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Published on: September 14, 2019
Mechanisms of natural gene therapy in dystrophic epidermolysis bullosa
Dimitra Kiritsi1, Marta Garcia2, Renske Brander3
1Department of Dermatology and Venereology, University Medical Center, Freiburg, Germany.
Abstract:
Revertant mosaicism has been reported in several inherited diseases, including the genetic skin fragility disorder epidermolysis bullosa (EB). Here, we describe the largest cohort of seven patients with revertant mosaicism and dystrophic EB (DEB), associated with mutations in the COL7A1 gene, and determine the underlying molecular mechanisms. We show that revertant mosaicism occurs both in autosomal dominantly and recessively inherited DEB. We found that null mutations resulting in complete loss of collagen VII and severe disease, as well as missense or splice-site mutations associated with some preserved collagen VII function and a milder phenotype, were corrected by revertant mosaicism. The mutation, subtype, and severity of the disease are thus not decisive for the presence of revertant mosaicism. Although collagen VII is synthesized and secreted by both keratinocytes and fibroblasts, evidence for reversion was only found in keratinocytes. The reversion mechanisms included back mutations/mitotic recombinations in 70% of the cases and second-site mutations affecting splicing in 30%. We conclude that revertant mosaicism is more common than previously assumed in patients with DEB, and our findings will have implications for future therapeutic strategies using the patient's naturally corrected cells as a source for cell-based therapies.
Insights
Revertant mosaicism, a genetic repair mechanism, is more common in dystrophic epidermolysis bullosa (DEB) than previously thought. This natural cellular correction offers potential for future cell-based therapies in DEB patients.
Area of Science:
- Genetics
- Dermatology
- Molecular Biology
Background:
- Epidermolysis bullosa (EB) is a group of inherited genetic skin fragility disorders.
- Dystrophic epidermolysis bullosa (DEB) is a severe form of EB caused by mutations in the COL7A1 gene, leading to defective collagen VII.
- Revertant mosaicism, where cells regain normal function despite a genetic mutation, has been observed in some inherited diseases.
Purpose of the Study:
- To investigate the prevalence and molecular mechanisms of revertant mosaicism in a cohort of patients with dystrophic epidermolysis bullosa (DEB).
- To determine if the type of COL7A1 mutation or disease severity influences the occurrence of revertant mosaicism.
- To explore the potential of revertant mosaicism for future cell-based therapeutic strategies in DEB.
Main Methods:
- Analysis of a cohort of seven patients with revertant mosaicism and DEB.
- Molecular characterization of COL7A1 mutations and revertant cell populations.
- Investigation of reversion mechanisms in affected tissues, distinguishing between keratinocytes and fibroblasts.
Main Results:
- Revertant mosaicism was identified in both autosomal dominant and recessive DEB, irrespective of mutation type or disease severity.
- The underlying mechanisms of reversion included back mutations/mitotic recombination (70%) and second-site mutations affecting splicing (30%).
- Evidence of reversion was exclusively found in keratinocytes, not fibroblasts, despite collagen VII synthesis by both cell types.
Conclusions:
- Revertant mosaicism is a more frequent phenomenon in DEB than previously recognized.
- The findings highlight the potential of utilizing naturally corrected cells from DEB patients for cell-based therapeutic approaches.
- Understanding these reversion mechanisms could pave the way for novel treatment strategies for inherited skin fragility disorders.
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