Functional Invalidation of Putative Sudden Infant Death Syndrome-Associated Variants in the KCNH2-Encoded Kv11.1 Channel

Jennifer L Smith, David J Tester, Allison R Hall, Don E Burgess, Chun-Chun Hsu, Samy Claude Elayi, Corey L Anderson, Craig T January, Jonathan Z Luo, Dustin N Hartzel, Uyenlinh L Mirshahi, Michael F Murray, Tooraj Mirshahi, Michael J Ackerman, Brian P Delisle

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摘要

BACKGROUND: Heterologous functional validation studies of putative long-QT syndrome subtype 2-associated variants clarify their pathological potential and identify disease mechanism(s) for most variants studied. The purpose of this study is to clarify the pathological potential for rare nonsynonymous KCNH2 variants seemingly associated with sudden infant death syndrome. METHODS: Genetic testing of 292 sudden infant death syndrome cases identified 9 KCNH2 variants: E90K, R181Q, A190T, G294V, R791W, P967L, R1005W, R1047L, and Q1068R. Previous studies show R181Q-, P967L-, and R1047L-Kv11.1 channels function similar to wild-type Kv11.1 channels, whereas Q1068R-Kv11.1 channels accelerate inactivation gating. We studied the biochemical and biophysical properties for E90K-, G294V-, R791W-, and R1005W-Kv11.1 channels expressed in human embryonic kidney 293 cells; examined the electronic health records of patients who were genotype positive for the sudden infant death syndrome-linked KCNH2 variants; and simulated their functional impact using computational models of the human ventricular action potential. RESULTS: Western blot and voltage-clamping analyses of cells expressing E90K-, G294V-, R791W-, and R1005W-Kv11.1 channels demonstrated these variants express and generate peak Kv11.1 current levels similar to cells expressing wild-type-Kv11.1 channels, but R791W- and R1005W-Kv11.1 channels accelerated deactivation and activation gating, respectively. Electronic health records of patients with the sudden infant death syndrome-linked KCNH2 variants showed that the patients had median heart rate-corrected QT intervals <480 ms and none had been diagnosed with long-QT syndrome or experienced cardiac arrest. Simulating the impact of dysfunctional gating variants predicted that they have little impact on ventricular action potential duration. CONCLUSIONS: We conclude that these rare Kv11.1 missense variants are not long-QT syndrome subtype 2-causative variants and therefore do not represent the pathogenic substrate for sudden infant death syndrome in the variant-positive infants.
原文英語
頁(從 - 到)e005859
期刊Circulation: Arrhythmia and Electrophysiology
11
發行號5
DOIs
出版狀態已發佈 - 五月 2018

指紋

Sudden Infant Death
Long QT Syndrome
Electronic Health Records
Action Potentials
Validation Studies
Genetic Testing
Heart Arrest
Constriction
Heart Rate
Western Blotting
Genotype
Kidney

引用此文

Functional Invalidation of Putative Sudden Infant Death Syndrome-Associated Variants in the KCNH2-Encoded Kv11.1 Channel. / Smith, Jennifer L; Tester, David J; Hall, Allison R; Burgess, Don E; Hsu, Chun-Chun; Claude Elayi, Samy; Anderson, Corey L; January, Craig T; Luo, Jonathan Z; Hartzel, Dustin N; Mirshahi, Uyenlinh L; Murray, Michael F; Mirshahi, Tooraj; Ackerman, Michael J; Delisle, Brian P.

於: Circulation: Arrhythmia and Electrophysiology, 卷 11, 編號 5, 05.2018, p. e005859.

