Epidermolysis bullosa simplex due toKRT5mutations: mutation-related differences in cellular fragility and the protective effects of trimethylamineN-oxide in cultured primary keratinocytes

Chamcheu, J. C., Virtanen, M., Navsaria, H., Bowden, Paul Edward, Vahlquist, A. and Törmä, H. 2010. Epidermolysis bullosa simplex due toKRT5mutations: mutation-related differences in cellular fragility and the protective effects of trimethylamineN-oxide in cultured primary keratinocytes. British Journal of Dermatology 162 (5) , pp. 980-989. 10.1111/j.1365-2133.2009.09615.x

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Abstract

Background Epidermolysis bullosa simplex (EBS) is a mechanobullous skin fragility disease characterized by cytolysis of basal keratinocytes and intraepidermal blistering often caused by mutations in keratin genes (KRT5 or KRT14). No remedies exist for these disorders presenting a need for development of novel therapies. Objectives To identify new genotype–phenotype relationships in vivo and in cultured primary EBS keratinocytes in vitro, and to study the cytoskeletal stabilizing effects of trimethylamine N-oxide (TMAO) in heat-stressed EBS cells. Methods Genomic DNA and cDNA samples from three Swedish patients with EBS were analysed for keratin mutations. Primary EBS keratinocyte cultures were established, heat stressed with and without added TMAO, followed by evaluation of cellular fragility. Results In addition to the previously reported KRT5 mutation (V186L) in one patient, two patients were found to have a novel I183M and recurrent E475G replacements in KRT5. Cultured EBS keratinocytes did not exhibit keratin aggregates or cell loss, except in the patient with the p.I183M mutation who showed 3% aggregates and 2% cell loss. Upon transient heat stress the number of aggregate- containing cells increased to 21%, 27% and 13%, respectively, in the p.I183M, p.E475G and p.V186L mutant cells. Interestingly, pretreatment with TMAO prior to heat stress, dose dependently reduced the number of aggregatecontaining cells and cell loss. Conclusion These results revealed a genotype–phenotype correlation in EBS keratinocytes upon heat stress and suggest protein stabilization as a new therapeutic strategy.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General) R Medicine > RL Dermatology
Uncontrolled Keywords:	chemical chaperone, heat stress, keratin filament aggregates, keratin mutation, keratinocytes, protein stability
Publisher:	Wiley-Blackwell
ISSN:	0007-0963
Last Modified:	12 Jun 2019 02:22
URI:	https://orca.cardiff.ac.uk/id/eprint/26141

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