Details for: CLCN4

Gene ID: 1183

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: CLCN4

Ensembl ID: ENSG00000073464

Description: chloride voltage-gated channel 4

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • retinal cone cell CL0000573
    CSI 5.01
    rCSI 8.07%
    PRS 78.48
  • retina horizontal cell CL0000745
    CSI 3.53
    rCSI 5.39%
    PRS 84.15
  • retinal ganglion cell CL0000740
    CSI 3.38
    rCSI 7.46%
    PRS 74.92
  • astrocyte of the cerebral cortex CL0002605
    CSI 3.21
    rCSI 7.21%
    PRS 72.68
  • sst GABAergic cortical interneuron CL4023017
    CSI 3.2
    rCSI 4.12%
    PRS 73.12
  • retinal pigment epithelial cell CL0002586
    CSI 3.18
    rCSI 6.32%
    PRS 83.18
  • ON-bipolar cell CL0000749
    CSI 2.79
    rCSI 4.15%
    PRS 86.43
  • cerebellar granule cell CL0001031
    CSI 2.76
    rCSI 4.06%
    PRS 81.07
  • Mueller cell CL0000636
    CSI 2.61
    rCSI 5.96%
    PRS 79.78
  • cerebral cortex neuron CL0010012
    CSI 2.55
    rCSI 10.41%
    PRS 79.37
  • cerebral cortex endothelial cell CL1001602
    CSI 2.55
    rCSI 4.41%
    PRS 80.51
  • corticothalamic-projecting glutamatergic cortical neuron CL4023013
    CSI 2.44
    rCSI 14.37%
    PRS 72.39
  • rod bipolar cell CL0000751
    CSI 2.13
    rCSI 3.84%
    PRS 81.47
  • regular ventricular cardiac myocyte CL0002131
    CSI 2.08
    rCSI 12.97%
    PRS 80.07
  • inhibitory interneuron CL0000498
    CSI 2.07
    rCSI 4.78%
    PRS 76.78
  • choroid plexus epithelial cell CL0000706
    CSI 2.03
    rCSI 3.33%
    PRS 78.56
  • VIP GABAergic cortical interneuron CL4023016
    CSI 1.99
    rCSI 2.38%
    PRS 72.11
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 1.91
    rCSI 2.37%
    PRS 69.77
  • retinal bipolar neuron CL0000748
    CSI 1.87
    rCSI 3.51%
    PRS 77.4
  • L2/3 intratelencephalic projecting glutamatergic neuron CL4030059
    CSI 1.82
    rCSI 3.96%
    PRS 75.4
  • OFF-bipolar cell CL0000750
    CSI 1.77
    rCSI 2.42%
    PRS 86.98
  • type B pancreatic cell CL0000169
    CSI 1.67
    rCSI 3.69%
    PRS 86.9
  • glycinergic amacrine cell CL4030028
    CSI 1.66
    rCSI 4.31%
    PRS 81.09
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 1.58
    rCSI 2.65%
    PRS 71.97
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 1.55
    rCSI 5.57%
    PRS 69.93
  • sncg GABAergic cortical interneuron CL4023015
    CSI 1.53
    rCSI 2.46%
    PRS 73.16
  • glutamatergic neuron CL0000679
    CSI 1.48
    rCSI 3.05%
    PRS 74.59
  • retinal rod cell CL0000604
    CSI 1.46
    rCSI 2.58%
    PRS 82.57
  • L6b glutamatergic cortical neuron CL4023038
    CSI 1.4
    rCSI 4.39%
    PRS 73.28
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 1.4
    rCSI 5.29%
    PRS 72.26
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 1.36
    rCSI 2.4%
    PRS 71.42
  • GABAergic amacrine cell CL4030027
    CSI 1.36
    rCSI 4.66%
    PRS 73.78
  • S cone cell CL0003050
    CSI 1.35
    rCSI 5.95%
    PRS 81.67
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 1.3
    rCSI 3.15%
    PRS 69.72
  • indirect pathway medium spiny neuron CL4023029
    CSI 1.2
    rCSI 28.99%
    PRS 69.97
  • direct pathway medium spiny neuron CL4023026
    CSI 1.11
    rCSI 26.53%
    PRS 69.53
  • L5/6 near-projecting glutamatergic neuron CL4030067
    CSI 1.06
    rCSI 3.5%
    PRS 74.33
  • L4 intratelencephalic projecting glutamatergic neuron CL4030063
    CSI 0.97
    rCSI 2.31%
    PRS 75.44
  • amacrine cell CL0000561
    CSI 0.96
    rCSI 2.77%
    PRS 77.82
  • GABAergic neuron CL0000617
    CSI 0.94
    rCSI 3.16%
    PRS 72.3
  • chandelier pvalb GABAergic cortical interneuron CL4023036
    CSI 0.8
    rCSI 2.51%
    PRS 75.4
  • OFF midget ganglion cell CL4033047
    CSI 0.37
    rCSI 7.52%
    PRS 78.33
  • ON midget ganglion cell CL4033046
    CSI 0.3
    rCSI 6.09%
    PRS 77.45
  • medium spiny neuron CL1001474
    CSI 0.26
    rCSI 2.22%
    PRS 77.33

