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FLASH GENE
Symbol CLCN3 contributors: mct - updated : 15-09-2021
HGNC name chloride channel 3
HGNC id 2021
Corresponding disease
NEDHYBA neurodevelopmental disorder with hypotonia and brain abnormalities
NEDSBA neurodevelopmental disorder with seizures and brain abnormalities
Location 4q33      Physical location : 170.541.721 - 170.642.156
Synonym symbol(s) CLC3, CLC-3, DKFZp564I0463
DNA
TYPE functioning gene
STRUCTURE 103.09 kb     13 Exon(s)
10 Kb 5' upstream gene genomic sequence study
MAPPING cloned Y linked N status confirmed
RNA
TRANSCRIPTS type messenger
text
  • alternative splicing of CLCN3 results in proteins with different subcellular localizations, but leaves the transport function of the proteins unaffected (PMID: 26342074)
  • identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    - - 3953 - - . predominantly in epithelial cells . present in late endosomes/lysosomes 2007 17882904
    - - - - - present in late endosomes/lysosomes 2007 17882904
    longer C-terminal domain,containing a consensus motif for binding to the second PDZ domain of SLC9A3R1
    13 - 6635 - 818 - 2007 17882904
    14 - 6711 - 866 - 2007 17882904
    12 - 6554 - 791 - 2007 17882904
    12 - 6182 - 791 - 2007 17882904
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestivemouthtongue  highly
    Endocrinepancreas    
    Hearing/Equilibriumear   highly
    Nervousbrain     Homo sapiens
    Reproductivefemale systemovary  highly
    Urinarykidneyrenal medullapyramids   Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularsmoothvessel   Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • twelve alpha helical membrane spanning protein cytoplasmic N and C terminals
  • a CBS domain
  • HOMOLOGY
    Homologene
    FAMILY CLC family of anion channels and transporters
    CATEGORY transport channel
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,organelle,lysosome
    intracellular,cytoplasm,cytosolic,vesicle
    text
  • localizes to early and late endosomes as well as to synaptic vesicles (SV)
  • basic FUNCTION
  • required for normal NADPH oxidase activation in response to both particulate and soluble stimuli
  • may be playing an important role in neuronal cell function through regulation of membrane excitability by protein kinase C
  • involved in oxidant-dependent events in the polymorphonuclear leukocyte, including endotoxin priming and the maintenance of cellular quiescence
  • is important in volume-regulated anion channel Cl(-) currents function and cell volume regulation, and participates in the fibroblast-to-myofibroblast transition
  • innvolved in premitotic condensation that is an integral part of cell division, and is a critical regulator of the cell cycle in normal and malignant glial cells (
  • may contribute to the acidification of synaptic vesicles and endosomes
  • function in osteodifferentiation may be through the RUNX2 pathway
  • required for endosome-dependent signaling by the Nox1 NADPH oxidase in smooth muscle cells
  • might likely be important for normal excitatory and/or inhibitory neurotransmission in central neurons
  • controls fast excitatory synaptic transmission by regulating the amount of neurotransmitter as well as the release probability of synaptic vesicles (SV)
  • CLCN3 chloride channel acts likely as a mechanically sensitive channel to regulate osteodifferentiation in osteoblasts
  • CLCN3 and CLCN5 are necessary components for S1P-induced excitatory Cl- currents but not for the amplification of TRPV1-mediated currents in sensory neurons
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • specific interaction of ClCN3 and CAMK2G (in ClCN3-expressing cells, inhibition of CAMK2G reduced glioma invasion to the same extent as direct inhibition of ClCN3)
  • unique oligomerization properties of CLCN4 permit regulated targeting of ClCN4 to various endosomal compartment systems via expression of different CLCN3 splice variants
  • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) NEDHYBA , NEDSBA
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --low  
    markedly reduces neointimal hyperplasia following vascular injury
    tumoral     --over  
    on the plasma membrane of human glioma cells where its activity is regulated through phosphorylation via Ca(2+)/calmodulin-dependent protein kinase II (CAMK2G)
    constitutional       loss of function
    causes severe neurodegeneration
    constitutional     --over  
    jn endometriosis, positively correlated with endometrioma size
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    immunologyinflammatory 
    target for the prevention of inflammatory and proliferative vascular diseases
    cancerangiogenesis 
    target for the prevention of inflammatory and proliferative vascular diseases
    ANIMAL & CELL MODELS
  • ClC-3-null mice exhibited a reduction in neointimal area of the carotid artery 28 days after injury
  • Clcn3-/- mice display severe neurodegeneration, leading to an almost complete loss of the hippocampus within a few months of life and to blindness from an early complete loss of photoreceptors