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Disease-associated HCN4 V759I variant is not sufficient to impair cardiac pacemaking

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Disease-associated HCN4 V759I variant is not sufficient to impair cardiac pacemaking. / Erlenhardt, Nadine; Kletke, Olaf; Wohlfarth, Franziska; Komadowski, Marlene A; Clasen, Lukas; Makimoto, Hisaki; Rinné, Susanne; Kelm, Malte; Jungen, Christiane; Decher, Niels; Meyer, Christian; Klöcker, Nikolaj.

In: PFLUG ARCH EUR J PHY, Vol. 472, No. 12, 12.2020, p. 1733-1742.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Erlenhardt, N, Kletke, O, Wohlfarth, F, Komadowski, MA, Clasen, L, Makimoto, H, Rinné, S, Kelm, M, Jungen, C, Decher, N, Meyer, C & Klöcker, N 2020, 'Disease-associated HCN4 V759I variant is not sufficient to impair cardiac pacemaking', PFLUG ARCH EUR J PHY, vol. 472, no. 12, pp. 1733-1742. https://doi.org/10.1007/s00424-020-02481-3

APA

Erlenhardt, N., Kletke, O., Wohlfarth, F., Komadowski, M. A., Clasen, L., Makimoto, H., Rinné, S., Kelm, M., Jungen, C., Decher, N., Meyer, C., & Klöcker, N. (2020). Disease-associated HCN4 V759I variant is not sufficient to impair cardiac pacemaking. PFLUG ARCH EUR J PHY, 472(12), 1733-1742. https://doi.org/10.1007/s00424-020-02481-3

Vancouver

Erlenhardt N, Kletke O, Wohlfarth F, Komadowski MA, Clasen L, Makimoto H et al. Disease-associated HCN4 V759I variant is not sufficient to impair cardiac pacemaking. PFLUG ARCH EUR J PHY. 2020 Dec;472(12):1733-1742. https://doi.org/10.1007/s00424-020-02481-3

Bibtex

@article{679d7e9e2ef545608ee7f6d3ee03598e,
title = "Disease-associated HCN4 V759I variant is not sufficient to impair cardiac pacemaking",
abstract = "The hyperpolarization-activated cation current If is a key determinant for cardiac pacemaker activity. It is conducted by subunits of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel family, of which HCN4 is predominant in mammalian heart. Both loss-of-function and gain-of-function mutations of the HCN4 gene are associated with sinus node dysfunction in humans; however, their functional impact is not fully understood yet. Here, we sought to characterize a HCN4 V759I variant detected in a patient with a family history of sick sinus syndrome. The genomic analysis yielded a mono-allelic HCN4 V759I variant in a 49-year-old woman presenting with a family history of sick sinus syndrome. This HCN4 variant was previously classified as putatively pathogenic because genetically linked to sudden infant death syndrome and malignant epilepsy. However, detailed electrophysiological and cell biological characterization of HCN4 V759I in Xenopus laevis oocytes and embryonic rat cardiomyocytes, respectively, did not reveal any obvious abnormality. Voltage dependence and kinetics of mutant channel activation, modulation of cAMP-gating by the neuronal HCN channel auxiliary subunit PEX5R, and cell surface expression were indistinguishable from wild-type HCN4. In good agreement, the clinically likewise affected mother of the patient does not exhibit the reported HCN4 variance. HCN4 V759I resembles an innocuous genetic HCN channel variant, which is not sufficient to disturb cardiac pacemaking. Once more, our work emphasizes the importance of careful functional interpretation of genetic findings not only in the context of hereditary cardiac arrhythmias.",
keywords = "Action Potentials, Animals, Bradycardia/diagnosis, Cells, Cultured, Female, Heart Rate, Humans, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics, Middle Aged, Muscle Proteins/genetics, Mutation, Missense, Myocytes, Cardiac/metabolism, Potassium Channels/genetics, Protein Transport, Rats, Rats, Wistar, Xenopus",
author = "Nadine Erlenhardt and Olaf Kletke and Franziska Wohlfarth and Komadowski, {Marlene A} and Lukas Clasen and Hisaki Makimoto and Susanne Rinn{\'e} and Malte Kelm and Christiane Jungen and Niels Decher and Christian Meyer and Nikolaj Kl{\"o}cker",
year = "2020",
month = dec,
doi = "10.1007/s00424-020-02481-3",
language = "English",
volume = "472",
pages = "1733--1742",
journal = "PFLUG ARCH EUR J PHY",
issn = "0031-6768",
publisher = "Springer",
number = "12",

