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

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".

• Authors: Frances J D Smith, Susan M Morley, W H Irwin McLean
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 122 Issue 1 Pg. 73-7 (Jan 2004) ISSN: 0022-202X [Print] United States
• PMID: 14962092 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Codon, Nonsense
• KRT14 protein, human
• KRT5 protein, human
• Keratin-14
• Keratin-15
• Keratin-5
• Krt14 protein, mouse
• Krt15 protein, mouse
• Keratins

Topics

• 3T3 Cells
• Adult
• Animals
• Codon, Nonsense
• DNA Mutational Analysis
• Epidermolysis Bullosa Simplex (genetics, pathology, therapy)
• Female
• Genetic Therapy
• Humans
• Keratin-14
• Keratin-15
• Keratin-5
• Keratinocytes (cytology)
• Keratins (genetics)
• Mice
• Mosaicism
• Mutation, Missense