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CLCN2 chloride voltage-gated channel 2 [ Homo sapiens (human) ]

Gene ID: 1181, updated on 20-Dec-2019

Summary

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Official Symbol
CLCN2provided by HGNC
Official Full Name
chloride voltage-gated channel 2provided by HGNC
Primary source
HGNC:HGNC:2020
See related
Ensembl:ENSG00000114859 MIM:600570
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
CLC2; ECA2; ECA3; EGI3; EGMA; EJM6; EJM8; CIC-2; EGI11; HALD2; LKPAT; clC-2
Summary
This gene encodes a voltage-gated chloride channel. The encoded protein is a transmembrane protein that maintains chloride ion homeostasis in various cells. Defects in this gene may be a cause of certain epilepsies. Four transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2012]
Expression
Broad expression in testis (RPKM 8.7), colon (RPKM 7.2) and 24 other tissues See more
Orthologs
mouse all

Genomic context

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See CLCN2 in Genome Data Viewer
Location:
3q27.1
Exon count:
25
Annotation release Status Assembly Chr Location
109.20191205 current GRCh38.p13 (GCF_000001405.39) 3 NC_000003.12 (184346185..184361605, complement)
105 previous assembly GRCh37.p13 (GCF_000001405.25) 3 NC_000003.11 (184063973..184079439, complement)

Chromosome 3 - NC_000003.12Genomic Context describing neighboring genes Neighboring gene proteasome 26S subunit, non-ATPase 2 Neighboring gene eukaryotic translation initiation factor 4 gamma 1 Neighboring gene small nucleolar RNA, C/D box 66 Neighboring gene family with sequence similarity 131 member A Neighboring gene RNA polymerase II subunit H Neighboring gene thrombopoietin

Genomic regions, transcripts, and products

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Go to nucleotide: Graphics FASTA GenBank

Expression

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  • 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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Related articles in PubMed

  1. ClC-2 knockdown prevents cerebrovascular remodeling via inhibition of the Wnt/β-catenin signaling pathway. Lu J, et al. Cell Mol Biol Lett, 2018. PMID 29988306, Free PMC Article
  2. Leukoencephalopathy-causing CLCN2 mutations are associated with impaired Cl- channel function and trafficking. Gaitán-Peñas H, et al. J Physiol, 2017 Nov 15. PMID 28905383, Free PMC Article
  3. Identification of the fatty acid activation site on human ClC-2. Cuppoletti J, et al. Am J Physiol Cell Physiol, 2017 Jun 1. PMID 28424169
  4. Gating the glutamate gate of CLC-2 chloride channel by pore occupancy. De Jesús-Pérez JJ, et al. J Gen Physiol, 2016 Jan. PMID 26666914, Free PMC Article
  5. CLCN2-Related Leukoencephalopathy van der Knaap MS, et al. , 1993. PMID 26539602

See all (54) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into Functions

What's a GeneRIF?
  1. CLCN2 mutations cause primary aldosteronism, this highlight the importance of chloride in aldosterone biosynthesis and CLCN2 as the foremost chloride conductor of resting glomerulosa cells.
    Title: A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism.
  2. A role of anion channels in glomerulosa membrane potential determination, aldosterone production and hypertension. The mutations are the cause of a substantial fraction of early-onset primary aldosteronism.
    Title: CLCN2 chloride channel mutations in familial hyperaldosteronism type II.
  3. The inhibitory effects of ClC-2 knockout on HBVSMC proliferation and motility were associated with inactivation of the Wnt/beta-catenin signaling pathway, as evidenced by inhibition of beta-catenin phosphorylation and nuclear translocation, and decrease of GSK-3beta phosphorylation and survivin and cyclin D1 expression.
    Title: ClC-2 knockdown prevents cerebrovascular remodeling via inhibition of the Wnt/β-catenin signaling pathway.
  4. Leukoencephalopathy-causing CLCN2 mutations impair chloride channel gating and trafficking.
    Title: Leukoencephalopathy-causing CLCN2 mutations are associated with impaired Cl<sup>-</sup> channel function and trafficking.
  5. ClC-2 mRNA level was significantly increased in patients with non-alcoholic steatohepatitis, which positively correlated with the plasma levels of alanine transaminase (ALT), aspartate transaminase (AST) and insulin.
    Title: Lack of ClC-2 Alleviates High Fat Diet-Induced Insulin Resistance and Non-Alcoholic Fatty Liver Disease.
  6. The findings show that RGET691 of human ClC-2 (possible binding site) plays an important functional role in fatty acid activation of human ClC-2.
    Title: Identification of the fatty acid activation site on human ClC-2.
  7. Hyperpolarization activates CLC-2 mainly by driving intracellular anions into the channel pores.
    Title: Gating the glutamate gate of CLC-2 chloride channel by pore occupancy.
  8. The extracellular domain of GlialCAM is necessary for cell junction targeting and for mediating interactions with itself or with MLC1 and ClC-2.
    Title: Structural determinants of interaction, trafficking and function in the ClC-2/MLC1 subunit GlialCAM involved in leukodystrophy.
  9. both ubiquitous (AP-1A) and epithelium-specific (AP-1B) forms of the tetrameric clathrin adaptor AP-1 are capable of carrying out basolateral sorting of ClC-2.
    Title: Basolateral sorting of chloride channel 2 is mediated by interactions between a dileucine motif and the clathrin adaptor AP-1.
  10. SPAK and OSR1 are powerful negative regulators of the cell volume regulatory Cl- channel ClC-2
    Title: Regulation of ClC-2 activity by SPAK and OSR1.
Submit: New GeneRIF Correction See all GeneRIFs (42)