研究成果: 雜誌貢獻文章

Smith, JL, Tester, DJ, Hall, AR, Burgess, DE, Hsu, C-C, Claude Elayi, S, Anderson, CL, January, CT, Luo, JZ, Hartzel, DN, Mirshahi, UL, Murray, MF, Mirshahi, T, Ackerman, MJ & Delisle, BP 2018, 'Functional Invalidation of Putative Sudden Infant Death Syndrome-Associated Variants in the KCNH2-Encoded Kv11.1 Channel', Circulation: Arrhythmia and Electrophysiology, 卷 11, 編號 5, 頁 e005859. https://doi.org/10.1161/CIRCEP.117.005859
Smith, Jennifer L ; Tester, David J ; Hall, Allison R ; Burgess, Don E ; Hsu, Chun-Chun ; Claude Elayi, Samy ; Anderson, Corey L ; January, Craig T ; Luo, Jonathan Z ; Hartzel, Dustin N ; Mirshahi, Uyenlinh L ; Murray, Michael F ; Mirshahi, Tooraj ; Ackerman, Michael J ; Delisle, Brian P. / Functional Invalidation of Putative Sudden Infant Death Syndrome-Associated Variants in the KCNH2-Encoded Kv11.1 Channel. 於: Circulation: Arrhythmia and Electrophysiology. 2018 ; 卷 11, 編號 5. 頁 e005859.
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abstract = "BACKGROUND: Heterologous functional validation studies of putative long-QT syndrome subtype 2-associated variants clarify their pathological potential and identify disease mechanism(s) for most variants studied. The purpose of this study is to clarify the pathological potential for rare nonsynonymous KCNH2 variants seemingly associated with sudden infant death syndrome.METHODS: Genetic testing of 292 sudden infant death syndrome cases identified 9 KCNH2 variants: E90K, R181Q, A190T, G294V, R791W, P967L, R1005W, R1047L, and Q1068R. Previous studies show R181Q-, P967L-, and R1047L-Kv11.1 channels function similar to wild-type Kv11.1 channels, whereas Q1068R-Kv11.1 channels accelerate inactivation gating. We studied the biochemical and biophysical properties for E90K-, G294V-, R791W-, and R1005W-Kv11.1 channels expressed in human embryonic kidney 293 cells; examined the electronic health records of patients who were genotype positive for the sudden infant death syndrome-linked KCNH2 variants; and simulated their functional impact using computational models of the human ventricular action potential.RESULTS: Western blot and voltage-clamping analyses of cells expressing E90K-, G294V-, R791W-, and R1005W-Kv11.1 channels demonstrated these variants express and generate peak Kv11.1 current levels similar to cells expressing wild-type-Kv11.1 channels, but R791W- and R1005W-Kv11.1 channels accelerated deactivation and activation gating, respectively. Electronic health records of patients with the sudden infant death syndrome-linked KCNH2 variants showed that the patients had median heart rate-corrected QT intervals <480 ms and none had been diagnosed with long-QT syndrome or experienced cardiac arrest. Simulating the impact of dysfunctional gating variants predicted that they have little impact on ventricular action potential duration.CONCLUSIONS: We conclude that these rare Kv11.1 missense variants are not long-QT syndrome subtype 2-causative variants and therefore do not represent the pathogenic substrate for sudden infant death syndrome in the variant-positive infants.",
author = "Smith, {Jennifer L} and Tester, {David J} and Hall, {Allison R} and Burgess, {Don E} and Chun-Chun Hsu and {Claude Elayi}, Samy and Anderson, {Corey L} and January, {Craig T} and Luo, {Jonathan Z} and Hartzel, {Dustin N} and Mirshahi, {Uyenlinh L} and Murray, {Michael F} and Tooraj Mirshahi and Ackerman, {Michael J} and Delisle, {Brian P}",
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T1 - Functional Invalidation of Putative Sudden Infant Death Syndrome-Associated Variants in the KCNH2-Encoded Kv11.1 Channel

AU - Smith, Jennifer L

AU - Tester, David J

AU - Hall, Allison R

AU - Burgess, Don E

AU - Hsu, Chun-Chun

AU - Claude Elayi, Samy

AU - Anderson, Corey L

AU - January, Craig T

AU - Luo, Jonathan Z

AU - Hartzel, Dustin N

AU - Mirshahi, Uyenlinh L

AU - Murray, Michael F

AU - Mirshahi, Tooraj

AU - Ackerman, Michael J

AU - Delisle, Brian P

N1 - © 2018 American Heart Association, Inc.

