Figure 1
Revertant Mosaicism in a Patient with NonHerlitz Junctional Epidermolysis Bullosa. A hyperpigmented revertant patch is visible on the wrist, surrounded by pink, blistered skin. The site of the biopsy of the patch is circled in black ink. The patient is Patient 13.
Source publication
To the Editor: Revertant mosaicism occurs when an inherited disease-causing mutation is corrected by a spontaneous genetic event within a somatic cell, followed by expansion of this reverted cell.1 This phenomenon has been recognized as the cause of milder-than-expected clinical phenotypes in patients with primary immunodeficiency syndromes or musc...
Context in source publication
Context 1
... cause of milder-than-expected clin- ical phenotypes in patients with primary immu- nodeficiency syndromes or muscular dystrophy. 2 In the skin of patients with the hereditary blis- tering disease epidermolysis bullosa, revertant mo- saicism is manifested as small patches of homo- geneously pigmented skin surrounded by skin that blisters easily ( Fig. ...
Citations
... At the time of the initial description of RM in a genodermatosis in 1997, RM was considered an extraordinary phenomenon. However, since that initial description, RM has been identified in all major types of EB (Table 1) [63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78], and, in 2012, we were able to confirm revertant skin patches in all ten Dutch patients with the intermediate type of JEB due to pathogenic COL17A1 variants [79]. Around the same time, Choate et al. demonstrated that each of the multiple healthy 'confetti-like' spots in patients with ichthyosis with confetti (IWC) due to germline variants in KRT10 (IWC-I) or KRT1 (IWC-II) represent a separate occurrence of RM in a single keratinocyte clone [80,81]. ...
... In subsequent years, various reversion mechanisms have been uncovered for mutations in EB-related genes. Of the different reversion mechanisms described in EB, most involve correction through a somatic, small intragenic mutational event (referred to as second-site mutation) such as somatic point mutations in a germline nonsense codon that revert it to the wildtype or to a different but functional codon [68,75], or alter the splicing of a mutated exon [66,[73][74][75]77,79,86]. A special class of additional point mutations is 'back-mutation' in which the somatic event reverts the mutant nucleotide to wildtype. ...
... Of note, in the cases with presumed back-mutations, it was not always possible to distinguish a back-mutation from a mitotic recombination event [75,86]. Other somatic, small intragenic mutational events that have been reported are deletions or duplications of one or a few nucleotides that either directly restore a disturbed mutant reading frame or modify mutant splicing patterns and thereby restore mutant reading frames [69][70][71]73,78,79]. Such correction events were observed frequently in Kindler EB as certain repetitive nucleotide sequences in FERMT1 appear to be particularly prone to the duplication or deletion of single nucleotides due to slipped mispairing [69,70]. ...
Revertant mosaicism (RM) is the intriguing phenomenon in which nature itself has successfully done what medical science is so eagerly trying to achieve: correcting the effect of disease-causing germline variants and thereby reversing the disease phenotype back to normal. RM was molecularly confirmed for the first time in a genodermatosis in 1997, the genetic skin condition junctional epidermolysis bullosa (EB). At that time, RM was considered an extraordinary phenomenon. However, several important discoveries have changed this conception in the past few decades. First, RM has now been identified in all major subtypes of EB. Second, RM has also been identified in many other genodermatoses. Third, a theoretical mathematical exercise concluded that reverse mutations should be expected in all patients with a recessive subtype of EB or any other genodermatosis. This has shifted the paradigm from RM being an extraordinary phenomenon to it being something that every physician working in the field of genodermatoses should be looking for in every patient. It has also raised hope for new treatment options in patients with genodermatoses. In this review, we summarize the current knowledge on RM and discuss the perspectives of RM for the future treatment of patients with genodermatoses.
... In this subtype, Jonhman and Pasmooji reported the first cases with revertant mosaicism, both in collagen and laminin deficiency, sustained by the reexpression of the deficient protein on skin specimens. Revertant mosaicism has since been documented in EB forms, implicating the COL17A1, KRT14, LAMB3, COL7A1, and FERMT1 genes [80,81]. Cases with self-improving JEB and milder than expected phenotypes were also reported. ...