}

RIS

TY - JOUR

T1 - Disease-associated HCN4 V759I variant is not sufficient to impair cardiac pacemaking

AU - Erlenhardt, Nadine

AU - Kletke, Olaf

AU - Wohlfarth, Franziska

AU - Komadowski, Marlene A

AU - Clasen, Lukas

AU - Makimoto, Hisaki

AU - Rinné, Susanne

AU - Kelm, Malte

AU - Jungen, Christiane

AU - Decher, Niels

AU - Meyer, Christian

AU - Klöcker, Nikolaj

PY - 2020/12

Y1 - 2020/12

N2 - The hyperpolarization-activated cation current If is a key determinant for cardiac pacemaker activity. It is conducted by subunits of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel family, of which HCN4 is predominant in mammalian heart. Both loss-of-function and gain-of-function mutations of the HCN4 gene are associated with sinus node dysfunction in humans; however, their functional impact is not fully understood yet. Here, we sought to characterize a HCN4 V759I variant detected in a patient with a family history of sick sinus syndrome. The genomic analysis yielded a mono-allelic HCN4 V759I variant in a 49-year-old woman presenting with a family history of sick sinus syndrome. This HCN4 variant was previously classified as putatively pathogenic because genetically linked to sudden infant death syndrome and malignant epilepsy. However, detailed electrophysiological and cell biological characterization of HCN4 V759I in Xenopus laevis oocytes and embryonic rat cardiomyocytes, respectively, did not reveal any obvious abnormality. Voltage dependence and kinetics of mutant channel activation, modulation of cAMP-gating by the neuronal HCN channel auxiliary subunit PEX5R, and cell surface expression were indistinguishable from wild-type HCN4. In good agreement, the clinically likewise affected mother of the patient does not exhibit the reported HCN4 variance. HCN4 V759I resembles an innocuous genetic HCN channel variant, which is not sufficient to disturb cardiac pacemaking. Once more, our work emphasizes the importance of careful functional interpretation of genetic findings not only in the context of hereditary cardiac arrhythmias.

AB - The hyperpolarization-activated cation current If is a key determinant for cardiac pacemaker activity. It is conducted by subunits of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel family, of which HCN4 is predominant in mammalian heart. Both loss-of-function and gain-of-function mutations of the HCN4 gene are associated with sinus node dysfunction in humans; however, their functional impact is not fully understood yet. Here, we sought to characterize a HCN4 V759I variant detected in a patient with a family history of sick sinus syndrome. The genomic analysis yielded a mono-allelic HCN4 V759I variant in a 49-year-old woman presenting with a family history of sick sinus syndrome. This HCN4 variant was previously classified as putatively pathogenic because genetically linked to sudden infant death syndrome and malignant epilepsy. However, detailed electrophysiological and cell biological characterization of HCN4 V759I in Xenopus laevis oocytes and embryonic rat cardiomyocytes, respectively, did not reveal any obvious abnormality. Voltage dependence and kinetics of mutant channel activation, modulation of cAMP-gating by the neuronal HCN channel auxiliary subunit PEX5R, and cell surface expression were indistinguishable from wild-type HCN4. In good agreement, the clinically likewise affected mother of the patient does not exhibit the reported HCN4 variance. HCN4 V759I resembles an innocuous genetic HCN channel variant, which is not sufficient to disturb cardiac pacemaking. Once more, our work emphasizes the importance of careful functional interpretation of genetic findings not only in the context of hereditary cardiac arrhythmias.

KW - Action Potentials

KW - Animals

KW - Bradycardia/diagnosis

KW - Cells, Cultured

KW - Female

KW - Heart Rate

KW - Humans

KW - Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics

KW - Middle Aged

KW - Muscle Proteins/genetics

KW - Mutation, Missense

KW - Myocytes, Cardiac/metabolism

KW - Potassium Channels/genetics

KW - Protein Transport

KW - Rats

KW - Rats, Wistar

KW - Xenopus

U2 - 10.1007/s00424-020-02481-3

DO - 10.1007/s00424-020-02481-3

M3 - SCORING: Journal article

C2 - 33095298

VL - 472

SP - 1733

EP - 1742

JO - PFLUG ARCH EUR J PHY

JF - PFLUG ARCH EUR J PHY

SN - 0031-6768

IS - 12

ER -