The reference OMIM entry for this protein is 600580

Chloride channel 3; clcn3
Clc3

CLONING

Borsani et al. (1995) described the isolation and characterization of a human gene (CLCN3) and its mouse homolog (Clcn3) sharing significant sequence and structural similarities to members of the voltage-gated chloride channel family: CLCN1 (118425) and CLCN4 (302910). The CLCN3 gene was found to be expressed primarily in tissues derived from neuroectoderm. Within the brain Clcn3 expression was particularly evident in the hippocampus, olfactory cortex, and olfactory bulb. CLCN3 encodes a 760-amino acid protein that differs by only 2 amino acid residues from the protein encoded by Clcn3. CLCN3 protein also shows a high similarity with GEF1, an integral membrane protein of the yeast Saccharomyces cerevisiae known to be involved in respiration and iron-limited cell growth, and with the predicted protein product of a DNA sequence from the mold Septoria nodorum. The high degree of sequence conservation in distantly related species indicates that the gene has retained a fundamental function throughout evolution.

MAPPING

By analysis of genomic DNAs from human/rodent hybrids containing different human chromosomes, Borsani et al. (1995) mapped the CLCN3 gene to human chromosome 4. Mills et al. (1996) mapped the CLCN3 gene to human 4q32 and to mouse chromosome 8. Using FISH, linkage analysis in the CEPH families, and hybridization to a YAC panel, Taine et al. (1998) concluded that the gene is located in band 4q33.

ANIMAL MODEL

CLCN3 is thought to mediate swelling-activated plasma membrane currents, but Stobrawa et al. (2001) showed that this broadly expressed chloride channel is present in endosomal compartments and synaptic vesicles of neurons. While swelling-activated currents are unchanged in mice with disrupted Clcn3, acidification of synaptic vesicles is impaired and there is severe postnatal degeneration of the retina and hippocampus. Electrophysiologic analysis of juvenile hippocampal slices revealed no major functional abnormalities despite slightly increased amplitudes of miniature excitatory postsynaptic currents. Mice almost lacking the hippocampus survive and show several behavioral abnormalities but are still able to acquire motor skills. Clcn3 -/- mice were smaller than their littermates at all ages except immediately after birth. Although they showed overall higher mortality, Clcn3 -/- mice survived for more than a year. The nearly complete loss of hippocampal structures in adult knockout mice was not due to an early developmental defect but rather was caused by a selective degeneration starting about 2 weeks after birth. Clcn3 -/- mice were blind as a consequence of severe retinal degeneration that led to a complete loss of photoreceptors by postnatal day 28. Immunohistochemistry revealed that Clcn3 is concentrated in the inner and outer plexiform layers, the regions of synaptic connections. In summary, Stobrawa et al. (2001) showed that CLCN3 is an intracellular chloride channel. It is also present on synaptic vesicles, where it contributes to their acidification. The phenotype of Clcn3 knockout mice strongly suggests that CLCN3 is not the only chloride channel of synaptic vesicles, and Stobrawa et al. (2001) suggested that other CLC channels may have similar roles. To determine the physiologic role of CLC3, Yoshikawa et al. (2002) generated CLC3-deficient mice, Clcn3 -/-, by targeted gene disruption. Together with developmental retardation and higher mortality, the null mice showed neurol ... More on the omim web site

Subscribe to this protein entry history

Aug. 24, 2020: Protein entry updated
Automatic update: Entry updated from uniprot information.

Oct. 20, 2018: Protein entry updated
Automatic update: OMIM entry 600580 was added.

Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).