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

Gespeichert in:

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]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2017

Schlagwörter:	Arrhythmia Genetics Sick sinus syndrome Zebrafish Sudden cardiac death

Übergeordnetes Werk:	In: Cellular Physiology and Biochemistry - Cell Physiol Biochem Press GmbH & Co KG, 2002, 42(2017), 5, Seite 2021-2029
Übergeordnetes Werk:	volume:42 ; year:2017 ; number:5 ; pages:2021-2029

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc Journal toc

DOI / URN:	10.1159/000479897

Katalog-ID:	DOAJ074338129

Internformat


LEADER	01000caa a22002652 4500
001	DOAJ074338129
003	DE-627
005	20230502145332.0
007	cr uuu---uuuuu
008	230228s2017 xx \|\|\|\|\|o 00\| \|\|eng c
024	7		\|a 10.1159/000479897 \|2 doi
035			\|a (DE-627)DOAJ074338129
035			\|a (DE-599)DOAJ7737dfc076d945d09d15b2a1c15f6913
040			\|a DE-627 \|b ger \|c DE-627 \|e rakwb
041			\|a eng
050		0	\|a QP1-981
050		0	\|a QD415-436
100	0		\|a Chuanchau J. Jou \|e verfasserin \|4 aut
245	1	2	\|a A Functional Assay for Sick Sinus Syndrome Genetic Variants
264		1	\|c 2017
336			\|a Text \|b txt \|2 rdacontent
337			\|a Computermedien \|b c \|2 rdamedia
338			\|a Online-Ressource \|b cr \|2 rdacarrier
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
773	0	8	\|i In \|t Cellular Physiology and Biochemistry \|d Cell Physiol Biochem Press GmbH & Co KG, 2002 \|g 42(2017), 5, Seite 2021-2029 \|w (DE-627)300189702 \|w (DE-600)1482056-0 \|x 14219778 \|7 nnns
773	1	8	\|g volume:42 \|g year:2017 \|g number:5 \|g pages:2021-2029
856	4	0	\|u https://doi.org/10.1159/000479897 \|z kostenfrei
856	4	0	\|u https://doaj.org/article/7737dfc076d945d09d15b2a1c15f6913 \|z kostenfrei
856	4	0	\|u http://www.karger.com/Article/FullText/479897 \|z kostenfrei
856	4	2	\|u https://doaj.org/toc/1015-8987 \|y Journal toc \|z kostenfrei
856	4	2	\|u https://doaj.org/toc/1421-9778 \|y Journal toc \|z kostenfrei
912			\|a GBV_USEFLAG_A
912			\|a SYSFLAG_A
912			\|a GBV_DOAJ
912			\|a SSG-OLC-PHA
912			\|a GBV_ILN_20
912			\|a GBV_ILN_22
912			\|a GBV_ILN_23
912			\|a GBV_ILN_24
912			\|a GBV_ILN_31
912			\|a GBV_ILN_39
912			\|a GBV_ILN_40
912			\|a GBV_ILN_60
912			\|a GBV_ILN_62
912			\|a GBV_ILN_63
912			\|a GBV_ILN_69
912			\|a GBV_ILN_70
912			\|a GBV_ILN_73
912			\|a GBV_ILN_74
912			\|a GBV_ILN_95
912			\|a GBV_ILN_105
912			\|a GBV_ILN_110
912			\|a GBV_ILN_151
912			\|a GBV_ILN_161
912			\|a GBV_ILN_170
912			\|a GBV_ILN_206
912			\|a GBV_ILN_213
912			\|a GBV_ILN_230
912			\|a GBV_ILN_285
912			\|a GBV_ILN_293
912			\|a GBV_ILN_374
912			\|a GBV_ILN_602
912			\|a GBV_ILN_2014
912			\|a GBV_ILN_2018
912			\|a GBV_ILN_2153
912			\|a GBV_ILN_4012
912			\|a GBV_ILN_4037
912			\|a GBV_ILN_4112
912			\|a GBV_ILN_4125
912			\|a GBV_ILN_4126
912			\|a GBV_ILN_4249
912			\|a GBV_ILN_4305
912			\|a GBV_ILN_4306
912			\|a GBV_ILN_4307
912			\|a GBV_ILN_4313
912			\|a GBV_ILN_4322
912			\|a GBV_ILN_4323
912			\|a GBV_ILN_4324
912			\|a GBV_ILN_4325
912			\|a GBV_ILN_4338
912			\|a GBV_ILN_4367
912			\|a GBV_ILN_4700
951			\|a AR
952			\|d 42 \|j 2017 \|e 5 \|h 2021-2029

