Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K(ATP) channel Kir6.1 as a pathogenic substrate for J-wave syndromes
J-wave syndromes have emerged conceptually to encompass the pleiotropic expression of J-point abnormalities including Brugada syndrome (BrS) and early repolarization syndrome (ERS). KCNJ8, which encodes the cardiac K(ATP) Kir6.1 channel, recently has been implicated in ERS following identification o...
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| Veröffentlicht in: | Heart rhythm 2010-10, Vol.7 (10), p.1466 |
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| creator | Medeiros-Domingo, Argelia Tan, Bi-Hua Crotti, Lia Tester, David J Eckhardt, Lee Cuoretti, Alessandra Kroboth, Stacie L Song, Chunhua Zhou, Qing Kopp, Doug Schwartz, Peter J Makielski, Jonathan C Ackerman, Michael J |
| description | J-wave syndromes have emerged conceptually to encompass the pleiotropic expression of J-point abnormalities including Brugada syndrome (BrS) and early repolarization syndrome (ERS). KCNJ8, which encodes the cardiac K(ATP) Kir6.1 channel, recently has been implicated in ERS following identification of the functionally uncharacterized missense mutation S422L.
The purpose of this study was to further explore KCNJ8 as a novel susceptibility gene for J-wave syndromes.
Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, comprehensive open reading frame/splice site mutational analysis of KCNJ8 was performed in 101 unrelated patients with J-wave syndromes, including 87 with BrS and 14 with ERS. Six hundred healthy individuals were examined to assess the allelic frequency for all variants detected. KCNJ8 mutation(s) was engineered by site-directed mutagenesis and coexpressed heterologously with SUR2A in COS-1 cells. Ion currents were recorded using whole-cell configuration of the patch-clamp technique.
One BrS case and one ERS case hosted the identical missense mutation S422L, which was reported previously. KCNJ8-S422L involves a highly conserved residue and was absent in 1,200 reference alleles. Both cases were negative for mutations in all known BrS and ERS susceptibility genes. K(ATP) current of the Kir6.1-S422L mutation was increased significantly over the voltage range from 0 to 40 mV compared to Kir6.1-WT channels (n = 16-21; P |
| doi_str_mv | 10.1016/j.hrthm.2010.06.016 |
| format | Article |
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The purpose of this study was to further explore KCNJ8 as a novel susceptibility gene for J-wave syndromes.
Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, comprehensive open reading frame/splice site mutational analysis of KCNJ8 was performed in 101 unrelated patients with J-wave syndromes, including 87 with BrS and 14 with ERS. Six hundred healthy individuals were examined to assess the allelic frequency for all variants detected. KCNJ8 mutation(s) was engineered by site-directed mutagenesis and coexpressed heterologously with SUR2A in COS-1 cells. Ion currents were recorded using whole-cell configuration of the patch-clamp technique.
One BrS case and one ERS case hosted the identical missense mutation S422L, which was reported previously. KCNJ8-S422L involves a highly conserved residue and was absent in 1,200 reference alleles. Both cases were negative for mutations in all known BrS and ERS susceptibility genes. K(ATP) current of the Kir6.1-S422L mutation was increased significantly over the voltage range from 0 to 40 mV compared to Kir6.1-WT channels (n = 16-21; P <.05).
These findings further implicate KCNJ8 as a novel J-wave syndrome susceptibility gene and a marked gain of function in the cardiac K(ATP) Kir6.1 channel secondary to KCNJ8-S422L as a novel pathogenic mechanism for the phenotypic expression of both BrS and ERS.</description><identifier>EISSN: 1556-3871</identifier><identifier>DOI: 10.1016/j.hrthm.2010.06.016</identifier><identifier>PMID: 20558321</identifier><language>eng</language><publisher>United States</publisher><subject>Adult ; Arrhythmias, Cardiac - genetics ; Arrhythmias, Cardiac - physiopathology ; Brugada Syndrome - genetics ; Brugada Syndrome - physiopathology ; Cells, Cultured ; Chromatography, High Pressure Liquid ; Computers, Handheld ; DNA Mutational Analysis ; Electrocardiography ; Female ; Genetic Predisposition to Disease - genetics ; Humans ; KATP Channels - metabolism ; Male ; Mutagenesis, Site-Directed ; Mutation, Missense ; Myocardium - metabolism ; Potassium Channels, Inwardly Rectifying - genetics ; Sequence Analysis, DNA ; Transfection</subject><ispartof>Heart rhythm, 2010-10, Vol.7 (10), p.1466</ispartof><rights>Copyright © 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20558321$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Medeiros-Domingo, Argelia</creatorcontrib><creatorcontrib>Tan, Bi-Hua</creatorcontrib><creatorcontrib>Crotti, Lia</creatorcontrib><creatorcontrib>Tester, David J</creatorcontrib><creatorcontrib>Eckhardt, Lee</creatorcontrib><creatorcontrib>Cuoretti, Alessandra</creatorcontrib><creatorcontrib>Kroboth, Stacie L</creatorcontrib><creatorcontrib>Song, Chunhua</creatorcontrib><creatorcontrib>Zhou, Qing</creatorcontrib><creatorcontrib>Kopp, Doug</creatorcontrib><creatorcontrib>Schwartz, Peter J</creatorcontrib><creatorcontrib>Makielski, Jonathan C</creatorcontrib><creatorcontrib>Ackerman, Michael J</creatorcontrib><title>Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K(ATP) channel Kir6.1 as a pathogenic substrate for J-wave syndromes</title><title>Heart rhythm</title><addtitle>Heart Rhythm</addtitle><description>J-wave syndromes have emerged conceptually to encompass the pleiotropic expression of J-point abnormalities including Brugada syndrome (BrS) and early repolarization syndrome (ERS). KCNJ8, which encodes the cardiac K(ATP) Kir6.1 channel, recently has been implicated in ERS following identification of the functionally uncharacterized missense mutation S422L.
