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Distinct Impact of Two Keratin Mutations Causing Epidermolysis Bullosa Simplex on Keratinocyte Adhesion and Stiffness.

Abstract
Keratin filaments constitute the major component of the epidermal cytoskeleton from heterodimers of type I and type II keratin subunits. Missense mutations in keratin 5 or keratin 14, highly expressed in the basal epidermis, cause the severe skin blistering disease epidermolysis bullosa simplex (EBS) in humans by rendering the keratin cytoskeleton sensitive to mechanical stress; yet, the mechanisms by which individual mutations cause cell fragility are incompletely understood. Here, we compared the K14p.Arg125Pro with the K5p.Glu477Asp mutation, both giving rise to severe generalized EBS, by stable expression in keratin-free keratinocytes. This revealed distinctly different effects on keratin cytoskeletal organization, in agreement with in vivo observations, thus validating the cell system. Although the K14p.Arg125Pro mutation led to impaired desmosomes, downregulation of desmosomal proteins, and weakened epithelial sheet integrity upon shear stress, the K5p.Glu477Asp mutation did not impair these functions, although causing EBS with squamous cell carcinoma in vivo. Atomic force microscopy demonstrated that K14 mutant cells were even less resistant against deformation compared with keratin-free keratinocytes. Thus, a keratin mutation causing EBS compromises cell stiffness to a greater extent than the lack of keratins. Finally, re-expression of K14 in K14 mutant cells did not rescue the above defects. Collectively, our findings have implications for EBS therapy approaches.
AuthorsMelanie Homberg, Lena Ramms, Nicole Schwarz, Georg Dreissen, Rudolf E Leube, Rudolf Merkel, Bernd Hoffmann, Thomas M Magin
JournalThe Journal of investigative dermatology (J Invest Dermatol) Vol. 135 Issue 10 Pg. 2437-2445 (Oct 2015) ISSN: 1523-1747 [Electronic] United States
PMID25961909 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • KRT14 protein, human
  • KRT5 protein, human
  • Keratin-14
  • Keratin-5
Topics
  • Cell Adhesion (genetics)
  • Cells, Cultured
  • Cytoskeleton (metabolism)
  • Disease Progression
  • Epidermolysis Bullosa Simplex (genetics, pathology)
  • Humans
  • Intermediate Filaments (genetics)
  • Keratin-14 (genetics)
  • Keratin-5 (genetics)
  • Keratinocytes (cytology, metabolism)
  • Mutation, Missense
  • Sampling Studies
  • Severity of Illness Index
  • Skin (pathology)
  • Statistics, Nonparametric

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