Alternative titles; symbols
HGNC Approved Gene Symbol: CLDN5
Cytogenetic location: 22q11.21 Genomic coordinates (GRCh38): 22:19,523,024-19,525,337 (from NCBI)
Claudin-5 (CLDN5), like other members of the claudin family, is a component of the tight junction, a specialized membrane domain that forms a physical barrier around epithelial and endothelial cells (summary by Morita et al., 1999).
Using exon trapping, Sirotkin et al. (1997) identified a novel short fragment cDNA within the region of 22q11 that is commonly deleted in patients with velocardiofacial syndrome (VCFS; 192430). They cloned a corresponding full-length cDNA from a human infant brain library. The gene, termed transmembrane protein deleted in velocardiofacial syndrome (TMVCF), encodes a 219-amino acid protein with a predicted mass of 23 kD. The amino acid sequence has strong homology to the rat RVP.1 (rat ventral prostate) protein, a prostate-specific protein whose function is unknown. Computer analyses predicted 2 transmembrane domains.
Tight junctions (TJs) constitute continuous seals around cells that serve as a physical barrier preventing solutes and water from passing freely through the paracellular space. Claudins are components of TJ strands. By sequence analysis, Morita et al. (1999) determined that TMVCF is a member of the claudin family and designated it claudin-5. When expressed in mammalian cells, an epitope-tagged claudin-5 was concentrated at TJs.
Coyne et al. (2003) determined that human bronchi and bronchioles express CLDN1 (603718), CLDN3 (602910), CLDN4 (602909), CLDN5, and CLDN7 (609131). CLDN1 and CLDN4 localized to the apical TJ region and in lateral intercellular junctions, with staining surrounding basal cells that anchor the columnar epithelium to the basal lamina. In contrast, CLDN3 and CLDN5 localized exclusively to the apical-most region of the TJs. CLDN7 colocalized with ZO1 (TJP1; 601009) in lateral intercellular junctions, with little or no staining near TJs.
Following overexpression in mouse fibroblasts and human airway epithelium, Coyne et al. (2003) found that claudins concentrated at cell borders when cells achieved confluence. Mouse fibroblasts expressing CLDN5 formed TJ strands composed primarily of particles and particle arrays, similar to those seen in gap junctions, whereas fibroblasts expressing CLDN1, CLDN3, or both formed TJ strands that lacked particle arrays. Coyne et al. (2003) determined that CLDN1 and CLDN3 decreased solute permeability in overexpressing cells, while CLDN5 increased permeability. CLDN1 and CLDN3 existed predominantly in monomeric form in human airway epithelium and in an airway epithelium cell line. In contrast, CLDN5 existed predominantly in pentameric and hexameric configurations. Coimmunoprecipitation studies revealed specific heterophilic interactions that could form between these 3 claudins.
Analysis of genomic DNA by Sirotkin et al. (1997) revealed that the TMVCF gene contains no introns.
By use of yeast artificial chromosomes, Sirotkin et al. (1997) localized the TMVCF gene between polymorphic markers D22S944 and D22S941 on chromosome 22q11, both of which are deleted in more than 80% of VCFS patients.
In the course of comparative mapping of the human 22q11 region in mice, Puech et al. (1997) demonstrated that the Tmvcf gene is located on mouse chromosome 16.
In mice with experimental autoimmune encephalitis (EAE), a mouse model of a central nervous system inflammatory disease, Argaw et al. (2009) observed widespread breakdown of the blood-brain barrier (BBB) associated with upregulation of astrocyte-derived Vegf (192240) and decreased expression of Cldn5 and occludin (Ocln; 602876) in the microvascular endothelium. VEGF was found to specifically downregulate CLDN5 and OCLN mRNA and protein in cultured human brain microvessel endothelial cells. Microinjection of VEGF in mouse cerebral cortex disrupted Cldn5 and Ocln and induced loss of barrier function. Functional studies revealed that expression of recombinant Cldn5 protected brain microvascular endothelial cell cultures from a VEGF-induced increase in permeability, whereas recombinant Ocln expressed under the same promoter was not protective. The findings implicated VEGF-mediated disruption of endothelial CLDN5 as a significant mechanism of BBB breakdown in the inflamed central nervous system.
Argaw, A. T., Gurfein, B. T., Zhang, Y., Zameer, A., John, G. R. VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown. Proc. Nat. Acad. Sci. 106: 1977-1982, 2009. [PubMed: 19174516] [Full Text: https://doi.org/10.1073/pnas.0808698106]
Coyne, C. B., Gambling, T. M., Boucher, R. C., Carson, J. L., Johnson, L. G. Role of claudin interactions in airway tight junctional permeability. Am. J. Physiol. Lung Cell. Molec. Physiol. 285: L1166-L1178, 2003. [PubMed: 12909588] [Full Text: https://doi.org/10.1152/ajplung.00182.2003]
Morita, K., Furuse, M., Fujimoto, K., Tsukita, S. Claudin multigene family encoding four-transmembrane domain protein components of tight junction strands. Proc. Nat. Acad. Sci. 96: 511-516, 1999. [PubMed: 9892664] [Full Text: https://doi.org/10.1073/pnas.96.2.511]
Puech, A., Saint-Jore, B., Funke, B., Gilbert, D. J., Sirotkin, H., Copeland, N. G., Jenkins, N. A., Kucherlapati, R., Morrow, B., Skoultchi, A. I. Comparative mapping of the human 22q11 chromosomal region and the orthologous region in mice reveals complex changes in gene organization. Proc. Nat. Acad. Sci. 94: 14608-14613, 1997. [PubMed: 9405660] [Full Text: https://doi.org/10.1073/pnas.94.26.14608]
Sirotkin, H., Morrow, B., Saint-Jore, B., Puech, A., Das Gupta, R., Patanjali, S. R., Skoultchi, A., Weissman, S. M., Kucherlapati, R. Identification, characterization, and precise mapping of a human gene encoding a novel membrane-spanning protein from the 22q11 region deleted in velo-cardio-facial syndrome. Genomics 42: 245-251, 1997. [PubMed: 9192844] [Full Text: https://doi.org/10.1006/geno.1997.4734]