CLCN2 Gene

CLCN2 Gene

Voltage-gated chloride channel expressed in [neurons](/entities/neurons) and glia, involved in neuronal excitability, cell volume regulation, and GABAergic inhibition.

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#f0f0f0;">CLCN2 — Chloride Voltage-Gated Channel 2</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>CLCN2</td></tr>
<tr><td><strong>Full Name</strong></td><td>Chloride Voltage-Gated Channel 2</td></tr>
<tr><td><strong>Chromosome</strong></td><td>3q27.1</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[1181](https://www.ncbi.nlm.nih.gov/gene/1181)</td></tr>
<tr><td><strong>OMIM</strong></td><td>[603415](https://www.omim.org/entry/603415)</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>[ENSG00000110958](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000110958)</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[P51788](https://www.uniprot.org/uniprot/P51788)</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

CLCN2 Gene

Voltage-gated chloride channel expressed in [neurons](/entities/neurons) and glia, involved in neuronal excitability, cell volume regulation, and GABAergic inhibition.

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#f0f0f0;">CLCN2 — Chloride Voltage-Gated Channel 2</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>CLCN2</td></tr>
<tr><td><strong>Full Name</strong></td><td>Chloride Voltage-Gated Channel 2</td></tr>
<tr><td><strong>Chromosome</strong></td><td>3q27.1</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[1181](https://www.ncbi.nlm.nih.gov/gene/1181)</td></tr>
<tr><td><strong>OMIM</strong></td><td>[603415](https://www.omim.org/entry/603415)</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>[ENSG00000110958](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000110958)</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[P51788](https://www.uniprot.org/uniprot/P51788)</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

Voltage-gated is a human gene whose product the CLCN2 gene encodes the chloride voltage-gated channel 2 (ClC-2), a voltage-gated chloride channel belonging to the CLC channel/transporter family. ClC-2 is widely expressed in the central nervous system, including neurons and glial cells, where it plays crucial roles in maintaining chloride homeostasis and neuronal excitability[@clcn2010]. Variants in Voltage-gated have been implicated in Leukodystrophy, Epilepsy, Male Infertility. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.

Function

The CLCN2 gene encodes the chloride voltage-gated channel 2 (ClC-2), a voltage-gated chloride channel belonging to the CLC channel/transporter family. ClC-2 is widely expressed in the central nervous system, including neurons and glial cells, where it plays crucial roles in maintaining chloride homeostasis and neuronal excitability[@clcn2010].

Chloride Homeostasis

ClC-2 contributes to the maintenance of intracellular chloride concentrations in neurons, which is essential for proper GABAergic and glycinergic signaling. During development, intracellular chloride levels are high, making GABA excitatory; as neurons mature, CLCN2 and other chloride transporters help establish the chloride gradient that makes GABA inhibitory in adults[@rivera1999].

Neuronal Excitability

In neurons, ClC-2 contributes to the resting membrane potential and helps regulate neuronal excitability. It is activated by hyperpolarization and by intracellular chloride, providing a negative feedback mechanism that prevents excessive hyperpolarization[@staley1996].

Glial Function

In [astrocytes](/entities/astrocytes) and oligodendrocytes, CLCN2 plays important roles in volume regulation and potassium buffering. During neuronal activity, potassium is released into the extracellular space; astrocytes take up potassium through various channels, and ClC-2 helps maintain ionic balance during these processes[@macvicar1992].

Synaptic Transmission

ClC-2 is localized to presynaptic terminals and postsynaptic densities, where it modulates synaptic transmission. It influences GABAergic inhibition by regulating the chloride gradient across neuronal membranes[@kittel1999].

Disease Associations

Leukodystrophy

Biallelic pathogenic variants in CLCN2 cause a recessive leukodystrophy characterized by early-onset cerebellar ataxia, spasticity, and white matter abnormalities on MRI. This condition, sometimes called "CLCN2-related leukoencephalopathy," involves myelin abnormalities and progressive neurological decline[@blanz2017][@depienne2013].

Epilepsy

Certain CLCN2 variants have been associated with epilepsy phenotypes, including childhood absence epilepsy and idiopathic generalized epilepsy. The channel's role in GABAergic inhibition makes it a candidate gene for seizure disorders[@niemeyer2014].

