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Category Symbol Source: HGNC EntrezGene Ensembl GeneCards RNA genes CroW21

GIFtS
-

HCN4 Gene

protein-coding GIFtS: 64
GCID: GC15M073612

hyperpolarization activated cyclic nucleotide-gated potassium...

Explore 13 diseases affiliated with
HCN4 via

MalaCards

our new
Human Malady Compendium

(According to ¹HGNC, ²Entrez Gene,
³UniProtKB/Swiss-Prot, ⁴UniProtKB/TrEMBL, ⁵OMIM, ⁶GeneLoc, ⁷Ensembl, ⁸DME, ⁹miRBase, and/or ¹⁰fRNAdb)
About This Section

Aliases
Hyperpolarization Activated Cyclic Nucleotide-Gated Potassium Channel 4¹ ²
SSS2² ⁵
Hyperpolarization Activated Cyclic Nucleotide-Gated Cation Channel 4²
Potassium/Sodium Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel 4²

External Ids:	HGNC: 16882¹	Entrez Gene: 10021²	Ensembl: ENSG00000138622⁷	OMIM: 605206⁵	UniProtKB: Q9Y3Q4³

Export aliases for HCN4 gene to outside databases

Previous GC identifers: GC15M069662 GC15M066718 GC15M071189 GC15M071329 GC15M071400 GC15M050443

(According to Entrez Gene, Tocris Bioscience, Wikipedia's Gene Wiki, PharmGKB,
UniProtKB/Swiss-Prot, and/or UniProtKB/TrEMBL)
About This Section

Entrez Gene summary for HCN4:

This gene encodes a member of the hyperpolarization-activated cyclic nucleotide-gated potassium channels. The encoded

protein shows slow kinetics of activation and inactivation, and is necessary for the cardiac pacemaking process. This

channel may also mediate responses to sour stimuli. Mutations in this gene have been linked to sick sinus syndrome 2,

also known as atrial fibrillation with bradyarrhythmia or familial sinus bradycardia. Two pseudogenes have been

identified on chromosome 15. (provided by RefSeq, Oct 2008)

UniProtKB/Swiss-Prot: HCN4_HUMAN, Q9Y3Q4

Function: Hyperpolarization-activated ion channel with very slow activation and inactivation exhibiting weak

selectivity for potassium over sodium ions. May contribute to the native pacemaker currents in heart (If) and in

neurons (Ih). Activated by cAMP. May mediate responses to sour stimuli

Gene Wiki entry for HCN4

(According to GeneLoc and/or HGNC, and/or
Entrez Gene (NCBI build 37),
and/or miRBase,
Genomic Views according to UCSC (hg19) and Ensembl (release 69), Regulatory elements and Epigenetics data according to QIAGEN, SABiosciences, and/or SwitchGear Genomics)
About This Section

RefSeq DNA sequence:

NC_000015.9 NC_018926.1 NT_010194.17

Regulatory elements:

SABiosciences Regulatory transcription factor binding sites in the HCN4 gene promoter:
HOXA9B HOXA9 Pax-5 Lmo2 Meis-1b RORalpha1 PPAR-gamma1 PPAR-gamma2 c-Myc Meis-1
Other transcription factors

SwitchGear Promoter luciferase reporter plasmid: HCN4 promoter sequence

Search SABiosciences Chromatin IP Primers for HCN4

Epigenetics:

QIAGEN PyroMark CpG Assay predesigned Pyrosequencing DNA Methylation assays in human, mouse, rat HCN4

Genomic Location:
Genomic View: UCSC Golden Path with GeneCards custom track

Entrez Gene cytogenetic band: 15q24.1 Ensembl cytogenetic band: 15q24.1 HGNC cytogenetic band: 15q24.1

HCN4 Gene in genomic location: bands according to Ensembl, locations according to (and/or Entrez Gene and/or Ensembl if different)
HCN4 gene location

GeneLoc information about chromosome 15 GeneLoc Exon Structure

GeneLoc location for GC15M073612: view genomic region (about GC identifiers)

Start:	73,612,200 bp from pter	End:	73,661,605 bp from pter
Size:	49,406 bases	Orientation:	minus strand

