Novel Mechanism of Revertant Mosaicism in Dowling - Meara Epidermolysis Bullosa Simplex

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Abstract

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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Smith, F. J. D., Morley, S. M., & McLean, W. H. I. (2004). Novel Mechanism of Revertant Mosaicism in Dowling - Meara Epidermolysis Bullosa Simplex. Journal of Investigative Dermatology, 122(1), 73–77. https://doi.org/10.1046/j.0022-202X.2003.22129.x

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