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J Invest Dermatol. 2004 Jan;122(1):73-7.

Novel mechanism of revertant mosaicism in Dowling-Meara epidermolysis bullosa simplex.

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  • 1Epithelial Genetics Group, Human Genetics Unit, Ninewells Medical School, University of Dundee, UK.


The severe Dowling-Meara form of epidermolysis bullosa simplex is caused by dominant-negative mutations in keratins 5 and 14, which are specifically expressed in the basal keratinocytes of the epidermis. The most common mutation in the Dowling-Meara form of epidermolysis bullosa simplex patients is the missense mutation R125C in exon 1 of the K14 gene. We made a primary keratinocyte cell line from a sporadic case known to carry the R125C mutation as part of an ongoing gene therapy initiative. The full-length K14 cDNA was sequenced using keratinocyte mRNA. Unexpectedly, a second mutation was identified in K14: a heterozygous 1 bp insertion mutation (242insG) upstream of the R125C mutation. This frameshift mutation creates a premature termination codon immediately downstream, thereby nullifying the dominant-negative allele. The second mutation was only present in DNA derived from keratinocytes and was absent from lymphocyte DNA. This case represents a novel mechanism of revertant mosaicism and is an example of "natural gene therapy".

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