(According to ¹UniProtKB, HORDE, neXtProt, Ensembl, and/or Reactome, Modification sites according to ²PhosphoSitePlus, Specific Peptides from DME, Protein expression images according to data from SPIRE MOPED and PaxDb, RefSeq according to NCBI, PDB rendering according to OCA and/or Proteopedia, Recombinant Proteins from EMD Millipore, R&D Systems, GenScript, Enzo Life Sciences, OriGene, Novus Biologicals, Sino Biological, ProSpec, and/or Uscn,
Biochemical Assays by EMD Millipore, R&D Systems, OriGene, GenScript, Cell Signaling Technology, Enzo Life Sciences, and/or Uscn, Ontologies according to Gene Ontology Consortium 01 Mar 2013 and Entrez Gene, Antibodies by EMD Millipore, R&D Systems, GenScript, Cell Signaling Technology, OriGene, Novus Biologicals, Thermo Fisher Scientific, Abcam, and/or Uscn)
About This Section

UniProtKB/Swiss-Prot: HCN4_HUMAN, Q9Y3Q4 (See protein sequence)

Recommended Name: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4

Size: 1203 amino acids; 129042 Da

Subunit: The potassium channel is probably composed of a homo- or heterotetrameric complex of pore-forming subunits

Subcellular location: Membrane; Multi-pass membrane protein

Miscellaneous: Inhibited by extracellular cesium ions

3 PDB 3D structures from and Proteopedia for HCN4:

3OTF (3D)

3U11 (3D)

4HBN (3D)

Secondary accessions: Q9UMQ7

Explore the universe of human proteins at neXtProt for HCN4: NX_Q9Y3Q4

Post-translational modifications:

View modification sites using PhosphoSitePlus²

View neXtProt modification sites for NX_Q9Y3Q4

HCN4 Protein expression data from MOPED and PaxDb: About this image

REFSEQ proteins: NP_005468.1

ENSEMBL proteins:

ENSP00000261917

Reactome Protein details: Q9Y3Q4
Human Recombinant Protein Products:

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	Uscn Proteins for HCN4

Gene Ontology (GO): 3 cellular component terms (GO ID links to tree view): About this table

GO ID	Qualified GO term	Evidence	PubMed IDs
GO:0005886	plasma membrane	TAS	--
GO:0016021	integral to membrane	IEA	--
GO:0043195	terminal bouton	IEA	--

HCN4 for ontologies About GeneDecksing

HCN4 Antibody Products:

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	Uscn ELISAs and CLIAs for HCN4

(According to InterPro, ProtoNet, UniProtKB, and/or BLOCKS, Sets of similar genes according to GeneDecks)
About This Section

HCN4 for domains About GeneDecksing

5/7 InterPro domains/families (see all 7):

IPR018488 cNMP-bd_CS

IPR018490 cNMP-bd-like

IPR005821 Ion_trans_dom

IPR000595 cNMP-bd_dom

IPR003938 K_chnl_volt-dep_EAG/ELK/ERG

Graphical View of Domain Structure for InterPro Entry Q9Y3Q4

ProtoNet protein and cluster: Q9Y3Q4

2 Blocks protein families:

IPB000595 Cyclic nucleotide-binding domain

IPB013621 Ion transport N-terminal

UniProtKB/Swiss-Prot: HCN4_HUMAN, Q9Y3Q4

Domain: The segment S4 is probably the voltage-sensor and is characterized by a series of positively charged amino

acids at every third position

Similarity: Belongs to the potassium channel HCN family

Similarity: Contains 1 cyclic nucleotide-binding domain

(According to ¹UniProtKB, Genatlas, LifeMap Discovery™, IUBMB, and/or ²DME, Human phenotypes from GenomeRNAi, Animal models from MGI Mar 06 2013,
bound targets from SABiosciences, miRNA Gene Targets from miRTarBase shRNA from OriGene, RNAi from EMD Millipore, siRNAs from OriGene, QIAGEN, microRNA from QIAGEN, Gene Editing from DNA2.0, Clones from EMD Millipore, OriGene, SwitchGear Genomics, GenScript, Sino Biological, DNA2.0, and Vector BioLabs, Cell Lines from GenScript, LifeMap BioReagents, In Situ Hybridization Assays from Advanced Cell Diagnostics, Ontologies according to Gene Ontology Consortium 01 Mar 2013 via Entrez Gene.)
About This Section

Function Summary:

