CLCN5 chloride channel, voltage-sensitive 5 [Homo sapiens (human)] - Gene

Summary

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Official Symbol: CLCN5provided by HGNC
Official Full Name: chloride channel, voltage-sensitive 5provided by HGNC
Primary source: HGNC:2023
See related: Ensembl:ENSG00000171365; HPRD:02053; MIM:300008; Vega:OTTHUMG00000021514
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: XRN; CLC5; XLRH; CLCK2; ClC-5; DENTS; NPHL1; NPHL2; hCIC-K2
Summary: This gene encodes a member of the ClC family of chloride ion channels and ion transporters. The encoded protein is primarily localized to endosomal membranes and may function to facilitate albumin uptake by the renal proximal tubule. Mutations in this gene have been found in Dent disease and renal tubular disorders complicated by nephrolithiasis. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2013]

Genomic context

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Location :: Xp11.23-p11.22

Sequence :: Chromosome: X; NC_000023.10 (49687225..49863892)

See CLCN5 in Epigenomics, MapViewer

Chromosome X - NC_000023.10 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Genomic Sequence

Go to nucleotideGraphics FASTA GenBank

Go to reference sequence details

Bibliography

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GeneRIFs: Gene References Into Functions What's a GeneRIF?

ClC-5 overexpression found in biopsies of proteinuric patients suggests that proteinuria may play a part in its expression and that podocytes are likely to have a key role in albumin handling in proteinuric states
Title: Involvement of the tubular ClC-type exchanger ClC-5 in glomeruli of human proteinuric nephropathies.
The molecular events underlying the transient currents of ClC-5 emerging from these results can be explained by an inward movement of the side chain of Glu(ext), followed by the binding of extracellular Cl(-) ions.
Title: On the mechanism of gating charge movement of ClC-5, a human Cl(-)/H(+) antiporter.
protonation of the gating glutamate 211 at the central anion-binding site of ClC-5 is mediated by the proton glutamate 268.
Title: Glutamate 268 regulates transport probability of the anion/proton exchanger ClC-5.
Heterogeneity in the processing of CLCN5 mutants related to Dent disease.
Title: Heterogeneity in the processing of CLCN5 mutants related to Dent disease.
A novel CLCN5 mutation is reported in a boy with Bartter-like syndrome and partial growth hormone deficiency.
Title: A novel CLCN5 mutation in a boy with Bartter-like syndrome and partial growth hormone deficiency.
data suggest that voltage sensing is an intrinsic property of the CLC-5 protein and that permeant anions, particularly Cl(-), modulate a voltage-dependent transition to an activated state from which Cl(-)/H(+) exchange can occur
Title: Voltage-dependent charge movement associated with activation of the CLC-5 2Cl-/1H+ exchanger.
Suggest that CLC-5 is directly involved in endosomal acidification by exchanging endosomal Cl(-) for H(+).
Title: Direct endosomal acidification by the outwardly rectifying CLC-5 Cl(-)/H(+) exchanger.
We discuss the putative role of ClC-5 in receptor-mediated endocytosis and protein uptake by the proximal renal tubule and the possible molecular and cellular consequences of disease-causing mutations[review]
Title: ClC transporters: discoveries and challenges in defining the mechanisms underlying function and regulation of ClC-5.
Propose that protons bind to the extracellular gating glutamate E211 in CLC-5 to block transport.
Title: Proton block of the CLC-5 Cl-/H+ exchanger.
Interaction with KIF3B alters CLC-5 cell surface expression, chloride current, and alters albumin endocytosis. Interaction with KIF3B facilitates microtubular transport and endocytosis of CLC-5-containing vesicles away from cell surface.
Title: CLC-5 and KIF3B interact to facilitate CLC-5 plasma membrane expression, endocytosis, and microtubular transport: relevance to pathophysiology of Dent's disease.

