Clinical and electrophysiological characterization of a novel mutation R863X in HERG C-terminus associated with long QT syndrome
We have found a novel nonsense mutation in the C-terminus of HERG in a four-generation Chinese family with long QT syndrome and investigated the molecular mechanism of this mutation in vitro. Six family members, including the proband, were clinically affected. Syncope and ventricular tachycardia of...
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Veröffentlicht in: | Journal of molecular medicine (Berlin, Germany) Germany), 2004-03, Vol.82 (3), p.189-196 |
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creator | SIYONG TENG LIJUAN MA RUTAI HUI YINGXUE DONG CHUNXIA LIN JUE YE BÄHRING, Robert VARDANYAN, Vitya YANZONG YANG ZHIHU LIN OLAF PONGS |
description | We have found a novel nonsense mutation in the C-terminus of HERG in a four-generation Chinese family with long QT syndrome and investigated the molecular mechanism of this mutation in vitro. Six family members, including the proband, were clinically affected. Syncope and ventricular tachycardia of torsades de pointes were triggered by startling or emotional stress, and beta-adrenergic blockade treatment was ineffective. Haplotype analysis showed that only LQT2 markers cosegregated with the disease, and sequence analysis revealed a substitution of T with C at nucleotide position 2770 of the HERG gene (U04270), which creates a stop codon at amino acid position 863 (R863X) of the HERG protein, leading to a deletion of 296 amino acids. Whole cell patch clamp studies showed that the R863X HERG could not induce time-dependent current. Coexpression of R863X with wild-type HERG showed reduced current densities and accelerated voltage-dependent inactivation of HERG channels. Subcellular localization of R863X-EGFP revealed that the mutant did not traffic to the cell surface. These data suggest that R863X failed to form functional HERG channels, contributing to a prolongation of the QT interval and long QT syndrome with a dominant phenotype. These findings provide new insights into the structure-function relationships of the HERG C-terminus. |
doi_str_mv | 10.1007/s00109-003-0504-1 |
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Six family members, including the proband, were clinically affected. Syncope and ventricular tachycardia of torsades de pointes were triggered by startling or emotional stress, and beta-adrenergic blockade treatment was ineffective. Haplotype analysis showed that only LQT2 markers cosegregated with the disease, and sequence analysis revealed a substitution of T with C at nucleotide position 2770 of the HERG gene (U04270), which creates a stop codon at amino acid position 863 (R863X) of the HERG protein, leading to a deletion of 296 amino acids. Whole cell patch clamp studies showed that the R863X HERG could not induce time-dependent current. Coexpression of R863X with wild-type HERG showed reduced current densities and accelerated voltage-dependent inactivation of HERG channels. Subcellular localization of R863X-EGFP revealed that the mutant did not traffic to the cell surface. These data suggest that R863X failed to form functional HERG channels, contributing to a prolongation of the QT interval and long QT syndrome with a dominant phenotype. These findings provide new insights into the structure-function relationships of the HERG C-terminus.