The keratins are the typical intermediate filament proteins of epithelia, showing an outstanding degree of molecular diversity. Heteropolymeric filaments are formed by pairing of type I and type II molecules. In humans 54 functional keratin genes exist. They are expressed in highly specific patterns related to the epithelial type and stage of cellular differentiation. About half of all keratins—including numerous keratins characterized only recently—are restricted to the various compartments of hair follicles. As part of the epithelial cytoskeleton, keratins are important for the mechanical stability and integrity of epithelial cells and tissues. Moreover, some keratins also have regulatory functions and are involved in intracellular signaling pathways, e.g. protection from stress, wound healing, and apoptosis. Applying the new consensus nomenclature, this article summarizes, for all human keratins, their cell type and tissue distribution and their functional significance in relation to transgenic mouse models and human hereditary keratin diseases. Furthermore, since keratins also exhibit characteristic expression patterns in human tumors, several of them (notably K5, K7, K8/K18, K19, and K20) have great importance in immunohistochemical tumor diagnosis of carcinomas, in particular of unclear metastases and in precise classification and subtyping. Future research might open further fields of clinical application for this remarkable protein family.

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The human keratins: biology and pathology

Injury to stratified epithelia causes a strong induction of keratins 6 (K6) and 16 (K16) in post-mitotic keratinocytes located at the wound edge. We show that induction of K6 and K16 occurs within 6 h after injury to human epidermis. Their subsequent accumulation in keratinocytes correlates with the profound reorganization of keratin filaments from a pan-cytoplasmic distribution to one in which filaments are aggregated in a juxtanuclear location, opposite to the direction of cell migration. This filament reorganization coincides with additional cytoarchitectural changes and the onset of re-epithelialization after 18 h post-injury. By following the assembly of K6 and K16 in vitro and in cultured cells, we find that relative to K5 and K14, a well-characterized keratin pair that is constitutively expressed in epidermis, K6 and K16 polymerize into short 10-nm filaments that accumulate near the nucleus, a property arising from K16. Forced expression of human K16 in skin keratinocytes of transgenic mice causes a retraction of keratin filaments from the cell periphery, often in a polarized fashion. These results imply that K16 may not have a primary structural function akin to epidermal keratins. Rather, they suggest that in the context of epidermal wound healing, the function of K16 could be to promote a reorganization of the cytoplasmic array of keratin filaments, an event that precedes the onset of keratinocyte migration into the wound site.

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Onset of re-epithelialization after skin injury correlates with a reorganization of keratin filaments in wound edge keratinocytes: defining a potential role for keratin 16.

We have conducted a historical cohort study to assess cardiovascular mortality among pso- riasis patients. Using the Swedish Inpatient Registry, we selected 8991 patients hospitalized for psoriasis at dermatological wards. To represent an outpatient cohort, 19,757 members of the Swedish Psoriasis Association were selected. Mortality from cardio- vascular diseases was compared with the general population. We found no increased cardiovascular mortality among outpatients with psoriasis (stan- dardized mortality ratio, SMR 0.94; 95% confidence interval, CI: 0.89-0.99). The overall risk among in- patients admitted at least once was increased by 50% (SMR 1.52; 95% CI: 1.44-1.60). The excess risk in- creased with increasing number of hospital admis- sions (p for trend <0.001). Cardiovascular mortality was higher among those admitted at younger ages (p for trend <0.001; SMR 2.62, 95% CI: 1.91-3.49, for patients aged 20 to 39 years at first admission). Young age at first admission appeared to further in- crease the risk among those who were repeatedly admitted. We conclude that a diagnosis of psoriasis per se does not appear to increase the risk for car- diovascular mortality. Severe psoriasis, however, here measured as repeated admissions, and early age at first admission, is associated with increased risk for cardiovascular death.

Increased risk for cardiovascular mortality in psoriasis inpatients but not in outpatients.