Submit: New GeneRIF Correction See all (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

Dent disease, an X-linked disorder of proximal renal tubular dysfunction, is characterized by low molecular weight (LMW) proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and chronic kidney disease (CKD). Males younger than age ten years may manifest only low molecular weight (LMW) proteinuria and/or hypercalciuria, which are usually asymptomatic. Thirty to 80% of affected males develop end-stage renal disease (ESRD) between ages 30 and 50 years; in some instances ESRD does not develop until the sixth decade of life or later. Rickets or osteomalacia are occasionally observed, and mild short stature, although underappreciated, may be a common occurrence. Disease severity can vary within the same family. Males with Dent disease 2 (caused by mutations in OCRL) are at increased risk for intellectual disability. Due to random X-chromosome inactivation, some female carriers may manifest hypercalciuria and, rarely, renal calculi and moderate LMW proteinuria. Females rarely if ever develop CKD.

Diagnosis Testing

The diagnosis is based on renal findings and/or a family history consistent with X-linked inheritance. A mutation in CLCN5 accounts for approximately 60% of those with Dent disease (known as Dent disease 1); a mutation in OCRL accounts for approximately 15% of those with Dent disease (known as Dent disease 2). Molecular genetic testing for both genes is clinically available.

Genetic Counseling

Dent disease is inherited in an X-linked manner. The father of an affected male will not have the disease nor will he be a carrier of the mutation. If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%: males who inherit the mutation will be affected; females who inherit the mutation will be carriers and will usually not be significantly affected. Affected males pass the disease-causing mutation to all of their daughters (who become carriers) and none of their sons. Carrier testing for at-risk female relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutation in the family has been identified.

Interactions

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Products	Interactant	Other Gene	Source	Pubs	Description
P51795	P23528	CFL1	HPRD	PubMed
P51795	Q96QZ7	MAGI1	HPRD	PubMed
P51795	Q9H0M0	WWP1	HPRD	PubMed
P51795	O00308	WWP2	HPRD	PubMed
BioGRID:107598	BioGRID:113164	UBC	BioGRID	PubMed	Affinity Capture-MS

Pathways from BioSystems

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Ion channel transport, organism-specific biosystem (from REACTOME)
Ion channel transport, organism-specific biosystemIon channels mediate the flow of ions across the plasma membrane of cells. They are integral membrane proteins, typically a multimer of proteins, which, when arranged in the membrane, create a pore f...
Stimuli-sensing channels, organism-specific biosystem (from REACTOME)
Stimuli-sensing channels, organism-specific biosystemIon channels that mediate sensations such as pain, warmth, cold, taste pressure and vision. Channels that mediate these sensations include acid-sensing ion channels (ASICs) (Wang & Xu 2011, Qadri et ...
Transmembrane transport of small molecules, organism-specific biosystem (from REACTOME)
Transmembrane transport of small molecules, organism-specific biosystem
Transmembrane transport of small molecules

General gene information

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Markers

WI-21198 (e-PCR)
- UniSTS:17470

STS-X81836 (e-PCR)
- UniSTS:60517

DXS8222 (e-PCR)
- UniSTS:34170

A007D27 (e-PCR)
- UniSTS:3226

DXS7647 (e-PCR)
- UniSTS:3007

DXS9840 (e-PCR)
- UniSTS:474056

stdJ519N18SP6 (e-PCR)
- UniSTS:181741

A007H45 (e-PCR)
- UniSTS:58106

Genotypes

See CLCN5 SNP Geneview Report
See CLCN5 SNP Genotype Report
See CLCN5 SNP Variation Viewer Report

Homology

Homologs of the CLCN5 gene: The CLCN5 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, S.cerevisiae, K.lactis, E.gossypii, S.pombe, M.oryzae, and N.crassa.
Map Viewer (Mouse, Rat)
OrthoDB: The Hierarchical Catalog of Eukaryotic Orthologs

Clone Names

FLJ11432

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
ATP binding	IEA Inferred from Electronic Annotation more info
antiporter activity	IEA Inferred from Electronic Annotation more info
chloride channel activity	TAS Traceable Author Statement more info	PubMed
voltage-gated chloride channel activity	IEA Inferred from Electronic Annotation more info

Process	Evidence Code	Pubs
endocytosis	IEA Inferred from Electronic Annotation more info
excretion	TAS Traceable Author Statement more info	PubMed
ion transmembrane transport	TAS Traceable Author Statement more info
transmembrane transport	TAS Traceable Author Statement more info
transport	TAS Traceable Author Statement more info	PubMed

