Revertant mosaicism in genodermatoses

Lim, Young Hee; Fisher, Jonathan; Choate, Keith

doi:10.1007/s00018-017-2468-2

Cited by 24 publications

(22 citation statements)

References 75 publications

(119 reference statements)

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“…It is predicted that approximately 36% of patients with RDEB exhibit visible mosaic patches, although documented cases have revealed only a subset of isolated keratinocytes harbour corrective mutations . The prevalence and appearance of clinically evident revertant cells, whether keratinocytes or fibroblasts, requires more than a DNA‐level correction . The genetic correction needs to be present in cells with replicative potential and confer some selective advantage to enable resilient reversion.…”

Section: Discussionmentioning

confidence: 99%

“…19 The prevalence and appearance of clinically evident revertant cells, whether keratinocytes or fibroblasts, requires more than a DNAlevel correction. 3 The genetic correction needs to be present in cells with replicative potential and confer some selective advantage to enable resilient reversion. In the case of keratinocytes, this must occur in the less differentiated precursors of the stratum basale.…”

Section: Discussionmentioning

confidence: 99%

“…Revertant somatic mosaicism, the spontaneous partial or complete reversal of an affected somatic cell or group of cells to a functionally wild-type state, has been previously described in numerous nonhaematological disorders, including epidermolysis bullosa (EB). [1][2][3] Somatic cells of the skin have a high incidence of reversion, in part because of high cell proliferation rates. 4 Interestingly, chromosomal inversions have been identified as a potential modifier of clinical phenotypes.…”

Section: What Is the Translational Message?mentioning

confidence: 99%

“…In contrast, all previous examples of mosaicism in EB have been identified in epidermal keratinocytes. 2,3,12,13 Materials and methods…”

Section: What Is the Translational Message?mentioning

confidence: 99%

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Revertant mosaic fibroblasts in recessive dystrophic epidermolysis bullosa

et al. 2019

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Summary Background Revertant mosaicism has been described previously in recessive dystrophic epidermolysis bullosa (RDEB), manifesting as regions of skin with normal mechanical and biological characteristics. Here we report the discovery of revertant dermal fibroblasts, unique in that all other documented cases of revertant mosaicism occur in epidermal keratinocytes. Objectives To determine the cause of revertant mosaicism found in a patient with RDEB from isolated epidermal keratinocytes and dermal fibroblasts in blister and mosaic skin regions. Methods Skin biopsies were taken from blister and mosaic skin regions of a patient with RDEB. Allele identification was confirmed and the type VII collagen (C7) content and COL7A1 expression profile of isolated keratinocytes and fibroblasts was determined. Results Keratinocytes isolated from the mosaic area had a slight increase in C7, although overall expression of COL7A1 was unchanged between blister and mosaic fibroblasts. Differential allele expression was identified in blister and mosaic fibroblasts using targeted RNA sequencing (TREx), where the allele harbouring a point mutation was preferentially expressed over that containing a frameshift mutation. A crossing over event was identified in mosaic fibroblasts that was not present in blister fibroblasts, yielding a functional COL7A1 allele in a subset of cells. Conclusions In documenting a novel case of revertant mosaicism in RDEB, we have identified dermal fibroblasts as having the capacity to correct blistering functionally. We have also pioneered the use of TREx in quantifying allele‐specific expression. Using fibroblasts instead of keratinocytes for RDEB therapies offers advantages in the local and systemic therapy of RDEB. What's already known about this topic? Revertant mosaicism has been previously documented in patients with recessive dystrophic epidermolysis bullosa (RDEB), however, it has only been found in epidermal keratinocytes. What does this study add? We have demonstrated that COL7A1 gene reversion in dermal fibroblasts occurs and is able to form functional skin in a patient with RDEB. Additionally, we have pioneered a new application for targeted RNA sequencing in quantifying allele‐specific expression in fibroblasts and keratinocytes. What is the translational message? This opens up possibilities for using fibroblasts as local and systemic therapy for patients with RDEB.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: What Is the Translational Message?mentioning

confidence: 99%

“…In contrast, all previous examples of mosaicism in EB have been identified in epidermal keratinocytes. 2,3,12,13 Materials and methods…”

Section: What Is the Translational Message?mentioning

confidence: 99%

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Revertant mosaic fibroblasts in recessive dystrophic epidermolysis bullosa

et al. 2019

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“…80 Only one case of an autologous epidermal graft derived from EB revertant keratinocytes has been reported in the published work, and only a small amount of COL17 expression was observed in this COL17A1-mutated JEB patient. 81 This may be due to the nature of revertant mosaicism, which requires cell division for mitotic recombination or second-site mutations, 82 leading to gene corrections. Two major hypotheses have been proposed to regulate epidermal maintenance: (i) the hierarchical model; and (ii) the stochastic model.…”

Section: Col7 In Epidermal Keratinocytesmentioning

confidence: 99%

Epidermal aspects of type VII collagen: Implications for dystrophic epidermolysis bullosa and epidermolysis bullosa acquisita

Watanabe

Natsuga

Shinkuma

et al. 2018

The Journal of Dermatology

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Type VII collagen (COL7), a major component of anchoring fibrils in the epidermal basement membrane zone, has been characterized as a defective protein in dystrophic epidermolysis bullosa and as an autoantigen in epidermolysis bullosa acquisita. Although COL7 is produced and secreted by both epidermal keratinocytes and dermal fibroblasts, the role of COL7 with regard to the epidermis is rarely discussed. This review focuses on COL7 physiology and pathology as it pertains to epidermal keratinocytes. We summarize the current knowledge of COL7 production and trafficking, its involvement in keratinocyte dynamics, and epidermal carcinogenesis in COL7 deficiency and propose possible solutions to unsolved issues in this field.

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Genetics and the Skin

McGrath

2024

Rook's Textbook of Dermatology

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The science and clinical application of genetics to patients with skin diseases continues to evolve rapidly. In this chapter, recent advances in human genetics relevant to dermatologists are reviewed. The content also covers access to modern databases linked to human disease, new findings on disease mutations, updates on investigative genetic techniques, and outlines advances in how to diagnose genetic skin diseases, both rare and common. Recent progress in prenatal diagnosis is also presented.

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Revertant mosaicism in genodermatoses

Cited by 24 publications

References 75 publications

Revertant mosaic fibroblasts in recessive dystrophic epidermolysis bullosa

Revertant mosaic fibroblasts in recessive dystrophic epidermolysis bullosa

Epidermal aspects of type VII collagen: Implications for dystrophic epidermolysis bullosa and epidermolysis bullosa acquisita

Genetics and the Skin

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