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FLASH GENE
Symbol CLCN5 contributors: mct - updated : 03-09-2021
HGNC name chloride channel 5 (nephrolithiasis 2, X-linked, Dent disease)
HGNC id 2023
Corresponding disease
FILWP familial idiopathic low molecular weight proteinuria
HYP2 hypophosphatemia, with vitamin D resistant rickets 2
NPHL1 nephrolithiasis, recessive, with renal failure
NPHL2 nephrolithiasis 2
Location Xp11.23      Physical location : 49.687.224 - 49.863.892
Synonym name chloride channel protein 5
Synonym symbol(s) CLC5, XRN, XLRH, CLCK2, CLC5, hCIC-K2, hClC-K2, DENTS, FLJ11432
DNA
TYPE functioning gene
STRUCTURE 176.64 kb     18 Exon(s)
10 Kb 5' upstream gene genomic sequence study
regulatory sequence Promoter
text structure AP1-like element and CAMP responsive element
MAPPING cloned Y linked   status confirmed
RNA
TRANSCRIPTS type messenger
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
18 - 10108 - 816 in the kidney 2014 25001568
18 - 9849 - 816 in the kidney 2014 25001568
12 - 9472 - 746 in the kidney 2014 25001568
4 - 643 - 64 - 2014 25001568
12 - 9543 - 766 in the kidney 2014 25001568
EXPRESSION
Type restricted
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
urinarykidneyHenle's loopascending thick limb  
Urinarykidneytubuleconvoluted tubuleproximal tubule  Homo sapiens
cells
SystemCellPubmedSpeciesStageRna symbol
Digestiveepithelial cell Homo sapiens
Urinaryepithelial cell 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
  • two CBS forming a stable globular domain within its intracellular carboxy-terminus, implicated in intracellular targetting and trafficking as well as protein-protein interactions
  • C terminal internalization motif resembling the PY motif
  • HOMOLOGY
    interspecies ortholog to rattus clcn5
    ortholog to murine Clcn5
    Homologene
    FAMILY CLC family of voltage-gated chloride channels
    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
    text
  • expressed in endosomes and apical membranes of renal tubules
  • basic FUNCTION
  • chloride voltage-gated channel, likely involved in the receptor-mediated endocytic pathway
  • functioning as electrogenic Cl-/H+ exchanger, carrying a substantial amount of protons across the plasma membrane when activated by positive voltages
  • playing a role in the activation of apical protein endocytosis in kidney proximal tubules by regulating trafficking of megalin and cubilin at the brush border
  • electrically shunting Cl- channel in early endosomes, facilitating intraluminal acidification
  • may compensate the charge accumulation by endosomal proton pumps
  • playing a definitive role in the trafficking and acidification-dependent recycling of apical membrane proteins
  • regulates dentin development through TGFB1 pathway
  • interaction with KIF3B is important for CLCN5 plasma membrane expression and for facilitating endocytosis and microtubular transport in the kidney
  • endosomal chloride concentration, which is raised by CLCN5 in exchange for protons accumulated by the H+-ATPase, may play a role in endocytosis
  • essential for the endocytic activity of the proximal tubule cells and the tubular clearance of proteins filtered in the glomeruli
  • role of CFTR and CLCN5 in modulating vacuolar H+-ATPase activity in kidney proximal tubule
  • Cl-/H+ antiporters that carry out fundamental physiological tasks by transporting Cl- across plasma membrane and intracellular compartments
  • in addition to defective endocytosis, proximal tubule cells lacking CLCN5 show a trafficking defect in apical receptors and transporters, as well as lysosomal dysfunction and typical features of dedifferentiation, proliferation and oxidative stress
  • 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
  • interacts with kinesin family member 3B (KIF3B), a heterotrimeric motor protein that facilitates fast anterograde translocation of membranous organelles
  • HNF1A directly regulates the expression of CLCN5 in the renal proximal tubule and yield insights into the mechanisms governing epithelial differentiation and specialized transport activities in the kidney
  • cell & other
    REGULATION
    activated by positive voltages
    ASSOCIATED DISORDERS
    corresponding disease(s) NPHL1 , NPHL2 , FILWP , HYP2
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    in glomeruli of glomerulonephritis
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
    CIC-( CL- mouse model for Dent's syndrome (NPHL2)