PY - 2018/5

Y1 - 2018/5

N2 - BACKGROUND: Heterologous functional validation studies of putative long-QT syndrome subtype 2-associated variants clarify their pathological potential and identify disease mechanism(s) for most variants studied. The purpose of this study is to clarify the pathological potential for rare nonsynonymous KCNH2 variants seemingly associated with sudden infant death syndrome.METHODS: Genetic testing of 292 sudden infant death syndrome cases identified 9 KCNH2 variants: E90K, R181Q, A190T, G294V, R791W, P967L, R1005W, R1047L, and Q1068R. Previous studies show R181Q-, P967L-, and R1047L-Kv11.1 channels function similar to wild-type Kv11.1 channels, whereas Q1068R-Kv11.1 channels accelerate inactivation gating. We studied the biochemical and biophysical properties for E90K-, G294V-, R791W-, and R1005W-Kv11.1 channels expressed in human embryonic kidney 293 cells; examined the electronic health records of patients who were genotype positive for the sudden infant death syndrome-linked KCNH2 variants; and simulated their functional impact using computational models of the human ventricular action potential.RESULTS: Western blot and voltage-clamping analyses of cells expressing E90K-, G294V-, R791W-, and R1005W-Kv11.1 channels demonstrated these variants express and generate peak Kv11.1 current levels similar to cells expressing wild-type-Kv11.1 channels, but R791W- and R1005W-Kv11.1 channels accelerated deactivation and activation gating, respectively. Electronic health records of patients with the sudden infant death syndrome-linked KCNH2 variants showed that the patients had median heart rate-corrected QT intervals <480 ms and none had been diagnosed with long-QT syndrome or experienced cardiac arrest. Simulating the impact of dysfunctional gating variants predicted that they have little impact on ventricular action potential duration.CONCLUSIONS: We conclude that these rare Kv11.1 missense variants are not long-QT syndrome subtype 2-causative variants and therefore do not represent the pathogenic substrate for sudden infant death syndrome in the variant-positive infants.

AB - BACKGROUND: Heterologous functional validation studies of putative long-QT syndrome subtype 2-associated variants clarify their pathological potential and identify disease mechanism(s) for most variants studied. The purpose of this study is to clarify the pathological potential for rare nonsynonymous KCNH2 variants seemingly associated with sudden infant death syndrome.METHODS: Genetic testing of 292 sudden infant death syndrome cases identified 9 KCNH2 variants: E90K, R181Q, A190T, G294V, R791W, P967L, R1005W, R1047L, and Q1068R. Previous studies show R181Q-, P967L-, and R1047L-Kv11.1 channels function similar to wild-type Kv11.1 channels, whereas Q1068R-Kv11.1 channels accelerate inactivation gating. We studied the biochemical and biophysical properties for E90K-, G294V-, R791W-, and R1005W-Kv11.1 channels expressed in human embryonic kidney 293 cells; examined the electronic health records of patients who were genotype positive for the sudden infant death syndrome-linked KCNH2 variants; and simulated their functional impact using computational models of the human ventricular action potential.RESULTS: Western blot and voltage-clamping analyses of cells expressing E90K-, G294V-, R791W-, and R1005W-Kv11.1 channels demonstrated these variants express and generate peak Kv11.1 current levels similar to cells expressing wild-type-Kv11.1 channels, but R791W- and R1005W-Kv11.1 channels accelerated deactivation and activation gating, respectively. Electronic health records of patients with the sudden infant death syndrome-linked KCNH2 variants showed that the patients had median heart rate-corrected QT intervals <480 ms and none had been diagnosed with long-QT syndrome or experienced cardiac arrest. Simulating the impact of dysfunctional gating variants predicted that they have little impact on ventricular action potential duration.CONCLUSIONS: We conclude that these rare Kv11.1 missense variants are not long-QT syndrome subtype 2-causative variants and therefore do not represent the pathogenic substrate for sudden infant death syndrome in the variant-positive infants.

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