UniProtKB/Swiss-Prot: HCN4_HUMAN, Q9Y3Q4

Function: Hyperpolarization-activated ion channel with very slow activation and inactivation exhibiting weak

selectivity for potassium over sodium ions. May contribute to the native pacemaker currents in heart (If) and in

neurons (Ih). Activated by cAMP. May mediate responses to sour stimuli

Genatlas biochemistry entry for HCN4:

hyperpolarization-activated and cyclic nucleotide gated potassium channel 4,expressed in the brain,predominantly in

thalamus,heart and testis,playing a critical role in shaping the autonomous activity of single neurons and the

periodocity of network oscillations

miRNA Products:		miRTarBase miRNAs that target HCN4: hsa-mir-1 (MIRT000933), hsa-mir-133a (MIRT000329)

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		8/61 QIAGEN miScript miRNA Assays for microRNAs that regulate HCN4 (see all 61):
		hsa-miR-642a hsa-miR-520f hsa-miR-300 hsa-miR-631 hsa-miR-106a hsa-miR-128 hsa-miR-218 hsa-miR-149

		SwitchGear 3'UTR luciferase reporter plasmid: HCN4 3' UTR sequence

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Gene Editing
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Cell Line Products:		GenScript Custom overexpressing Cell Line Services for HCN4
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In Situ Assay
Products:

Advanced Cell Diagnostics RNAscope RNA in situ hybridization assays for HCN4

Gene Ontology (GO): 5/6 molecular function terms (GO ID links to tree view) (see all 6): About this table

GO ID	Qualified GO term	Evidence	PubMed IDs
GO:0005222	intracellular cAMP activated cation channel activity	IEA	--
GO:0005249	voltage-gated potassium channel activity	IEA	--
GO:0005261	cation channel activity	TAS	10228147
GO:0005272	sodium channel activity	IEA	--
GO:0005515	protein binding	--	--

HCN4 for ontologies About GeneDecksing

2 GenomeRNAi human phenotypes for HCN4:

Decreased Salmonella enterica

Decreased viability with pacli

Animal Models:
Mouse knock-outs for HCN4: Hcn4^tm1Lex Hcn4^tm1.1Jsr
7 MGI mutant phenotypes (inferred from 8 alleles) (MGI details for Hcn4):

cardiovascular system	growth/size	homeostasis/metabolism	mortality/aging	muscle
no phenotypic analysis	normal

HCN4 for phenotypes About GeneDecksing

(Pathways according to EMD Millipore, R&D Systems, Cell Signaling Technology, KEGG, PharmGKB, BioSystems, Reactome, Tocris Bioscience, GeneGo (Thomson Reuters), QIAGEN, and/or UniProtKB, Sets of similar genes according to GeneDecks, Interaction Networks according to SABiosciences, and/or STRING, Interactions according to ¹UniProtKB, ²MINT, ³I2D, and/or ⁴STRING, with links to IntAct and Ensembl, Ontologies according to Gene Ontology Consortium 01 Mar 2013 via Entrez Gene).
About This Section

Unified GeneCards pathways - 5/8 super-pathways (see all 8) About this table

See pathways by source

Super-pathway

contained gene-specific pathways

Potassium Channels

Potassium Channels

1.00

HCN channels

HCN channels

1.00

Antiarrhythmic Pathway, Pharmacodynamics

Antiarrhythmic Pathway, Pharmacodynamics

1.00

Synaptic transmission: ion currents

Synaptic transmission: ion currents

1.00

Potassium transporters: inward current

Potassium transporters: inward current

1.00

Pathway sources
See GeneCards unified pathways
Show all pathways

3 EMD Millipore Pathways for HCN4

	Potassium transporters- inward current
	Synaptic transmission- ion currents
	Sodium channels and transporters- inward current

1 Downloadable PowerPoint Slide of QIAGEN Pathway Central Maps for HCN4

Sperm Motility

3 Reactome Pathways for HCN4

	Potassium Channels
	HCN channels
	Neuronal System

1 PharmGKB Pathway for HCN4

Antiarrhythmic Pathway, Pharmacodynamics

HCN4 for pathways About GeneDecksing

Interactions:

Search SABiosciences Gene Network Central^TM Interacting Genes and Proteins Networks for HCN4

STRING Interaction Network Preview (showing 5 interactants - click image to see more details)

