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Defining keratin protein function in skin epithelia: Epidermolysis Bullosa Simplex and its aftermath

2 , 3 , 1

The Journal of Investigative Dermatology

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      Abstract

      Epidermolysis bullosa simplex (EBS) is a rare genetic condition typified by superficial bullous lesions following incident frictional trauma to the skin. Most cases of EBS are due to dominantly-acting mutations in keratin 14 (K14) or K5, the type I and II intermediate filament (IF) proteins that co-polymerize to form a pan-cytoplasmic network of 10nm filaments in basal keratinocytes of epidermis and related epithelia. Defects in K5–K14 filament network architecture cause basal keratinocytes to become fragile, and account for their rupture upon exposure to mechanical trauma. The discovery of the etiology and pathophysiology of EBS was intimately linked to the quest for an understanding of the properties and function of keratin filaments in skin epithelia. Since then, continued cross-fertilization between basic science efforts and clinical endeavors has highlighted several additional functional roles for keratin proteins in the skin, suggested new avenues for effective therapies for keratin-based diseases, and expanded our understanding of the remarkable properties of skin as an organ system.

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      Most cited references 142

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      The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells.

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        New consensus nomenclature for mammalian keratins

        Keratins are intermediate filament–forming proteins that provide mechanical support and fulfill a variety of additional functions in epithelial cells. In 1982, a nomenclature was devised to name the keratin proteins that were known at that point. The systematic sequencing of the human genome in recent years uncovered the existence of several novel keratin genes and their encoded proteins. Their naming could not be adequately handled in the context of the original system. We propose a new consensus nomenclature for keratin genes and proteins that relies upon and extends the 1982 system and adheres to the guidelines issued by the Human and Mouse Genome Nomenclature Committees. This revised nomenclature accommodates functional genes and pseudogenes, and although designed specifically for the full complement of human keratins, it offers the flexibility needed to incorporate additional keratins from other mammalian species.
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          A structural scaffolding of intermediate filaments in health and disease.

          The cytoplasm of animal cells is structured by a scaffolding composed of actin microfilaments, microtubules, and intermediate filaments. Intermediate filaments, so named because their 10-nanometer diameter is intermediate between that of microfilaments (6 nanometers) and microtubules (23 nanometers), assemble into an anastomosed network within the cytoplasm. In combination with a recently identified class of cross-linking proteins that mediate interactions between intermediate filaments and the other cytoskeletal networks, evidence is reviewed here that intermediate filaments provide a flexible intracellular scaffolding whose function is to structure cytoplasm and to resist stresses externally applied to the cell. Mutations that weaken this structural framework increase the risk of cell rupture and cause a variety of human disorders.
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            Author and article information

            Affiliations
            [1 ]Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205 USA
            [2 ]Department of Biological Chemistry, Johns Hopkins University, Baltimore, MD 21205 USA
            [3 ]Department of Dermatology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205 USA
            Author notes
            [* ]To whom correspondence should be addressed: Pierre A. Coulombe, Ph.D, Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe Street, W8041, Baltimore, MD 21205, Tel: 410-955-3671, pcoulomb@ 123456jhsph.edu
            Journal
            0426720
            4839
            J Invest Dermatol
            The Journal of Investigative Dermatology
            0022-202X
            1523-1747
            5 December 2011
            26 January 2012
            March 2012
            1 September 2012
            : 132
            : 3
            : 763-775
            3279600
            22277943
            10.1038/jid.2011.450
            nihpa342087
            Categories
            Article

            Dermatology

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