Novel calmodulin mutations associated with congenital long QT syndrome affect calcium current in human cardiomyocytes

Daniel C. Pipilas; Christopher N. Johnson; Gregory Webster; Jurg Schlaepfer; Florence Fellmann; Nicole Sekarski; Lisa M. Wren; Kateryna V. Ogorodnik; Daniel M. Chazin; Walter J. Chazin; Lia Crotti; Zahurul A. Bhuiyan; Alfred L. George

doi:10.1016/j.hrthm.2016.06.038

Novel calmodulin mutations associated with congenital long QT syndrome affect calcium current in human cardiomyocytes

Daniel C. Pipilas, Christopher N. Johnson, Gregory Webster, Jurg Schlaepfer, Florence Fellmann, Nicole Sekarski, Lisa M. Wren, Kateryna V. Ogorodnik, Daniel M. Chazin, Walter J. Chazin, Lia Crotti, Zahurul A. Bhuiyan, Alfred L. George^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

37 Scopus citations

Abstract

Background Calmodulin (CaM) mutations are associated with cardiac arrhythmia susceptibility including congenital long QT syndrome (LQTS). Objective The purpose of this study was to determine the clinical, genetic, and functional features of 2 novel CaM mutations in children with life-threatening ventricular arrhythmias. Methods The clinical and genetic features of 2 congenital arrhythmia cases associated with 2 novel CaM gene mutations were ascertained. Biochemical and functional investigations were conducted on the 2 mutations. Results A novel de novo CALM2 mutation (D132H) was discovered by candidate gene screening in a male infant with prenatal bradycardia born to healthy parents. Postnatal course was complicated by profound bradycardia, prolonged corrected QT interval (651 ms), 2:1 atrioventricular block, and cardiogenic shock. He was resuscitated and was treated with a cardiac device. A second novel de novo mutation in CALM1 (D132V) was discovered by clinical exome sequencing in a 3-year-old boy who suffered a witnessed cardiac arrest secondary to ventricular fibrillation. Electrocardiographic recording after successful resuscitation revealed a prolonged corrected QT interval of 574 ms. The Ca²⁺ affinity of CaM-D132H and CaM-D132V revealed extremely weak binding to the C-terminal domain, with significant structural perturbations noted for D132H. Voltage-clamp recordings of human induced pluripotent stem cell–derived cardiomyocytes transiently expressing wild-type or mutant CaM demonstrated that both mutations caused impaired Ca²⁺-dependent inactivation of voltage-gated Ca²⁺ current. Neither mutant affected voltage-dependent inactivation. Conclusion Our findings implicate impaired Ca²⁺-dependent inactivation in human cardiomyocytes as the plausible mechanism for long QT syndrome associated with 2 novel CaM mutations. The data further expand the spectrum of genotype and phenotype associated with calmodulinopathy.

Original language	English (US)
Pages (from-to)	2012-2019
Number of pages	8
Journal	Heart rhythm
Volume	13
Issue number	10
DOIs	https://doi.org/10.1016/j.hrthm.2016.06.038
State	Published - Oct 1 2016

Keywords

Arrhythmia
Calcium channel
Calmodulin
Long QT syndrome

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine
Physiology (medical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.hrthm.2016.06.038

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Pipilas, D. C., Johnson, C. N., Webster, G., Schlaepfer, J., Fellmann, F., Sekarski, N., Wren, L. M., Ogorodnik, K. V., Chazin, D. M., Chazin, W. J., Crotti, L., Bhuiyan, Z. A., & George, A. L. (2016). Novel calmodulin mutations associated with congenital long QT syndrome affect calcium current in human cardiomyocytes. Heart rhythm, 13(10), 2012-2019. https://doi.org/10.1016/j.hrthm.2016.06.038