</description><identifier>ISSN: 0946-2716</identifier><identifier>EISSN: 1432-1440</identifier><identifier>DOI: 10.1007/s00109-003-0504-1</identifier><identifier>PMID: 14714110</identifier><language>eng</language><publisher>Berlin: Springer</publisher><subject>Animals ; Base Sequence ; Biological and medical sciences ; Cardiac dysrhythmias ; Cardiology. Vascular system ; Cation Transport Proteins - chemistry ; Cation Transport Proteins - genetics ; Cell Membrane - metabolism ; CHO Cells ; Cloning, Molecular ; Cricetinae ; DNA Mutational Analysis ; Electrophysiology - methods ; Ether-A-Go-Go Potassium Channels ; Female ; Gene Deletion ; General aspects ; Haplotypes ; Heart ; Humans ; Long QT Syndrome - genetics ; Male ; Medical sciences ; Microscopy, Confocal ; Models, Genetic ; Molecular Sequence Data ; Mutation ; Patch-Clamp Techniques ; Pedigree ; Phenotype ; Potassium Channels - chemistry ; Potassium Channels - genetics ; Potassium Channels, Voltage-Gated ; Protein Structure, Tertiary ; Structure-Activity Relationship ; Time Factors</subject><ispartof>Journal of molecular medicine (Berlin, Germany), 2004-03, Vol.82 (3), p.189-196</ispartof><rights>2004 INIST-CNRS</rights><rights>Springer-Verlag 2004</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-4f212f620350c033dd195ad4030fbc2dea1205d78892f921cb0cc4ee8e9f71df3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,782,786,27931,27932</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15554775$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14714110$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>SIYONG TENG</creatorcontrib><creatorcontrib>LIJUAN MA</creatorcontrib><creatorcontrib>RUTAI HUI</creatorcontrib><creatorcontrib>YINGXUE DONG</creatorcontrib><creatorcontrib>CHUNXIA LIN</creatorcontrib><creatorcontrib>JUE YE</creatorcontrib><creatorcontrib>BÄHRING, Robert</creatorcontrib><creatorcontrib>VARDANYAN, Vitya</creatorcontrib><creatorcontrib>YANZONG YANG</creatorcontrib><creatorcontrib>ZHIHU LIN</creatorcontrib><creatorcontrib>OLAF PONGS</creatorcontrib><title>Clinical and electrophysiological characterization of a novel mutation R863X in HERG C-terminus associated with long QT syndrome</title><title>Journal of molecular medicine (Berlin, Germany)</title><addtitle>J Mol Med (Berl)</addtitle><description>We have found a novel nonsense mutation in the C-terminus of HERG in a four-generation Chinese family with long QT syndrome and investigated the molecular mechanism of this mutation in vitro. Six family members, including the proband, were clinically affected. Syncope and ventricular tachycardia of torsades de pointes were triggered by startling or emotional stress, and beta-adrenergic blockade treatment was ineffective. Haplotype analysis showed that only LQT2 markers cosegregated with the disease, and sequence analysis revealed a substitution of T with C at nucleotide position 2770 of the HERG gene (U04270), which creates a stop codon at amino acid position 863 (R863X) of the HERG protein, leading to a deletion of 296 amino acids. Whole cell patch clamp studies showed that the R863X HERG could not induce time-dependent current. Coexpression of R863X with wild-type HERG showed reduced current densities and accelerated voltage-dependent inactivation of HERG channels. Subcellular localization of R863X-EGFP revealed that the mutant did not traffic to the cell surface. These data suggest that R863X failed to form functional HERG channels, contributing to a prolongation of the QT interval and long QT syndrome with a dominant phenotype. These findings provide new insights into the structure-function relationships of the HERG C-terminus.