Epidermolysis bullosa simplex due to KRT5 mutations: mutation-related differences in cellular fragility and the protective effects of trimethylamine N-oxide in cultured primary keratinocytes.

[epidermolysis bullosa simplex]

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 (KRT 5 or KRT 14 ). No remedies exist for these disorders presenting a need for development of novel therapies .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 .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 .In addition to the previously reported KRT 5 mutation (V 186 L ) in one patient , two patients were found to have a novel I 18 3 M and recurrent E 475 G replacements in KRT 5 . Cultured EBS keratinocytes did not exhibit keratin aggregates or cell loss , except in the patient with the p .I 18 3 M 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 .I 18 3 M , p .E 475 G and p .V 186 L mutant cells . Interestingly , pretreatment with TMAO prior to heat stress , dose dependently reduced the number of aggregate-containing cells and cell loss .These results revealed a genotype-phenotype correlation in EBS keratinocytes upon heat stress and suggest protein stabilization as a new therapeutic strategy .

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Diseases presenting "new genotype-phenotype relationships in vivo" symptom

epidermolysis bullosa simplex

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