Epidermolysis bullosa is a heterogeneous group of rare genetic disorders characterized by mucocutaneous fragility and blister formation after minor friction or trauma. There are four major epidermolysis bullosa types based on the ultrastructural level of tissue cleavage: simplex, junctional, dystrophic, and Kindler epidermolysis bullosa. They are caused by mutations in genes that encode the proteins that are part of the hemidesmosomes and focal adhesion complex. Some of these disorders can be associated with extracutaneous manifestations, which are sometimes fatal. They are inherited in an autosomal recessive or autosomal dominant manner. This review is focused on the phenomena of heterogeneity (locus, allelic, mutational, and clinical) in epidermolysis bullosa, and on the correlation genotype-phenotype.
... 4-6 RM refers to the spontaneous repair of the disease-causing mutation by a secondary genetic event, with subsequent (partial) restoration of protein expression and function. It has been identified as a disease modifier in all major types and several subtypes of EB. 1,5,7 In line with this concept, the duplication clearance may be attributable to gene conversion as a molecular mechanism underlying RM (Fig. 2c). Moreover, loss of the maternal SNP could reflect an additional back mutation. ...
... Following PCR amplification, haplotype, and direct sequencing, researchers concluded that COL17A1 gene conversion-nonreciprocal transfer at a specific gene locus where part of an allele was replaced by the homologous segment from another allele-was the most likely mechanism. RM has since been documented in EBS, JEB generalized intermediate, RDEB, DDEB, and Kindler syndrome, implicating COL17A1, KRT14, LAMB3, COL7A1, and FERMT1 genes [15][16][17][18][19][20][21][22][23][24][25][26][27][28] (Figure 2, Table 1), and the topic of prior reviews [19,29,30]. Clinically, patches of revertant mosaic keratinocytes in COL17A1 are identifiable as relatively hyperpigmented patches of skin compared to the surrounding affected epidermis [31]. ...
Epidermolysis bullosa (EB) is a group of genetic blistering diseases characterized by mechanically fragile skin and mucocutaneous involvement. Historically, disease management has focused on supportive care. The development of new genetic, cellular, and recombinant protein therapies has shown promise, and this review summarizes a unique gene and cell therapy phenomenon termed revertant mosaicism (RM). RM is the spontaneous correction of a disease-causing mutation. It has been reported in most EB subtypes, some with relatively high frequency, and has been observed in both keratinocytes and fibroblasts. RM manifests as identifiable patches of unaffected, blister-resistant skin and can occur through a variety of molecular mechanisms, including true back mutation, intragenic crossover, mitotic gene conversion, and second-site mutation. RM cells represent a powerful autologous platform for therapy, and leveraging RM cells as a therapeutic substrate may avoid the inherent mutational risks of gene therapy/editing. However, further examination of the genomic integrity and long-term functionality of RM-derived cells, as well in vivo testing of systemic therapies with RM cells, is required to realize the full therapeutic promise of naturally occurring RM in EB.
... Somatic reversion involves the correction of a pathogenic mutation in cells that is a naturally occurring phenomenon so that it is described as "natural gene therapy" [11]. Multiple reversion events result in somatic mosaicism characterized by partial or complete reversion of mutated somatic cells to a wild-type allele resulting in two genetically distinct populations of cells within an individual [12][13][14]. Lately, an increasing number of studies have identified revertant somatic mosaicism in patients affected with PIDs, in which the co-existence of mutant and revertant cells has been described [14]. To the best of our knowledge, only a few cases of X-SCID have been reported with revertant mutations in the IL2RG gene revealing somatic mosaicism [10,[15][16][17][18][19][20][21][22][23]. ...