@article{6a2ae0719a234b97aa035c65ea24c52a,

title = "Novel calmodulin mutations associated with congenital long QT syndrome affect calcium current in human cardiomyocytes",

abstract = "Background Calmodulin (CaM) mutations are associated with cardiac arrhythmia susceptibility including congenital long QT syndrome (LQTS). Objective The purpose of this study was to determine the clinical, genetic, and functional features of 2 novel CaM mutations in children with life-threatening ventricular arrhythmias. Methods The clinical and genetic features of 2 congenital arrhythmia cases associated with 2 novel CaM gene mutations were ascertained. Biochemical and functional investigations were conducted on the 2 mutations. Results A novel de novo CALM2 mutation (D132H) was discovered by candidate gene screening in a male infant with prenatal bradycardia born to healthy parents. Postnatal course was complicated by profound bradycardia, prolonged corrected QT interval (651 ms), 2:1 atrioventricular block, and cardiogenic shock. He was resuscitated and was treated with a cardiac device. A second novel de novo mutation in CALM1 (D132V) was discovered by clinical exome sequencing in a 3-year-old boy who suffered a witnessed cardiac arrest secondary to ventricular fibrillation. Electrocardiographic recording after successful resuscitation revealed a prolonged corrected QT interval of 574 ms. The Ca2+ affinity of CaM-D132H and CaM-D132V revealed extremely weak binding to the C-terminal domain, with significant structural perturbations noted for D132H. Voltage-clamp recordings of human induced pluripotent stem cell–derived cardiomyocytes transiently expressing wild-type or mutant CaM demonstrated that both mutations caused impaired Ca2+-dependent inactivation of voltage-gated Ca2+ current. Neither mutant affected voltage-dependent inactivation. Conclusion Our findings implicate impaired Ca2+-dependent inactivation in human cardiomyocytes as the plausible mechanism for long QT syndrome associated with 2 novel CaM mutations. The data further expand the spectrum of genotype and phenotype associated with calmodulinopathy.",

keywords = "Arrhythmia, Calcium channel, Calmodulin, Long QT syndrome",

author = "Pipilas, {Daniel C.} and Johnson, {Christopher N.} and Gregory Webster and Jurg Schlaepfer and Florence Fellmann and Nicole Sekarski and Wren, {Lisa M.} and Ogorodnik, {Kateryna V.} and Chazin, {Daniel M.} and Chazin, {Walter J.} and Lia Crotti and Bhuiyan, {Zahurul A.} and George, {Alfred L.}",

note = "Funding Information: This work was supported by the National Institutes of Health (grant no. HL083374, to Dr George), Fondation Suisse de Cardiologie (grant no. 29283, to Dr Bhuiyan), endowment funding from the Vanderbilt University (to Dr Chazin), National Institutes of Health postdoctoral fellowship (fellowship no. F32-HL117612, to Dr Johnson), and a Howard Hughes Medical Institute Medical Research Fellowship (to Mr Pipilas). Publisher Copyright: {\textcopyright} 2016 Heart Rhythm Society",

year = "2016",

month = oct,

day = "1",

doi = "10.1016/j.hrthm.2016.06.038",

language = "English (US)",

volume = "13",

pages = "2012--2019",

journal = "Heart Rhythm",

issn = "1547-5271",

publisher = "Elsevier",

number = "10",

}

Pipilas, DC, Johnson, CN, Webster, G, Schlaepfer, J, Fellmann, F, Sekarski, N, Wren, LM, Ogorodnik, KV, Chazin, DM, Chazin, WJ, Crotti, L, Bhuiyan, ZA & George, AL 2016, 'Novel calmodulin mutations associated with congenital long QT syndrome affect calcium current in human cardiomyocytes', Heart rhythm, vol. 13, no. 10, pp. 2012-2019. https://doi.org/10.1016/j.hrthm.2016.06.038

TY - JOUR

T1 - Novel calmodulin mutations associated with congenital long QT syndrome affect calcium current in human cardiomyocytes

AU - Pipilas, Daniel C.

AU - Johnson, Christopher N.

AU - Webster, Gregory

AU - Schlaepfer, Jurg

AU - Fellmann, Florence

AU - Sekarski, Nicole

AU - Wren, Lisa M.

AU - Ogorodnik, Kateryna V.

AU - Chazin, Daniel M.

AU - Chazin, Walter J.

AU - Crotti, Lia

AU - Bhuiyan, Zahurul A.

AU - George, Alfred L.

