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FLASH GENE

Symbol

KCNQ1

contributors: mct - updated : 26-04-2017

HGNC name	potassium voltage-gated channel, KQT-like subfamily, member 1
HGNC id	6294

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	404.12 kb     16 Exon(s)

10 Kb 5' upstream gene genomic sequence study

text structure

14 exons plus alternative exons 1a1, 1a2, 1d, 1b, 1c, 2a, including an antisense overlapping methylated CpG island associated with an antisense paternal transcript (KCNQ1OT1 in the differentially methylated region, DMR) see symbol

MAPPING

cloned

Y

linked

N

status

confirmed

regionally located

encompassing all the BWS breakpoints within the BWSCR cluster

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000218 16 splicing 3262 NP_000209 74.7 676 - 2009 19056345 also called variant 1/isoform 1 including exons 1a1, 1a2 variant 3 - - - isoform 3 - - - 1997 9108097 including exons 1b, 1c variant 4 - - - isoform 4 - - - 1997 9108097 including exons 1b, 1c, 2a variant 5 - - - isoform 5 - - - 1997 9302275 including exon 1c variant 0 - - - isoform 0 - - - 1997 930227 including exons 1d, 1a2 NM_181798 16 splicing 3029 NP_861463 61 549 - 2009 19056345 also called variant 2/isoform 2 differing in the 5' UTR and CDS compared to variant 1 maybe identical to another isoform

EXPRESSION

Type

widely

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 blood / hematopoietic spleen       lowly Cardiovascular heart       predominantly Homo sapiens Endocrine thyroid       highly Hearing/Equilibrium ear inner       Reproductive female system ovary     lowly   male system testis     lowly Respiratory lung       lowly Urinary kidney

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial secretory glandular endocrine

cells

System Cell Pubmed Species Stage Rna symbol Blood/Hematopoietic leukocyte Endocrine thyroid cell Muscular myocyte

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

embryo, pregnancy

Text	apical surface of the vestibular dark cells, placenta

IMPRINTING	paternally
text	paternally imprinted (centromeric imprinting domain at 11p15, containing TSSC3, TSSC5 and KCNQ1)
	is imprinted in early cardiac development but becomes biallelic after midgestation

PROTEIN

PHYSICAL PROPERTIES		Hydrophobic
STRUCTURE

motifs/domains	N-terminal juxtamembranous domain critical for channel surface expression, an trafficking
	six putative membrane-spanning domains (S1 to S6)
	an hydrophobic pore including the P domain with the K+ channel signature
	TM domains five and six, sensitive to changes in membrane potential, invoved in channel function but this depends on the electrical charge or the size of amino acid residue
	a C terminal assembly domain for KVLQT1 subunits, that may be important for the subunit dominant-negative actions

mono polymer

heteromer , polymer

HOMOLOGY

interspecies	homolog to Drosophila shaker-related subfamily
	ortholog to rattus Kcnq1
	ortholog to murine Kcnq1
	homolog to C. elegans kqt-31

Homologene

FAMILY	KCNE protein family
	KQT subfamily

CATEGORY

transport channel

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,endosome
	intracellular,cytoplasm,organelle,lysosome
	intracellular,cytoplasm,cytosolic,vesicle
text	located in or toward the apical membrane of the cells

basic FUNCTION	required for the repolarization phase of the cardiac action potential
	playing a role in muscle contraction
	role of a number of KCNQ channel members in controlling basal anion secretion in the airway epithelium
	potassium channel subunits KCNQ1 and KCNE2 form a thyroid-stimulating hormone–stimulated, constitutively active, thyrocyte K+ channel required for normal thyroid hormone biosynthesis
	KCNQ1 voltage-gated potassium channel and its auxiliary subunit KCNE1 play a crucial role in the regulation of the heartbeat
	is endocytosed upon initiation of the polarization process and sent for degradation by the lysosomal pathway
	KCNQ1 voltage sensors move relatively independently, but the channel can conduct before all voltage sensors have activated
	crucial for heart development and function (PUID: 23028363)
	KCNQ1 ion channels require a lipid to couple voltage sensing to pore opening
	plays a critical role in the cardiac action potential
	plays important roles in the cardiac action potential
	is a voltage-gated potassium channel and its channel activity is regulated by membrane potentials
	in cardiac myocytes, KCNQ1/KCNE1 complexes are thought to give rise to the delayed rectifier current IKs, which contributes to cardiac action potential repolarization

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

text	cation transport

PATHWAY

metabolism

signaling

sensory transduction/hearing

a component	associating with KCNE1 to form the slow delayed-rectifier IKS channel (KCNQ1 and KCNE1 subunits coassemble to form the I(Ks) channel)
	forming multimer with KCNE1, KCNE3
	directly associates with KCNE4, and can co-associate together with KCNE1 in the same KCNQ1 complex to form a 'triple subunit' complex (KCNE1-KCNQ1-KCNE4)
	KCNQ1, KCNQ5 form heterotetrameric channels increasing the diversity of structures which fine-tune blood vessel reactivity