Mutations of the IL2RG gene, which encodes for the interleukin-2 receptor common gamma chain (γC, CD132), can lead to X-linked severe combined immunodeficiency (X-SCID) associated with a T−B+NK− phenotype as a result of dysfunctional γC-JAK3-STAT5 signaling. Lately, hypomorphic mutations of the IL2RG gene have been described causing atypical SCID with a milder phenotype. Here, we report three brothers with low-normal lymphocyte counts and susceptibility to recurrent respiratory infections and cutaneous warts. The clinical presentation combined with dysgammaglobulinemia suspected an inherited immunity disorder, which has been proven by Next Generation Sequencing as a novel c.458T > C; p.Ile153Thr IL2RG missense-mutation. Subsequent functional characterization revealed impaired T-cell proliferation, low TREC levels and a skewed TCR Vβ repertoire in all three patients. Interestingly, investigation of various subpopulations showed normal expression of CD132 but with partially impaired STAT5 phosphorylation compared to healthy controls. Additionally, we performed precise genetic analysis of subpopulations revealing spontaneous somatic reversion, predominately in lymphoid derived CD3+, CD4+ and CD8+ T cells. Our data demonstrate that the atypical SCID phenotype noticed in these three brothers is due to the combination of hypomorphic IL-2RG function and somatic reversion.
... Those observations also further underline the importance of parallel evolution. Multiple revertant clones evolving in parallel have, for example, been reported in patients with Wiskott-Aldrich syndrome [49], ichthyosis [50,51], and in various types of genodermatoses [52][53][54][55][56] (Figure 1D). ...
Somatic evolution of cells within the body is well known to lead to cancers. However, spread of somatic mutations within a tissue over time may also contribute to the pathogenesis of non-neoplastic diseases. Recent years have seen the publication of many studies aiming to characterize somatic evolution in healthy tissues. A logical next step is to extend such work to diseased conditions. As our understanding of the interplay between somatic mutations and non-neoplastic disease grows, opportunities for the joint study of germline and somatic variants will present themselves. Here, we present our thoughts on the utility of somatic mutations for understanding both the causes and consequences of common complex disease and the challenges that remain for the joint study of the soma and germline.
... To circumnavigate the limitation of diminishing reversion during cell expansion, revertant JEB and RDEB cells were shown to be converted into iPSCs and subsequently differentiated into naturally gene-corrected keratinocytes. 17,18 In RDEB, revertant mosaicism has been reported in 36% of patients, 19 including cases of reversion in patients' fibroblasts. 20 However, although 'natural' cell therapy using revertant cells has shown some potential in patients with JEB, no clinical application has been reported for RDEB. ...
Introduction:
Combinatorial cell and gene therapies for life-threatening inherited skin disorders have shown tremendous potential for preclinical and clinical implementation with significant progress made for recessive dystrophic epidermolysis bullosa (RDEB). To date, various cell lineages including resident skin cells and adult stem cells have been investigated for gene and cell therapy for RDEB reaching the clinical trial stage.
Sources of data:
Sources of data are key recent literature, ClinicalTrials.gov, Clinicaltrialsregister.eu and pharma press releases.
Areas of agreement:
Cell-based gene transfer using autologous patients' cells has demonstrated positive outcomes in preclinical and clinical trials and highlighted the importance of targeting resident skin stem cells to achieve a meaningful long-term effect. Additionally, adult stem cells, such as mesenchymal stromal cells, have the potential to ameliorate systemic manifestations of the disease.
Areas of controversy:
While proven safe, the clinical trials of localized treatment have reported only modest and transient improvements. On the other hand, the risks associated with systemic therapies remain high and should be carefully weighed against the potential benefits. It is unclear to what extent adult stem cells can contribute to skin regeneration/wound healing.
Growing points:
Further research is warranted in order to fulfil the potential of cellular therapies for RDEB. The development of combinatorial gene and cell-based approaches is required to achieve long-term clinical benefits.
Areas timely for developing research:
Induced pluripotent stem cells can potentially provide a valuable source of autologous patient material for cellular therapies. In addition, recent advances in the field of gene editing can overcome hurdles associated with conventional gene addition approaches.
Data availability statement:
No new data were generated or analysed in support of this review.
... Revertant mosaicism has been reported in all types of EB and accounts for skin areas with improved mechanical stability due to spontaneous repair of the disease-causing variant. 74 Thirdly, digenic mutations in two EB-associated genes, e.g. both KRT5 and KRT14 75 , EXPH5 and COL17A1 76 or PLEC1 and ITGB4 77 variants have been reported to lead to unexpected phenotypes. A fourth type of genetic modifier mechanism is represented by variants in genes that are not directly associated with EB, but their products may modulate or influence EB-associated proteins. ...
