Alternative titles; symbols
HGNC Approved Gene Symbol: CLDN1
SNOMEDCT: 724278007;
Cytogenetic location: 3q28 Genomic coordinates (GRCh38): 3:190,305,707-190,322,446 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q28 | Ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis | 607626 | Autosomal recessive | 3 |
Tight junctions (TJs) represent one mode of cell-to-cell adhesion in epithelial or endothelial cell sheets. TJs constitute continuous seals around cells that serve as a physical barrier preventing solutes and water from passing freely though the paracellular space. In freeze-fracture electron micrographs, TJs appear as a set of continuous networking intramembranous particle strands (TJ strands) or fibrils in the outwardly facing cytoplasmic leaflet, with complementary grooves in the inwardly facing extracytoplasmic leaflet. Occludin (OCLN; 602876) is an integral membrane protein localizing at TJs. Furuse et al. (1998) determined partial protein sequences of two 22-kD proteins that copurified with occludin in a TJ fraction isolated from chicken liver. By searching an EST database with the peptide sequences, they identified a partial human cDNA encoding claudin-1 and a partial mouse cDNA encoding claudin-2. The proteins were designated claudins from the Latin word 'claudere' (to close), reflecting their association with TJs. Furuse et al. (1998) screened a mouse liver library with the partial cDNAs and isolated cDNAs corresponding to the entire coding region of each gene. The predicted proteins are 38% identical and both contain 4 transmembrane domains. Immunofluorescence and immunoelectron microscopy revealed that both epitope-tagged claudin-1 and claudin-2 were targeted to and incorporated into the TJ strand itself.
By using differential display to identify genes expressed in senescent human mammary epithelial cells, Swisshelm et al. (1999) isolated cDNAs encoding the human claudin-1 homolog, which they referred to as 'senescence-associated epithelial membrane protein-1' (SEMP1). The predicted 211-amino acid human and mouse proteins are 91% identical. However, the authors reported that sequence analysis revealed only 3 transmembrane domains in SEMP1. Northern blot analysis indicated that the SEMP1 gene was widely expressed as a 4-kb mRNA in human tissues. Additional smaller transcripts were detected in some tissues.
Kubota et al. (1999) demonstrated that mouse Cldn1, Cldn2 (300520), and Cldn3 possessed Ca(2+)-independent cell adhesion activity following expression in a mouse fibroblast cell line. Electron microscopy revealed many points of contact between tight junctions of adjacent transfected cells.
By microarray analysis, Miwa et al. (2001) found that CLDN1 was activated upon beta-catenin (CTNNB1; 116806) overexpression in a human colon cancer cell line. Downregulation of CTNNB1 also reduced CLDN1 expression. Miwa et al. (2001) identified 2 putative TCF4 (TCF7L2; 602228)-binding elements in the 5-prime flanking region of CLDN1, and using reporter gene assays and electrophoretic mobility shift assays, they determined that the association of CTNNB1 with TCF4 drove CLDN1 expression. In addition, CLDN1 expression was elevated in all 16 colon cancers examined. Immunohistochemical analysis of normal colonic mucosae detected weak CLDN1 staining at the apical border of lateral cell membranes. In cancer cells, enhanced CLDN1 signals were detected at cell-cell boundaries and in the cytoplasm, where CLDN1 showed a nonpolarized distribution. Normal colocalization of CLDN1 with ZO1 was lost in the colon cancer cells.
By immunofluorescence microscopy of normal mouse skin, Furuse et al. (2002) found that Cldn1 and Cldn4 (602909) concentrated within continuous TJs in the stratum granulosum.
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 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 TJ. 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.
Dhawan et al. (2005) reported increased expression of CLDN1 in human primary colon carcinoma, particularly in metastatic lesions, where it was frequently mislocalized from the cell membrane to the cytoplasm and nucleus. Genetic manipulation of CLDN1 expression in colon cancer cell lines induced changes in cellular phenotype, with structural and functional changes in markers of epithelial-mesenchymal transition. Differences in CLDN1 expression had significant effects on the growth of xenografted tumors and metastasis in athymic mice. Dhawan et al. (2005) concluded that CLDN1 regulates cellular transformation and metastatic behavior in colon cancer.
Using immunohistochemical analysis, Dube et al. (2007) found that CLDN1, CLDN3, CLDN4, and CLDN8 (611231) 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.
