A novel trafficking-defective HCN4 mutation is associated with early-onset atrial fibrillation

Macri, Vincenzo; Mahida, Saagar; Zhang, Michael L.; Sinner, Moritz F.; Dolmatova, Elena; Tucker, Nathan R.; McLellan, Micheal A.; Shea, Marisa A.; Milan, David J.; Lunetta, Kathryn L.; Benjamin, Emelia J.; Ellinor, Patrick T.

doi:10.1016/j.hrthm.2014.03.002

Cited by 67 publications

(59 citation statements)

References 26 publications

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“…A recessive mutation in zebrafish led to a decreased heart rate, which was associated with a significantly reduced If current [41,42]. Furthermore, a mutation of human HCN4 has been found in patients suffering from SAN dysfunction [43][44][45]. These results indicate that HCN4 plays a pivotal role in the generation of sinus rhythm.…”

Section: Discussionmentioning

confidence: 94%

Age-dependent down-regulation of hyperpolarization-activated cyclic nucleotide-gated channel 4 causes deterioration of canine sinoatrial node function

Deng

et al. 2017

ABBS

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The activity of pacemaker cells in the sinoatrial node (SAN) is an indicator of normal sinus rhythm. Clinical studies have revealed that the dysfunction of the SAN progressively increases with aging. In this study, we determined the changes in hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) expression and the relationship between aging and canine SAN dysfunction. The results of cardiac electrophysiological determination revealed that the intrinsic heart rate decreased from 168 ± 11 beats min −1 in young canines to 120 ± 9 beats min −1 in adults and to 88 ± 9 beats min −1 in aged canines. The sinus node recovery time (SNRT) increased from 412 ± 32 ms in young canines to 620 ± 56 ms in adults and to 838 ± 120 ms in aged canines. Corrected SNRT (CSNRT) increased from 55 ± 12 ms in young canines to 117 ± 27 ms in adults and to 171 ± 37 ms in aged canines. These results indicated that SAN function deteriorated with aging in the canine heart. However, histological staining illustrated that fibrosis was not significantly increased with aging in canine SAN. Real-time polymerase chain reaction indicated that the expression of HCN4 mRNA was downregulated in the elderly canine SAN. Similarly, we also verified that HCN4 protein expression within the SAN declined with aging via immunofluorescence staining and western blot analysis. Taken together, our data show that electrical remodeling, related to the down-regulation of HCN4, is responsible for the gradually increased incidence of SAN dysfunction with aging. Our results provide further evidence for explaining the mechanisms of age-related deterioration in the SAN.

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Section: Discussionmentioning

confidence: 94%

Age-dependent down-regulation of hyperpolarization-activated cyclic nucleotide-gated channel 4 causes deterioration of canine sinoatrial node function

Deng

et al. 2017

ABBS

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“…In summary, a genetic analysis of the complete HCN4 gene in 57 unrelated probands with idiopathic or familial SSS was performed, among them, three nucleotide variants resulting in non-synonymous amino acid exchanges were found. Two (HCN4-R378C, and HCN4-R550H) were novel, whereas HCN4-E1193Q had been recently published in a proband with early-onset atrial fibrillation, Brugada syndrome, with epilepsy, and with restrictive cardiomyopathy [12]. The mutations were positioned in the transmembrane domain (HCN4-R378C) or in the intracellular C-terminus (HCN4-R550H and HCN4-E1193Q), (Fig.…”

Section: Identification Of the Three Hcn4 Gene Mutations In Patientsmentioning

confidence: 99%

In Vitro Analyses of Novel HCN4 Gene Mutations

Möller¹,

Silbernagel

Wrobel³

et al. 2018

Cell Physiol Biochem

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Background/Aims: The hyperpolarization-activated cyclic nucleotide-gated cation channel HCN4 contributes significantly to the generation of basic cardiac electrical activity in the sinus node and is a mediator of modulation by β–adrenergic stimulation. Heterologous expression of sick sinus syndrome (SSS) and bradycardia associated mutations within the human HCN4 gene results in altered channel function. The main aim was to describe the functional characterization of three (two novel and one known) missense mutations of HCN4 identified in families with SSS. Methods: Here, the two-electrode voltage clamp technique on Xenopus laevis oocytes and confocal imaging on transfected COS7 cells respectively, were used to analyze the functional effects of three HCN4 mutations; R378C, R550H, and E1193Q. Membrane surface expressions of wild type and the mutant channels were assessed by confocal microscopy, chemiluminescence assay, and Western blot in COS7 and HeLa cells. Results: The homomeric mutant channels R550H and E1193Q showed loss of function through increased rates of deactivation and distinctly reduced surface expression in all three homomeric mutant channels. HCN4 channels containing R550H and E1193Q mutant subunits only showed minor effects on the voltage dependence and rates of activation/deactivation. In contrast, homomeric R378C exerted a left-shifted activation curve and slowed activation kinetics. These effects were reduced in heteromeric co-expression of R378C with wild-type (WT) channels. Conclusion: Dysfunction of homomeric/heteromeric mutant HCN4-R378C, R550H, and E1193Q channels in the present study was primarily caused by loss of function due to decreased channel surface expression.

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“…HCN4 is expressed in the sinoatrial (SA) node and underlies the I f current normally responsible for the pacemaker current in nodal myocytes. Mutations of this channel may lead to diminished action potential frequency (heart rate slowing) and delayed after depolarizations that might trigger AF [94]. As discussed above, Pitx2 represses Hcn4 expression in the left atrium[84][83].…”

Section: Identification Of Af-associated Genetic Loci Through Genome mentioning

confidence: 99%

Genomics of Atrial Fibrillation

Gutiérrez

Chung

2016

Curr Cardiol Rep

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Atrial fibrillation (AF) is a common clinical arrhythmia that appears to be highly heritable, despite representing a complex interplay of several disease processes that generally do not manifest until later in life. In this manuscript we will review the genetic basis of this complex trait established through studies of familial AF, linkage and candidate gene studies of common AF, genome wide association studies (GWAS) of common AF, and transcriptomic studies of AF. Since AF is associated with a five-fold increase in the risk of stroke, we also review the intersection of common genetic factors associated with both of these conditions. Similarly, we highlight the intersection of common genetic markers associated with some risk factors for AF, such as hypertension and obesity, and AF. Lastly, we describe a paradigm where genetic factors predispose to the risk of AF, but which may require additional stress and trigger factors in older age to allow for the clinical manifestation of AF.

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A novel trafficking-defective HCN4 mutation is associated with early-onset atrial fibrillation

Cited by 67 publications

References 26 publications

Age-dependent down-regulation of hyperpolarization-activated cyclic nucleotide-gated channel 4 causes deterioration of canine sinoatrial node function

Age-dependent down-regulation of hyperpolarization-activated cyclic nucleotide-gated channel 4 causes deterioration of canine sinoatrial node function

In Vitro Analyses of Novel HCN4 Gene Mutations

Genomics of Atrial Fibrillation

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