R534C mutation in hERG causes a trafficking defect in iPSC-derived cardiomyocytes from patients with type 2 long QT syndrome
Patient-specific cardiomyocytes obtained from induced pluripotent stem cells (CM-iPSC) offer unprecedented mechanistic insights in the study of inherited cardiac diseases. The objective of this work was to study a type 2 long QT syndrome (LQTS2)-associated mutation (c.1600C > T in KCNH2, p.R534C...
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| creator | Mesquita, Fernanda C. P. Arantes, Paulo C. Kasai-Brunswick, Tais H. Araujo, Dayana S. Gubert, Fernanda Monnerat, Gustavo Silva dos Santos, Danúbia Neiman, Gabriel Leitão, Isabela C. Barbosa, Raiana A. Q. Coutinho, Jorge L. Vaz, Isadora M. dos Santos, Marcus N. Borgonovo, Tamara Cruz, Fernando E. S. Miriuka, Santiago Medei, Emiliano H. Campos de Carvalho, Antonio C. Carvalho, Adriana B. |
| description | Patient-specific cardiomyocytes obtained from induced pluripotent stem cells (CM-iPSC) offer unprecedented mechanistic insights in the study of inherited cardiac diseases. The objective of this work was to study a type 2 long QT syndrome (LQTS2)-associated mutation (c.1600C > T in KCNH2, p.R534C in hERG) in CM-iPSC. Peripheral blood mononuclear cells were isolated from two patients with the R534C mutation and iPSCs were generated. In addition, the same mutation was inserted in a control iPSC line by genome editing using CRISPR/Cas9. Cells expressed pluripotency markers and showed spontaneous differentiation into the three embryonic germ layers. Electrophysiology demonstrated that action potential duration (APD) of LQTS2 CM-iPSC was significantly longer than that of the control line, as well as the triangulation of the action potentials (AP), implying a longer duration of phase 3. Treatment with the I
Kr
inhibitor E4031 only caused APD prolongation in the control line. Patch clamp showed a reduction of I
Kr
on LQTS2 CM-iPSC compared to control, but channel activation was not significantly affected. Immunofluorescence for hERG demonstrated perinuclear staining in LQTS2 CM-iPSC. In conclusion, CM-iPSC recapitulated the LQTS2 phenotype and our findings suggest that the R534C mutation in KCNH2 leads to a channel trafficking defect to the plasma membrane. |
| doi_str_mv | 10.1038/s41598-019-55837-w |
| format | Article |
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Kr
inhibitor E4031 only caused APD prolongation in the control line. Patch clamp showed a reduction of I
Kr
on LQTS2 CM-iPSC compared to control, but channel activation was not significantly affected. Immunofluorescence for hERG demonstrated perinuclear staining in LQTS2 CM-iPSC. In conclusion, CM-iPSC recapitulated the LQTS2 phenotype and our findings suggest that the R534C mutation in KCNH2 leads to a channel trafficking defect to the plasma membrane.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-019-55837-w</identifier><identifier>PMID: 31844156</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/100 ; 13/106 ; 13/109 ; 13/44 ; 38/23 ; 631/532/1360 ; 631/532/2064/2158 ; 631/57/2270/1140 ; 631/80/304 ; 9/74 ; Action Potentials - genetics ; Adolescent ; Adult ; Cardiomyocytes ; Cell Membrane - genetics ; ERG1 Potassium Channel - genetics ; Female ; Gene Editing - methods ; Genome editing ; Humanities and Social Sciences ; Humans ; Induced Pluripotent Stem Cells - physiology ; Leukocytes, Mononuclear - physiology ; Long QT syndrome ; Long QT Syndrome - genetics ; Male ; multidisciplinary ; Mutation ; Mutation - genetics ; Myocytes, Cardiac - physiology ; Phenotype ; Protein Transport - genetics ; Science ; Science (multidisciplinary) ; Stem cells ; Young Adult</subject><ispartof>Scientific reports, 2019-12, Vol.9 (1), p.19203-9, Article 19203</ispartof><rights>The Author(s) 2019</rights><rights>2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-61838955fdbb0ab9b21a591084e3c6840cf113def024e1f749899728db86c3063</citedby><cites>FETCH-LOGICAL-c474t-61838955fdbb0ab9b21a591084e3c6840cf113def024e1f749899728db86c3063</cites><orcidid>0000-0002-7830-7868 ; 0000-0002-0062-3043</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915575/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915575/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31844156$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mesquita, Fernanda C. P.</creatorcontrib><creatorcontrib>Arantes, Paulo C.</creatorcontrib><creatorcontrib>Kasai-Brunswick, Tais H.</creatorcontrib><creatorcontrib>Araujo, Dayana S.