5 Interacting proteins for HCN4 (Q9Y3Q4³ ENSP00000261917⁴) via UniProtKB, MINT, STRING, and/or I2D

Interactant		Interaction Details
GeneCard	External ID(s)	Interaction Details
ABL1	P00519³, ENSP00000361423⁴	I2D: score=1 STRING: ENSP00000361423
FYN	P06241³, ENSP00000357656⁴	I2D: score=1 STRING: ENSP00000357656
HCN1	O60741³, ENSP00000307342⁴	I2D: score=1 STRING: ENSP00000307342
HCN2	Q9UL51³, ENSP00000251287⁴	I2D: score=2 STRING: ENSP00000251287
HCN3	Q9P1Z3³, ENSP00000357342⁴	I2D: score=1 STRING: ENSP00000357342

About this table

Gene Ontology (GO): 5/6 biological process terms (GO ID links to tree view) (see all 6): About this table

GO ID	Qualified GO term	Evidence	PubMed IDs
GO:0001701	in utero embryonic development	IEA	--
GO:0006812	cation transport	TAS	10228147
GO:0006936	muscle contraction	TAS	10228147
GO:0007268	synaptic transmission	TAS	--
GO:0008015	blood circulation	NAS	10228147

HCN4 for ontologies About GeneDecksing

(Chemical Compounds according to UniProtKB, Enzo Life Sciences, EMD Millipore, Tocris Bioscience HMDB, BitterDB, and/or Novoseek, and Drugs according to DrugBank, Enzo Life Sciences, and/or PharmGKB, with drugs/clinical trials/news search links to CenterWatch)
About This Section

HCN4 for compounds About GeneDecksing

Browse Small Molecules at EMD Millipore

Browse drugs & compounds from Enzo Life Sciences

Browse Tocris compounds for HCN4

2 HMDB Compounds for HCN4 About this table

Compound	Synonyms	CAS #	PubMed Ids
Cyclic AMP	Cyclic AMP (see all 19)	60-92-4	--
Sodium	Sodium (see all 2)	7440-23-5	--

2 Novoseek chemical compound relationships for HCN4 gene About this table

Compound	-log (P-Val)	Hits	PubMed IDs for Articles with Shared Sentences (# sentences)
potassium	29	2	19324302 (1)
phenylalanine	28.6	3	16079136 (1), 12813043 (1)

Search CenterWatch for drugs/clinical trials and news about HCN4

(Secondary structures according to fRNAdb,
GenBank/EMBL/DDBJ Accessions according to
Unigene (Build 235 Homo sapiens; Mar 10 2013) or GenBank,
RefSeq according to Entrez Gene,
DOTS (version 10), and/or AceView, transcript ids from Ensembl with links to UCSC,
exon structure from GeneLoc, alternative splicing isoforms according to ASD and/or ECgene,
RNAi Products from EMD Millipore,
siRNAs from OriGene, QIAGEN, shRNA from OriGene, microRNA from QIAGEN,
Tagged/untagged cDNA clones from OriGene, SwitchGear Genomics, GenScript, DNA2.0, Vector BioLabs, Primers from OriGene, SABiosciences, and/or QIAGEN )
About This Section

REFSEQ mRNAs for HCN4 gene:

NM_005477.2

Unigene Cluster for HCN4:

Hyperpolarization activated cyclic nucleotide-gated potassium channel 4

Hs.86941 [show with all ESTs]

Unigene Representative Sequence: NM_005477

1 Ensembl transcript including schematic representation, and UCSC links where relevant:

ENST00000261917(uc002avp.3)

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		QIAGEN Custom miScript Target Protector blocks miRNA-binding site of human, mouse, rat HCN4
		8/61 QIAGEN miScript miRNA Assays for microRNAs that regulate HCN4 (see all 61):
		hsa-miR-642a hsa-miR-520f hsa-miR-300 hsa-miR-631 hsa-miR-106a hsa-miR-128 hsa-miR-218 hsa-miR-149

		SwitchGear 3'UTR luciferase reporter plasmid: HCN4 3' UTR sequence

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		QIAGEN QuantiFast Probe-based Assays in human, mouse, rat HCN4

Additional cDNA sequence:

AJ132429.1 AJ238850.1 DQ854814.1

2 DOTS entries:

DT.108315 DT.108314

24/42 AceView cDNA sequences (see all 42):

