A Functional Assay for Sick Sinus Syndrome Genetic Variants
Background/Aims: Congenital Sick Sinus Syndrome (SSS) is a disorder associated with sudden cardiac death due to severe bradycardia and prolonged pauses. Mutations in HCN4, the gene encoding inward Na+/K+ current (If), have been described as a cause of congenital SSS. The objective of this study is t...
Ausführliche Beschreibung
Autor*in: |
Chuanchau J. Jou [verfasserIn] Cammon B. Arrington [verfasserIn] Spencer Barnett [verfasserIn] Jiaxiang Shen [verfasserIn] Scott Cho [verfasserIn] Xiaoming Sheng [verfasserIn] Patrick C. McCullagh [verfasserIn] Neil E. Bowles [verfasserIn] Chase M. Pribble [verfasserIn] Elizabeth V. Saarel [verfasserIn] Thomas A. Pilcher [verfasserIn] Susan P. Etheridge [verfasserIn] Martin Tristani-Firouzi [verfasserIn] |
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E-Artikel |
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Sprache: |
Englisch |
Erschienen: |
2017 |
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Übergeordnetes Werk: |
In: Cellular Physiology and Biochemistry - Cell Physiol Biochem Press GmbH & Co KG, 2002, 42(2017), 5, Seite 2021-2029 |
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Übergeordnetes Werk: |
volume:42 ; year:2017 ; number:5 ; pages:2021-2029 |
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Link aufrufen |
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DOI / URN: |
10.1159/000479897 |
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Katalog-ID: |
DOAJ074338129 |
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520 | |a Background/Aims: Congenital Sick Sinus Syndrome (SSS) is a disorder associated with sudden cardiac death due to severe bradycardia and prolonged pauses. Mutations in HCN4, the gene encoding inward Na+/K+ current (If), have been described as a cause of congenital SSS. The objective of this study is to develop an SSS model in embryonic zebrafish, and use zebrafish as a moderate-throughput assay to functionally characterize HCN4 variants. Methods: To determine the function of hcn4 in zebrafish, embryos were either bathed in the If -specific blocker (ZD-7288), or endogenous hcn4 expression was knocked down using splice-blocking morpholinos. To assess whether the zebrafish model discriminates benign from pathogenic variants, we tested four HCN4 mutations known to cause human SSS and four variants of unknown significance (VUS). Results: Pharmacological blockade and knockdown of hcn4 in zebrafish phenocopied human SSS, displaying bradycardia and cardiac pauses in intact embryos and explanted hearts. The zebrafish assay correctly identified all disease-causing variants. Of the VUS, the assay predicted 2 as benign and 2 as hypomorphic variants. Conclusions: We conclude that our embryonic zebrafish assay is a novel and effective tool to functionally characterize human HCN4 variants, which can be translated into important clinical prognostic information. | ||
650 | 4 | |a Arrhythmia | |
650 | 4 | |a Genetics | |
650 | 4 | |a Sick sinus syndrome | |
650 | 4 | |a Zebrafish | |
650 | 4 | |a Sudden cardiac death | |
653 | 0 | |a Physiology | |
653 | 0 | |a Biochemistry | |
700 | 0 | |a Cammon B. Arrington |e verfasserin |4 aut | |
700 | 0 | |a Spencer Barnett |e verfasserin |4 aut | |
700 | 0 | |a Jiaxiang Shen |e verfasserin |4 aut | |
700 | 0 | |a Scott Cho |e verfasserin |4 aut | |
700 | 0 | |a Xiaoming Sheng |e verfasserin |4 aut | |
700 | 0 | |a Patrick C. McCullagh |e verfasserin |4 aut | |
700 | 0 | |a Neil E. Bowles |e verfasserin |4 aut | |
700 | 0 | |a Chase M. Pribble |e verfasserin |4 aut | |
700 | 0 | |a Elizabeth V. Saarel |e verfasserin |4 aut | |
700 | 0 | |a Thomas A. Pilcher |e verfasserin |4 aut | |
700 | 0 | |a Susan P. Etheridge |e verfasserin |4 aut | |
700 | 0 | |a Martin Tristani-Firouzi |e verfasserin |4 aut | |
