Claudins are members of the much larger pfam00822 or PMP-22/EMP/MP20/Claudin family. These claudin relatives share the tetraspanning topology and W-GLW-C-C signature motif in the first extracellular loop. Beyond these structural similarities, their functions appear highly divergent and only some are believed to create intercellular barriers. The most homologous to claudins are MP20 (eye lens specific membrane protein) (Steele et al. 1998); epithelial membrane proteins (EMP-1, -2, -3) (Jetten and Suter 2000), and peripheral myelin protein 22 (PMP22) (Notterpek et al. 2001). PMP-22 is highly expressed in Schwann cells and required for myelin formation (Bronstein 2000). Several forms of human peripheral polyneuropathies arise from PMP22 mutations, deletions, or gene duplications (Brancolini et al. 2000) (Table 2)
Surprisingly,although PMP22 is only 19% identical to human claudin-1, it has been found in tight junctions in liver, intestine (Notterpek et al. 2001), and the blood-brain barrier (Roux et al. 2004), and when expressed in MDCK cells, it increases TER (Roux et al. 2005). More distant members of the pfam00822 family include the subfamily of g subunits of voltage-dependent calcium channels. These are required for proper membrane delivery of channel complexes (Tomita et al. 2004). One of these, stargazin, which is an AMPA receptor regulator, was recently shown to mediate cell– cell adhesion when expressed in fibroblasts, suggesting some distantly related members of this family may have retained claudin’s cell–cell adhesive property