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FLASH GENE

Symbol

KCNH2

contributors: mct - updated : 21-09-2018

HGNC name	potassium voltage-gated channel, subfamily H (eag-related), member 2
HGNC id	6251

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	BRGS10 Brugada syndrome 10 LQT2 long QT syndrome with ventricular tachyarrhythmia, type 2 SQT1 short QT syndrome-1
Location	7q36.1      Physical location : 150.642.049 - 150.675.014
Synonym name	human ether-a-go-go related gene
	ether-a-go-go-related gene potassium channel 1
	cause of Long QT Syndrome Type 2
	potassium channel HERG1
	Eag-related protein 1
Synonym symbol(s)	HERG, LQT2, ERG1, SQT1, HERG1, Kv11.1

DNA

TYPE	functioning gene
STRUCTURE	33.36 kb     15 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

confirmed

Map	cen - D7S2450 - KCNH2 - D7S483 - SLC4A2 - D7S550 - qter

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed variant 5 - - 3575 isoform 5 - 1058 smooth muscle specific 2002 12427763 also called ERG1 sm truncated C terminus of 101 amino acids, stop codon of the exon 14 NM_172057 11 - 3191 NP_742054 - 819 in the heart, colon 2002 12427763 alsos called HERG1B or variant 3/isoform c NM_172056 9 - 3164 NP_742053 - 888 in the heart 2002 12427763 also called HERG uso or variant 2/isoform b 15 exons, alternatively spliced variant at exon 9 of HERG1 , truncated isoform has an alternate 36-AA N-terminal end NM_000238 15 splicing 4307 NP_000229 126.7 1159 - 2002 12427763 also called ERG1 Ia or variant 1/isoform a variant 4 - - 4720 isoform 4 - - brain-specific 2002 12427763 also called KCNH2-3.1 FJ938021 lacks a domain that is crucial for slow channel deactivation overexpression in primary cortical neurons induces a rapidly deactivating K+ current and a high-frequency, nonadapting firing pattern KCNH2-3.1 mRNA expression was significantly increased within the hippocampal formation of subjects with schizophrenia versus healthy control subjects lacks the first 102AA of hERG1a, which are replaced by 6 unique amino acids NM_001204798 5 - 2463 NP_001191727 - 548 - 2002 12427763

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Homo sapiens Digestive intestine small intestine         intestine large intestine colon   highly Endocrine parathyroid       highly Nervous brain         Homo sapiens Reproductive female system ovary     highly Urinary kidney       highly Visual eye       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular smooth       Homo sapiens

cells

System Cell Pubmed Species Stage Rna symbol Blood/Hematopoietic leukocyte Muscular myocyte Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	cytosolic N terminus domain, highly conserved, controlling desactivation by association with K+ channel, with a Per-Arnt-Sim (PAS) domain, regulating its deactivation kinetics , PAS domain that is also implicated in the assembly and stabilization of the assembled tetrameric channel
	six membrane spanning domains with an hydrophobic pore flanked by TM domains 5 and 6
	arginine-rich fourth TM domain controling voltage dependent gating
	one cyclic nucleotide binding domain
	a voltage-sensor domain (VSD) that is important for sensing voltage changes across the membrane
	cytosolic C terminus, with significant role in cardiac repolarization, sensitive to changes in membrane potential (PAS associated C terminal domain-Par)
	C-terminal region containing a cyclic-nucleotide-binding homology domain (CNBHD) and C-linker that couples the CNBHD to the pore; it is required for the channel gating though molecular interactions with the eag domain

secondary structure

when the PAS domain is present, the N-Cap amphipathic helix must also be present for channels to traffic to the cell membrane

HOMOLOGY

interspecies	homolog to Drosophila eag
	homolog to murine Dcnh2

intraspecies

homolog to cyclic nucleotide gated channel

Homologene

FAMILY	potassium channel family
	H (Eag) subfamily

CATEGORY

motor/contractile , transport channel

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm
	intracellular,nuclear envelope
text	KCNH2 expression in the plasma membrane is regulated by CAV3 via NEDD4L