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10.1159/000479897 doi (DE-627)DOAJ074338129 (DE-599)DOAJ7737dfc076d945d09d15b2a1c15f6913 DE-627 ger DE-627 rakwb eng QP1-981 QD415-436 Chuanchau J. Jou verfasserin aut A Functional Assay for Sick Sinus Syndrome Genetic Variants 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background/Aims: Congenital Sick Sinus Syndrome (SSS) is a disorder associated with sudden cardiac death due to severe bradycardia and prolonged pauses. Mutations in HCN4, the gene encoding inward Na+/K+ current (If), have been described as a cause of congenital SSS. The objective of this study is to develop an SSS model in embryonic zebrafish, and use zebrafish as a moderate-throughput assay to functionally characterize HCN4 variants. Methods: To determine the function of hcn4 in zebrafish, embryos were either bathed in the If -specific blocker (ZD-7288), or endogenous hcn4 expression was knocked down using splice-blocking morpholinos. To assess whether the zebrafish model discriminates benign from pathogenic variants, we tested four HCN4 mutations known to cause human SSS and four variants of unknown significance (VUS). Results: Pharmacological blockade and knockdown of hcn4 in zebrafish phenocopied human SSS, displaying bradycardia and cardiac pauses in intact embryos and explanted hearts. The zebrafish assay correctly identified all disease-causing variants. Of the VUS, the assay predicted 2 as benign and 2 as hypomorphic variants. Conclusions: We conclude that our embryonic zebrafish assay is a novel and effective tool to functionally characterize human HCN4 variants, which can be translated into important clinical prognostic information. Arrhythmia Genetics Sick sinus syndrome Zebrafish Sudden cardiac death Physiology Biochemistry Cammon B. Arrington verfasserin aut Spencer Barnett verfasserin aut Jiaxiang Shen verfasserin aut Scott Cho verfasserin aut Xiaoming Sheng verfasserin aut Patrick C. McCullagh verfasserin aut Neil E. Bowles verfasserin aut Chase M. Pribble verfasserin aut Elizabeth V. Saarel verfasserin aut Thomas A. Pilcher verfasserin aut Susan P. Etheridge verfasserin aut Martin Tristani-Firouzi verfasserin aut In Cellular Physiology and Biochemistry Cell Physiol Biochem Press GmbH & Co KG, 2002 42(2017), 5, Seite 2021-2029 (DE-627)300189702 (DE-600)1482056-0 14219778 nnns volume:42 year:2017 number:5 pages:2021-2029 https://doi.org/10.1159/000479897 kostenfrei https://doaj.org/article/7737dfc076d945d09d15b2a1c15f6913 kostenfrei http://www.karger.com/Article/FullText/479897 kostenfrei https://doaj.org/toc/1015-8987 Journal toc kostenfrei https://doaj.org/toc/1421-9778 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_374 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2018 GBV_ILN_2153 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 42 2017 5 2021-2029 |
spelling |
10.1159/000479897 doi (DE-627)DOAJ074338129 (DE-599)DOAJ7737dfc076d945d09d15b2a1c15f6913 DE-627 ger DE-627 rakwb eng QP1-981 QD415-436 Chuanchau J. Jou verfasserin aut A Functional Assay for Sick Sinus Syndrome Genetic Variants 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background/Aims: Congenital Sick Sinus Syndrome (SSS) is a disorder associated with sudden cardiac death due to severe bradycardia and prolonged pauses. Mutations in HCN4, the gene encoding inward Na+/K+ current (If), have been described as a cause of congenital SSS. The objective of this study is to develop an SSS model in embryonic zebrafish, and use zebrafish as a moderate-throughput assay to functionally characterize HCN4 variants. Methods: To determine the function of hcn4 in zebrafish, embryos were either bathed in the If -specific blocker (ZD-7288), or endogenous hcn4 expression was knocked down using splice-blocking morpholinos. To assess whether the zebrafish model discriminates benign from pathogenic variants, we tested four HCN4 mutations known to cause human SSS and four variants of unknown significance (VUS). Results: Pharmacological blockade and knockdown of hcn4 in zebrafish phenocopied human SSS, displaying bradycardia and cardiac pauses in intact embryos and explanted hearts. The zebrafish assay correctly identified all disease-causing variants. Of the VUS, the assay predicted 2 as benign and 2 as hypomorphic variants. Conclusions: We conclude that our embryonic zebrafish assay is a novel and effective tool to functionally characterize human HCN4 variants, which can be translated into important clinical prognostic information. Arrhythmia Genetics Sick sinus syndrome Zebrafish Sudden cardiac death Physiology Biochemistry Cammon B. Arrington verfasserin aut Spencer Barnett verfasserin aut Jiaxiang Shen verfasserin aut Scott Cho verfasserin aut Xiaoming Sheng verfasserin aut Patrick C. McCullagh verfasserin aut Neil E. Bowles verfasserin aut Chase M. Pribble verfasserin aut Elizabeth V. Saarel verfasserin aut Thomas A. Pilcher verfasserin aut Susan P. Etheridge verfasserin aut Martin Tristani-Firouzi verfasserin aut In Cellular Physiology and Biochemistry Cell Physiol Biochem Press GmbH & Co KG, 2002 42(2017), 5, Seite 2021-2029 (DE-627)300189702 (DE-600)1482056-0 14219778 nnns volume:42 year:2017 number:5 pages:2021-2029 https://doi.org/10.1159/000479897 kostenfrei https://doaj.org/article/7737dfc076d945d09d15b2a1c15f6913 kostenfrei http://www.karger.com/Article/FullText/479897 kostenfrei https://doaj.org/toc/1015-8987 Journal toc kostenfrei https://doaj.org/toc/1421-9778 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_374 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2018 GBV_ILN_2153 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 42 2017 5 2021-2029 |
allfields_unstemmed |
10.1159/000479897 doi (DE-627)DOAJ074338129 (DE-599)DOAJ7737dfc076d945d09d15b2a1c15f6913 DE-627 ger DE-627 rakwb eng QP1-981 QD415-436 Chuanchau J. Jou verfasserin aut A Functional Assay for Sick Sinus Syndrome Genetic Variants 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background/Aims: Congenital Sick Sinus Syndrome (SSS) is a disorder associated with sudden cardiac death due to severe bradycardia and prolonged pauses. Mutations in HCN4, the gene encoding inward Na+/K+ current (If), have been described as a cause of congenital SSS. The objective of this study is to develop an SSS model in embryonic zebrafish, and use zebrafish as a moderate-throughput assay to functionally characterize HCN4 variants. Methods: To determine the function of hcn4 in zebrafish, embryos were either bathed in the If -specific blocker (ZD-7288), or endogenous hcn4 expression was knocked down using splice-blocking morpholinos. To assess whether the zebrafish model discriminates benign from pathogenic variants, we tested four HCN4 mutations known to cause human SSS and four variants of unknown significance (VUS). Results: Pharmacological blockade and knockdown of hcn4 in zebrafish phenocopied human SSS, displaying bradycardia and cardiac pauses in intact embryos and explanted hearts. The zebrafish assay correctly identified all disease-causing variants. Of the VUS, the assay predicted 2 as benign and 2 as hypomorphic variants. Conclusions: We conclude that our embryonic zebrafish assay is a novel and effective tool to functionally characterize human HCN4 variants, which can be translated into important clinical prognostic information. Arrhythmia Genetics Sick sinus syndrome Zebrafish Sudden cardiac death Physiology Biochemistry Cammon B. Arrington verfasserin aut Spencer Barnett verfasserin aut Jiaxiang Shen verfasserin aut Scott Cho verfasserin aut Xiaoming Sheng verfasserin aut Patrick C. McCullagh verfasserin aut Neil E. Bowles verfasserin aut Chase M. Pribble verfasserin aut Elizabeth V. Saarel verfasserin aut Thomas A. Pilcher verfasserin aut Susan P. Etheridge verfasserin aut Martin Tristani-Firouzi verfasserin aut In Cellular Physiology and Biochemistry Cell Physiol