Diseases of epidermal keratins and their linker proteins

Abstract

Epidermal keratins, a diverse group of structural proteins, form intermediate filament networks responsible for the structural integrity of keratinocytes. The networks extend from the nucleus of the epidermal cells to the plasma membrane where the keratins attach to linker proteins which are part of desmosomal and hemidesmosomal attachment complexes. The expression of specific keratin genes is regulated by differentiation of the epidermal cells within the stratifying squamous epithelium. Progress in molecular characterization of the epidermal keratins and their linker proteins has formed the basis to identify mutations which are associated with distinct cutaneous manifestations in patients with genodermatoses. The precise phenotype of each disease apparently reflects the spatial level of expression of the mutated genes, as well as the types and positions of the mutations and their consequences at mRNA and protein levels. Identification of specific mutations in keratinization disorders has provided the basis for improved diagnosis and subclassification with prognostic implications and has formed the platform for prenatal testing and preimplantation genetic diagnosis. Finally, precise knowledge of the mutations is a prerequisite for development of gene therapy approaches to counteract, and potentially cure, these often devastating and currently intractable diseases. KeywordsEpidermal keratins; intermediate filaments; epidermal differentiation; hemidesmosomes; desmosomes; genodermatoses; skin fragility; epidermolysis bullosa; epidermolytic hyperkeratosis; ichthyosis Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. BIOLOGY OF EPIDERMAL KERATINSKeratins NIH Public Access Author ManuscriptExp Cell Res. Author manuscript; available in PMC 2008 November 4. Published in final edited form as:Exp Cell Res. 2007 June 10; 313(10): 1995-2009. doi:10.1016/j.yexcr.2007.03.029. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript dimensional and highly dynamic cytoskeleton spanning between the nucleus and the cell membrane, where they are anchored by interactions with desmosomal and hemidesmosomal linker proteins (Fig. 1). This organization provides both structural stability and flexibility, and ensures the mechanical integrity of different epithelial tissues. Keratins are expressed as obligate heterodimers of acidic (type I) and basic (type II) proteins, which assemble, through a multi-step process, into intermediate filaments (Fig. 2). The genes encoding type I and type II keratins cluster on chromosomal regions 17q12-q21 and 12q11-q13, respectively. Keratin ...

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