AI990839 AI638000 NM_005477 BX090501 BM979827 BE552405 AV726930 AA902394

AI990915 BE045688 AJ132429 BE327046 AI989696 AW770740 AI671859 AI458708

BE467684 AA969962 BE221167 AA995375 BE327512 AI273647 BE463817 AW770658

GeneLoc Exon Structure

(RNA expression data according to H-InvDB, NONCODE, miRBase, and RNAdb, Expression images according to data from BioGPS, Illumina Human BodyMap, and CGAP SAGE, Sets of similar genes according to GeneDecks, in vivo and in vitro expression data from LifeMap Discovery™, plus additional links to Genevestigator, and/or SOURCE, and/or BioGPS, and/or UniProtKB,
PCR Arrays from SABiosciences, Primers from OriGene, SABiosciences, and/or QIAGEN, In Situ Hybridization Assays from Advanced Cell Diagnostics)
About This Section

HCN4 expression in normal human tissues (normalized intensities)
See probesets specificity/sensitivity at GeneAnnot
About this imageBioGPS
CGAP TAG: CATTTTATAA

About this image

HCN4 expression in embryonic tissues and stem cells

Expression by the Database of Embryonic development, Stem cell research, and Regenerative medicine About this table

3 LifeMap In Vivo Development Anatomical Compartments/Cells

Tissue

Anatomical Compartment

Cell

Category (developmental path)

Heart

Atrioventricular Node

Atrioventricular Node Cells

Selective marker (cell-identifying gene)

Myocardium

Heart

Sinoatrial Node

Sinoatrial Node Cells

Myocardium

Eye

Inner Nuclear Layer

Type3a Off Cone Bipolar Cells

Bipolar, Retina

Expression:

Positive

Negative

Selective marker

Experimental details:

Curated

Microarrays

In-situ hybridization

Stem Cell Differentiation: 2 LifeMap Cells

Name

Category

Early cardiomyocytes (Differentiation of c...)

Floating colonies of cardiomyocytes (Differentiation of c...)

See HCN4 Protein Expression from SPIRE MOPED and PaxDB
Genevestigator expression for HCN4

SOURCE GeneReport for Unigene cluster: Hs.86941

UniProtKB/Swiss-Prot: HCN4_HUMAN, Q9Y3Q4

Tissue specificity: Highly expressed in thalamus, testis and in heart, both in ventricle and atrium. Detected at much

lower levels in amygdala, substantia nigra, cerebellum and hippocampus

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In Situ
Assay Products:

Advanced Cell Diagnostics RNAscope RNA in situ hybridization assays for HCN4

(Orthologs according to ^1,2HomoloGene (²older version, for species not in ¹newer version), ³euGenes, ⁴SGD , ⁵MGI Mar 06 2013, with possible further links to Flybase and/or WormBase, and/or ⁶Ensembl pan taxonomic compara , Gene Trees according to Ensembl and TreeFam)
About This Section

This gene was present in the common ancestor of eukaryotes.

Orthologs for HCN4 gene from 6/20 species (see all 20) About this table

Organism	Taxonomic classification	Gene	Description	Human Similarity	Orthology Type	Details
chicken (Gallus gallus)	Aves	HCN4¹	hyperpolarization activated cyclic nucleotide-gated more	74.87(n) 79.6(a)		427478 XM_425050.3 XP_425050.3
lizard (Anolis carolinensis)	Reptilia	-- --	--	62(a) 60(a)	1 ↔ many 1 ↔ many	GL343517.1(269592-307961) GL343517.1(227271-254187)
zebrafish (Danio rerio)	Actinopterygii	hcn4⁶ hcn4l⁶ (see all 3)	hyperpolarization activated cyclic nucleotide-gate... hyperpolarization activated cyclic nucleotide-gate... (see all 3)	63(a) 54(a) (see all 3)	1 ↔ many 1 ↔ many (see all 3)	18(804501-943685) 25(30195791-30296040)
fruit fly (Drosophila melanogaster)	Insecta	Ih³	intracellular cyclic nucleotide activated cation more	54(a)		--
thale cress (Arabidopsis thaliana)	eudicotyledons	KAT1¹	Potassium channel KAT1	37.28(n) 23.21(a)		834666 NM_123993.2 NP_199436.1
rice (Oryza sativa)	Liliopsida	Os02g0245800¹	hypothetical protein	38.3(n) 24.41(a)		4328864 NM_001052957.1 NP_001046422.2

ENSEMBL Gene Tree for HCN4 (if available)
TreeFam Gene Tree for HCN4 (if available)

(Paralogs according to ¹HomoloGene,
²Ensembl, and ³SIMAP, Pseudogenes according to ⁴Pseudogene.org Build 68)
About This Section