Biochem Press GmbH & Co KG, 2002 42(2017), 5, Seite 2021-2029 (DE-627)300189702 (DE-600)1482056-0 14219778 nnns volume:42 year:2017 number:5 pages:2021-2029 https://doi.org/10.1159/000479897 kostenfrei https://doaj.org/article/7737dfc076d945d09d15b2a1c15f6913 kostenfrei http://www.karger.com/Article/FullText/479897 kostenfrei https://doaj.org/toc/1015-8987 Journal toc kostenfrei https://doaj.org/toc/1421-9778 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_374 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2018 GBV_ILN_2153 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 42 2017 5 2021-2029 |
allfieldsGer |
10.1159/000479897 doi (DE-627)DOAJ074338129 (DE-599)DOAJ7737dfc076d945d09d15b2a1c15f6913 DE-627 ger DE-627 rakwb eng QP1-981 QD415-436 Chuanchau J. Jou verfasserin aut A Functional Assay for Sick Sinus Syndrome Genetic Variants 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background/Aims: Congenital Sick Sinus Syndrome (SSS) is a disorder associated with sudden cardiac death due to severe bradycardia and prolonged pauses. Mutations in HCN4, the gene encoding inward Na+/K+ current (If), have been described as a cause of congenital SSS. The objective of this study is to develop an SSS model in embryonic zebrafish, and use zebrafish as a moderate-throughput assay to functionally characterize HCN4 variants. Methods: To determine the function of hcn4 in zebrafish, embryos were either bathed in the If -specific blocker (ZD-7288), or endogenous hcn4 expression was knocked down using splice-blocking morpholinos. To assess whether the zebrafish model discriminates benign from pathogenic variants, we tested four HCN4 mutations known to cause human SSS and four variants of unknown significance (VUS). Results: Pharmacological blockade and knockdown of hcn4 in zebrafish phenocopied human SSS, displaying bradycardia and cardiac pauses in intact embryos and explanted hearts. The zebrafish assay correctly identified all disease-causing variants. Of the VUS, the assay predicted 2 as benign and 2 as hypomorphic variants. Conclusions: We conclude that our embryonic zebrafish assay is a novel and effective tool to functionally characterize human HCN4 variants, which can be translated into important clinical prognostic information. Arrhythmia Genetics Sick sinus syndrome Zebrafish Sudden cardiac death Physiology Biochemistry Cammon B. Arrington verfasserin aut Spencer Barnett verfasserin aut Jiaxiang Shen verfasserin aut Scott Cho verfasserin aut Xiaoming Sheng verfasserin aut Patrick C. McCullagh verfasserin aut Neil E. Bowles verfasserin aut Chase M. Pribble verfasserin aut Elizabeth V. Saarel verfasserin aut Thomas A. Pilcher verfasserin aut Susan P. Etheridge verfasserin aut Martin Tristani-Firouzi verfasserin aut In Cellular Physiology and Biochemistry Cell Physiol Biochem Press GmbH & Co KG, 2002 42(2017), 5, Seite 2021-2029 (DE-627)300189702 (DE-600)1482056-0 14219778 nnns volume:42 year:2017 number:5 pages:2021-2029 https://doi.org/10.1159/000479897 kostenfrei https://doaj.org/article/7737dfc076d945d09d15b2a1c15f6913 kostenfrei http://www.karger.com/Article/FullText/479897 kostenfrei https://doaj.org/toc/1015-8987 Journal toc kostenfrei https://doaj.org/toc/1421-9778 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_374 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2018 GBV_ILN_2153 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 42 2017 5 2021-2029 |
