73 www. ums. ac. uk of the many highly specialised epithelial tissues has its own profile of keratin gene expression, as exemplified in Figure 2. When genetic mutations occur in one of the genes encoding a keratin protein, or in one of many types of keratin-associated protein, the result is very often a keratinizing disorder–an inherited disease where a specific epithelial tissue or a specific subset of epithelial tissues is abnormally fragile4. The affected tissue tends to blister or flake apart and often, in response to this inherent fragility, the tissue “fights back” by overgrowing–a phenomenon known as hyperkeratosis. The majority of keratinizing disorders affect the epidermis and/or its adnexal structures such as hair and nail, or sweat and sebaceous glands, although a number of these diseases affect other epithelia such as mucosal or corneal epithelia. In addition, the keratin cytoskeleton is attached to cell membranes and in some cases, the extracellular matrix, via transmembrane structures which act as rivets bolting cytoskeletons of neighbouring cells together and anchoring them to the underlying stroma5. Thus, the epithelial cytoskeleton is not an isolated structure confined to each individual cell but actually extends through the entire tissue, which is well anchored to adjacent tissues. In an analogy, this is like building a wall from bricks which are properly cemented together rather than just piling the bricks on top of one another–the former structure is obviously much stronger. When genetic mutations occur that affect one of the many proteins that make up these “rivets” between the cells, again the result is structural failure and another set of related keratinizing disorders. In some situations where even further strength is required, the keratin cytoskeleton is chemically cross-linked or modified in other ways, analogous to changing the composition of concrete or adding reinforcing rods6, 7. Again, mutations in the genes encoding these modifying enzymes or additional keratin-associated proteins lead to a further group of keratinizing disorders. The hardest epithelial tissues of all are hair and nail. These tissues express modified keratins containing inordinate amounts of the amino acid cysteine which forms numerous chemical cross-links to further strengthen the cytoskeleton8. Defects in these genes lead to hair and nail disorders.

Overall, human epithelial cells are the building blocks of many important tissues in the body and are constructed from these cells. Within these cells is a dense meshwork of strengthening fibres made from keratin and keratin-associated proteins which can be altered according to the structural requirements of a given epithelium. Failure of any part of this system due to spontaneous or inherited mutations leads a disorder of keratinisation.