Abstract Human claudin-1 is an integral protein compo- nent of tight junctions, a structure controlling cell-to-cell adhesion and, consequently, regulating paracellular and transcellular transport of solutes across human epithelia and endothelia. Recently, a claudin-1 (CLDN1) cDNA has been isolated from human mammary epithelial cells (HMECs). CLDN1 expression in HMECs, in contrast to low or undetectable levels of expression in a number of breast tumors and breast cancer cell lines, points to CLDN1 as a possible tumor-suppressor gene. In order to evaluate the CLDN-1 gene in sporadic and hereditary breast cancer, we have characterized its genomic organi- zation and have screened the four coding exons for so- matic mutations in 96 sporadic breast carcinomas and for germline mutations in 93 breast cancer patients with a strong family history of breast cancer. In addition, we have compared the 5’-upstream sequences of the human and murine CLDN1 genes to identify putative promoter sequences and have examined both the promoter and cod- ing regions of the human gene in the breast cancer cell lines showing decreased CLDN1 expression. In the spo- radic tumors and hereditary breast cancer patients, we have 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 pro- moter or coding sequences have been identified that would explain the loss of CLDN1 expression. Other regu- latory or epigenetic factors may be involved in the down- regulation of this gene during breast cancer development. Introduction Tight junctions (TJs) play a major role in cell-to-cell ad- hesion of endothelial and epithelial cells. Composed of multiple peripheral and integral membrane proteins, TJs are crucial in compartmentalization in multicellular or- ganisms as they form continuous seals between adjacent cells to prevent paracellular diffusion of solutes. In addi- tion to this so-called barrier function, TJs contribute to trans- cellular transport by acting as a fence within the mem- brane bilayer. TJs circumscribe the cells at the most apical part of the junctional complex, maintaining cellular polar- ity between the compositionally distinct apical and baso- lateral plasma membrane domains. Hereby, a characteris- tic distribution of membrane molecules such as ion chan- nels, ion pumps and carrier enzymes ensure the active transport of molecules to regulate the physiological state of the endothelia and epithelia (for reviews, see Anderson and Van Itallie 1999; Tsukita and Furuse 2000). Occludin was the first TJ-associated integral mem- brane protein to be identified and was found by raising monoclonal antibodies against an isolated chicken liver junctional fraction (Furuse et al. 1993). Structural (Fuji- moto 1995; Furuse et al. 1996) and functional (McCarthy et al. 1996; Balda et al. 1996; Chen et al. 1997; Wong and Gumbiner 1997) relevance within the TJ complex has been attributed to occludin, but when mouse fibroblasts lacking TJs were transfected with the cDNA of occludin, only small numbers of fragmented TJ strand-like struc- tures were induced (Furuse et al. 1998b). This and the finding that occludin-deficient embryonic stem cells de- velop phenotypically intact TJs (Saitou et al. 1998), have suggested that occludin is an accessory protein with a sub- ordinate TJ function and indicate the existence of addi- tional unidentified components of TJs. Re-evaluation of the liver junctional fraction finally led to the identification of two homologous murine cDNAs, designated claudin-1 and claudin-2 (Furuse et al. 1998a). The murine claudins show no sequence similarity to oc- cludin but have four putative transmembrane domains, a Franziska Krämer · Karen White · Manfred Kubbies · Karen Swisshelm · Bernhard H. F. Weber Genomic organization of claudin-1 and its assessment in hereditary and sporadic breast cancer Hum Genet (2000) 107 : 249–256 Digital Object Identifier (DOI) 10.1007/s004390000375 Received: 19 June 2000 / Accepted: 24 July 2000 / Published online: 6 September 2000 ORIGINAL INVESTIGATION F. Krämer · K. White · B. H. F. Weber (✉) Institut für Humangenetik, Universität Würzburg, Am-Hubland, 97074 Würzburg, Germany e-mail: bweb@biozentrum.uni-wuerzburg.de, Tel.: +49 931 888 4062, Fax: +49 931 888 4069 M. Kubbies Department of Cell Analytics, Roche Pharmaceutical Research, Penzberg, Germany K. Swisshelm Department of Pathology, University of Washington, Seattle, USA © Springer-Verlag 2000