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10.1159/000479897 doi (DE-627)DOAJ074338129 (DE-599)DOAJ7737dfc076d945d09d15b2a1c15f6913 DE-627 ger DE-627 rakwb eng QP1-981 QD415-436 Chuanchau J. Jou verfasserin aut A Functional Assay for Sick Sinus Syndrome Genetic Variants 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background/Aims: Congenital Sick Sinus Syndrome (SSS) is a disorder associated with sudden cardiac death due to severe bradycardia and prolonged pauses. Mutations in HCN4, the gene encoding inward Na+/K+ current (If), have been described as a cause of congenital SSS. The objective of this study is to develop an SSS model in embryonic zebrafish, and use zebrafish as a moderate-throughput assay to functionally characterize HCN4 variants. Methods: To determine the function of hcn4 in zebrafish, embryos were either bathed in the If -specific blocker (ZD-7288), or endogenous hcn4 expression was knocked down using splice-blocking morpholinos. To assess whether the zebrafish model discriminates benign from pathogenic variants, we tested four HCN4 mutations known to cause human SSS and four variants of unknown significance (VUS). Results: Pharmacological blockade and knockdown of hcn4 in zebrafish phenocopied human SSS, displaying bradycardia and cardiac pauses in intact embryos and explanted hearts. The zebrafish assay correctly identified all disease-causing variants. Of the VUS, the assay predicted 2 as benign and 2 as hypomorphic variants. Conclusions: We conclude that our embryonic zebrafish assay is a novel and effective tool to functionally characterize human HCN4 variants, which can be translated into important clinical prognostic information. Arrhythmia Genetics Sick sinus syndrome Zebrafish Sudden cardiac death Physiology Biochemistry Cammon B. Arrington verfasserin aut Spencer Barnett verfasserin aut Jiaxiang Shen verfasserin aut Scott Cho verfasserin aut Xiaoming Sheng verfasserin aut Patrick C. McCullagh verfasserin aut Neil E. Bowles verfasserin aut Chase M. Pribble verfasserin aut Elizabeth V. Saarel verfasserin aut Thomas A. Pilcher verfasserin aut Susan P. Etheridge verfasserin aut Martin Tristani-Firouzi verfasserin aut In Cellular Physiology and Biochemistry Cell Physiol Biochem Press GmbH & Co KG, 2002 42(2017), 5, Seite 2021-2029 (DE-627)300189702 (DE-600)1482056-0 14219778 nnns volume:42 year:2017 number:5 pages:2021-2029 https://doi.org/10.1159/000479897 kostenfrei https://doaj.org/article/7737dfc076d945d09d15b2a1c15f6913 kostenfrei http://www.karger.com/Article/FullText/479897 kostenfrei https://doaj.org/toc/1015-8987 Journal toc kostenfrei https://doaj.org/toc/1421-9778 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_374 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2018 GBV_ILN_2153 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 42 2017 5 2021-2029 |
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A Functional Assay for Sick Sinus Syndrome Genetic Variants |
abstract |
Background/Aims: Congenital Sick Sinus Syndrome (SSS) is a disorder associated with sudden cardiac death due to severe bradycardia and prolonged pauses. Mutations in HCN4, the gene encoding inward Na+/K+ current (If), have been described as a cause of congenital SSS. The objective of this study is to develop an SSS model in embryonic zebrafish, and use zebrafish as a moderate-throughput assay to functionally characterize HCN4 variants. Methods: To determine the function of hcn4 in zebrafish, embryos were either bathed in the If -specific blocker (ZD-7288), or endogenous hcn4 expression was knocked down using splice-blocking morpholinos. To assess whether the zebrafish model discriminates benign from pathogenic variants, we tested four HCN4 mutations known to cause human SSS and four variants of unknown significance (VUS). Results: Pharmacological blockade and knockdown of hcn4 in zebrafish phenocopied human SSS, displaying bradycardia and cardiac pauses in intact embryos and explanted hearts. The zebrafish assay correctly identified all disease-causing variants. Of the VUS, the assay predicted 2 as benign and 2 as hypomorphic variants. Conclusions: We conclude that our embryonic zebrafish assay is a novel and effective tool to functionally characterize human HCN4 variants, which can be translated into important clinical prognostic information. |
abstractGer |
