Keratin and skin disorders

Cancer Research UK Cell Structure Research Group, Division of Cell and Developmental Biology, University of Dundee School of Life Sciences, MSI/WTB Complex, Dow Street, Dundee DD1 5EH, UK.
The Journal of Pathology (Impact Factor: 7.43). 11/2004; 204(4):355-66. DOI: 10.1002/path.1643
Source: PubMed


The association of keratin mutations with genetic skin fragility disorders is now one of the best-established examples of cytoskeleton disorders. It has served as a paradigm for many other diseases and has been highly informative for the study of intermediate filaments and their associated components, in helping to understand the functions of this large family of structural proteins. The keratin diseases have shown unequivocally that, at least in the case of the epidermal keratins, a major function of intermediate filaments is to provide physical resilience for epithelial cells. This review article reflects on the variety of phenotypes arising from mutations in keratins and the reasons for this variation.

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Available from: Ellen Birgitte Lane,
    • "In fact, various reports of diseases resembling epidermolysis bullosa (EBS) have appeared in which no mutations in K5 or K14 have been detected (Rugg et al. 1994; Lane and McLean 2004; see also a recent review by Fine et al. 2014). Should some of these cases be indeed attributable to K78 mutations, then the determination of whether K78 is also expressed in the lower suprabasal layers will be of interest as it might lead to subtle alterations in the clinical picture when compared with that of K5-or K14-basal layer-related EBS cases. "
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    ABSTRACT: Among the 26 human type II keratins, K78 is the only one that has not yet been explored with regard to its expression characteristics. Here, we show that, at both the transcriptional and translational levels, K78 is strongly expressed in the basal and parabasal cell layers with decreasing intensity in the lower suprabasal cells of keratinising and non-keratinising squamous epithelia and keratinocyte cultures. The same pattern has been detected at the transcriptional level in the corresponding mouse epithelia. Murine K78 protein, which contains an extraordinary large extension of its tail domain, which is unique among all known keratins, is not detectable by the antibody used. Concomitant studies in human epithelia have confirmed K78 co-expression with the classical basal keratins K5 and K14. Similarly, K78 co-expression with the differentiation-related type I keratins K10 (epidermis) and K13 (non-keratinising epithelia) occurs in the parabasal cell layer, whereas that of the corresponding type II keratins K1 (epidermis) and K4 (non-keratinising epithelia) unequivocally starts subsequent to the respective type I keratins. Our data concerning K78 expression modify the classical concept of keratin pair K5/K14 representing the basal compartment and keratin pairs K1/K10 or K4/K13 defining the differentiating compartment of stratified epithelia. Moreover, the K78 expression pattern and the decoupled K1/K10 and K4/K13 expression define the existence of a hitherto unperceived early differentiation stage in the parabasal layer characterized by K78/K10 or K78/K13 expression.
    Cell and Tissue Research 09/2015; DOI:10.1007/s00441-015-2278-5 · 3.57 Impact Factor
    • "Palmoplantar keratoderma (PPK) is a group of heterogenous genodermatoses characterised by hyperkeratotic skin in the palms and soles, clinically grouped into three patterns: diffuse, focalised and punctate. Keratin 9, expressed in suprabasal cells of the epidermis of palm and sole, where it contributes to reinforcing the skin in these regions to greater stress, is the source of several mutations causing epidermolytic palmoplantar keratoderma (EPPK) (Lane and McLean 2004). EPPK is inherited in an autosomal dominant fashion and manifests shortly after birth with diffuse hyperkeratosis of the palms and soles (Fig. 1d), with sharp demarcation and an erythematous margin (Chamcheu et al. 2011). "
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    ABSTRACT: Mutations in keratin genes cause a diverse spectrum of skin, hair and mucosal disorders. Cutaneous disorders include epidermolysis bullosa simplex, palmoplantar keratoderma, epidermolytic ichthyosis and pachyonychia congenita. Both clinical and laboratory observations confirm a major role for keratins in maintaining epidermal cell-cell adhesion. When normal tissue homeostasis is disturbed, for example, during wound healing and cancer, keratins play an important non-mechanical role. Post-translational modifications including glycosylation and phosphorylation of keratins play an important role in protection of epithelial cells from injury. Keratins also play a role in modulation of the immune response. A current focus in the area of keratins and disease is the development of new treatments including small inhibitory RNA (siRNA) to mutant keratins and small molecules to modulate keratin expression.
    Cell and Tissue Research 01/2015; 360(3). DOI:10.1007/s00441-014-2105-4 · 3.57 Impact Factor
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    • "In this model, the link between the dermatological and immunological components would be mediated via barrier disturbance allowing frequent cutaneous infections, which in turn would cause secondary eosinophilia, Tfh polarisation and differentiation of IgE-secreting plasma cells. In support of this model is the known association of mutations in the keratin genes with other palmoplantar keratodermas [15], indicating that primary changes in keratinocytes can indeed drive the major dermatological features. In addition, elevated IgE and other immunological features are observed, albeit rarely, in primary dermatological diseases such as Netherton syndrome and Ichthyosis vulgaris [16]. "
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    ABSTRACT: Background Olmsted syndrome is a rare congenital skin disorder presenting with periorifical hyperkeratotic lesions and mutilating palmoplantar keratoderma, which is often associated with infections of the keratotic area. A recent study identified de novo mutations causing constitutive activation of TRPV3 as a cause of the keratotic manifestations of Olmsted syndrome. Methods Genetic, clinical and immunological profiling was performed on a case study patient with the clinical diagnosis of Olmsted syndrome. Results The patient was found to harbour a previously undescribed 1718G-C transversion in TRPV3, causing a G573A point mutation. In depth clinical and immunological analysis found multiple indicators of immune dysregulation, including frequent dermal infections, inflammatory infiltrate in the affected skin, hyper IgE production and elevated follicular T cells and eosinophils in the peripheral blood. Conclusions These results provide the first comprehensive assessment of the immunological features of Olmsted syndrome. The systemic phenotype of hyper IgE and persistent eosinophilia suggest a primary or secondary role of immunological processes in the pathogenesis of Olmsted syndrome, and have important clinical consequences with regard to the treatment of Olmsted syndrome patients.
    Orphanet Journal of Rare Diseases 05/2013; 8(1):79. DOI:10.1186/1750-1172-8-79 · 3.36 Impact Factor
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