Indexfelder

author_variant	c j cj c a ca s b sb j s js s c sc x s xs p m pm n b nb c p cp e s es t p tp s e se m t f mtf
matchkey_str	article:14219778:2017----::fntoaasyoscsnsydoe
hierarchy_sort_str	2017
callnumber-subject-code	QP
publishDate	2017
allfields	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
allfieldsSound	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
language	English
source	In Cellular Physiology and Biochemistry 42(2017), 5, Seite 2021-2029 volume:42 year:2017 number:5 pages:2021-2029
sourceStr	In Cellular Physiology and Biochemistry 42(2017), 5, Seite 2021-2029 volume:42 year:2017 number:5 pages:2021-2029
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Arrhythmia Genetics Sick sinus syndrome Zebrafish Sudden cardiac death Physiology Biochemistry
isfreeaccess_bool	true
container_title	Cellular Physiology and Biochemistry
authorswithroles_txt_mv	Chuanchau J. Jou @@aut@@ Cammon B. Arrington @@aut@@ Spencer Barnett @@aut@@ Jiaxiang Shen @@aut@@ Scott Cho @@aut@@ Xiaoming Sheng @@aut@@ Patrick C. McCullagh @@aut@@ Neil E. Bowles @@aut@@ Chase M. Pribble @@aut@@ Elizabeth V. Saarel @@aut@@ Thomas A. Pilcher @@aut@@ Susan P. Etheridge @@aut@@ Martin Tristani-Firouzi @@aut@@
publishDateDaySort_date	2017-01-01T00:00:00Z
hierarchy_top_id	300189702
id	DOAJ074338129
language_de	englisch
fullrecord	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">DOAJ074338129</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230502145332.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">230228s2017 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1159/000479897</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ074338129</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJ7737dfc076d945d09d15b2a1c15f6913</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">QP1-981</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">QD415-436</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Chuanchau J. Jou</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="2"><subfield code="a">A Functional Assay for Sick Sinus Syndrome Genetic Variants</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2017</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="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.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Arrhythmia</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Genetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Sick sinus syndrome</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Zebrafish</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Sudden cardiac death</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Physiology</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Biochemistry</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Cammon B. Arrington</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Spencer Barnett</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Jiaxiang Shen</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Scott Cho</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Xiaoming Sheng</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Patrick C. McCullagh</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Neil E. Bowles</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Chase M. Pribble</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Elizabeth V. Saarel</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Thomas A. Pilcher</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Susan P. Etheridge</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Martin Tristani-Firouzi</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">In</subfield><subfield code="t">Cellular Physiology and Biochemistry</subfield><subfield code="d">Cell Physiol Biochem Press GmbH & Co KG, 2002</subfield><subfield code="g">42(2017), 5, Seite 2021-2029</subfield><subfield code="w">(DE-627)300189702</subfield><subfield code="w">(DE-600)1482056-0</subfield><subfield code="x">14219778</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:42</subfield><subfield code="g">year:2017</subfield><subfield code="g">number:5</subfield><subfield code="g">pages:2021-2029</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doi.org/10.1159/000479897</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doaj.org/article/7737dfc076d945d09d15b2a1c15f6913</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">http://www.karger.com/Article/FullText/479897</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">https://doaj.org/toc/1015-8987</subfield><subfield code="y">Journal toc</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">https://doaj.org/toc/1421-9778</subfield><subfield code="y">Journal toc</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_DOAJ</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-PHA</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_20</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_22</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_23</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_24</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_31</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_39</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_60</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_62</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_63</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_69</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_70</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_73</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_74</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_95</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_105</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_151</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_161</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_170</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_206</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_213</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_230</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_285</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_293</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_374</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_602</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2014</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2018</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2153</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4012</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4037</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4112</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4125</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4126</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4249</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4305</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4306</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4307</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4313</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4322</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4323</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4324</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4325</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4338</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4367</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4700</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">42</subfield><subfield code="j">2017</subfield><subfield code="e">5</subfield><subfield code="h">2021-2029</subfield></datafield></record></collection>
callnumber-first	Q - Science
author	Chuanchau J. Jou
spellingShingle	Chuanchau J. Jou misc QP1-981 misc QD415-436 misc Arrhythmia misc Genetics misc Sick sinus syndrome misc Zebrafish misc Sudden cardiac death misc Physiology misc Biochemistry A Functional Assay for Sick Sinus Syndrome Genetic Variants
authorStr	Chuanchau J. Jou
ppnlink_with_tag_str_mv	@@773@@(DE-627)300189702
format	electronic Article
delete_txt_mv	keep
author_role	aut aut aut aut aut aut aut aut aut aut aut aut aut
collection	DOAJ
remote_str	true
callnumber-label	QP1-981
illustrated	Not Illustrated
issn	14219778
topic_title	QP1-981 QD415-436 A Functional Assay for Sick Sinus Syndrome Genetic Variants Arrhythmia Genetics Sick sinus syndrome Zebrafish Sudden cardiac death
topic	misc QP1-981 misc QD415-436 misc Arrhythmia misc Genetics misc Sick sinus syndrome misc Zebrafish misc Sudden cardiac death misc Physiology misc Biochemistry