Background/Aims: Congenital Sick Sinus Syndrome (SSS) is a disorder associated with sudden cardiac death due to severe bradycardia and prolonged pauses. Mutations in HCN4, the gene encoding inward Na+/K+ current (If), have been described as a cause of congenital SSS. The objective of this study is to develop an SSS model in embryonic zebrafish, and use zebrafish as a moderate-throughput assay to functionally characterize HCN4 variants. Methods: To determine the function of hcn4 in zebrafish, embryos were either bathed in the If -specific blocker (ZD-7288), or endogenous hcn4 expression was knocked down using splice-blocking morpholinos. To assess whether the zebrafish model discriminates benign from pathogenic variants, we tested four HCN4 mutations known to cause human SSS and four variants of unknown significance (VUS). Results: Pharmacological blockade and knockdown of hcn4 in zebrafish phenocopied human SSS, displaying bradycardia and cardiac pauses in intact embryos and explanted hearts. The zebrafish assay correctly identified all disease-causing variants. Of the VUS, the assay predicted 2 as benign and 2 as hypomorphic variants. Conclusions: We conclude that our embryonic zebrafish assay is a novel and effective tool to functionally characterize human HCN4 variants, which can be translated into important clinical prognostic information. |
abstract_unstemmed |
Background/Aims: Congenital Sick Sinus Syndrome (SSS) is a disorder associated with sudden cardiac death due to severe bradycardia and prolonged pauses. Mutations in HCN4, the gene encoding inward Na+/K+ current (If), have been described as a cause of congenital SSS. The objective of this study is to develop an SSS model in embryonic zebrafish, and use zebrafish as a moderate-throughput assay to functionally characterize HCN4 variants. Methods: To determine the function of hcn4 in zebrafish, embryos were either bathed in the If -specific blocker (ZD-7288), or endogenous hcn4 expression was knocked down using splice-blocking morpholinos. To assess whether the zebrafish model discriminates benign from pathogenic variants, we tested four HCN4 mutations known to cause human SSS and four variants of unknown significance (VUS). Results: Pharmacological blockade and knockdown of hcn4 in zebrafish phenocopied human SSS, displaying bradycardia and cardiac pauses in intact embryos and explanted hearts. The zebrafish assay correctly identified all disease-causing variants. Of the VUS, the assay predicted 2 as benign and 2 as hypomorphic variants. Conclusions: We conclude that our embryonic zebrafish assay is a novel and effective tool to functionally characterize human HCN4 variants, which can be translated into important clinical prognostic information. |
collection_details |
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container_issue |
5 |
title_short |
A Functional Assay for Sick Sinus Syndrome Genetic Variants |
url |
https://doi.org/10.1159/000479897 https://doaj.org/article/7737dfc076d945d09d15b2a1c15f6913 http://www.karger.com/Article/FullText/479897 https://doaj.org/toc/1015-8987 https://doaj.org/toc/1421-9778 |
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true |
author2 |
Cammon B. Arrington Spencer Barnett Jiaxiang Shen Scott Cho Xiaoming Sheng Patrick C. McCullagh Neil E. Bowles Chase M. Pribble Elizabeth V. Saarel Thomas A. Pilcher Susan P. Etheridge Martin Tristani-Firouzi |
author2Str |
Cammon B. Arrington Spencer Barnett Jiaxiang Shen Scott Cho Xiaoming Sheng Patrick C. McCullagh Neil E. Bowles Chase M. Pribble Elizabeth V. Saarel Thomas A. Pilcher Susan P. Etheridge Martin Tristani-Firouzi |
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QP - Physiology |
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doi_str |
10.1159/000479897 |
callnumber-a |
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up_date |
2024-07-03T22:36:22.293Z |
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