</description><subject>Animals</subject><subject>Base Sequence</subject><subject>Biological and medical sciences</subject><subject>Cardiac dysrhythmias</subject><subject>Cardiology. Vascular system</subject><subject>Cation Transport Proteins - chemistry</subject><subject>Cation Transport Proteins - genetics</subject><subject>Cell Membrane - metabolism</subject><subject>CHO Cells</subject><subject>Cloning, Molecular</subject><subject>Cricetinae</subject><subject>DNA Mutational Analysis</subject><subject>Electrophysiology - methods</subject><subject>Ether-A-Go-Go Potassium Channels</subject><subject>Female</subject><subject>Gene Deletion</subject><subject>General aspects</subject><subject>Haplotypes</subject><subject>Heart</subject><subject>Humans</subject><subject>Long QT Syndrome - genetics</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Microscopy, Confocal</subject><subject>Models, Genetic</subject><subject>Molecular Sequence Data</subject><subject>Mutation</subject><subject>Patch-Clamp Techniques</subject><subject>Pedigree</subject><subject>Phenotype</subject><subject>Potassium Channels - chemistry</subject><subject>Potassium Channels - genetics</subject><subject>Potassium Channels, Voltage-Gated</subject><subject>Protein Structure, Tertiary</subject><subject>Structure-Activity Relationship</subject><subject>Time Factors</subject><issn>0946-2716</issn><issn>1432-1440</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNpdkV1rVDEQhoModlv9Ad5IEOzd0cnXycmlLLUVCmKp4F3I5qObck6yJudU1it_uqm7UPBqYOaZYXgfhN4Q-EAA5McKQEB1AKwDAbwjz9CKcEY7wjk8RytQvO-oJP0JOq31vtFSKP4SnRAuCScEVujPeowpWjNikxz2o7dzybvtvsY85rt_A7s1xdjZl_jbzDEnnAM2OOUHP-JpmQ-9m6FnP3BM-Ori5hKvu4ZPMS0Vm1qzjWb2Dv-K8xaPOd3hb7e47pMrefKv0ItgxupfH-sZ-v754nZ91V1_vfyy_nTdWSb6ueOBEhp6CkyABcacI0oYx4FB2FjqvCEUhJPDoGhQlNgNWMu9H7wKkrjAztD54e6u5J-Lr7OeYrV-HE3yeam6paR6YLKB7_4D7_NSUvtNUyL7AbhSDSIHyJZca_FB70qcTNlrAvrRjT640c2NfnSjSdt5ezy8bCbvnjaOMhrw_giY2oIPxSQb6xMnhOBSCvYXjZaXFA</recordid><startdate>20040301</startdate><enddate>20040301</enddate><creator>SIYONG TENG</creator><creator>LIJUAN MA</creator><creator>RUTAI HUI</creator><creator>YINGXUE DONG</creator><creator>CHUNXIA LIN</creator><creator>JUE YE</creator><creator>BÄHRING, Robert</creator><creator>VARDANYAN, Vitya</creator><creator>YANZONG YANG</creator><creator>ZHIHU LIN</creator><creator>OLAF PONGS</creator><general>Springer</general><general>Springer Nature B.V</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>20040301</creationdate><title>Clinical and electrophysiological characterization of a novel mutation R863X in HERG C-terminus associated with long QT syndrome</title><author>SIYONG TENG ; LIJUAN MA ; RUTAI HUI ; YINGXUE DONG ; CHUNXIA LIN ; JUE YE ; BÄHRING, Robert ; VARDANYAN, Vitya ; YANZONG YANG ; ZHIHU LIN ; OLAF PONGS</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-4f212f620350c033dd195ad4030fbc2dea1205d78892f921cb0cc4ee8e9f71df3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Animals</topic><topic>Base Sequence</topic><topic>Biological and medical sciences</topic><topic>Cardiac dysrhythmias</topic><topic>Cardiology. Vascular system</topic><topic>Cation Transport Proteins - chemistry</topic><topic>Cation Transport Proteins - genetics</topic><topic>Cell Membrane - metabolism</topic><topic>CHO Cells</topic><topic>Cloning, Molecular</topic><topic>Cricetinae</topic><topic>DNA Mutational Analysis</topic><topic>Electrophysiology - methods</topic><topic>Ether-A-Go-Go Potassium Channels</topic><topic>Female</topic><topic>Gene Deletion</topic><topic>General aspects</topic><topic>Haplotypes</topic><topic>Heart</topic><topic>Humans</topic><topic>Long QT Syndrome - genetics</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Microscopy, Confocal</topic><topic>Models, Genetic</topic><topic>Molecular Sequence Data</topic><topic>Mutation</topic><topic>Patch-Clamp Techniques</topic><topic>Pedigree</topic><topic>Phenotype</topic><topic>Potassium Channels - chemistry</topic><topic>Potassium Channels - genetics</topic><topic>Potassium Channels, Voltage-Gated</topic><topic>Protein Structure, Tertiary</topic><topic>Structure-Activity Relationship</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>SIYONG