INTERACTION

DNA

RNA

small molecule	metal binding,
	K+

protein	KCNE2 resulting in a drastic change of current amplitude and gating properties
	interacting with NEDD4, NEDD4L (KCNQ1 internalization and stability is physiologically regulated by its NEDD4/NEDD4-like-dependent ubiquitylation)
	interaction with KCNE1 (distal C-terminus interacts with the coiled-coil helix C of KCNQ1 tetramerization domain)
	protein-protein interaction between the KCNE1 C-terminal domain and the KCNQ1 S6 activation gate and S4-S5 linker
	KCNE2 influences blood-cerebrospinal fluid anion flux by regulating KCNQ1 and KCNA3 in the choroid plexus epithelium
	CTNNB1 enhanced the KCNE1/KCNQ1 protein abundance in the cell membrane
	KCNQ1 channels in both the absence and the presence of KCNE1 undergo likely sequential gating transitions leading to channel opening even before all voltage sensor domains (VSDs)have moved
	in later developmental stages, KCNQ1OT1 has a role in modulating KCNQ1 levels, since its absence leads to overexpression of KCNQ1
	direct interactions between KCNQ1 and KCNH2 occuring in both intact heterologous cells and primary cardiomyocytes and are mediated by their COOH termini
	KCNQ1 is regulated by non-pore forming regulatory KCNE beta-subunits
	KCNE1 (mutation affecting KCNE1 activation through interaction with KCNQ1), association of KCNE1 subunit is necessary for maintaining the normal conductance and kinetics of KCNQ1 channel
	Klotho upregulates KCNQ1/KCNE1 channel activity by “mainly” enhancing channel protein abundance in the plasma cell membrane
	conductance and dynamics of KCNQ1 could be modulated by different single transmembrane helical auxiliary proteins (such as KCNE1, KCNE2)
	when co-expressed in oocytes, CALML3 rendered KCNQ1 channels resistant to the voltage-dependent depletion of phosphatidylinositol 4,5-bisphosphate by voltage-sensitive phosphatase
	STK39 and OXSR1 participate in the regulation of KCNQ1/KCNE1 protein abundance and activity
	SGMS1 positively regulates KCNQ1/KCNE1 channel density in a protein kinase D-dependent manner
	KCNQ1/KCNE1 channel does not require INPP5J or PI(4)P for anterograde trafficking, but is heavily reliant on INPP5J for channel function once at the plasma membrane (PM)

cell & other

REGULATION

inhibited by

KCNE4 (has a dramatic inhibitory effect on KCNQ1 that differs substantially from the activating effects of KCNE1 and KCNE3)

Other

by PKA-dependent phosphorylation requiring a macromolecular complex including PRKARZA, PPP1CA and yotiao (AKAP9)

ASSOCIATED DISORDERS

corresponding disease(s)

JLNS1 , LQT1 , ATFB3 , SQT2

related resource

Long QT Syndrome Database Gene Connection for the Heart Congenital Long QT Syndrome

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional   deletion     maybe disrupted in (some) Beckwith-Wiedemann syndromes, see KCNQ1OT1 constitutional germinal mutation       massive truncation of the C-terminal domain of KCNQ1 subunit (Y461X) severely impairs channel assembly, trafficking, and function and homozygous inheritance might cause arrhythmic disorders due to the total loss of the cardiac slow delayed rectifier K+ current

Susceptibility

to arrhythmia or sudden death to type 2 diabetes mellitus to atrial fibrillation to sudden infant death syndrome (with short or long QT)

Variant & Polymorphism SNP , other	2031+932 A>G increasing the risk of risk of arrhythmia or sudden death
	polymorphisms increasing the risk of to type 2 diabetes mellitus
	variants associated to sudden infant death syndrome (with short or long QT)
	K1493R associated to atrial fibrillation (leads to a significant positive shift in voltage-dependence of inactivation and a large ramp current near resting membrane potential, indicating a gain-of-function)

Candidate gene	physical interaction between KCNQ1 and KCNE1 is potentially affected in some LQTS mutations
Marker
Therapy target
	System Type Disorder Pubmed cardiovascular rythm   modulation of KCNQ1 splicing may help prevent arrhythmia

ANIMAL & CELL MODELS

	targeted disruption of mouse Kcnq1
	Kcne2-deficient mice had hypothyroidism, dwarfism, alopecia, goiter and cardiac abnormalities including hypertrophy, fibrosis, and reduced fractional shortening
	potential therapeutic target for thyroid disorders