1998</risdate><volume>19</volume><issue>4</issue><spage>366</spage><epage>370</epage><pages>366-370</pages><issn>1061-4036</issn><abstract>Febrile seizures affect approximately 3% of all children under six years of age and are by far the most common seizure disorder. A small proportion of children with febrile seizures later develop ongoing epilepsy with afebrile seizures. Segregation analysis suggests the majority of cases have complex inheritance but rare families show apparent autosomal dominant inheritance. Two putative loci have been mapped (FEB1 and FEB2), but specific genes have not yet been identified. We recently described a clinical subset, termed generalized epilepsy with febrile seizures plus (GEFS+), in which many family members have seizures with fever that may persist beyond six years of age or be associated with afebrile generalized seizures. We now report linkage, in another large GEFS+ family, to chromosome region 19q13.1 and identification of a mutation in the voltage-gated sodium (Na+)-channel beta1 subunit gene (SCN1B). The mutation changes a conserved cysteine residue disrupting a putative disulfide bridge which normally maintains an extracellular immunoglobulin-like fold. Co-expression of the mutant beta1 subunit with a brain Na+-channel alpha subunit in Xenopus laevis oocytes demonstrates that the mutation interferes with the ability of the subunit to modulate channel-gating kinetics consistent with a loss-of-function allele. This observation develops the theme that idiopathic epilepsies are a family of channelopathies and raises the possibility of involvement of other Na+-channel subunit genes in febrile seizures and generalized epilepsies with complex inheritance patterns.</abstract><cop>United States</cop><pmid>9697698</pmid><tpages>5</tpages></addata></record> |
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subjects | Amino Acid Sequence Animals Chromosomes, Human, Pair 19 - genetics DNA Mutational Analysis Epilepsy, Generalized - genetics Female Genetic Linkage Humans Male Molecular Sequence Data Oocytes Patch-Clamp Techniques Pedigree Point Mutation - genetics Seizures, Febrile - genetics Sodium Channels - genetics Sodium Channels - physiology Tasmania Xenopus laevis |
title | Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B |
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