TENG</creatorcontrib><creatorcontrib>LIJUAN MA</creatorcontrib><creatorcontrib>RUTAI HUI</creatorcontrib><creatorcontrib>YINGXUE DONG</creatorcontrib><creatorcontrib>CHUNXIA LIN</creatorcontrib><creatorcontrib>JUE YE</creatorcontrib><creatorcontrib>BÄHRING, Robert</creatorcontrib><creatorcontrib>VARDANYAN, Vitya</creatorcontrib><creatorcontrib>YANZONG YANG</creatorcontrib><creatorcontrib>ZHIHU LIN</creatorcontrib><creatorcontrib>OLAF PONGS</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of molecular medicine (Berlin, Germany)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>SIYONG TENG</au><au>LIJUAN MA</au><au>RUTAI HUI</au><au>YINGXUE DONG</au><au>CHUNXIA LIN</au><au>JUE YE</au><au>BÄHRING, Robert</au><au>VARDANYAN, Vitya</au><au>YANZONG YANG</au><au>ZHIHU LIN</au><au>OLAF PONGS</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Clinical and electrophysiological characterization of a novel mutation R863X in HERG C-terminus associated with long QT syndrome</atitle><jtitle>Journal of molecular medicine (Berlin, Germany)</jtitle><addtitle>J Mol Med (Berl)</addtitle><date>2004-03-01</date><risdate>2004</risdate><volume>82</volume><issue>3</issue><spage>189</spage><epage>196</epage><pages>189-196</pages><issn>0946-2716</issn><eissn>1432-1440</eissn><abstract>We have found a novel nonsense mutation in the C-terminus of HERG in a four-generation Chinese family with long QT syndrome and investigated the molecular mechanism of this mutation in vitro. Six family members, including the proband, were clinically affected. Syncope and ventricular tachycardia of torsades de pointes were triggered by startling or emotional stress, and beta-adrenergic blockade treatment was ineffective. Haplotype analysis showed that only LQT2 markers cosegregated with the disease, and sequence analysis revealed a substitution of T with C at nucleotide position 2770 of the HERG gene (U04270), which creates a stop codon at amino acid position 863 (R863X) of the HERG protein, leading to a deletion of 296 amino acids. Whole cell patch clamp studies showed that the R863X HERG could not induce time-dependent current. Coexpression of R863X with wild-type HERG showed reduced current densities and accelerated voltage-dependent inactivation of HERG channels. Subcellular localization of R863X-EGFP revealed that the mutant did not traffic to the cell surface. These data suggest that R863X failed to form functional HERG channels, contributing to a prolongation of the QT interval and long QT syndrome with a dominant phenotype. These findings provide new insights into the structure-function relationships of the HERG C-terminus.</abstract><cop>Berlin</cop><pub>Springer</pub><pmid>14714110</pmid><doi>10.1007/s00109-003-0504-1</doi><tpages>8</tpages></addata></record> |
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subjects | Animals Base Sequence Biological and medical sciences Cardiac dysrhythmias Cardiology. Vascular system Cation Transport Proteins - chemistry Cation Transport Proteins - genetics Cell Membrane - metabolism CHO Cells Cloning, Molecular Cricetinae DNA Mutational Analysis Electrophysiology - methods Ether-A-Go-Go Potassium Channels Female Gene Deletion General aspects Haplotypes Heart Humans Long QT Syndrome - genetics Male Medical sciences Microscopy, Confocal Models, Genetic Molecular Sequence Data Mutation Patch-Clamp Techniques Pedigree Phenotype Potassium Channels - chemistry Potassium Channels - genetics Potassium Channels, Voltage-Gated Protein Structure, Tertiary Structure-Activity Relationship Time Factors |
title | Clinical and electrophysiological characterization of a novel mutation R863X in HERG C-terminus associated with long QT syndrome |
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