Component	Evidence Code	Pubs
Golgi membrane	IEA Inferred from Electronic Annotation more info
apical part of cell	IDA Inferred from Direct Assay more info	PubMed
endosome membrane	TAS Traceable Author Statement more info
integral to plasma membrane	TAS Traceable Author Statement more info	PubMed
membrane	IDA Inferred from Direct Assay more info	PubMed

General protein information

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Preferred Names: H(+)/Cl(-) exchange transporter 5

Names: H(+)/Cl(-) exchange transporter 5; chloride channel 5; chloride transporter ClC-5; voltage-gated chloride ion channel CLCN5

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

NG_007159.2 RefSeqGene

Range

5001..181668

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_000084.3 → NP_000075.1 H(+)/Cl(-) exchange transporter 5 isoform b

Status: REVIEWED

Description

Transcript Variant: This variant (3, also known as type 3) lacks several 5' exons but has an alternate 5' exon, and it thus differs in the 5' UTR and uses a downstream start codon, compared to variant 1. The resulting isoform (b) has a shorter N-terminus, compared to isoform a.

Source sequence(s)

AA743724, AK290940, AK308089, AL663118, BX950885

Consensus CDS

CCDS14328.1

UniProtKB/Swiss-Prot

P51795

Conserved Domains (4) summary

COG0517
Location:583 – 729
Blast Score: 106

COG0517; FOG: CBS domain [General function prediction only]

cd04591
Location:595 – 731
Blast Score: 282

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 ...

cd03684
Location:79 – 570
Blast Score: 1493

ClC_3_like; ClC-3-like chloride channel proteins. This CD includes ClC-3, ClC-4, ClC-5 and ClC-Y1. ClC-3 was initially cloned from rat kidney. Expression of ClC-3 produces outwardly-rectifying Cl currents that are inhibited by protein kinase C activation. It has ...

pfam00654
Location:163 – 551
Blast Score: 575

Voltage_CLC; Voltage gated chloride channel
NM_001127898.2 → NP_001121370.1 H(+)/Cl(-) exchange transporter 5 isoform a

Status: REVIEWED

Description

Transcript Variant: This variant (2, also known as type 1) uses an alternate splice site in the 5' UTR, compared to variant 1. Both variants 1 and 2 encode the same isoform (a).

Source sequence(s)

AA743724, AK056560, AL663118, DA652242

Consensus CDS

CCDS48115.1

UniProtKB/Swiss-Prot

P51795

Conserved Domains (4) summary

COG0517
Location:653 – 799
Blast Score: 103

COG0517; FOG: CBS domain [General function prediction only]

cd04591
Location:665 – 801
Blast Score: 284

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 ...

cd03684
Location:149 – 640
Blast Score: 1510

ClC_3_like; ClC-3-like chloride channel proteins. This CD includes ClC-3, ClC-4, ClC-5 and ClC-Y1. ClC-3 was initially cloned from rat kidney. Expression of ClC-3 produces outwardly-rectifying Cl currents that are inhibited by protein kinase C activation. It has ...

pfam00654
Location:233 – 621
Blast Score: 583

Voltage_CLC; Voltage gated chloride channel
NM_001127899.2 → NP_001121371.1 H(+)/Cl(-) exchange transporter 5 isoform a

Status: REVIEWED

Description

Transcript Variant: This variant (1, also known as type 2) represents the longest transcript and encodes the longest isoform (a). Both variants 1 and 2 encode the same isoform.

Source sequence(s)

AA743724, AK092049, AL663118

Consensus CDS

CCDS48115.1

UniProtKB/Swiss-Prot

P51795

Related

ENSP00000365256, OTTHUMP00000023279, ENST00000376088, OTTHUMT00000056542

Conserved Domains (4) summary

COG0517
Location:653 – 799
Blast Score: 103

COG0517; FOG: CBS domain [General function prediction only]

cd04591
Location:665 – 801
Blast Score: 284

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 ...

cd03684
Location:149 – 640
Blast Score: 1510

ClC_3_like; ClC-3-like chloride channel proteins. This CD includes ClC-3, ClC-4, ClC-5 and ClC-Y1. ClC-3 was initially cloned from rat kidney. Expression of ClC-3 produces outwardly-rectifying Cl currents that are inhibited by protein kinase C activation. It has ...