Background:
Several new genes and clinical subtypes have been identified since publication in 2014 of the report of the last international consensus meeting on epidermolysis bullosa (EB).
Objective:
We sought to re-classify disorders with skin fragility, with a focus on EB, based on new clinical and molecular data.
Methods:
This was a consensus expert review.
Results:
In this latest consensus report, we introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype. Other disorders with skin fragility, where blisters are a minor part of the clinical picture or are not seen because skin cleavage is very superficial, are classified as separate categories. These include peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility. Because of the common manifestation of skin fragility, these "EB-related" disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care.
Conclusion:
The proposed classification scheme should be of value both to clinicians and researchers, emphasizing both clinical and genetic features of EB.
... However, he passionately dedicated his entire career to discovering new pathomechanisms and therapeutic approaches. Marcel's major scientific achievement was the discovery of revertant mosaicism (i.e., the phenomenon in which nature itself corrects diseasecausing gene mutations) in EB patients' skin and the unraveling of the genetic mechanisms behind this "natural gene therapy" (Jonkman and Pasmooij, 2009;Jonkman et al., 1997;Pasmooij et al., 2012). He subsequently explored different ways of exploiting this phenomenon to treat his patients. ...
... In theory, such genetic alterations, including point mutations, gene conversion, and recombination, can also lead to natural correction of pathogenic mutations at the somatic-cell level in genetic disorders. Somatic reversion of a mutant phenotype is referred to as revertant mosaicism and results from the correction of a disease-causing mutation in a somatic cell followed by the survival and clonal expansion of the revertant cell (Jonkman & Pasmooij, 2009). However, this clinically important "natural gene therapy" phenomenon has been documented in onlỹ 30 diseases, including seven genodermatoses caused by mutations in COL7A1 (recessive dystrophic epidermolysis bullosa [ (Jonkman & Pasmooij, 2009;Gudmundsson et al, 2017;Lim et al, 2017;van den Akker et al, 2018). ...
... Somatic reversion of a mutant phenotype is referred to as revertant mosaicism and results from the correction of a disease-causing mutation in a somatic cell followed by the survival and clonal expansion of the revertant cell (Jonkman & Pasmooij, 2009). However, this clinically important "natural gene therapy" phenomenon has been documented in onlỹ 30 diseases, including seven genodermatoses caused by mutations in COL7A1 (recessive dystrophic epidermolysis bullosa [ (Jonkman & Pasmooij, 2009;Gudmundsson et al, 2017;Lim et al, 2017;van den Akker et al, 2018). Although mutationfree induced pluripotent SCs established from revertant junctional EB keratinocytes are already on the way to clinical translation (Umegaki-Arao et al, 2014), the feasibility and generality of this therapeutic approach appear to be restricted by the currently limited number of diseases that are known to exhibit revertant mosaicism, warranting expansion of the repertoire of such diseases. ...
Revertant mosaicism is a phenomenon in which pathogenic mutations are rescued by somatic events, representing a form of natural gene therapy. Here, we report on the first evidence for revertant mosaicism in loricrin keratoderma (LK), an autosomal dominant form of ichthyosis caused by mutations in LOR on 1q21.3. We identified two unrelated LK families exhibiting dozens of previously unreported white spots, which increased in both number and size with age. Biopsies of these spots revealed that they had normal histology and that causal LOR mutations were lost. Notably, dense single nucleotide polymorphism mapping identified independent copy-neutral loss-of-heterozygosity events on chromosome 1q extending from regions centromeric to LOR to the telomere in all investigated spots, suggesting that somatic recombination represents a common reversion mechanism in LK. Furthermore, we demonstrated that reversion of LOR mutations confers a growth advantage to cells in vitro, but the clinically limited size of revertant spots suggests the existence of mechanisms constraining revertant clone expansion. Nevertheless, the identification of revertant mosaicism in LK might pave the way for revertant therapy for this intractable disease.
