Alternative titles; symbols
HGNC Approved Gene Symbol: CLDN4
Cytogenetic location: 7q11.23 Genomic coordinates (GRCh38): 7:73,830,996-73,832,690 (from NCBI)
Claudins, such as CLDN4, are components of epithelial cell tight junctions. Tight junctions regulate movement of solutes and ions through the paracellular space and prevent mixing of proteins and lipids in the outer leaflet of the apical and basolateral plasma membrane domains (Acharya et al., 2004).
The enterotoxin produced by the bacterium Clostridium perfringens is a simple protein with a molecular mass of approximately 35 kD. Known as a causative agent of diarrhea, it elicits fluid accumulation in the intestinal tract by altering the membrane permeability of intestinal epithelial cells. Pore formation in the cytoplasmic membrane is accepted as the underlying mechanism of this effect. The cytotoxic action of C. perfringens enterotoxin (CPE) requires its binding to specific receptors. At least 2 molecules with different affinities to CPE are considered to exist in various organs of a wide range of species. By searching an expressed sequence tag database for sequences showing homology to the high-affinity CPE receptor (CPER) of monkey kidney cells, Katahira et al. (1997) identified an infant human brain cDNA encoding CPETR1. The deduced 209-amino acid protein contains 4 putative transmembrane domains. Northern blot analysis of mouse tissues detected abundant Cpetr1 expression in small intestine and kidney, and lower levels in heart, lung, liver, and skeletal muscle; no expression was found in brain or spleen. In situ hybridization demonstrated that the expression of mouse Cpetr1 mRNA in the small intestine was restricted to cryptic enterocytes, indicating that the receptor is expressed in intestinal epithelial cells.
Using Northern blot analysis, Paperna et al. (1998) found a 1.8-kb CPETR1 transcript in adult and fetal human tissues. Expression was highest in adult thyroid, placenta, pancreas, lung, and kidney, and moderate in small intestine. Little to no CPETR1 was detected in other adult tissues examined. CPETR1 was detected in fetal lung and kidney, but not in fetal brain or liver. In whole embryonic mice, expression was low on embryonic day 7 and increased during development to embryonic day 17.
By sequence analysis, Morita et al. (1999) determined that CPER is a member of the claudin family and designated it claudin-4.
Katahira et al. (1997) confirmed that CPETR1 is a functional high-affinity receptor for CPE.
Using immunofluorescence and immunoelectron microscopy, Morita et al. (1999) found that claudin-4 localized specifically to tight junctions in mouse kidney.
By immunofluorescence microscopy of normal mouse skin, Furuse et al. (2002) found that Cldn1 (603718) and Cldn4 concentrated within continuous tight junctions in the stratum granulosum.
Colegio et al. (2002) found that expression of human claudin-4 in Madin-Darby canine kidney (MDCK) cells increased transmonolayer electrical resistance by selectively decreasing the paracellular permeability for Na+, but not for Cl-. The first extracellular domain of human claudin-4 has a single basic residue, lys65. Colegio et al. (2002) found that replacing lys65 with aspartic acid (K65D) via site-specific mutagenesis eliminated the ability of claudin-4 to discriminate against Na+.
Coyne et al. (2003) determined that human bronchi and bronchioles express CLDN1, CLDN3 (602910), CLDN4, CLDN5 (602101), and CLDN7 (609131). CLDN1 and CLDN4 localized to the apical tight junction 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 tight junction. CLDN7 colocalized with ZO1 (TJP1; 601009) in lateral intercellular junctions, with little or no staining near tight junctions.
Using immunofluorescence microscopy, Acharya et al. (2004) showed that Cldn4, Cldn8 (611231), and Cldn12 (611232) localized to the bladder epithelium of rat, mouse, and rabbit. These claudins specifically localized to tight junctions of the superficial umbrella cell layer, consistent with the high-resistance, low-permeability barrier function of this cell type.
Using immunohistochemical analysis, Dube et al. (2007) found that CLDN1, CLDN3, CLDN4, and CLDN8 were associated with the blood-epididymal barrier of the epididymal duct. In all 3 epididymal segments, CLDN1, CLDN3, and CLDN4 localized to tight junctions, along the lateral margins of adjacent principal cells, and at the interface between basal and principal cells. In contrast, CLDN8 localized to tight junctions in all 3 segments, along the lateral margins of principal cells in the caput, and at the interface between basal and principal cells in the corpus.
Paperna et al. (1998) determined that CLDN4 is an intronless gene.
By somatic cell hybrid analysis, Paperna et al. (1998) mapped the CLDN4 gene to chromosome 7q11.23. They mapped the mouse Cldn4 gene to a region of chromosome 5G1 that shares homology of synteny with human chromosome 7q11.23.
Acharya, P., Beckel, J., Ruiz, W. G., Wang, E., Rojas, R., Birder, L., Apodaca, G. Distribution of the tight junction proteins ZO-1, occludin, and claudin-4, -8, and -12 in bladder epithelium. Am. J. Physiol. Renal Physiol. 287: F305-F318, 2004. [PubMed: 15068973] [Full Text: https://doi.org/10.1152/ajprenal.00341.2003]
Colegio, O. R., Van Itallie, C. M., McCrea, H. J., Rahner, C., Anderson, J. M. Claudins create charge-selective channels in the paracellular pathway between epithelial cells. Am. J. Physiol. Cell Physiol. 283: C142-C147, 2002. [PubMed: 12055082] [Full Text: https://doi.org/10.1152/ajpcell.00038.2002]
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]
Dube, E., Chan, P. T. K., Hermo, L., Cyr, D. G. Gene expression profiling and its relevance to the blood-epididymal barrier in the human epididymis. Biol. Reprod. 76: 1034-1044, 2007. [PubMed: 17287494] [Full Text: https://doi.org/10.1095/biolreprod.106.059246]
Furuse, M., Hata, M., Furuse, K., Yoshida, Y., Haratake, A., Sugitani, Y., Noda, T., Kubo, A., Tsukita, S. Claudin-based tight junctions are crucial for the mammalian epidermal barrier: a lesson from claudin-1-deficient mice. J. Cell Biol. 156: 1099-1111, 2002. [PubMed: 11889141] [Full Text: https://doi.org/10.1083/jcb.200110122]
Katahira, J., Sugiyama, H., Inoue, N., Horiguchi, Y., Matsuda, M., Sugimoto, N. Clostridium perfringens enterotoxin utilizes two structurally related membrane proteins as functional receptors in vivo. J. Biol. Chem. 272: 26652-26658, 1997. [PubMed: 9334247] [Full Text: https://doi.org/10.1074/jbc.272.42.26652]
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]
Paperna, T., Peoples, R., Wang, Y.-K., Kaplan, P., Francke, U. Genes for the CPE receptor (CPETR1) and the human homolog of RVP1 (CPETR2) are localized within the Williams-Beuren syndrome deletion. Genomics 54: 453-459, 1998. [PubMed: 9878248] [Full Text: https://doi.org/10.1006/geno.1998.5619]