pfam00654
Location:233 – 621
Blast Score: 583

Voltage_CLC; Voltage gated chloride channel
NM_001272102.1 → NP_001259031.1 H(+)/Cl(-) exchange transporter 5 isoform c

Status: REVIEWED

Description

Transcript Variant: This variant (5) uses an alternate splice site in the 5' UTR, it lacks several 3' exons but has an alternate 3' terminal exon, and it thus differs in the 3' coding region and 3' UTR, compared to variant 1. The encoded isoform (c) has a distinct and shorter C-terminus, compared to isoform a.

Source sequence(s)

AK092049, BF513571

RNA

NR_073607.1 RNA Sequence

Status: REVIEWED

Description

Transcript Variant: This variant (4, also known as type 4) lacks several 5' exons but has an alternate 5' exon, compared to variant 1. This variant is represented as non-coding due to the presence of an upstream ORF that is predicted to interfere with translation of the downstream primary ORF. Translation of the upstream ORF renders the transcript a candidate for nonsense-mediated mRNA decay (NMD).

Source sequence(s)

AA743724, AL663118, X91906

RefSeqs of Annotated Genomes: Homo sapiens Annotation Release 104

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

Reference GRCh37.p10 PATCHES

Genomic

NW_004070880.1 Reference GRCh37.p10 PATCHES

Range

2142044..2318664

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Reference GRCh37.p10 Primary Assembly

Genomic

NC_000023.10 Reference GRCh37.p10 Primary Assembly

Range

49687225..49863892

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Alternate HuRef

Genomic

AC_000155.1 Alternate HuRef

Range

47156646..47337277

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Alternate CHM1_1.0

Genomic

NC_018934.1 Alternate CHM1_1.0

Range

49690658..49867411

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Nucleotide		Protein
Heading	Accession and Version	Protein
genomic	ABBA01063298.1 (772..31618)	None
genomic	ABBA01063299.1	None
genomic	ABBA01063300.1	None
genomic	ABBA01063301.1	None
genomic	ABBA01063302.1	None
genomic	ABBA01063303.1	None
genomic	ABBA01063304.1	None
genomic	ABBA01063305.1	None
genomic	ABBA01063306.1	None
genomic	ABBA01063307.1	None
genomic	ABBA01063308.1	None
genomic	ABBA01063309.1	None
genomic	ABBA01063310.1	None
genomic	ABBA01063311.1	None
genomic	ABBA01063312.1	None
genomic	ABBA01063313.1	None
genomic	ABBA01063314.1	None
genomic	ABBA01063315.1	None
genomic	ABBA01063316.1	None
genomic	ABBA01063317.1	None
genomic	ABBA01063318.1	None
genomic	ABBA01063319.1	None
genomic	AC231645.2 (40658..146610)	None
genomic	AC236430.4 (129378..200045)	None
genomic	AF222686.1 (25603..120182)	None
genomic	AL663118.2	None
genomic	AMYH01022321.1 (321022..365317)	None
genomic	AMYH01022322.1	None
genomic	AMYH01022323.1	None
genomic	AMYH01022324.1	None
genomic	AMYH01022325.1	None
genomic	AMYH01022326.1	None
genomic	CH471180.2	EAW89929.1
genomic	FO393402.1	None
mRNA	AA743724.1	None
mRNA	AK021494.1	None
mRNA	AK025562.1	None
mRNA	AK056560.1	BAG51748.1
mRNA	AK092049.1	BAG52474.1
mRNA	AK290940.1	BAF83629.1
mRNA	AK308089.1	None
mRNA	BC051691.1	None
mRNA	BC130429.1	AAI30430.1
mRNA	BC130431.1	AAI30432.1
mRNA	BF513571.1	None
mRNA	BK000969.1	DAA01544.1
mRNA	BX950885.1	None
mRNA	DA652242.1	None
mRNA	X81836.1	CAA57430.1
mRNA	X91906.1	CAA63000.1
other-genetic	HQ258649.1	ADR83400.1