</creatorcontrib><creatorcontrib>Gubert, Fernanda</creatorcontrib><creatorcontrib>Monnerat, Gustavo</creatorcontrib><creatorcontrib>Silva dos Santos, Danúbia</creatorcontrib><creatorcontrib>Neiman, Gabriel</creatorcontrib><creatorcontrib>Leitão, Isabela C.</creatorcontrib><creatorcontrib>Barbosa, Raiana A. Q.</creatorcontrib><creatorcontrib>Coutinho, Jorge L.</creatorcontrib><creatorcontrib>Vaz, Isadora M.</creatorcontrib><creatorcontrib>dos Santos, Marcus N.</creatorcontrib><creatorcontrib>Borgonovo, Tamara</creatorcontrib><creatorcontrib>Cruz, Fernando E. S.</creatorcontrib><creatorcontrib>Miriuka, Santiago</creatorcontrib><creatorcontrib>Medei, Emiliano H.</creatorcontrib><creatorcontrib>Campos de Carvalho, Antonio C.</creatorcontrib><creatorcontrib>Carvalho, Adriana B.</creatorcontrib><title>R534C mutation in hERG causes a trafficking defect in iPSC-derived cardiomyocytes from patients with type 2 long QT syndrome</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Patient-specific cardiomyocytes obtained from induced pluripotent stem cells (CM-iPSC) offer unprecedented mechanistic insights in the study of inherited cardiac diseases. The objective of this work was to study a type 2 long QT syndrome (LQTS2)-associated mutation (c.1600C > T in KCNH2, p.R534C in hERG) in CM-iPSC. Peripheral blood mononuclear cells were isolated from two patients with the R534C mutation and iPSCs were generated. In addition, the same mutation was inserted in a control iPSC line by genome editing using CRISPR/Cas9. Cells expressed pluripotency markers and showed spontaneous differentiation into the three embryonic germ layers. Electrophysiology demonstrated that action potential duration (APD) of LQTS2 CM-iPSC was significantly longer than that of the control line, as well as the triangulation of the action potentials (AP), implying a longer duration of phase 3. Treatment with the I
Kr
inhibitor E4031 only caused APD prolongation in the control line. Patch clamp showed a reduction of I
Kr
on LQTS2 CM-iPSC compared to control, but channel activation was not significantly affected. Immunofluorescence for hERG demonstrated perinuclear staining in LQTS2 CM-iPSC. In conclusion, CM-iPSC recapitulated the LQTS2 phenotype and our findings suggest that the R534C mutation in KCNH2 leads to a channel trafficking defect to the plasma membrane.</description><subject>13/100</subject><subject>13/106</subject><subject>13/109</subject><subject>13/44</subject><subject>38/23</subject><subject>631/532/1360</subject><subject>631/532/2064/2158</subject><subject>631/57/2270/1140</subject><subject>631/80/304</subject><subject>9/74</subject><subject>Action Potentials - genetics</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Cardiomyocytes</subject><subject>Cell Membrane - genetics</subject><subject>ERG1 Potassium Channel - genetics</subject><subject>Female</subject><subject>Gene Editing - methods</subject><subject>Genome editing</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Induced Pluripotent Stem Cells - physiology</subject><subject>Leukocytes, Mononuclear - physiology</subject><subject>Long QT syndrome</subject><subject>Long QT Syndrome - genetics</subject><subject>Male</subject><subject>multidisciplinary</subject><subject>Mutation</subject><subject>Mutation - genetics</subject><subject>Myocytes, Cardiac - physiology</subject><subject>Phenotype</subject><subject>Protein Transport - genetics</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Stem cells</subject><subject>Young Adult</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kU9vFSEUxYnR2Kb2C7gwJG7cTOXvDGxMzEutTZqota4Jw8B71Bl4AtOXSfzw0r5aqwvZQHJ_59x7OQC8xOgEIyreZoa5FA3CsuFc0K7ZPQGHBDHeEErI00fvA3Cc8zWqhxPJsHwODigWrOrbQ_DzklO2gtNcdPExQB_g5vTyDBo9Z5uhhiVp57z57sMaDtZZU24Z__nrqhls8jd2qGwafJyWaJZSNS7FCW6rnQ0lw50vG1iWrYUEjrGafLmCeQlDhewL8MzpMdvj-_sIfPtwerX62Fx8Ojtfvb9oDOtYaVosqJCcu6Hvke5lT7DmEiPBLDWtYMg4jGkdDhFmseuYFFJ2RAy9aA1FLT0C7_a-27mf7GDqYEmPapv8pNOiovbq70rwG7WON6qVmPOOV4M39wYp_phtLmry2dhx1MHGOav6zZ2kbdeKir7-B72Ocwp1vTuK0o5IUimyp0yKOSfrHobBSN3mq_b5qpqvustX7aro1eM1HiS_06wA3QO5lsLapj-9_2P7C4qdsTo</recordid><startdate>20191216</startdate><enddate>20191216</enddate><creator>Mesquita, Fernanda C. 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P. ; Arantes, Paulo C. ; Kasai-Brunswick, Tais H. ; Araujo, Dayana S. ; Gubert, Fernanda ; Monnerat, Gustavo ; Silva dos Santos, Danúbia ; Neiman, Gabriel ; Leitão, Isabela C. ; Barbosa, Raiana A. Q. ; Coutinho, Jorge L. ; Vaz, Isadora M. ; dos Santos, Marcus N. ; Borgonovo, Tamara ; Cruz, Fernando E. 