Property Summary

NCBI Gene PubMed Count 62
PubMed Score 253.28
PubTator Score 149.95

Knowledge Summary

Patent (5,277)


  Differential Expression (3)

Disease log2 FC p
osteosarcoma 1.076 3.1e-04
lung carcinoma 1.800 1.3e-30
psoriasis -1.700 3.3e-07

 GWAS Trait (1)

Gene RIF (42)

26206080 Our results confirm the genetic evidence for the involvement of the HCN4 mutations in the combined bradycardia-non compaction cardiomyopathy phenotype and illustrates that.
26005035 Aged patients with sinus rhythm exhibited significantly higher expression levels of HCN2 and HCN4 channel mRNA and protein (P<0.05), but significantly lower expression levels of miR1 and 133, compared with those of adult patients with sinus rhythm.
25944904 The study analyzed HCN4 intracellular region dynamics in the four states of the thermodynamic cycle arising from the coupling between cAMP binding and tetramerization equilibria.
25145518 The symptom complex of sinus node dysfunction and noncompaction cardiomyopathy is associated with heritable HCN4 defects.
25145517 Mutations in ion channel gene HCN4 may be associated with structural abnormalities of the myocardium.
25144323 study establishes the role of f-channels in cardiac automaticity and indicates that arrhythmia related to HCN loss-of-function may be managed by pharmacological or genetic inhibition of GIRK4 channels
24878962 used NMR to probe the changes caused by the binding of cAMP and of cCMP, a partial agonist, to the apo-cAMP-binding domain of HCN4
24607718 study identified a novel trafficking-defective mutation in the amino-terminus of HCN4 channel in individuals with early-onset atrial fibrillation (AF); findings support that novel loss-of-function mutations in the HCN4 channel may increase susceptibility and have a role in AF pathogenesis
24569893 Here, we review the changes in expression and kinetics of HCN4 mutant channels and provide an overview of their effects on If during the time course of a human SAN action potential, both under resting conditions and upon adrenergic stimulation. [review]
24492017 The HCN4-G1097W mutant channels displayed a loss-of-function type modulation on cardiac If channels and thus could predispose them to AV nodal dysfunction. These data provide a novel insight into the genetic basis for the AV block.
23974038 Cardiomyogenic progenitors derived from the first heart field and human pluripotent stem cells express HCN4.
23623143 Genetic alterations in ion channels that regulate cardiac rhythms may account for some cases of SIDS, as demonstrated by this report of 2 potentially pathogenic novel or rare variants in the HCN4 gene.
23311301 data show a developmental change in HCN4-Cav3 association in human embryonic stem cell-derived cardiomyocytes
23103389 Structural and functional description of the disease causing mutation in human HCN4.
23075627 The HCN4 channels generate currents with reduced amplitude, while the kinetics of activation and deactivation are not altered.
22683190 Anti-HCN4 antibodies in the brain might contribute to the pathogenesis of tic symptoms in Tourette's syndrome patients.
22613709 Data show that beta(2)-adrenergic receptors beta(2)ARs form protein complexes with the HCN4 channel, as well as with other subtypes of HCN channels.
21615589 Genetic analysis in 48 Sudden unexpected death in epilepsy cases identified six novel and three previously reported nonsynonymous (amino acid changing) variants in HCN1 , HCN2, HCN3 and HCN4.
21529705 These findings suggest HCN4 as a genetic susceptibility factor for mood and anxiety disorders
