HCN4 hyperpolarization activated cyclic nucleotide gated potassium channel 4 [Homo sapiens (human)] - Gene

Summary

Official Symbol: HCN4provided by HGNC
Official Full Name: hyperpolarization activated cyclic nucleotide gated potassium channel 4provided by HGNC
Primary source: HGNC:HGNC:16882
See related: Ensembl:ENSG00000138622 MIM:605206; AllianceGenome:HGNC:16882
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: SSS2; EIG18; BRGDA8
Summary: 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]
Expression: Biased expression in testis (RPKM 3.3), heart (RPKM 1.0) and 3 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 15q24.1

Exon count:: 9

Annotation release	Status	Assembly	Chr	Location
RS_2024_08	current	GRCh38.p14 (GCF_000001405.40)	15	NC_000015.10 (73319859..73368958, complement)
RS_2024_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	15	NC_060939.1 (71136994..71186091, complement)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	15	NC_000015.9 (73612200..73661299, complement)

Chromosome 15 - NC_000015.10 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Coexistent HCN4 and GATA5 Rare Variants and Atrial Fibrillation in a Large Spanish Family.
Title: Coexistent HCN4 and GATA5 Rare Variants and Atrial Fibrillation in a Large Spanish Family.
A gain-of-function HCN4 mutant in the HCN domain is responsible for inappropriate sinus tachycardia in a Spanish family.
Title: A gain-of-function HCN4 mutant in the HCN domain is responsible for inappropriate sinus tachycardia in a Spanish family.
Channel HCN4 mutation R666Q associated with sporadic arrhythmia decreases channel electrophysiological function and increases protein degradation.
Title: Channel HCN4 mutation R666Q associated with sporadic arrhythmia decreases channel electrophysiological function and increases protein degradation.
Virus-induced inhibition of cardiac pacemaker channel HCN4 triggers bradycardia in human-induced stem cell system.
Title: Virus-induced inhibition of cardiac pacemaker channel HCN4 triggers bradycardia in human-induced stem cell system.
Clinical Presentation of Left Ventricular Noncompaction Cardiomyopathy and Bradycardia in Three Families Carrying HCN4 Pathogenic Variants.
Title: Clinical Presentation of Left Ventricular Noncompaction Cardiomyopathy and Bradycardia in Three Families Carrying HCN4 Pathogenic Variants.
Altered cyclic nucleotide binding and pore opening in a diseased human HCN4 channel.
Title: Altered cyclic nucleotide binding and pore opening in a diseased human HCN4 channel.
Enhancement of pacing function by HCN4 overexpression in human pluripotent stem cell-derived cardiomyocytes.
Title: Enhancement of pacing function by HCN4 overexpression in human pluripotent stem cell-derived cardiomyocytes.
Phenotype/Genotype Relationship in Left Ventricular Noncompaction: Ion Channel Gene Mutations Are Associated With Preserved Left Ventricular Systolic Function and Biventricular Noncompaction: Phenotype/Genotype of Noncompaction.
Title: Phenotype/Genotype Relationship in Left Ventricular Noncompaction: Ion Channel Gene Mutations Are Associated With Preserved Left Ventricular Systolic Function and Biventricular Noncompaction: Phenotype/Genotype of Noncompaction.
Disease-associated HCN4 V759I variant is not sufficient to impair cardiac pacemaking.
Title: Disease-associated HCN4 V759I variant is not sufficient to impair cardiac pacemaking.
Gating movements and ion permeation in HCN4 pacemaker channels.
Title: Gating movements and ion permeation in HCN4 pacemaker channels.

Submit: New GeneRIF Correction See all GeneRIFs (71)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Brugada syndrome 8 MedGen: C2751083 OMIM: 613123 GeneReviews: Brugada Syndrome	Compare labs
Epilepsy, idiopathic generalized, susceptibility to, 18 MedGen: C5561983 OMIM: 619521 GeneReviews: Not available	Compare labs
Sick sinus syndrome 2, autosomal dominant MedGen: C1834144 OMIM: 163800 GeneReviews: Not available	Compare labs

EBI GWAS Catalog

Description
Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. EBI GWAS Catalog EBI GWAS CatalogPubMed
Meta-analysis identifies six new susceptibility loci for atrial fibrillation. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

RH92735 (e-PCR)
- UniSTS:87848

D15S215 (e-PCR), detects polymorphism
- UniSTS:37267

RH120947 (e-PCR)
- UniSTS:133806

PMC155041P1 (e-PCR)
- UniSTS:271324

PMC155041P2 (e-PCR)
- UniSTS:271325

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables cAMP binding	IEA Inferred from Electronic Annotation more info
enables identical protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables intracellularly cAMP-activated cation channel activity	IDA Inferred from Direct Assay more info	PubMed
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables voltage-gated potassium channel activity	IBA Inferred from Biological aspect of Ancestor more info
enables voltage-gated potassium channel activity	IDA Inferred from Direct Assay more info	PubMed
enables voltage-gated potassium channel activity	IMP Inferred from Mutant Phenotype more info	PubMed
enables voltage-gated potassium channel activity involved in SA node cell action potential depolarization	IMP Inferred from Mutant Phenotype more info	PubMed
enables voltage-gated sodium channel activity	IMP Inferred from Mutant Phenotype more info	PubMed