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P.</au><au>Arantes, Paulo C.</au><au>Kasai-Brunswick, Tais H.</au><au>Araujo, Dayana S.</au><au>Gubert, Fernanda</au><au>Monnerat, Gustavo</au><au>Silva dos Santos, Danúbia</au><au>Neiman, Gabriel</au><au>Leitão, Isabela C.</au><au>Barbosa, Raiana A. Q.</au><au>Coutinho, Jorge L.</au><au>Vaz, Isadora M.</au><au>dos Santos, Marcus N.</au><au>Borgonovo, Tamara</au><au>Cruz, Fernando E. S.</au><au>Miriuka, Santiago</au><au>Medei, Emiliano H.</au><au>Campos de Carvalho, Antonio C.</au><au>Carvalho, Adriana B.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>R534C mutation in hERG causes a trafficking defect in iPSC-derived cardiomyocytes from patients with type 2 long QT syndrome</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2019-12-16</date><risdate>2019</risdate><volume>9</volume><issue>1</issue><spage>19203</spage><epage>9</epage><pages>19203-9</pages><artnum>19203</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Patient-specific cardiomyocytes obtained from induced pluripotent stem cells (CM-iPSC) offer unprecedented mechanistic insights in the study of inherited cardiac diseases. The objective of this work was to study a type 2 long QT syndrome (LQTS2)-associated mutation (c.1600C > T in KCNH2, p.R534C in hERG) in CM-iPSC. Peripheral blood mononuclear cells were isolated from two patients with the R534C mutation and iPSCs were generated. In addition, the same mutation was inserted in a control iPSC line by genome editing using CRISPR/Cas9. Cells expressed pluripotency markers and showed spontaneous differentiation into the three embryonic germ layers. Electrophysiology demonstrated that action potential duration (APD) of LQTS2 CM-iPSC was significantly longer than that of the control line, as well as the triangulation of the action potentials (AP), implying a longer duration of phase 3. Treatment with the I
Kr
inhibitor E4031 only caused APD prolongation in the control line. Patch clamp showed a reduction of I
Kr
on LQTS2 CM-iPSC compared to control, but channel activation was not significantly affected. Immunofluorescence for hERG demonstrated perinuclear staining in LQTS2 CM-iPSC. In conclusion, CM-iPSC recapitulated the LQTS2 phenotype and our findings suggest that the R534C mutation in KCNH2 leads to a channel trafficking defect to the plasma membrane.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>31844156</pmid><doi>10.1038/s41598-019-55837-w</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-7830-7868</orcidid><orcidid>https://orcid.org/0000-0002-0062-3043</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Scientific reports, 2019-12, Vol.9 (1), p.19203-9, Article 19203 |
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| language | eng |
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| source | MEDLINE; Nature Free; Full-Text Journals in Chemistry (Open access); PubMed Central; Directory of Open Access Journals; Alma/SFX Local Collection; EZB Electronic Journals Library; Springer Nature OA Free Journals |
| subjects | 13/100 13/106 13/109 13/44 38/23 631/532/1360 631/532/2064/2158 631/57/2270/1140 631/80/304 9/74 Action Potentials - genetics Adolescent Adult Cardiomyocytes Cell Membrane - genetics ERG1 Potassium Channel - genetics Female Gene Editing - methods Genome editing Humanities and Social Sciences Humans Induced Pluripotent Stem Cells - physiology Leukocytes, Mononuclear - physiology Long QT syndrome Long QT Syndrome - genetics Male multidisciplinary Mutation Mutation - genetics Myocytes, Cardiac - physiology Phenotype Protein Transport - genetics Science Science (multidisciplinary) Stem cells Young Adult |
| title | R534C mutation in hERG causes a trafficking defect in iPSC-derived cardiomyocytes from patients with type 2 long QT syndrome |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T16%3A27%3A00IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=R534C%20mutation%20in%20hERG%20causes%20a%20trafficking%20defect%20in%20iPSC-derived%20cardiomyocytes%20from%20patients%20with%20type%202%20long%20QT%20syndrome&rft.jtitle=Scientific%20reports&rft.au=Mesquita,%20Fernanda%20C.%20P.&rft.date=2019-12-16&rft.volume=9&rft.issue=1&rft.spage=19203&rft.epage=9&rft.pages=19203-9&rft.artnum=19203&rft.issn=2045-2322&rft.eissn=2045-2322&rft_id=info:doi/10.1038/s41598-019-55837-w&rft_dat=%3Cproquest_pubme%3E2327337292%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2327337292&rft_id=info:pmid/31844156&rfr_iscdi=true |