21372143 HCN4 channels are expressed in different patterns in brain and heart; the N terminus is important for HCN4 channel activation
20662977 A novel mutation is found in HCN4 gene causing symptoms of sinus bradycardia in unrelated male Moroccan Jews.
20628086 Observational study of gene-disease association, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator)
20207172 Higher HCN4 mRNA levels in the hypertrophic cardiomyopathy hearts suggest that up-regulation of HCN4 gene expression might be responsible for ventricular arrhythmia that leads to sudden death.
20179882 hHCN4 hysteresis potentially plays a crucial role in human sinoatrial node pacemaking activity.
19913121 Observational study of gene-disease association. (HuGE Navigator)
19796353 In this review, we focus on genotype-phenotype correlation of HCN4 mutations and discuss the relative contribution of various ion channels to sinus node function.
19748888 novel mechanism using three endogenous Src kinases to rescue a trafficking defective HCN4 mutant channel (D553N) by enhancing the tyrosine phosphorylation of the mutant channel protein.
19570998 These data reveal the pathophysiologic mechanism of hHCN4-573X-linked sinoatrial node dysfunction in humans.
19238754 HCN4 associates with Cav3 to form a HCN4 macromolecular complex. Our results also indicated that disruption of caveolae using P104L alters HCN4 function and could cause a reduction of cardiac pacemaker activity.
19165230 The HCN4 channel played a preventive role in triggering bradycardia-induced ventricular arrhythmias.
17977941 Src tyrosine kinase enhances HCN4 currents by shifting their activation to more positive potentials and increasing the whole cell channel conductance as well as speeding the channel kinetics. Tyr(531) mediates most of Src's actions on HCN4 channels.
17646576 A missense mutation, G480R, in the ion channel pore domain caused sinus node dysfunction. Mutant HCN4 had reduced synthesis, was activated at more negative voltages, & had defective ion trafficking.
16777944 With computer modelling, we show that in channels with relatively slow opening kinetics and fast mode-shift transitions, such as HCN2 and HCN4 channels, the mode shift effects are not readily observable, except in the tail kinetics.
16407510 Sinus bradycardia in members of a large family was associated with a mutation in the gene coding for the pacemaker HCN4 ion channel.
15687126 Native I(f) channels in atrial myocardium are heteromeric complexes composed of HCN4 and/or HCN2.
15123648 Data suggest that the loss of function of HCN4 is associated with sinus nodal dysfunction.
14657344 A mouse model for a loss-of-function study of HCN4, which has a strong implication for the function of the related human protein.
12856183 co-expressed KCNE2 enhanced HCN4-generated current amplitudes, slowed the activation kinetics and shifted the voltage for half-maximal activation of currents to more negative voltages
12813043 the speed of activation of the HCN4 channel is determined by structural elements present in the S1, S1-S2 linker, and the S2 segment
12750403 A heterozygous 1-bp deletion (1631delC) in exon 5 of the human HCN4 gene was detected in a patient with idiopathic sinus bradycardia and chronotropic incompetence
12194012 HCN4 activates substantially slower than HCN2 and with a half-maximum activation voltage approximately equal 10 mV less negative, both isoforms activate more positively in myocytes suggesting cell-type specificity
11675786 The rat HCN1 and HCN4 were shown to mediate responses to sour stimuli, suggesting a potential new function for the related human proteins.