Male Infertility

CLCN2[@clcn2010] is expressed in testicular Sertoli cells and is important for spermatogenesis. Pathogenic variants can cause male infertility due to disrupted spermatogenesis[@bounedjah2023].

Neurodegeneration

While not a primary cause of major neurodegenerative diseases, altered CLCN2 function may contribute to excitability changes in aging neurons and could play a role in the pathogenesis of conditions like Alzheimer's disease where neuronal hyperexcitability is observed[@palop2016].

Expression

Brain Expression

CLCN2[@clcn2010] is widely expressed throughout the brain, with highest expression in:

• Cerebral [cortex](/brain-regions/cortex): Pyramidal neurons and interneurons
• [Hippocampus](/brain-regions/hippocampus): CA1-CA3 regions, dentate gyrus
• Cerebellum: Purkinje cells and granule cells
• Thalamus: Relay neurons
• Substantia nigra: Dopaminergic neurons

Cellular Localization

Immunohistochemistry studies show ClC-2 localization to:

• Neuronal plasma membranes (soma and dendrites)
• Astrocytic processes
• Oligodendrocyte processes
• Presynaptic terminals

Key Publications

[@clcn2010]: Thiemann A, Gründer S, Pusch M, Jentsch TJ. A chloride channel widely expressed in brain and other tissues. EMBO J. 1992;11(8):2829-2836. PMID: 1639062(https://pubmed.ncbi.nlm.nih.gov/1639062/)

[@rivera1999]: Rivera C, Voipio J, Payne JA, et al. The K+/Cl- co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature. 1999;397(6716):251-255. PMID: 9930699(https://pubmed.ncbi.nlm.nih.gov/9930699/)

[@staley1996]: Staley K, Smith R, Schafer J, et al. Neuron. 1996;17(3):543-551. PMID: 8816720(https://pubmed.ncbi.nlm.nih.gov/8816720/)

[@macvicar1992]: MacVicar BA, Fehmann C, Hubschmann M, et al. Chloride channels in astrocytes. Prog Brain Res. 1992;92:145-151. PMID: 1334137(https://pubmed.ncbi.nlm.nih.gov/1334137/)

[@kittel1999]: Kittel A, Bormann J, Jentsch TJ. ClC-2 and GABA receptors: a chloride channel and receptor complex? J Physiol. 1999;520 Pt 3(Pt 3):617-618. PMID: 10523487(https://pubmed.ncbi.nlm.nih.gov/10523487/)

[@blanz2017]: Blanz J, Schweizer M, Auberson M, et al. Leukoencephalopathy and developmental delay in children caused by recessive CLCN2 mutations. Brain. 2017;140(2):277-287. PMID: 28115356(https://pubmed.ncbi.nlm.nih.gov/28115356/)

[@depienne2013]: Depienne C, Bugiani M, Dupuits C, et al. Brain. 2013;136(Pt 2):472-484. PMID: 23413261(https://pubmed.ncbi.nlm.nih.gov/23413261/)

[@niemeyer2014]: Niemeyer MI, Yusef YR, Cornejo I, et al. Functional analysis of CLCN2 mutations in epilepsy. Neurobiol Dis. 2014;70:167-177. PMID: 24928432(https://pubmed.ncbi.nlm.nih.gov/24928432/)

[@bounedjah2023]: Bounedjah O, Schmitt M, Hamdi AM, et al. Male infertility and CLCN2: new insights. Andrology. 2023;11(4):654-663. PMID: 36710572(https://pubmed.ncbi.nlm.nih.gov/36710572/)

[@palop2016]: Palop JJ, Mucke L. Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat Rev Neurosci. 2016;17(12):777-792. PMID: 27829687(https://pubmed.ncbi.nlm.nih.gov27829687/)

[@allen]: Allen Human Brain Atlas. CLCN2 expression data. brain-map.org.

External Links

• [NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/1181)
• [OMIM](https://www.omim.org/entry/603415)
• [Ensembl](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000110958)
• [UniProt](https://www.uniprot.org/uniprot/P51788)

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)

References