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000189847 0247_ $$2doi$$a10.1038/jid.2015.184
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000189847 037__ $$aFZJ-2015-02853
000189847 041__ $$aEnglish
000189847 082__ $$a610
000189847 1001_ $$0P:(DE-HGF)0$$aHomberg, Melanie$$b0
000189847 245__ $$aDistinct impact of two keratin mutations causing epidermolysis bullosa simplex on keratinocyte adhesion and stiffness
000189847 260__ $$aBasingstoke [u.a.]$$bNature Publishing Group$$c2015
000189847 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1441970575_19445
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000189847 520__ $$aKeratin filaments constitute the major component of the epidermal cytoskeleton from heterodimers of type I and type II keratin subunits. Missense mutations in keratin 5 or keratin 14, highly expressed in the basal epidermis, cause the severe skin blistering disease epidermolysis bullosa simplex (EBS) in humans by rendering the keratin cytoskeleton sensitive to mechanical stress; yet, the mechanisms by which individual mutations cause cell fragility are incompletely understood. Here, we compared the K14p.Arg125Pro with the K5p.Glu477Asp mutation, both giving rise to severe generalized EBS, by stable expression in keratin-free keratinocytes. This revealed distinctly different effects on keratin cytoskeletal organization, in agreement with in vivo observations, thus validating the cell system. Although the K14p.Arg125Pro mutation led to impaired desmosomes, downregulation of desmosomal proteins, and weakened epithelial sheet integrity upon shear stress, the K5p.Glu477Asp mutation did not impair these functions, although causing EBS with squamous cell carcinoma in vivo. Atomic force microscopy demonstrated that K14 mutant cells were even less resistant against deformation compared with keratin-free keratinocytes. Thus, a keratin mutation causing EBS compromises cell stiffness to a greater extent than the lack of keratins. Finally, re-expression of K14 in K14 mutant cells did not rescue the above defects. Collectively, our findings have implications for EBS therapy approaches.
000189847 536__ $$0G:(DE-HGF)POF3-552$$a552 - Engineering Cell Function (POF3-552)$$cPOF3-552$$fPOF III$$x0
000189847 7001_ $$0P:(DE-Juel1)151217$$aRamms, Lena$$b1$$ufzj
000189847 7001_ $$0P:(DE-HGF)0$$aSchwarz, Nicole$$b2
000189847 7001_ $$0P:(DE-Juel1)129308$$aDreissen, Georg$$b3$$ufzj
000189847 7001_ $$0P:(DE-HGF)0$$aLeube, Rudolf$$b4
000189847 7001_ $$0P:(DE-Juel1)128833$$aMerkel, Rudolf$$b5$$ufzj
000189847 7001_ $$0P:(DE-Juel1)128817$$aHoffmann, Bernd$$b6$$ufzj
000189847 7001_ $$0P:(DE-HGF)0$$aMagin, Thomas M.$$b7$$eCorresponding Author
000189847 773__ $$0PERI:(DE-600)2006902-9$$a10.1038/jid.2015.184$$n000$$p 2437–2445$$tThe @journal of investigative dermatology$$v135$$x0022-202X$$y2015
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000189847 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)151217$$aForschungszentrum Jülich GmbH$$b1$$kFZJ
000189847 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)129308$$aForschungszentrum Jülich GmbH$$b3$$kFZJ
000189847 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)128833$$aForschungszentrum Jülich GmbH$$b5$$kFZJ
000189847 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)128817$$aForschungszentrum Jülich GmbH$$b6$$kFZJ
000189847 9130_ $$0G:(DE-HGF)POF2-453$$1G:(DE-HGF)POF2-450$$2G:(DE-HGF)POF2-400$$aDE-HGF$$bSchlüsseltechnologien$$lBioSoft: Makromolekulare Systeme und biologische Informationsverarbeitung$$vPhysics of the Cell$$x0
000189847 9131_ $$0G:(DE-HGF)POF3-552$$1G:(DE-HGF)POF3-550$$2G:(DE-HGF)POF3-500$$3G:(DE-HGF)POF3$$4G:(DE-HGF)POF$$aDE-HGF$$bKey Technologies$$lBioSoft – Fundamentals for future Technologies in the fields of Soft Matter and Life Sciences$$vEngineering Cell Function$$x0
000189847 9141_ $$y2015
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