CLCN4 chloride voltage-gated channel 4 [Homo sapiens (human)] - Gene

Summary

Official Symbol: CLCN4provided by HGNC
Official Full Name: chloride voltage-gated channel 4provided by HGNC
Primary source: HGNC:HGNC:2022
See related: Ensembl:ENSG00000073464 MIM:302910; AllianceGenome:HGNC:2022
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: CLC4; ClC-4; MRX15; MRX49; ClC-4A; MRXSRC
Summary: The CLCN family of voltage-dependent chloride channel genes comprises nine members (CLCN1-7, Ka and Kb) which demonstrate quite diverse functional characteristics while sharing significant sequence homology. Chloride channel 4 has an evolutionary conserved CpG island and is conserved in both mouse and hamster. This gene is mapped in close proximity to APXL (Apical protein Xenopus laevis-like) and OA1 (Ocular albinism type I), which are both located on the human X chromosome at band p22.3. The physiological role of chloride channel 4 remains unknown but may contribute to the pathogenesis of neuronal disorders. Alternate splicing results in two transcript variants that encode different proteins. [provided by RefSeq, Mar 2012]
Expression: Biased expression in brain (RPKM 20.8), heart (RPKM 5.1) and 10 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: Xp22.2

Exon count:: 13

Annotation release	Status	Assembly	Chr	Location
RS_2024_08	current	GRCh38.p14 (GCF_000001405.40)	X	NC_000023.11 (10156975..10237660)
RS_2024_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	X	NC_060947.1 (9739532..9820250)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	X	NC_000023.10 (10125015..10205700)

Chromosome X - NC_000023.11 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Genotype-phenotype correlation in CLCN4-related developmental and epileptic encephalopathy.
Title: Genotype-phenotype correlation in CLCN4-related developmental and epileptic encephalopathy.
absence of learning difficulties in a hyperactive boy with a terminal Xp deletion encompassing the MRX49 locus
Title: Absence of learning difficulties in a hyperactive boy with a terminal Xp deletion encompassing the MRX49 locus.
Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.
Title: Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.
The molecular and phenotypic spectrum of CLCN4-related epilepsy.
Title: The molecular and phenotypic spectrum of CLCN4-related epilepsy.
We report 10 additional families with nine novel CLCN4 variants, extend the molecular spectrum to include splice site variants and single-exon deletions, suggest genotype-phenotype correlation, and present detailed clinical phenotypic information about CLCN4-related disorder in 29 hemizygous males and 23 heterozygous females from 16 families.
Title: De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females.
Unique oligomerization properties of ClC-4 permit regulated targeting of ClC-4 to various endosomal compartment systems via expression of different ClC-3 splice variants.
Title: Preferential association with ClC-3 permits sorting of ClC-4 into endosomal compartments.
This study performed whole exome sequencing demonistrated that the true de novo variants represent mutations in genes (KCNH5, CLCN4, and ARHGEF15) not previously associated with epilepsies in humans.
Title: Exome sequencing reveals new causal mutations in children with epileptic encephalopathies.
the voltage dependence of uncoupled ClC-4 by protons and anions
Title: Anion- and proton-dependent gating of ClC-4 anion/proton transporter under uncoupling conditions.
CLCN4 is a novel driver of colon cancer progression.
Title: Gene trapping identifies chloride channel 4 as a novel inducer of colon cancer cell migration, invasion and metastases.
Studies showed that three novel CLC-5 mutations were identified, and mutations in OCRL1, CLC-4 and cofilin excluded in causing Dent's disease.
Title: Mutational analysis of CLC-5, cofilin and CLC-4 in patients with Dent's disease.

Submit: New GeneRIF Correction See all GeneRIFs (16)

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
Intellectual disability, X-linked 49 MedGen: C0796221 OMIM: 300114 GeneReviews: CLCN4-Related Neurodevelopmental Disorder	not available

Copy number response

Description
Copy number response Triplosensitivity No evidence available (Last evaluated 2022-07-27) ClinGen Genome Curation Page Haploinsufficency Little evidence for dosage pathogenicity (Last evaluated 2022-07-27) ClinGen Genome Curation PagePubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