Paralogs for HCN4 gene

KCNH6² KCNH3² KCNH5² HCN3² HCN2² KCNH4² CNGA2² CNGA1²

HCN1² KCNH7² KCNH2² CNGB1² CNGA4² CNGA3² CNGB3² KCNH1²

KCNH8²

3 SIMAP similar genes for HCN4 using alignment to 1 protein entry: HCN4_HUMAN:

HCN3 HCN1 HCN2

HCN4 for paralogs About GeneDecksing

(SNPs/Variants according to the ¹NCBI SNP Database, ²Ensembl, ³PupaSUITE, UniProtKB, and DNA2.0, Linkage Disequilibrium by HapMap, Structural Variations(CNVs/InDels/Inversions) from the Database of Genomic Variants, Mutations from the Human Gene Mutation Database (HGMD) and the Locus Specific Mutation Databases (LSDB), Blood group antigen gene mutations by BGMUT, Resequencing Primers from QIAGEN, Cancer Mutation PCR Arrays and Assays and Copy Number PCR Arrays from SABiosciences)
About This Section

SNP ID	Valid	Clinical significance	Chr 15 pos	Sequence	#	AA Chg	Type	More	#	Allele freq	Pop	Total sample	More
Genomic Data					Transcription Related Data				Allele Frequencies
				--	--	--		--	--
rs104894485^1,2	C	pathogenic	51932859(-)	`TCCACA/GACTAC`	2	N D	mis¹		0	--	--	--	--
rs12594132^1,2	C,A,H	--	50443311(+)	`AGTAGT/GGGGTG`	1	--	ds500¹		1		NA	2
rs3743493^1,2	C,	--	50443693(+)	`TTACCA/GGTTTC`	1	--	ut3¹		0	--	--	--	--
rs524457^1,2	C,F,O,A,H,	--	50443820(+)	`AAAATG/ACATGT`	1	--	ut3¹		16		MN NS EA NA CSA WA	2080
rs7167434^1,2	C,F,H,	--	50443844(+)	`GAAGAG/CGGTGG`	1	--	ut3¹		4		NS EA	394
rs74933243^1,2	C,F,	--	50443872(+)	`GGCAAG/CGNNNN`	1	--	ut3¹		1		NA	120
rs11631286^1,2	C,F,H,	--	50443911(+)	`ACCCCT/CGCTGC`	1	--	ut3¹		1		NA	8
rs117071871^1,2	C,F,	--	50445068(+)	`ACCTCA/GGCCCC`	1	--	ut3¹		1		NA	120
rs74786613^1,2		--	50445125(+)	`GGAGGC/TGTGGA`	1	--	ut3¹		0	--	--	--	--
rs185261766^1,2	C,	--	50445421(+)	`ACTTCC/TGTGTG`	1	--	ut3¹		0	--	--	--	--

HapMap Linkage Disequilibrium report for HCN4 (73612200 - 73661605 bp)
Structural Variations (Copy Number Variations, Insertions/Deletions, Inversions)
Database of Genomic Variants (DGV): 2 variations for HCN4
2 CNVs: 72278 77002
Human Gene Mutation Database (HGMD): HCN4

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(in which this Gene is Involved, According to MalaCards, OMIM, UniProtKB, the University of Copenhagen DISEASES database, Genatlas, GeneTests, GAD, HuGE Navigator, and/or TGDB.)
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HCN4 for disorders           About GeneDecksing

OMIM gene information: 605206
OMIM disorders: 163800  613123
UniProtKB/Swiss-Prot: HCN4_HUMAN, Q9Y3Q4

Defects in HCN4 are a cause of sick sinus syndrome type 2 (SSS2) [MIM:163800]; also known as atrial

fibrillation with bradyarrhythmia or familial sinus bradycardia. The term 'sick sinus syndrome' encompasses a variety

of conditions caused by sinus node dysfunction. The most common clinical manifestations are syncope, presyncope,

dizziness, and fatigue. Electrocardiogram typically shows sinus bradycardia, sinus arrest, and/or sinoatrial block.

