Genetic pathways in disorders of epidermal differentiation

Abstract

More than 100 human genetic skin diseases, impacting over 20% of the population, are characterized by disrupted epidermal differentiation. A significant proportion of the 90 genes identified in these disorders to date are concentrated within several functional pathways, suggesting the emergence of organizing themes in epidermal differentiation. Among these are the Notch, transforming growth factor β (TGFβ), IκB kinase (IKK), Ras/mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), p63, and Wnt signaling pathways, as well as core biological processes mediating calcium homeostasis, tissue integrity, cornification, and lipid biogenesis. Here, we review recent results supporting the central role of these pathways in epidermal differentiation, highlighting the integration of genetic information with functional studies to illuminate the biological actions of these pathways in humans as well as to guide development of future therapeutics to correct their dysfunction.

Figure 1. Epidermal differentiation and overview of disorders affecting differentiation

(a) Keratinocytes undergo a process of terminal differentiation involving stratification, which consists of the upward migration of keratinocytes from the basal layer containing progenitor cells into the spinous and granular layers; here, lamellar bodies provide the materials for formation of the impermeable epidermal barrier. (b) Mutations in keratin intermediate filaments 5 and 14 result in detachment from the basement membrane with disruption of the keratin intermediate filament network resulting in altered cytoskeletal architecture. (c) Mutations in components necessary for cell adhesion, such as corneodesmosome mutations exemplified here, result in increased intercellular spaces due to lack of cell-cell contact; mutations affecting this process of cornification result in defective barrier formation and dry, scaly skin. (d) Altered cell signaling can result in defective differentiation with increased proliferative capacity of basal progenitor cells, loss of cell adhesion, and the potential to become invasive squamous cell carcinoma.

Figure 2. Diseases of the epidermis

(a) Junctional epidermolysis bullosa features blistering and erosions at birth. (b) Lamellar ichthyosis is characterized by brown, tile-like scales over the entire body. (c) Ichthyosis vulgaris manifests as dry, scaly skin with diffuse general involvment. (d) Epidermolytic hyperkeratosis is characterized by recurrent blisters and hyperkerotic scales. (e) Nevus sebaceous presents as an orange plaqu with pebbly surface. (f) Squamous cell carcinoma appears sharply demarcated and can present with erosions, scaling, and hyperkeratosis.

Figure 3. Mutations in the Ras/MAPK and PI3-K/Akt pathway in cutaneous disorders

“RASopathies” are multi-system disorders characterized by epidermal phenotypes and typically resulting in tumor syndromes. Enumerated circles represent mutations observed in the following disorders: (1) Noonan syndrome exhibits mutations in PTPN11 (SHP-2) and KRAS. (2) Cardio-facio-cutaneous (CFC) syndrome exhibits mutations in KRAS, BRAF, and MEK. (3) Costello syndrome exhibits mutations in HRAS. (4) LEOPARD syndrome exhibits mutations in PTPN11. (5) Neurofibromatosis contains mutations in RasGAP, NF1. (6) Legius syndrome exhibits mutations in SPRED1. (7) Banayan-Zonona and Cowden's syndromes contain mutations in PTEN. Phenotypes associated with these mutations are listed in Table 1.