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [CLCN4](/details-gene/1183) is a protein-coding gene located on the X chromosome that encodes the chloride voltage-gated channel 4, a member of the CLC family of chloride channels and transporters. Functionally, it operates as a proton/chloride (H+/Cl-) exchange transporter, playing a critical role in regulating ion homeostasis within intracellular organelles. Expression data reveals that **Overall**, [CLCN4](/details-gene/1183) is a significant marker in the central nervous system, with particularly high relevance in various cell types of the retina, including the `[retinal cone cell](/details-cell/CL0000573)`, `[retina horizontal cell](/details-cell/CL0000745)`, and `[retinal ganglion cell](/details-cell/CL0000740)`. Consistent with its X-linked inheritance, mutations in [CLCN4](/details-gene/1183) have been associated with syndromic intellectual disability, seizure disorders, and behavioral abnormalities ([OMIM: 302910](https://omim.org/entry/302910), [OMIM: 300114](https://omim.org/entry/300114)), as documented in several studies ([Link](https://doi.org/10.1038/mp.2016.135)). ## Cellular Roles and Expression Landscape The expression profile of [CLCN4](/details-gene/1183) strongly indicates a specialized role in the nervous system, particularly in visual processing and general neuronal function. **Overall**, the gene shows its highest significance in a range of retinal cells. It is the top-ranked marker in `[retinal cone cell](/details-cell/CL0000573)` (CSI: 5.01) and is also highly significant in `[retina horizontal cell](/details-cell/CL0000745)`, `[retinal ganglion cell](/details-cell/CL0000740)`, `[retinal pigment epithelial cell](/details-cell/CL0002586)`, and various bipolar cells. This comprehensive expression across multiple, functionally distinct retinal layers suggests a fundamental role in maintaining the ionic environment required for phototransduction and neural signal transmission in the eye. Beyond the retina, [CLCN4](/details-gene/1183) is a key gene in diverse CNS cell types. It is highly expressed in glial cells like `[astrocyte of the cerebral cortex](/details-cell/CL0002605)` and in various neurons, including `[sst GABAergic cortical interneuron](/details-cell/CL4023017)`, `[cerebellar granule cell](/details-cell/CL0001031)`, and `[cerebral cortex neuron](/details-cell/CL0010012)`. This broad yet specific expression pattern within the nervous system points to a critical function in regulating neuronal excitability and synaptic processes. ## Pathways and Molecular Function The functions of the [CLCN4](/details-gene/1183) protein are centered on ion transport, which is consistent with its annotation as a member of the CLC family. Gene Ontology (GO) analysis highlights its molecular function as an `[Antiporter activity](/details-go/GO:0015297)` and `[Voltage-gated chloride channel activity](/details-go/GO:0005247)`, participating in the biological process of `[Chloride transmembrane transport](/details-go/GO:1902476)`. These activities are integral to the Reactome pathways of `[Ion channel transport](/details-reactome/R-HSA-983712)` and the broader `[Transport of small molecules](/details-reactome/R-HSA-382551)`. Cellular component annotations reveal that [CLCN4](/details-gene/1183) is predominantly localized to intracellular membrane systems. It is found in the `[Endoplasmic reticulum membrane](/details-go/GO:0005789)`, `[Early endosome membrane](/details-go/GO:0031901)`, `[Late endosome