Process	Evidence Code	Pubs
involved_in SA node cell action potential	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in blood circulation	NAS Non-traceable Author Statement more info	PubMed
involved_in cellular response to cAMP	IDA Inferred from Direct Assay more info	PubMed
involved_in cellular response to cGMP	IDA Inferred from Direct Assay more info	PubMed
involved_in membrane depolarization during SA node cell action potential	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in membrane depolarization during cardiac muscle cell action potential	IC Inferred by Curator more info	PubMed
involved_in monoatomic cation transport	IDA Inferred from Direct Assay more info	PubMed
involved_in muscle contraction	TAS Traceable Author Statement more info	PubMed
involved_in potassium ion import across plasma membrane	IDA Inferred from Direct Assay more info	PubMed
involved_in potassium ion transmembrane transport	IBA Inferred from Biological aspect of Ancestor more info
involved_in potassium ion transmembrane transport	IDA Inferred from Direct Assay more info	PubMed
involved_in potassium ion transmembrane transport	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of cardiac muscle cell action potential involved in regulation of contraction	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of cardiac muscle contraction	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of heart rate	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of heart rate by cardiac conduction	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of membrane depolarization	IBA Inferred from Biological aspect of Ancestor more info
involved_in regulation of membrane depolarization	IDA Inferred from Direct Assay more info	PubMed
involved_in regulation of membrane potential	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in sinoatrial node development	NAS Non-traceable Author Statement more info	PubMed
involved_in sodium ion import across plasma membrane	IDA Inferred from Direct Assay more info	PubMed
involved_in sodium ion transmembrane transport	IBA Inferred from Biological aspect of Ancestor more info
involved_in sodium ion transmembrane transport	IMP Inferred from Mutant Phenotype more info	PubMed

Component	Evidence Code	Pubs
part_of HCN channel complex	IBA Inferred from Biological aspect of Ancestor more info
part_of HCN channel complex	IDA Inferred from Direct Assay more info	PubMed
is_active_in axon	IBA Inferred from Biological aspect of Ancestor more info
is_active_in dendrite	IBA Inferred from Biological aspect of Ancestor more info
located_in perinuclear region of cytoplasm	IDA Inferred from Direct Assay more info	PubMed
located_in plasma membrane	IDA Inferred from Direct Assay more info	PubMed
located_in plasma membrane	TAS Traceable Author Statement more info

General protein information

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Preferred Names: potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4

Names: hyperpolarization activated cyclic nucleotide-gated cation channel 4

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_009063.1 RefSeqGene

Range

5307..54406

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_005477.3 → NP_005468.1 potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4

See identical proteins and their annotated locations for NP_005468.1

Status: REVIEWED

Source sequence(s)

AC068397, AJ132429, AJ238850, BM979827, BP291686

Consensus CDS

CCDS10248.1

UniProtKB/Swiss-Prot

Q9UMQ7, Q9Y3Q4

Related

ENSP00000261917.3, ENST00000261917.4

Conserved Domains (4) summary

COG0664
Location:589 → 724

Crp; cAMP-binding domain of CRP or a regulatory subunit of cAMP-dependent protein kinases [Signal transduction mechanisms]

cd00038
Location:595 → 703

CAP_ED; effector domain of the CAP family of transcription factors; members include CAP (or cAMP receptor protein (CRP)), which binds cAMP, FNR (fumarate and nitrate reduction), which uses an iron-sulfur cluster to sense oxygen) and CooA, a heme containing CO ...

pfam00520
Location:280 → 525

Ion_trans; Ion transport protein

pfam08412
Location:218 → 260

Ion_trans_N; Ion transport protein N-terminal

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

NC_000015.10 Reference GRCh38.p14 Primary Assembly

Range

73319859..73368958 complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_011521148.3 → XP_011519450.1 potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 isoform X1

Conserved Domains (3) summary

COG0664
Location:183 → 318

Crp; cAMP-binding domain of CRP or a regulatory subunit of cAMP-dependent protein kinases [Signal transduction mechanisms]

cd00038
Location:189 → 297

CAP_ED; effector domain of the CAP family of transcription factors; members include CAP (or cAMP receptor protein (CRP)), which binds cAMP, FNR (fumarate and nitrate reduction), which uses an iron-sulfur cluster to sense oxygen) and CooA, a heme containing CO ...

pfam00520
Location:5 → 119

Ion_trans; Ion transport protein