Entry of hepatitis C virus (HCV; see 609532) into cells involves glycosaminoglycans and 2 host proteins, SRBI (SCARB1; 601040) and CD81 (186845), that bind the viral E2 glycoprotein. However, some cell lines expressing all 3 of these factors are nonpermissive for viral entry. Using an iterative expression cloning approach, Evans et al. (2007) identified CLDN1 as essential for HCV entry. Expression of CLDN1 in some, but not all, nonpermissive cell lines allowed HCV entry, suggesting the existence of 1 or more additional HCV entry factors. Other CLDN family members failed to render nonpermissive cell lines permissive to HCV infection. Treatment with CLDN1 small interfering RNA inhibited HCV infection. Exchange of extracellular loops (EL) between CLDN1 and other CLDNs, as well as mutation analysis, showed that the N-terminal third of EL1 of CLDN1 was required for HCV entry. Treatment of cells with antibodies to CD81 or CLDN1 at different times showed that CD81 acted before CLDN1 in HCV entry. Evans et al. (2007) concluded that CLDN1 is a key factor for HCV entry and a novel target for antiviral drug development.
HCV achieves cell entry through attachment to CD81, SCARB1, and the TJ proteins CLDN1 and OCLN. Using fluorescence resonance energy transfer and stoichiometric imaging technologies, Harris et al. (2010) showed that the receptor-active CLDN1 associated with CD81 at the plasma membrane and that the association depended on ile32 and glu48 in EL1 of CLDN1. Receptor-inactive CLDN7 acquired the ability to associate with CD81 following mutation of met32 to ile and lys48 to glu. Association of CLDN1 with CD81 occurred predominantly at the basolateral membrane rather than at TJs. Harris et al. (2010) concluded that CLDN-CD81 complexes are essential in HCV infection and that their basolateral location in polarized hepatoma cells is consistent with viral entry into the liver via the sinusoidal blood.
Kramer et al. (2000) characterized the genomic organization of the CLDN1 gene and screened the 4 coding exons for somatic mutations in 96 sporadic breast cancers and for germline mutations in 93 breast cancer patients with a strong family history of breast cancer. In addition, they compared the 5-prime upstream sequences of the human and murine CLDN1 genes to identify putative promoter sequences and examined both the promoter and coding regions of the human gene in the breast cancer cell lines showing decreased CLDN1 expression. In the sporadic tumors and hereditary breast cancer patients, they found no evidence to support the involvement of aberrant CLDN1 in breast tumorigenesis. Likewise, in the breast cancer cell lines, no genetic alterations in the promoter or coding sequences were identified that would explain the loss of CLDN1 expression.
Using a human/hamster monochromosomal somatic cell hybrid panel, Halford et al. (2000) mapped the CLDN1 gene to chromosome 3. They refined the location to 3q28-q29 by analysis of a radiation hybrid panel.
In 4 affected individuals from 2 small inbred Moroccan kindreds, Baala et al. (2002) mapped a syndrome of ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis (ILVASC; 607626) to 3q27-q28. Hadj-Rabia et al. (2004) considered the CLDN1 gene as a strong candidate based on its mapping to the minimum linkage interval and on the expression pattern of the mouse ortholog. They noted that most human and animal cholestatic disorders are associated with changes in hepatocyte cytoskeleton and tight junctions. In the 4 patients previously described by Baala et al. (2002), Hadj-Rabia et al. (2004) studied the 4 exons and intron-exon junctions of the CLDN1 gene and identified a 2-bp deletion in exon 1 (200delTT; 603718.0001), resulting in a premature stop codon and a total absence of claudin-1 protein in the liver and skin. Hadj-Rabia et al. (2004) concluded that a lack of claudin-1 in NISCH syndrome may lead to increased paracellular permeability between epithelial cells. In conjunction with hypercholanemia (607748), which can be caused by mutation in the tight junction protein-2 gene (TJP2; 607709), the findings emphasized the role played by tight junction components in hereditary cholestasis.
Furuse et al. (2002) found that Cldn1-null mice were born in the expected mendelian ratios. At birth, homozygotes were macroscopically indistinguishable from wildtype and heterozygous littermates. However, their skin became wrinkled, and all homozygotes died within 1 day of birth. Dehydration assay and transepidermal water loss measurements revealed that the epidermal barrier was severely affected, although the layered organization of keratinocytes appeared normal. In Cldn1-null epidermis, subcutaneously injected tracer passed through the TJs toward the skin surface. Furuse et al. (2002) concluded that continuous claudin-based TJs are crucial for the barrier function of mammalian skin.
In 4 affected patients from 2 inbred Moroccan kindreds with ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis (ILVASC; 607626), previously described by Baala et al. (2002), Hadj-Rabia et al. (2004) identified a homozygous 2-bp deletion (200delTT) in exon 1 of the CLDN1 gene, resulting in a premature stop codon and total absence of claudin-1 protein in the liver and skin.
In a Swiss girl with ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis (ILVASC; 607626), Feldmeyer et al. (2006) identified a homozygous 1-bp deletion (358delG) in exon 2 of the CLDN1 gene, resulting in a premature stop codon and a truncated protein. RT-PCR and Western blot analysis confirmed absence of CLDN1 mRNA and protein in the patient. The parents, who were heterozygous for the mutation, originated from 2 small nearby villages.