membrane](/details-go/GO:0031902)`, and `[Lysosomal membrane](/details-go/GO:0005765)`. This localization is crucial for the acidification of these organelles, a process essential for receptor recycling, protein degradation, and cellular signaling. Studies have confirmed its localization to the endoplasmic reticulum and its sorting into endosomal compartments, which is facilitated by its association with other CLC proteins ([Link](https://doi.org/10.1096/fj.05-5588fje), [Link](https://doi.org/10.1074/jbc.m117.801951)). Furthermore, its presence in `[Synaptic vesicle](/details-go/GO:0008021)`s is consistent with its high expression in neurons and suggests a direct role in the synaptic vesicle cycle, potentially by facilitating the proton gradient required for neurotransmitter loading. ## Research Directions The established role of [CLCN4](/details-gene/1183) in ion exchange and its strong association with neurodevelopmental disorders provide a clear basis for further investigation. Its high expression in specific neuronal subtypes suggests that disruptions in its function could have cell-type-specific consequences that manifest as complex neurological symptoms. **Testable Hypotheses:** 1. Given the exceptionally high expression of [CLCN4](/details-gene/1183) across multiple retinal cell types, loss-of-function mutations likely impair the acidification of endolysosomal pathways in these cells, leading to defective protein processing or photoreceptor maintenance, thereby contributing to specific visual deficits reported in patients with [CLCN4](/details-gene/1183)-related disorders. 2. The localization of [CLCN4](/details-gene/1183) to synaptic vesicles and its high expression in both excitatory and inhibitory neurons suggests it is critical for establishing the electrochemical gradient needed for efficient neurotransmitter loading. Its dysfunction could alter the balance of synaptic transmission, providing a mechanistic explanation for the high incidence of seizure disorders observed in affected individuals ([Link](https://doi.org/10.1111/epi.12201)). **Proposed Experimental Approach:** To test the second hypothesis, a conditional knockout mouse model could be generated where [CLCN4](/details-gene/1183) is specifically deleted in forebrain neurons. Electrophysiological analysis, such as patch-clamp recordings from cortical or hippocampal neurons, could be performed to measure alterations in synaptic properties, including the frequency and amplitude of miniature excitatory and inhibitory postsynaptic currents (mEPSCs and mIPSCs). Furthermore, biochemical assays on purified synaptic vesicles from these mice could directly assess defects in pH regulation and neurotransmitter uptake, linking the molecular function of [CLCN4](/details-gene/1183) to synaptic physiology. **Therapeutic Potential:** As the associated pathologies are linked to loss-of-function mutations, the therapeutic goal would be to restore or augment [CLCN4](/details-gene/1183) activity. This presents a significant challenge. Gene therapy using AAV vectors to deliver a functional copy of the gene to the CNS could be a long-term possibility, although achieving widespread and regulated expression is a major hurdle. An alternative approach could involve screening for small molecule potentiators that enhance the transport activity of the residual or mutated protein. However, given its fundamental role in ion homeostasis across many cell types, any therapeutic intervention would require high specificity to avoid adverse off-target effects.