topic_unstemmed	misc QP1-981 misc QD415-436 misc Arrhythmia misc Genetics misc Sick sinus syndrome misc Zebrafish misc Sudden cardiac death misc Physiology misc Biochemistry
topic_browse	misc QP1-981 misc QD415-436 misc Arrhythmia misc Genetics misc Sick sinus syndrome misc Zebrafish misc Sudden cardiac death misc Physiology misc Biochemistry
format_facet	Elektronische Aufsätze Aufsätze Elektronische Ressource
format_main_str_mv	Text Zeitschrift/Artikel
carriertype_str_mv	cr
hierarchy_parent_title	Cellular Physiology and Biochemistry
hierarchy_parent_id	300189702
hierarchy_top_title	Cellular Physiology and Biochemistry
isfreeaccess_txt	true
familylinks_str_mv	(DE-627)300189702 (DE-600)1482056-0
title	A Functional Assay for Sick Sinus Syndrome Genetic Variants
ctrlnum	(DE-627)DOAJ074338129 (DE-599)DOAJ7737dfc076d945d09d15b2a1c15f6913
title_full	A Functional Assay for Sick Sinus Syndrome Genetic Variants
author_sort	Chuanchau J. Jou
journal	Cellular Physiology and Biochemistry
journalStr	Cellular Physiology and Biochemistry
callnumber-first-code	Q
lang_code	eng
isOA_bool	true
recordtype	marc
publishDateSort	2017
contenttype_str_mv	txt
container_start_page	2021
author_browse	Chuanchau J. Jou 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
container_volume	42
class	QP1-981 QD415-436
format_se	Elektronische Aufsätze
author-letter	Chuanchau J. Jou
doi_str_mv	10.1159/000479897
author2-role	verfasserin
title_sort	functional assay for sick sinus syndrome genetic variants
callnumber	QP1-981
title_auth	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	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
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
remote_bool	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
ppnlink	300189702
callnumber-subject	QP - Physiology
mediatype_str_mv	c
isOA_txt	true
hochschulschrift_bool	false
doi_str	10.1159/000479897
callnumber-a	QP1-981
up_date	2024-07-03T22:36:22.293Z
_version_	1803599145645113344
fullrecord_marcxml	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">DOAJ074338129</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230502145332.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">230228s2017 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1159/000479897</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ074338129</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJ7737dfc076d945d09d15b2a1c15f6913</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">QP1-981</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">QD415-436</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Chuanchau J. Jou</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="2"><subfield code="a">A Functional Assay for Sick Sinus Syndrome Genetic Variants</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2017</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="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.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Arrhythmia</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Genetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Sick sinus syndrome</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Zebrafish</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Sudden cardiac death</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Physiology</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Biochemistry</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Cammon B. Arrington</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Spencer Barnett</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Jiaxiang Shen</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Scott Cho</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Xiaoming Sheng</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Patrick C. McCullagh</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Neil E. Bowles</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Chase M. Pribble</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Elizabeth V. Saarel</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Thomas A. Pilcher</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Susan P. Etheridge</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Martin Tristani-Firouzi</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">In</subfield><subfield code="t">Cellular Physiology and Biochemistry</subfield><subfield code="d">Cell Physiol Biochem Press GmbH & Co KG, 2002</subfield><subfield code="g">42(2017), 5, Seite 2021-2029</subfield><subfield code="w">(DE-627)300189702</subfield><subfield code="w">(DE-600)1482056-0</subfield><subfield code="x">14219778</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:42</subfield><subfield code="g">year:2017</subfield><subfield code="g">number:5</subfield><subfield code="g">pages:2021-2029</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doi.org/10.1159/000479897</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doaj.org/article/7737dfc076d945d09d15b2a1c15f6913</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">http://www.karger.com/Article/FullText/479897</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">https://doaj.org/toc/1015-8987</subfield><subfield code="y">Journal toc</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">https://doaj.org/toc/1421-9778</subfield><subfield code="y">Journal toc</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_DOAJ</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-PHA</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_20</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_22</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_23</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_24</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_31</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_39</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_60</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_62</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_63</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_69</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_70</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_73</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_74</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_95</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_105</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_151</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_161</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_170</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_206</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_213</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_230</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_285</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_293</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_374</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_602</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2014</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2018</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2153</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4012</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4037</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4112</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4125</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4126</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4249</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4305</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4306</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4307</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4313</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4322</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4323</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4324</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4325</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4338</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4367</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4700</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">42</subfield><subfield code="j">2017</subfield><subfield code="e">5</subfield><subfield code="h">2021-2029</subfield></datafield></record></collection>
score	7.3986826

Nicht das Richtige dabei?

Schreiben Sie uns!

A Functional Assay for Sick Sinus Syndrome Genetic Variants

Nicht das Richtige dabei?

Zugang & Verfügbarkeit

Vorhandene Bände

Nicht das Richtige dabei?