Episodes of atrial tachycardias coexisting with sinus bradycardia ('tachycardia-bradycardia syndrome') are also common

in this disorder. SSS occurs most often in the elderly associated with underlying heart disease or previous cardiac

surgery, but can also occur in the fetus, infant, or child without heart disease or other contributing factors, in

which case it is considered to be a congenital disorder

Defects in HCN4 are the cause of Brugada syndrome type 8 (BRGDA8) [MIM:613123]. A tachyarrhythmia

characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the

ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation

occurs (called ventricular fibrillation), the individual will faint and may die in a few minutes if the heart is not

reset

13 diseases for HCN4: About MalaCards

sick sinus syndrome sick sinus syndrome 2 atrial fibrillation sinusitis

obsessive-compulsive disorder brugada syndrome 8 long qt syndrome brugada syndrome

hypertrophic cardiomyopathy mood disorder cardiomyopathy aldosteronism

neuronitis

2 diseases from the University of Copenhagen DISEASES database for HCN4:

Sick sinus syndrome Brugada syndrome

Human Genome Epidemiology (HuGE) Navigator: HCN4 (3 documents)

Export disorders for HCN4 gene to outside databases

(in PubMed. Associations of this gene to articles via ¹Entrez Gene, ²UniProtKB/Swiss-Prot, ³HGNC, ⁴GAD, ⁵PharmGKB, ⁶HMDB, ⁷DrugBank, ⁸UniProtKB/TrEMBL, ⁹ Novoseek, and/or ¹⁰fRNAdb)
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PubMed articles for HCN4 gene, integrated from 9 sources (see all 61):
(articles sorted by number of sources associating them with HCN4)

Utopia: connect your pdf to the dynamic
world of online information

Molecular characterization of a slowly gating human hyperpolarization-activated channel predominantly expressed in thalamus, heart, and testis. (PubMed id 10430953)^{1, 2, 3} Seifert R....Kaupp U.B. (1999)
Two pacemaker channels from human heart with profoundly different activation kinetics. (PubMed id 10228147)^{1, 2, 3} Ludwig A.... Biel M. (1999)
Role of HCN4 channel in preventing ventricular arrhythmia. (PubMed id 19165230)^{1, 2, 9} Ueda K....Kimura A. (2009)
A novel mutation in the HCN4 gene causes symptomatic sinus bradycardia in Moroccan Jews. (PubMed id 20662977)^{1, 2} Laish-Farkash A.... Luria D. (2010)
Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. (PubMed id 16407510)^{1, 2} Milanesi R.... DiFrancesco D. (2006)
International Union of Pharmacology. LI. Nomenclature and structure-function relationships of cyclic nucleotide-regulated channels. (PubMed id 16382102)^{1, 3} Hofmann F....Kaupp U.B. (2005)
Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia. (PubMed id 15123648)^{1, 2} Ueda K....Kimura A. (2004)
Molecular basis for the different activation kinetics of the pacemaker channels HCN2 and HCN4. (PubMed id 12813043)^{1, 9} Stieber J....Hofmann F. (2003)
Novel pharmacological activity of loperamide and CP-339,818 on human HCN channels characterized with an automated electrophysiology assay. (PubMed id 18162181)^{1, 9} Lee Y.T....Bowlby M.R. (2008)
Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia. (PubMed id 17646576)^{1, 9} Nof E....Glikson M. (2007)

(in PubMed, OMIM, and NCBI Bookshelf)
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		AND	OR
Aliases
Free Text

Query String		PubMed OMIM NCBI Bookshelf
	(Note: In FireFox, select the above section and copy using Ctrl-C)

(According to Entrez Gene, HGNC, AceView, euGenes, Ensembl, miRBase, ECgene, Kegg, and/or H-InvDB)
About This Section

Entrez Gene: 10021	HGNC: 16882	AceView: HCN4	Ensembl:ENSG00000138622	euGenes: HUgn10021
ECgene: HCN4	H-InvDB: HCN4

(According to HUGE)
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(According to PharmGKB, ATLAS, HORDE, IMGT, LEIDEN, UniProtKB/Swiss-Prot, and/or UniProtKB/TrEMBL,
Wikipedia and/or GeneReviews via UniProtKB/Swiss-Prot)
About This Section

Name	Description
PharmGKB entry for HCN4	Pharmacogenomics, SNPs, Pathways

Intellectual Property for HCN4 gene
(Patent information from GeneIP, Licensable technologies from WIS Yeda, Salk, Tufts, IP news from LifeMap Sciences, Inc.)

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Patent Information for HCN4 gene:
Search GeneIP for patents involving HCN4

GeneCards and IP:
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