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
Epilepsy with grand mal seizures on awakening
MedGen: C2750893 OMIM: 607628 GeneReviews: Not available
Compare labs
Hyperaldosteronism, familial, type II
MedGen: C1854107 OMIM: 605635 GeneReviews: Not available
Compare labs
Leukoencephalopathy with ataxia
MedGen: C3810242 OMIM: 615651 GeneReviews: CLCN2-Related Leukoencephalopathy
Compare labs

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Genotypes

Interactions

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Products Interactant Other Gene Complex Source Pubs Description

General gene information

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Markers

Homology

Gene Ontology Provided by GOA

Function Evidence Code Pubs
voltage-gated chloride channel activity IDA
Inferred from Direct Assay
more info
 PubMed 
Process Evidence Code Pubs
cell differentiation involved in salivary gland development IEA
Inferred from Electronic Annotation
more info
  
chloride transmembrane transport IEA
Inferred from Electronic Annotation
more info
  
ion transmembrane transport TAS
Traceable Author Statement
more info
  
regulation of aldosterone biosynthetic process IMP
Inferred from Mutant Phenotype
more info
 PubMed 
regulation of ion transmembrane transport IEA
Inferred from Electronic Annotation
more info
  
retina development in camera-type eye IEA
Inferred from Electronic Annotation
more info
  
Component Evidence Code Pubs
chloride channel complex IEA
Inferred from Electronic Annotation
more info
  
integral component of plasma membrane IBA
Inferred from Biological aspect of Ancestor
more info
 PubMed 
plasma membrane IDA
Inferred from Direct Assay
more info
 PubMed 
plasma membrane TAS
Traceable Author Statement
more info
  

General protein information

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Preferred Names
chloride channel protein 2
Names
chloride channel 2
chloride channel, voltage-sensitive 2

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

  1. NG_016422.1 RefSeqGene

    Range
    4999..20419
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. NM_001171087.3 → NP_001164558.1  chloride channel protein 2 isoform 2

    See identical proteins and their annotated locations for NP_001164558.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (2) uses an alternate in-frame splice junction at the 5' end of an exon compared to variant 1. The resulting isoform (2) has the same N- and C-termini but is shorter compared to isoform 1.
    Source sequence(s)
    AA524434, BC072004, DC403930
    Consensus CDS
    CCDS54691.1
    UniProtKB/Swiss-Prot
    P51788
    Related
    ENSP00000345056.7, ENST00000344937.11
    Conserved Domains (3) summary
    cd03683
    Location:90 → 550
    ClC_1_like; ClC-1-like chloride channel proteins. This CD includes isoforms ClC-0, ClC-1, ClC-2 and ClC_K. ClC-1 is expressed in skeletal muscle and its mutation leads to both recessively and dominantly-inherited forms of muscle stiffness or myotonia. ClC-K is ...
    cd04591
    Location:773 → 821
    CBS_pair_EriC_assoc_euk_bac; This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in the EriC CIC-type chloride channels in eukaryotes and bacteria. These ion channels are proteins with a seemingly simple task of allowing the passive flow of ...
    pfam00654
    Location:143 → 529
    Voltage_CLC; Voltage gated chloride channel

  2. NM_001171088.3 → NP_001164559.1  chloride channel protein 2 isoform 3

    Status: REVIEWED

    Description
    Transcript Variant: This variant (3) lacks an alternate in-frame exon compared to variant 1. The resulting isoform (3) has the same N- and C-termini but is shorter compared to isoform 1.
    Source sequence(s)
    AA524434, AC078797, AK302759, DC403930
    Consensus CDS
    CCDS54690.1
    UniProtKB/Swiss-Prot
    P51788
    Related
    ENSP00000400425.2, ENST00000434054.6
    Conserved Domains (3) summary
    cd03683
    Location:73 → 523
    ClC_1_like; ClC-1-like chloride channel proteins. This CD includes isoforms ClC-0, ClC-1, ClC-2 and ClC_K. ClC-1 is expressed in skeletal muscle and its mutation leads to both recessively and dominantly-inherited forms of muscle stiffness or myotonia. ClC-K is ...
    cd04591
    Location:746 → 794
    CBS_pair_EriC_assoc_euk_bac; This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in the EriC CIC-type chloride channels in eukaryotes and bacteria. These ion channels are proteins with a seemingly simple task of allowing the passive flow of ...
    pfam00654
    Location:99 → 502
    Voltage_CLC; Voltage gated chloride channel