Baala, L., Hadj-Rabia, S., Hamel-Teillac, D., Hadchouel, M., Prost, C., Leal, S. M., Jacquemin, E., Sefiani, A., de Prost, Y., Courtois, G., Munnich, A., Lyonnet, S., Vabres, P. Homozygosity mapping of a locus for a novel syndromic ichthyosis to chromosome 3q27-q28. J. Invest. Derm. 119: 70-76, 2002. [PubMed: 12164927] [Full Text: https://doi.org/10.1046/j.1523-1747.2002.01809.x]
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]
Dhawan, P., Singh, A. B., Deane, N. G., No, Y., Shiou, S.-R., Schmidt, C., Neff, J., Washington, M. K., Beauchamp, R. D. Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer. J. Clin. Invest. 115: 1765-1776, 2005. [PubMed: 15965503] [Full Text: https://doi.org/10.1172/JCI24543]
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]
Evans, M. J., von Hahn, T., Tscherne, D. M., Syder, A. J., Panis, M., Wolk, B., Hatziioannou, T., McKeating, J. A., Bieniasz, P. D., Rice, C. M. Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature 446: 801-805, 2007. Note: Erratum: Nature 446: 1 page following 805, 2007. [PubMed: 17325668] [Full Text: https://doi.org/10.1038/nature05654]
Feldmeyer, L., Huber, M., Fellmann, F., Beckmann, J. S., Frenk, E., Hohl, D. Confirmation of the origin of NISCH syndrome. Hum. Mutat. 27: 408-410, 2006. [PubMed: 16619213] [Full Text: https://doi.org/10.1002/humu.20333]
Furuse, M., Fujita, K., Hiiragi, T., Fujimoto, K., Tsukita, S. Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J. Cell Biol. 141: 1539-1550, 1998. [PubMed: 9647647] [Full Text: https://doi.org/10.1083/jcb.141.7.1539]
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]
Hadj-Rabia, S., Baala, L., Vabres, P., Hamel-Teillac, D., Jacquemin, E., Fabre, M., Lyonnet, S., De Prost, Y., Munnich, A., Hadchouel, M., Smahi, A. Claudin-1 gene mutations in neonatal sclerosing cholangitis associated with ichthyosis: a tight junction disease. Gastroenterology 127: 1386-1390, 2004. Note: Erratum: Gastroenterology 128: 524 only, 2005. [PubMed: 15521008] [Full Text: https://doi.org/10.1053/j.gastro.2004.07.022]
Halford, S., Spencer, P., Greenwood, J., Winton, H., Hunt, D. M., Adamson, P. Assignment of claudin-1 (CLDN1) to human chromosome 3q28-q29 with somatic cell hybrids. Cytogenet. Cell Genet. 88: 217, 2000. [PubMed: 10828592] [Full Text: https://doi.org/10.1159/000015553]
Harris, H. J., Davis, C., Mullins, J. G. L., Hu, K., Goodall, M., Farquhar, M. J., Mee, C. J., McCaffrey, K., Young, S., Drummer, H., Balfe, P., McKeating, J. A. Claudin association with CD81 defines hepatitis C virus entry. J. Biol. Chem. 285: 21092-21102, 2010. [PubMed: 20375010] [Full Text: https://doi.org/10.1074/jbc.M110.104836]
Kramer, F., White, K., Kubbies, M., Swisshelm, K., Weber, B. H. F. Genomic organization of claudin-1 and its assessment in hereditary and sporadic breast cancer. Hum. Genet. 107: 249-256, 2000. [PubMed: 11071387] [Full Text: https://doi.org/10.1007/s004390000375]
Kubota, K., Furuse, M., Sasaki, H., Sonoda, N., Fujita, K., Nagafuchi, A., Tsukita, S. Ca(2+)-independent cell-adhesion activity of claudins, a family of integral membrane proteins localized at tight junctions. Curr. Biol. 9: 1035-1038, 1999. [PubMed: 10508613] [Full Text: https://doi.org/10.1016/s0960-9822(99)80452-7]
Miwa, N., Furuse, M., Tsukita, S., Niikawa, N., Nakamura, Y., Furukawa, Y. Involvement of claudin-1 in the beta-catenin/Tcf signaling pathway and its frequent upregulation in human colorectal cancers. Oncol. Res. 12: 469-476, 2001. [PubMed: 11939410] [Full Text: https://doi.org/10.3727/096504001108747477]
Swisshelm, K., Machl, A., Planitzer, S., Robertson, R., Kubbies, M., Hosier, S. SEMP1, a senescence-associated cDNA isolated from human mammary epithelial cells, is a member of an epithelial membrane protein superfamily. Gene 226: 285-295, 1999. [PubMed: 9931503] [Full Text: https://doi.org/10.1016/s0378-1119(98)00553-8]