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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

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001127899 18 - 10108 NP_001121371 - 816 in the kidney 2014 25001568 NM_001127898 18 - 9849 NP_001121370 - 816 in the kidney 2014 25001568 NM_000084 12 - 9472 NP_000075 - 746 in the kidney 2014 25001568 NM_001272102 4 - 643 NP_001259031 - 64 - 2014 25001568 NM_001282163 12 - 9543 NP_001269092 - 766 in the kidney 2014 25001568

EXPRESSION

Type	restricted

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 urinary kidney Henle's loop ascending thick limb     Urinary kidney tubule convoluted tubule proximal tubule   Homo sapiens

cells

System Cell Pubmed Species Stage Rna symbol Digestive epithelial cell Homo sapiens Urinary epithelial 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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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)