  3. NM_001171089.3 → NP_001164560.1  chloride channel protein 2 isoform 4

    Status: REVIEWED

    Description
    Transcript Variant: This variant (4) lacks an alternate in-frame exon compared to variant 1. The resulting isoform (4) has the same N- and C-termini but is shorter compared to isoform 1.
    Source sequence(s)
    AA524434, AC078797, AK298952, DC403930
    Consensus CDS
    CCDS54692.1
    UniProtKB/Swiss-Prot
    P51788
    Related
    ENSP00000391928.1, ENST00000457512.1
    Conserved Domains (2) summary
    cd03683
    Location:90 → 567
    ClC_1_like; ClC-1-like chloride channel proteins. This CD includes isoforms ClC-0, ClC-1, ClC-2 and ClC_K. ClC-1 is expressed in skeletal muscle and its mutation leads to both recessively and dominantly-inherited forms of muscle stiffness or myotonia. ClC-K is ...
    pfam00654
    Location:143 → 546
    Voltage_CLC; Voltage gated chloride channel

  4. NM_004366.6 → NP_004357.3  chloride channel protein 2 isoform 1

    See identical proteins and their annotated locations for NP_004357.3

    Status: REVIEWED

    Description
    Transcript Variant: This variant (1) represents the longest transcript and encodes the longest isoform (1).
    Source sequence(s)
    AA524434, AC078797, AF026004, DC403930
    Consensus CDS
    CCDS3263.1
    UniProtKB/Swiss-Prot
    P51788
    Related
    ENSP00000265593.4, ENST00000265593.9
    Conserved Domains (3) summary
    cd03683
    Location:90 → 567
    ClC_1_like; ClC-1-like chloride channel proteins. This CD includes isoforms ClC-0, ClC-1, ClC-2 and ClC_K. ClC-1 is expressed in skeletal muscle and its mutation leads to both recessively and dominantly-inherited forms of muscle stiffness or myotonia. ClC-K is ...
    cd04591
    Location:790 → 838
    CBS_pair_EriC_assoc_euk_bac; This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in the EriC CIC-type chloride channels in eukaryotes and bacteria. These ion channels are proteins with a seemingly simple task of allowing the passive flow of ...
    pfam00654
    Location:143 → 546
    Voltage_CLC; Voltage gated chloride channel

RefSeqs of Annotated Genomes: Homo sapiens Updated Annotation Release 109.20191205

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

Reference GRCh38.p13 Primary Assembly

Genomic

  1. NC_000003.12 Reference GRCh38.p13 Primary Assembly

    Range
    184346185..184361605 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_006713489.1 → XP_006713552.1  chloride channel protein 2 isoform X1

    See identical proteins and their annotated locations for XP_006713552.1

    Conserved Domains (3) summary
    cd03683
    Location:90 → 567
    ClC_1_like; ClC-1-like chloride channel proteins. This CD includes isoforms ClC-0, ClC-1, ClC-2 and ClC_K. ClC-1 is expressed in skeletal muscle and its mutation leads to both recessively and dominantly-inherited forms of muscle stiffness or myotonia. ClC-K is ...
    cd04591
    Location:762 → 803
    CBS_pair_EriC_assoc_euk_bac; This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in the EriC CIC-type chloride channels in eukaryotes and bacteria. These ion channels are proteins with a seemingly simple task of allowing the passive flow of ...
    pfam00654
    Location:143 → 546
    Voltage_CLC; Voltage gated chloride channel

  2. XM_006713490.2 → XP_006713553.1  chloride channel protein 2 isoform X3

    Conserved Domains (3) summary
    cd04591
    Location:404 → 452
    CBS_pair_EriC_assoc_euk_bac; This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in the EriC CIC-type chloride channels in eukaryotes and bacteria. These ion channels are proteins with a seemingly simple task of allowing the passive flow of ...
    pfam00654
    Location:46 → 160
    Voltage_CLC; Voltage gated chloride channel
    cl02915
    Location:46 → 181
    Voltage_gated_ClC; CLC voltage-gated chloride channel. The ClC chloride channels catalyse the selective flow of Cl- ions across cell membranes, thereby regulating electrical excitation in skeletal muscle and the flow of salt and water across epithelial barriers. This ...

  3. XM_011512401.1 → XP_011510703.1  chloride channel protein 2 isoform X2

    Conserved Domains (2) summary
    cd03683
    Location:90 → 567
    ClC_1_like; ClC-1-like chloride channel proteins. This CD includes isoforms ClC-0, ClC-1, ClC-2 and ClC_K. ClC-1 is expressed in skeletal muscle and its mutation leads to both recessively and dominantly-inherited forms of muscle stiffness or myotonia. ClC-K is ...
    pfam00654
    Location:143 → 546
    Voltage_CLC; Voltage gated chloride channel

RNA

  1. XR_001740002.1 RNA Sequence

  2. XR_001740001.1 RNA Sequence

Nucleotide Protein
Heading Accession and Version
Protein Accession Links
GenPept Link UniProtKB Link
P51788.2 GenPept UniProtKB/Swiss-Prot:P51788

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