AA Sequence

RPEPVRSKLPSNL                                                            1191 - 1203

Text Mined References (62)

PMID Year Title
26206080 2015 HCN4 mutation as a molecular explanation on patients with bradycardia and non-compaction cardiomyopathy.
26005035 2015 Altered expression of hyperpolarization-activated cyclic nucleotide-gated channels and microRNA-1 and -133 in patients with age-associated atrial fibrillation.
25944904 2015 Role of Dynamics in the Autoinhibition and Activation of the Hyperpolarization-activated Cyclic Nucleotide-modulated (HCN) Ion Channels.
25145518 2014 The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel.
25145517 2014 HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy.
25144323 2014 Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation.
24878962 2014 A mechanism for the auto-inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel opening and its relief by cAMP.
24607718 2014 A novel trafficking-defective HCN4 mutation is associated with early-onset atrial fibrillation.
24569893 2014 Pacemaker activity of the human sinoatrial node: effects of HCN4 mutations on the hyperpolarization-activated current.
24492017 2014 A novel HCN4 mutation, G1097W, is associated with atrioventricular block.
23974038 2013 A HCN4+ cardiomyogenic progenitor derived from the first heart field and human pluripotent stem cells.
23623143 2013 Postmortem review and genetic analysis in sudden infant death syndrome: an 11-year review.
23583979 2013 Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.
23311301 2013 Molecular and functional evidence of HCN4 and caveolin-3 interaction during cardiomyocyte differentiation from human embryonic stem cells.
23103389 2012 Local and global interpretations of a disease-causing mutation near the ligand entry path in hyperpolarization-activated cAMP-gated channel.
23075627 2012 The HCN4 channel mutation D553N associated with bradycardia has a C-linker mediated gating defect.
22748890 2012 Investigation of hyperpolarization-activated cyclic nucleotide-gated channels in interstitial cells of Cajal of human bladder.
22683190 2012 Hyperpolarisation-activated cyclic nucleotide channel 4 (HCN4) involvement in Tourette's syndrome autoimmunity.
22613709 2012 Adrenergic regulation of HCN4 channel requires protein association with ?2-adrenergic receptor.
22544366 2012 Meta-analysis identifies six new susceptibility loci for atrial fibrillation.
22006928 2011 Tetramerization dynamics of C-terminal domain underlies isoform-specific cAMP gating in hyperpolarization-activated cyclic nucleotide-gated channels.
21615589 2011 Genetic analysis of hyperpolarization-activated cyclic nucleotide-gated cation channels in sudden unexpected death in epilepsy cases.
21529705 2011 Association of polymorphisms in HCN4 with mood disorders and obsessive compulsive disorder.
21372143 2011 Tissue-specific N terminus of the HCN4 channel affects channel activation.
20829353 2010 Structural basis for the cAMP-dependent gating in the human HCN4 channel.
20662977 2010 A novel mutation in the HCN4 gene causes symptomatic sinus bradycardia in Moroccan Jews.
20628086 2010 Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study.
20207172 Expression of hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN4) is increased in hypertrophic cardiomyopathy.
20179882 2010 Hysteresis in human HCN4 channels: a crucial feature potentially affecting sinoatrial node pacemaking.
19913121 2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.
19796353 2010 The Contribution of HCN4 to normal sinus node function in humans and animal models.
19748888 2009 Rescue of a trafficking defective human pacemaker channel via a novel mechanism: roles of Src, Fyn, and Yes tyrosine kinases.
19570998 2009 Control of heart rate by cAMP sensitivity of HCN channels.
19471099 2009 Transcriptional control of pacemaker channel genes HCN2 and HCN4 by Sp1 and implications in re-expression of these genes in hypertrophied myocytes.
19238754 2008 Caveolin-3 associates with and affects the function of hyperpolarization-activated cyclic nucleotide-gated channel 4.
19165230 2009 Role of HCN4 channel in preventing ventricular arrhythmia.
18383475 2008 Engineering physiologically controlled pacemaker cells with lentiviral HCN4 gene transfer.
18375593 2008 Control of cardiac rate by "funny" channels in health and disease.
18162181 2008 Novel pharmacological activity of loperamide and CP-339,818 on human HCN channels characterized with an automated electrophysiology assay.
17977941 2008 Src tyrosine kinase alters gating of hyperpolarization-activated HCN4 pacemaker channel through Tyr531.
17646576 2007 Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia.
17474147 2007 Systematic identification of SH3 domain-mediated human protein-protein interactions by peptide array target screening.
16777944 2006 Mode shifts in the voltage gating of the mouse and human HCN2 and HCN4 channels.
16484306 2006 Properties of ivabradine-induced block of HCN1 and HCN4 pacemaker channels.
16407510 2006 Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel.
16382102 2005 International Union of Pharmacology. LI. Nomenclature and structure-function relationships of cyclic nucleotide-regulated channels.
16079136 2005 A novel mechanism of modulation of hyperpolarization-activated cyclic nucleotide-gated channels by Src kinase.
15687126 2005 Single-channel properties support a potential contribution of hyperpolarization-activated cyclic nucleotide-gated channels and If to cardiac arrhythmias.
15342556 2004 Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions.
15123648 2004 Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia.
14724293 2004 Calcium influx through hyperpolarization-activated cation channels (I(h) channels) contributes to activity-evoked neuronal secretion.
14720471 2004 Pacemaker channels and sinus node arrhythmia.
14657344 2003 The hyperpolarization-activated channel HCN4 is required for the generation of pacemaker action potentials in the embryonic heart.
12928435 2003 Role of subunit heteromerization and N-linked glycosylation in the formation of functional hyperpolarization-activated cyclic nucleotide-gated channels.
12856183 2003 KCNE2 modulates current amplitudes and activation kinetics of HCN4: influence of KCNE family members on HCN4 currents.
12813043 2003 Molecular basis for the different activation kinetics of the pacemaker channels HCN2 and HCN4.
12750403 2003 Pacemaker channel dysfunction in a patient with sinus node disease.
12194012 2002 Functional comparison of HCN isoforms expressed in ventricular and HEK 293 cells.
11675786 2001 Hyperpolarization-activated channels HCN1 and HCN4 mediate responses to sour stimuli.
10430953 1999 Molecular characterization of a slowly gating human hyperpolarization-activated channel predominantly expressed in thalamus, heart, and testis.
10228147 1999 Two pacemaker channels from human heart with profoundly different activation kinetics.
8889548 1996 Normalization and subtraction: two approaches to facilitate gene discovery.