Revertant Mosaicism

Marjon Pasmooij, Groningen

What is revertant mosaicism?

Revertant mosaicism refers to the presence of healthy skin areas, where no blistering formation occurs, surrounded by affected skin. The blister formation in the affected skin areas is caused by mutations in the gene that is involved in the origin of epidermolysis bullosa. In the healthy skin areas without blistering an additional mutation has occurred in the disease-causing gene. This additional mutation corrects the first mutation, and subsequently leads to healthy skin. This process is called revertant mosaicism: a mosaic pattern in the skin as a result of a back mutation (= reversion). Sometimes this phenomenon is also referred to as "natural gene therapy", as the disease-causing mutation is "naturally" corrected.

Revertant mosaicism in all subtype of EB

The first patient with revertant mosaicism and EB was described in 1997. The 28-year-old patient with junctional EB had several revertant areas that did not blister on her hands, arms and ankle. In every distinct patch a different correcting mutation had occurred in the COL17A1 gene. At that time revertant mosaicism was thought to be rare. However, in 15 years, patients have been identified with revertant mosaicism in all four main subtypes of EB, i.e. EB simplex, junctional EB, dystrophic EB and Kindler syndrome. Since 2010, three patients have been described with dystrophic EB. Further, during the 41st annual ESDR meeting in Barcelona, the first patient with Kindler syndrome and revertant mosaicism was shown.


Revertant mosaicism occurs in all patients with generalised JEB-nH

Mutations in the type XVII collagen gene (COL17A1) result in non-Herlitz junctional EB (JEB-nH). The incidence of revertant mosaicism was identified in a cohort of 14 patients with JEB-nH caused by COL17A1 mutations. Ten patients had generalised blistering, whereas four patients had localised blistering. Revertant mosaicism was confirmed in the DNA in 6 out of 10 generalized JEB-nH patients. The clinically healthy areas manifested as patches of homogeneously pigmented skin. EB nevi can also be hyperpigmented, though EB nevi can be distinguished from the revertant skin patches, as EB nevi are often irregularly pigmented plaques that may give rise to small satellite nevi surrounding the primary nevus, whereas the revertant areas are homogenously pigmented macules without satellites. Further, photo-material and clinical history of the other four generalized JEB-nH patients demonstrated that each patient has revertant skin areas. In contrast, revertant mosaicism was not detected in the four localised JEB-nH patients.

Possibilities for therapy

Revertant mosaicism offers opportunities for cell therapies in which the patient's own naturally corrected cells are used as a source. The revertant skin cells might be used for obtaining a skin graft of naturally corrected cells to treated affected skin. Another exciting possibility is combining natural gene therapy with induced pluripotent stem (iPS) cell technology. Patient-specific skin cells from revertant mosaic patches could be used as source for patient-specific iPS cells. These iPS cells can then be differentiated back to skin cells and provide an essentially unlimited number of patient-specific cells for grafting. Alternatively, iPS cells may be differentiated into both hematopoietic and mesenchymal stem cells, which can home into blistered areas of the skin following bone marrow transplantation.


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