The purpose of this study was to further explore KCNJ8 as a novel susceptibility gene for J-wave syndromes.
Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, comprehensive open reading frame/splice site mutational analysis of KCNJ8 was performed in 101 unrelated patients with J-wave syndromes, including 87 with BrS and 14 with ERS. Six hundred healthy individuals were examined to assess the allelic frequency for all variants detected. KCNJ8 mutation(s) was engineered by site-directed mutagenesis and coexpressed heterologously with SUR2A in COS-1 cells. Ion currents were recorded using whole-cell configuration of the patch-clamp technique.
One BrS case and one ERS case hosted the identical missense mutation S422L, which was reported previously. KCNJ8-S422L involves a highly conserved residue and was absent in 1,200 reference alleles. Both cases were negative for mutations in all known BrS and ERS susceptibility genes. K(ATP) current of the Kir6.1-S422L mutation was increased significantly over the voltage range from 0 to 40 mV compared to Kir6.1-WT channels (n = 16-21; P <.05).
These findings further implicate KCNJ8 as a novel J-wave syndrome susceptibility gene and a marked gain of function in the cardiac K(ATP) Kir6.1 channel secondary to KCNJ8-S422L as a novel pathogenic mechanism for the phenotypic expression of both BrS and ERS.</description><subject>Adult</subject><subject>Arrhythmias, Cardiac - genetics</subject><subject>Arrhythmias, Cardiac - physiopathology</subject><subject>Brugada Syndrome - genetics</subject><subject>Brugada Syndrome - physiopathology</subject><subject>Cells, Cultured</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Computers, Handheld</subject><subject>DNA Mutational Analysis</subject><subject>Electrocardiography</subject><subject>Female</subject><subject>Genetic Predisposition to Disease - genetics</subject><subject>Humans</subject><subject>KATP Channels - metabolism</subject><subject>Male</subject><subject>Mutagenesis, Site-Directed</subject><subject>Mutation, Missense</subject><subject>Myocardium - metabolism</subject><subject>Potassium Channels, Inwardly Rectifying - genetics</subject><subject>Sequence Analysis, DNA</subject><subject>Transfection</subject><issn>1556-3871</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kL1OwzAYRS0kREvhCZCQRxgc_JM4yVhVUGgrQKJ79dX-QlI1TmQ7oI68ORU_07k6wx0OIVeCJ4ILfbdLah_rNpH8aLhOju6EjEWWaaaKXIzIeQg7zmWpuTojI8mzrFBSjMnXHBrHuopVgzOx6Rxthwg_4y2VckUbR2ONdDl7XhQMneksWmrA2wYMXd5M16-31NTgHO7psvE6ERQCBdpDrLt3dI2hYdiG6CEirTpPF-wTPpCGg7O-azFckNMK9gEv_zgh64f79eyRrV7mT7PpivVZJhiWqDBFVSorFGba5LnOQWmtbQU6FdJwXkqVgzbWQGpBWCNKlSuFpqg4qgm5_r3th22LdtP7pgV_2PynUN9LpF9X</recordid><startdate>201010</startdate><enddate>201010</enddate><creator>Medeiros-Domingo, Argelia</creator><creator>Tan, Bi-Hua</creator><creator>Crotti, Lia</creator><creator>Tester, David J</creator><creator>Eckhardt, Lee</creator><creator>Cuoretti, Alessandra</creator><creator>Kroboth, Stacie L</creator><creator>Song, Chunhua</creator><creator>Zhou, Qing</creator><creator>Kopp, Doug</creator><creator>Schwartz, Peter J</creator><creator>Makielski, Jonathan C</creator><creator>Ackerman, Michael J</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>201010</creationdate><title>Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K(ATP) channel Kir6.1 as a pathogenic substrate for J-wave syndromes</title><author>Medeiros-Domingo, Argelia ; Tan, Bi-Hua ; Crotti, Lia ; Tester, David J ; Eckhardt, Lee ; Cuoretti, Alessandra ; Kroboth, Stacie L ; Song, Chunhua ; Zhou, Qing ; Kopp, Doug ; Schwartz, Peter J ; Makielski, Jonathan C ; Ackerman, Michael J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p551-e9e3e4e393d13e56c7767a3666dfa6412c009237a6cdca4da1dc193733ec8f0e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Adult</topic><topic>Arrhythmias, Cardiac - genetics</topic><topic>Arrhythmias, Cardiac - physiopathology</topic><topic>Brugada Syndrome - genetics</topic><topic>Brugada Syndrome - physiopathology</topic><topic>Cells, Cultured</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Computers, Handheld</topic><topic>DNA Mutational Analysis</topic><topic>Electrocardiography</topic><topic>Female</topic><topic>Genetic Predisposition to Disease - genetics</topic><topic>Humans</topic><topic>KATP Channels - metabolism</topic><topic>Male</topic><topic>Mutagenesis, Site-Directed</topic><topic>Mutation, Missense</topic><topic>Myocardium - metabolism</topic><topic>Potassium Channels, Inwardly Rectifying - genetics</topic><topic>Sequence Analysis, DNA</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Medeiros-Domingo, Argelia</creatorcontrib><creatorcontrib>Tan, Bi-Hua</creatorcontrib><creatorcontrib>Crotti, Lia</creatorcontrib><creatorcontrib>Tester, David J</creatorcontrib><creatorcontrib>Eckhardt, Lee</creatorcontrib><creatorcontrib>Cuoretti, Alessandra</creatorcontrib><creatorcontrib>Kroboth, Stacie L</creatorcontrib><creatorcontrib>Song, Chunhua</creatorcontrib><creatorcontrib>Zhou, Qing</creatorcontrib><creatorcontrib>Kopp, Doug</creatorcontrib><creatorcontrib>Schwartz, Peter J</creatorcontrib><creatorcontrib>Makielski, Jonathan C</creatorcontrib><creatorcontrib>Ackerman, Michael J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Heart rhythm</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Medeiros-Domingo, Argelia</au><au>Tan, Bi-Hua</au><au>Crotti, Lia</au><au>Tester, David J</au><au>Eckhardt, Lee</au><au>Cuoretti, Alessandra</au><au>Kroboth, Stacie L</au><au>Song, Chunhua</au><au>Zhou, Qing</au><au>Kopp, Doug</au><au>Schwartz, Peter J</au><au>Makielski, Jonathan C</au><au>Ackerman, Michael J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K(ATP) channel Kir6.1 as a pathogenic substrate for J-wave syndromes</atitle><jtitle>Heart rhythm</jtitle><addtitle>Heart Rhythm</addtitle><date>2010-10</date><risdate>2010</risdate><volume>7</volume><issue>10</issue><spage>1466</spage><pages>1466-</pages><eissn>1556-3871</eissn><abstract>J-wave syndromes have emerged conceptually to encompass the pleiotropic expression of J-point abnormalities including Brugada syndrome (BrS) and early repolarization syndrome (ERS). KCNJ8, which encodes the cardiac K(ATP) Kir6.1 channel, recently has been implicated in ERS following identification of the functionally uncharacterized missense mutation S422L.
The purpose of this study was to further explore KCNJ8 as a novel susceptibility gene for J-wave syndromes.
Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, comprehensive open reading frame/splice site mutational analysis of KCNJ8 was performed in 101 unrelated patients with J-wave syndromes, including 87 with BrS and 14 with ERS. Six hundred healthy individuals were examined to assess the allelic frequency for all variants detected. KCNJ8 mutation(s) was engineered by site-directed mutagenesis and coexpressed heterologously with SUR2A in COS-1 cells. Ion currents were recorded using whole-cell configuration of the patch-clamp technique.
One BrS case and one ERS case hosted the identical missense mutation S422L, which was reported previously. KCNJ8-S422L involves a highly conserved residue and was absent in 1,200 reference alleles. Both cases were negative for mutations in all known BrS and ERS susceptibility genes. K(ATP) current of the Kir6.1-S422L mutation was increased significantly over the voltage range from 0 to 40 mV compared to Kir6.1-WT channels (n = 16-21; P <.05).
These findings further implicate KCNJ8 as a novel J-wave syndrome susceptibility gene and a marked gain of function in the cardiac K(ATP) Kir6.1 channel secondary to KCNJ8-S422L as a novel pathogenic mechanism for the phenotypic expression of both BrS and ERS.</abstract><cop>United States</cop><pmid>20558321</pmid><doi>10.1016/j.hrthm.2010.06.016</doi></addata></record> |
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| ispartof | Heart rhythm, 2010-10, Vol.7 (10), p.1466 |
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| subjects | Adult Arrhythmias, Cardiac - genetics Arrhythmias, Cardiac - physiopathology Brugada Syndrome - genetics Brugada Syndrome - physiopathology Cells, Cultured Chromatography, High Pressure Liquid Computers, Handheld DNA Mutational Analysis Electrocardiography Female Genetic Predisposition to Disease - genetics Humans KATP Channels - metabolism Male Mutagenesis, Site-Directed Mutation, Missense Myocardium - metabolism Potassium Channels, Inwardly Rectifying - genetics Sequence Analysis, DNA Transfection |
| title | Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K(ATP) channel Kir6.1 as a pathogenic substrate for J-wave syndromes |
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