Research
- Our Main Objectives
- Introduction to Keratin Genes and Proteins
- Assembly and Organization of Keratin Filaments
- Keratins fulfill Multiple Roles in Skin and other Epithelia
- Keratin Gene Expression in Epidermis: Basic Principles and Disease Associations
- Introduction to Skin Epithelia
- Figure 1 - Introduction to Keratins
- Table 1 - Keratin-based, Inherited Skin Bullous Disease Affecting Primarily the Epidermis
Keratin Gene Expression in Epidermis: Basic Principles and Disease Associations
An astounding two-thirds of known keratin genes are expressed in skin epithelia alone. In normal interfollicular epidermis, progenitor basal keratinocytes express the K5-K14 pair, and small amounts of K15. Upon commitment to differentiation, keratinocytes rapidly turn on the expression of K1-K10 as they switch off K5-K14 transcription. At a later stage, i.e., in the granular layer, K2 gene expression occurs. Departure from this blueprint reflects either a regional specialization or a departure from normal differentiation. For instance, K9 is prominently expressed post-mitotically in the thick primary epidermal ridges of palmar-plantar epidermis, whereas K6, K16 and K17 occur primarily in the thinner, secondary ridges connecting them. Otherwise, K6, K16 and K17 are induced, generally at the expense of K1-K10, in the post-mitotic layers of interfollicular epidermis under conditions of environmental challenges (e.g., tissue injury, UV exposure, viral infection) and in specific diseases (e.g., psoriasis, carcinoma). The latter phenomenon has also been a focal point of our research for many years.
Mutations altering the coding sequence of keratins expressed in human epidermis account for a growing number of skin diseases (See Table 1) (also, see the IF mutation database at www.interfil.org). With few exceptions, the associated pathology results from the fragile state of keratinocytes expressing the mutated keratin protein. These diseases are individually rare (typically, less than 1:20,000 live births), but they can be devastating to patients, in that they affect affect their quality of life, and are occasionally lethal. For many of these diseases, there is a good correlation between the keratin gene affected, the nature of the mutation and the extent to which it alters the assembly properties of keratins, and the severity of clinical presentation. In all cases, however, treatment options are only palliative in nature and of limited benefit to the patient.