CLCN4_3951 (e-PCR)
- UniSTS:462105

DXS6975E (e-PCR)
- UniSTS:50242

G20389 (e-PCR)
- UniSTS:17750

A005P03 (e-PCR)
- UniSTS:17751

DXS7108 (e-PCR)
- UniSTS:49522

STS-X77197 (e-PCR)
- UniSTS:56470

A008T30 (e-PCR)
- UniSTS:8343

SHGC-78004 (e-PCR)
- UniSTS:101544

CLCN4 (e-PCR)
- UniSTS:506538

A004U24 (e-PCR)
- UniSTS:76461

G60164 (e-PCR)
- UniSTS:137423

STS-AA018252 (e-PCR)
- UniSTS:72946

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables ATP binding	IEA Inferred from Electronic Annotation more info
enables antiporter activity	IDA Inferred from Direct Assay more info	PubMed
enables antiporter activity	IMP Inferred from Mutant Phenotype more info	PubMed
enables antiporter activity	TAS Traceable Author Statement more info
enables chloride channel activity	IDA Inferred from Direct Assay more info	PubMed
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables voltage-gated chloride channel activity	IBA Inferred from Biological aspect of Ancestor more info

Process	Evidence Code	Pubs
involved_in chloride transmembrane transport	IEA Inferred from Electronic Annotation more info
acts_upstream_of_or_within chloride transport	IDA Inferred from Direct Assay more info	PubMed
involved_in chloride transport	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in monoatomic ion transmembrane transport	TAS Traceable Author Statement more info
involved_in non-motile cilium assembly	IEA Inferred from Electronic Annotation more info

Component	Evidence Code	Pubs
is_active_in Golgi apparatus	IBA Inferred from Biological aspect of Ancestor more info
located_in ciliary base	IEA Inferred from Electronic Annotation more info
is_active_in early endosome	IBA Inferred from Biological aspect of Ancestor more info
located_in early endosome membrane	IEA Inferred from Electronic Annotation more info
located_in endoplasmic reticulum membrane	IDA Inferred from Direct Assay more info	PubMed
located_in endosome membrane	IDA Inferred from Direct Assay more info	PubMed
located_in endosome membrane	TAS Traceable Author Statement more info
located_in intracellular membrane-bounded organelle	IDA Inferred from Direct Assay more info
located_in late endosome membrane	IEA Inferred from Electronic Annotation more info
located_in lysosomal membrane	IDA Inferred from Direct Assay more info	PubMed
is_active_in plasma membrane	IBA Inferred from Biological aspect of Ancestor more info
located_in recycling endosome	IDA Inferred from Direct Assay more info	PubMed
located_in recycling endosome membrane	IEA Inferred from Electronic Annotation more info
is_active_in synaptic vesicle	IBA Inferred from Biological aspect of Ancestor more info

General protein information

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Preferred Names: H(+)/Cl(-) exchange transporter 4

Names: chloride channel 4; chloride channel protein 4; chloride channel, voltage-sensitive 4; chloride transporter ClC-4

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_012496.1 RefSeqGene

Range

5031..85716

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_001256944.2 → NP_001243873.1 H(+)/Cl(-) exchange transporter 4 isoform 2

See identical proteins and their annotated locations for NP_001243873.1

Status: REVIEWED

Description

Transcript Variant: This variant (2) differs in the 5' UTR and lacks an in-frame portion of the 5' coding region, compared to variant 1. The resulting isoform (2) has a shorter N-terminus, compared to isoform 1.

Source sequence(s)

AC003666, AK299611, BP310547

Consensus CDS

CCDS59159.1

UniProtKB/TrEMBL

Q4G0X3

Related

ENSP00000501922.1, ENST00000674669.1

Conserved Domains (2) summary

cd03684
Location:42 → 490

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 ...

cd04591
Location:513 → 651

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 ...
NM_001830.4 → NP_001821.2 H(+)/Cl(-) exchange transporter 4 isoform 1

See identical proteins and their annotated locations for NP_001821.2

Status: REVIEWED

Description

Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1).

Source sequence(s)

AB019432, AC003666, BP310547

Consensus CDS

CCDS14137.1

UniProtKB/Swiss-Prot

A1L3U1, B7Z5Z4, P51793, Q9UBU1

UniProtKB/TrEMBL

Q4G0X3

Related

ENSP00000370213.4, ENST00000380833.9

Conserved Domains (2) summary

cd03684
Location:78 → 584

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 ...

cd04591
Location:595 → 745

CBS_pair_voltage-gated_CLC_euk_bac; Two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with the voltage gated CLC (chloride channel) in eukaryotes and bacteria