basic FUNCTION	potassium voltage-gated channel
	similar to IKr, the cardiac rapid delayed rectified potassium channel
	mediating the rapidly activating component of the delayed rectifying potassium current in heart (IKr)
	forms the ion channel responsible for the rapidly acting delayed rectifier potassium current, I(Kr), and its blockade is a significant contributor to prolongation of the QT interval
	alpha-subunit of the potassium channel underlying the rapid component of the cardiac delayed rectifier current
	contribute to threshold excitability (potential link between auditory hyperexcitability and acoustic startle triggering of cardiac events in familial LQT2)
	during biogenesis of channels KCNH2, is more likely to assemble with KCNE1 than KCNE2 due to distinctly different trafficking rates and retention in the cell rather than differences in relative affinity
	plays an essential role in the final repolarization of the ventricular action potential
	plays an important role in the repolarization of cardiac action potentials, and alterations therein can cause life-threatening cardiac arrhythmias
	pore-forming subunit of the rapid component of the delayed rectifier K(+) channel
	essential for cardiac repolarization but is also a source of cardiotoxicity because unintended KCNH2 inhibition by diverse pharmaceuticals can cause arrhythmias and sudden cardiac death
	inward rectifier voltage-gated potassium channel, of primary importance for the regulation of the membrane potential of cardiomyocytes
	potassium channel that conducts the rapidly activating delayed rectifier current in the heart
	is crucial for the cardiac action potential by contributing to the fast delayed-rectifier potassium current
	encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel (IKr), which is important for cardiac repolarization

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component	part of ERG channels control the excitability of medial vestibular nucleus neurones, their discharge regularity and probably their resonance properties
	CAV3, NEDD4L, and KCNH2 likely form a complex in the plasma membrane

INTERACTION

DNA

RNA

small molecule

protein	PRKACA-dependent regulation of KCNH2 synthesis occurs at the ER surface
	function of APC/CTNNB1 in the regulation of KCNH2 channels
	direct interactions between KCNQ1 and KCNH2 occuring in both intact heterologous cells and primary cardiomyocytes and are mediated by their COOH termini
	CAV3 enhances ubiquitin ligase NEDD4L interaction with mature KCNH2 channels in the plasma membrane, leading to decreased channel expression
	SGK1 enhances the expression level of mature KCNH2 channels by inhibiting NEDD4L as well as by promoting RAB11-mediated KCNH2 recycling (PMMID: 23589291)
	RAB4A decreases the KCNH2 density at the plasma membrane by increasing the endogenous NEDD4L expression
	RNF207 is an important regulator of action potential duration, likely via effects on KCNH2 trafficking and localization in a heat shock protein-dependent manner
	GTPase RAB11A, is involved in the recycling of KCNH2
	NDFIP1 is primarily localized in the Golgi apparatus where it recruits NEDD4L to mediate the degradation of mature KCNH2 proteins during channel trafficking to the plasma membrane
	damage of KCNH2 mediated by proteases such as calpain may contribute to ischemia-associated QT prolongation and sudden cardiac death
	TBX20 can be considered a KCNH2-modifying gene
	hypoxia reduces mature KCNH2 channels through calpain up-regulation

cell & other

REGULATION

inhibited by

acidic pH inhibiting KCNH2 channel maximal conductance and accelerating deactivation, likely by different mechanisms

Other	undergo ER export in COPII vesicles and endosomal recycling prior to being processed in the Golgi
	regulated by FHL2 (interacts with and regulates the KCNH2 channel)

ASSOCIATED DISORDERS

corresponding disease(s)

LQT2 , SQT1 , BRGS10

related resource

Long QTSyndrome Database Long QT Syndrome Database

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   marks an early step of the progression of normality to cancer in the esophagus through a metaplastic and dysplastic stage tumoral       gain of function in endometrial cancers (absent in endometrial hyperplasia) tumoral     --over   in myelodysplastic syndromes (MDS) constitutional       loss of function results in defects in cardiogenesis and vasculogenesis

Susceptibility

to arhytmic events when mutation in the pore region (in LQT2 patients) to schizophrenia to sudden infant death syndrome (with short or long QT)

Variant & Polymorphism SNP , other	2690A>C increasing the risk of arrhythmia or sudden death
	Six SNPs were significantly associated with schizophrenia
	variants associated to sudden infant death syndrome (with short or long QT)

Candidate gene
Marker	might be a potential tumor marker of MDS
Therapy target
	System Type Disorder Pubmed cancer hemopathy   inhibition of KCNH2 might be a novel therapeutic measure for MDS (myelodysplastic syndrome)

ANIMAL & CELL MODELS