Genular Protein ID: 1632650736

Symbol: CLCN4_HUMAN

Name: H(+)/Cl(-) exchange transporter 4

UniProtKB Accession Codes:

P51793 A1L3U1 B7Z5Z4 Q9UBU1

Database IDs:

ABCD 1 AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CDD 2 CTD 1 ChEBI 6 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 9 Ensembl 2 ExpressionAtlas 1 GO 20 Gene3D 3 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 5 KEGG 1 MANE-Select 1 MIM 3 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 2 OrthoDB 1 PANTHER 2 PIR 1 PRINTS 2 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 Pumba 1 RNAct 1 Reactome 1 RefSeq 2 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 8069296

Title: A gene from the Xp22.3 region shares homology with voltage-gated chloride channels.

PubMed ID: 8069296

DOI: 10.1093/hmg/3.4.547

PubMed ID: 10564087

Title: Identification of an acid-activated Cl- channel from human skeletal muscles.

PubMed ID: 10564087

DOI: 10.1152/ajpcell.1999.277.5.c948

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15772651

Title: The DNA sequence of the human X chromosome.

PubMed ID: 15772651

DOI: 10.1038/nature03440

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 17023393

Title: The human ClC-4 protein, a member of the CLC chloride channel/transporter family, is localized to the endoplasmic reticulum by its N-terminus.

PubMed ID: 17023393

DOI: 10.1096/fj.05-5588fje

PubMed ID: 18063579

Title: Determinants of anion-proton coupling in mammalian endosomal CLC proteins.

PubMed ID: 18063579

DOI: 10.1074/jbc.m708368200

PubMed ID: 28972156

Title: Preferential association with ClC-3 permits sorting of ClC-4 into endosomal compartments.

PubMed ID: 28972156

DOI: 10.1074/jbc.m117.801951

PubMed ID: 29845874

Title: CLC Chloride Channels and Transporters: Structure, Function, Physiology, and Disease.

PubMed ID: 29845874

DOI: 10.1152/physrev.00047.2017

PubMed ID: 23647072

Title: Exome sequencing reveals new causal mutations in children with epileptic encephalopathies.

PubMed ID: 23647072

DOI: 10.1111/epi.12201

PubMed ID: 26034137

Title: Increased burden of de novo predicted deleterious variants in complex congenital diaphragmatic hernia.

PubMed ID: 26034137

DOI: 10.1093/hmg/ddv196

PubMed ID: 27550844

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.

PubMed ID: 27550844

DOI: 10.1038/mp.2016.135

PubMed ID: 25644381

Title: X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes.

PubMed ID: 25644381

DOI: 10.1038/mp.2014.193

Sequence Information:

  • Length: 760
  • Mass: 84917
  • Checksum: 3A5A25D1FEF3F217
  • Sequence:
    • MVNAGAMSGS GNLMDFLDEP FPDVGTYEDF HTIDWLREKS RDTDRHRKIT SKSKESIWEF 
IKSLLDAWSG WVVMLLIGLL AGTLAGVIDL AVDWMTDLKE GVCLSAFWYS HEQCCWTSNE 
TTFEDRDKCP LWQKWSELLV NQSEGASAYI LNYLMYILWA LLFAFLAVSL VRVFAPYACG 
SGIPEIKTIL SGFIIRGYLG KWTLLIKTVT LVLVVSSGLS LGKEGPLVHV ACCCGNFFSS 
LFSKYSKNEG KRREVLSAAA AAGVSVAFGA PIGGVLFSLE EVSYYFPLKT LWRSFFAALV 
AAFTLRSINP FGNSRLVLFY VEYHTPWYMA ELFPFILLGV FGGLWGTLFI RCNIAWCRRR 
KTTRLGKYPV LEVIVVTAIT AIIAYPNPYT RQSTSELISE LFNDCGALES SQLCDYINDP 
NMTRPVDDIP DRPAGVGVYT AMWQLALALI FKIVVTIFTF GMKIPSGLFI PSMAVGAIAG 
RMVGIGVEQL AYHHHDWIIF RNWCRPGADC VTPGLYAMVG AAACLGGVTR MTVSLVVIMF 
ELTGGLEYIV PLMAAAVTSK WVADAFGKEG IYEAHIHLNG YPFLDVKDEF THRTLATDVM 
RPRRGEPPLS VLTQDSMTVE DVETLIKETD YNGFPVVVSR DSERLIGFAQ RRELILAIKN 
ARQRQEGIVS NSIMYFTEEP PELPANSPHP LKLRRILNLS PFTVTDHTPM ETVVDIFRKL 
GLRQCLVTRS GRLLGIITKK DVLRHMAQMA NQDPESIMFN