Molecular Genetics of Inherited Disorders of Epidermal Keratins


Keratins are a major constituent of the epidermal cell cytoskeleton. Apart from their contribution to cell ability to resist mechanical stress, they have been shown to regulate additional biological processes of importance such as protein synthesis, cell migration and apoptosis. Much of this knowledge has been gained through the study of rare disorders, known as keratinopathies, which are caused by mutations in genes encoding the various epidermal keratins. Recently, novel therapeutic approaches for keratin disorders have been tested successfully, thus raising new hopes for the treatment of this group of inherited skin diseases.

Key concepts

  • Keratins are major constituent of epithelial cell cytoskeleton and confer to the cell the ability to resist mechanical stress.

  • Keratins play additional nonstructural role such regulation of cell growth, protein synthesis, cell migration and apoptosis.

  • Keratin disorders manifest with clinical and pathological features that reflect the site of expression of the mutant keratins and the specific function of the keratin domain affected by the causative mutation.

  • Keratin disorders are characterized by genetic heterogeneity, namely a single clinical phenotype can result from mutations in different (but sometimes functionally related) genes (e.g. epidermolysis bullosa caused by mutations in at least five genes).

  • Keratin disorders are characterized by phenotypic heterogeneity, namely mutations in the very same gene can give rise to multiple distinct phenotypes (e.g. mutations in KRT1 can cause at least four distinct diseases).

  • Keratin mutations exert a dominant negative effect; hence current approaches are aimed at eliminating the mutant proteins from the skin. Based on this concept, a first clinical trial in humans has recently been launched to test the effect of a siRNA to treat pachyonychia congenita.

Keywords: keratin; epidermolysis bullosa; ichthyosis; nail; skin

Figure 1.

Skin and keratin structures. (a) Schematic structure of the skin, epidermal layers (right side) and major site of expression of epidermal keratins (left side) and (b) schematic structure of epidermal keratin protein with domain distribution. The regions most often affected by keratin mutations are marked in orange.

Figure 2.

EBS clinical features. (a) Severe palmar blistering in a 3‐month‐old affected girl; (b) plantar keratoderma; (c) circinate erythematous plaques covered with blisters in a 3‐year‐old boy affected with epidermolysis bullosa simplex with migratory circinate erythema and (d) flexural hyperpigmentation and depressed scars in the arm pit of patient with DDD.

Figure 3.

Diseases of suprabasal keratins. (a) Hyperkeratosis and erosions of the palms in a BCIE patient; (b) typical histopathological features in bullous congenital ichthyosiform erythroderma with marked vacuolar degeneration of the suprabasal epidermal layers; (c) epidermolytic epidermal nevus featuring hyperkeratotic papules distributed in a linear fashion and (d) diffuse palmoplantar keratoderma in a patient with epidermolytic palmoplantar keratoderma.

Figure 4.

PC clinical features. (a) Thickening and yellowish discolouration of the toenails in PC; (b) focal plantar keratoderma; (c) oral leukokeratosis (whitish covering of the tongue) and (d) multiple skin‐coloured cutaneous tumours (steatocystomata by histology).



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Further Reading

Caputo R and Tadini G (2006) Atlas of Genodermatoses, Atlas of Genodermatoses. London: Taylor and Francis.

Sybert VP (1997) Genetic Skin Disorders. New York: Oxford University Press.

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How to Cite close
Sprecher, Eli(Mar 2009) Molecular Genetics of Inherited Disorders of Epidermal Keratins. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021472]