N1 - Funding Information: This work was supported by the National Institutes of Health (grant no. HL083374, to Dr George), Fondation Suisse de Cardiologie (grant no. 29283, to Dr Bhuiyan), endowment funding from the Vanderbilt University (to Dr Chazin), National Institutes of Health postdoctoral fellowship (fellowship no. F32-HL117612, to Dr Johnson), and a Howard Hughes Medical Institute Medical Research Fellowship (to Mr Pipilas). Publisher Copyright: © 2016 Heart Rhythm Society

PY - 2016/10/1

Y1 - 2016/10/1

N2 - Background Calmodulin (CaM) mutations are associated with cardiac arrhythmia susceptibility including congenital long QT syndrome (LQTS). Objective The purpose of this study was to determine the clinical, genetic, and functional features of 2 novel CaM mutations in children with life-threatening ventricular arrhythmias. Methods The clinical and genetic features of 2 congenital arrhythmia cases associated with 2 novel CaM gene mutations were ascertained. Biochemical and functional investigations were conducted on the 2 mutations. Results A novel de novo CALM2 mutation (D132H) was discovered by candidate gene screening in a male infant with prenatal bradycardia born to healthy parents. Postnatal course was complicated by profound bradycardia, prolonged corrected QT interval (651 ms), 2:1 atrioventricular block, and cardiogenic shock. He was resuscitated and was treated with a cardiac device. A second novel de novo mutation in CALM1 (D132V) was discovered by clinical exome sequencing in a 3-year-old boy who suffered a witnessed cardiac arrest secondary to ventricular fibrillation. Electrocardiographic recording after successful resuscitation revealed a prolonged corrected QT interval of 574 ms. The Ca2+ affinity of CaM-D132H and CaM-D132V revealed extremely weak binding to the C-terminal domain, with significant structural perturbations noted for D132H. Voltage-clamp recordings of human induced pluripotent stem cell–derived cardiomyocytes transiently expressing wild-type or mutant CaM demonstrated that both mutations caused impaired Ca2+-dependent inactivation of voltage-gated Ca2+ current. Neither mutant affected voltage-dependent inactivation. Conclusion Our findings implicate impaired Ca2+-dependent inactivation in human cardiomyocytes as the plausible mechanism for long QT syndrome associated with 2 novel CaM mutations. The data further expand the spectrum of genotype and phenotype associated with calmodulinopathy.

AB - Background Calmodulin (CaM) mutations are associated with cardiac arrhythmia susceptibility including congenital long QT syndrome (LQTS). Objective The purpose of this study was to determine the clinical, genetic, and functional features of 2 novel CaM mutations in children with life-threatening ventricular arrhythmias. Methods The clinical and genetic features of 2 congenital arrhythmia cases associated with 2 novel CaM gene mutations were ascertained. Biochemical and functional investigations were conducted on the 2 mutations. Results A novel de novo CALM2 mutation (D132H) was discovered by candidate gene screening in a male infant with prenatal bradycardia born to healthy parents. Postnatal course was complicated by profound bradycardia, prolonged corrected QT interval (651 ms), 2:1 atrioventricular block, and cardiogenic shock. He was resuscitated and was treated with a cardiac device. A second novel de novo mutation in CALM1 (D132V) was discovered by clinical exome sequencing in a 3-year-old boy who suffered a witnessed cardiac arrest secondary to ventricular fibrillation. Electrocardiographic recording after successful resuscitation revealed a prolonged corrected QT interval of 574 ms. The Ca2+ affinity of CaM-D132H and CaM-D132V revealed extremely weak binding to the C-terminal domain, with significant structural perturbations noted for D132H. Voltage-clamp recordings of human induced pluripotent stem cell–derived cardiomyocytes transiently expressing wild-type or mutant CaM demonstrated that both mutations caused impaired Ca2+-dependent inactivation of voltage-gated Ca2+ current. Neither mutant affected voltage-dependent inactivation. Conclusion Our findings implicate impaired Ca2+-dependent inactivation in human cardiomyocytes as the plausible mechanism for long QT syndrome associated with 2 novel CaM mutations. The data further expand the spectrum of genotype and phenotype associated with calmodulinopathy.

KW - Arrhythmia

KW - Calcium channel

KW - Calmodulin

KW - Long QT syndrome

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UR - http://www.scopus.com/inward/citedby.url?scp=84994297132&partnerID=8YFLogxK

U2 - 10.1016/j.hrthm.2016.06.038

DO - 10.1016/j.hrthm.2016.06.038

M3 - Article

C2 - 27374306

AN - SCOPUS:84994297132

VL - 13

SP - 2012

EP - 2019

JO - Heart Rhythm

JF - Heart Rhythm

SN - 1547-5271

IS - 10

ER -

Novel calmodulin mutations associated with congenital long QT syndrome affect calcium current in human cardiomyocytes

Abstract

Keywords

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UN SDGs

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