Keratins are obligate heterodimer proteins that form the intermediate filament cytoskeleton of all epithelial cells. Keratins are tissue and differentiation specific and are expressed in pairs of types I and II proteins. The spectrum of inherited human keratin diseases has steadily increased since the causative role of mutations in the basal keratinocyte keratins 5 and 14 in epidermolysis bullosa simplex (EBS) was first reported in 1991. At the time of writing, mutations in 15 epithelial keratins and two trichocyte keratins have been associated with human diseases which include EBS, bullous congenital ichthyosiform erythroderma, epidermolytic palmoplantar keratoderma, ichthyosis bullosa of Siemens, diffuse and focal non-epidermolytic palmoplantar keratoderma, pachyonychia congenita and monilethrix. Mutations in extracutaneous keratins have been reported in oral white sponge naevus and Meesmann's corneal dystrophy. New subtleties of phenotype-genotype correlation are emerging within the keratin diseases with widely varying clinical presentations attributable to similar mutations within the same keratin. Mutations in keratin-associated proteins have recently been reported for the first time. This article reviews clinical, ultrastructural and molecular aspects of all the keratin diseases described to date and delineates potential future areas of research in this field.

Human keratin diseases: the increasing spectrum of disease and subtlety of the phenotype-genotype correlation.

Epithelial tissues function to protect the organism from physical, chemical, and microbial damage and are essential for survival. To perform this role, epithelial keratinocytes undergo a well-defin...

Epithelial Structural Proteins of the Skin and Oral Cavity: Function in Health and Disease

Pachyonychia congenita (PC) is a group of autosomal dominant disorders characterized by dystrophic nails and other ectodermal aberrations A gene for Jackson–Lawler PC was recently mapped to the type I keratin cluster on 17q Here, we show that a heterozygous missense mutation in the helix initiation motif of K17 (Asn92Asp) co–segregates with the disease in this kindred We also show that Jadassohn–Lewandowsky PC is caused by a heterozygous missense mutation in the helix initiation peptide of K16 (Leu130Pro) The known expression patterns of these keratins in epidermal structures correlates with the specific abnormalities observed in each form of PC

Keratin 16 and keratin 17 mutations cause pachyonychia congenita.

Keratins K6 and K16 are expressed in suprabasal interfollicular epidermis in wound healing and other pathological conditions associated with hyperproliferation, such as psoriasis and are induced when keratinocytes are cultured in vitro. However, these keratins are also constitutively expressed in normal suprabasal mucosal and palmoplantar keratinocytes. Mutations in keratins have been reported in the basal keratin pair K5 and K14 in epidermolysis bullosa simplex and in suprabasal epidermal keratins K1, K2 and K10 in epidermolytic ichthyoses. Two families with autosomal dominant disorder of focal non epidermolytic palmoplantar keratoderma, have oral mucosal and follicular lesions in addition to the palmoplantar hyperkeratosis. Previous studies have shown linkage in these families to the type I keratin gene cluster at 17q12-q21 and this report shows that the cDNA of affected members of both families have novel heterozygous mutations in the expressed keratin 16 gene. These mutations (R10C and N8S) lie in the helix initiation motif of the 1A domain. These mutations do not appear to cause epidermolysis on light or electron microscopy, which may reflect differences in function, assembly or interaction of the 'hyperproliferative' or 'mucoregenerative' keratins from other major types of keratins. The mutations reported here are the first to describe the molecular pathology of focal non epidermolytic palmoplantar keratoderma.

W.A.D. Griffiths

Papers

Keratin 16 and keratin 17 mutations cause pachyonychia congenita.

Novel mutations in keratin 16 gene underly focal non-epidermolytic palmoplantar keratoderma (NEPPK) in two families

The Significance of Surface Changes in Parakeratotic Horn

Frameshift mutation in the V2 domain of keratin I causes the striate form of palmoplantar keratoderma

Identification of novel mutations in keratin 16 gene in 2 families with focal non-epidermolytic palmplantar keratoderma (NEPPK).