Revertant mosaicism in skin: natural gene therapy

Abstract

Revertant mosaicism is a naturally occurring phenomenon involving spontaneous correction of a pathogenic mutation in a somatic cell. Recent studies suggest that it is not a rare event and that it could be clinically relevant to phenotypic expression and patient treatment. Indeed, revertant cell therapy represents a potential "natural gene therapy" because in vivo reversion obviates the need for further genetic correction. Revertant mosaicism has been observed in several inherited conditions, including epidermolysis bullosa, a heterogeneous group of blistering skin disorders. These diseases provide a useful model for studying revertant mosaicism because of the visual and accessible nature of skin. This overview highlights the latest developments in revertant mosaicism and the translational implications germane to heritable skin disorders. Revertant mosaicismSomatic reversion of a mutant phenotype was first identified in Lesch-Nyhan syndrome in 1988 [1]. This phenomenon has since been reported in other hematological conditions, such as primary immunodeficiency diseases and Fanconi's anemia, and nonhematological disorders, including epidermolysis bullosa (EB), Duchenne muscular dystrophy and tyrosinemia [2]. Revertant somatic mosaicism, a term popularized by Jonkman et al. [3], is characterized by the spontaneous partial or complete reversal of an affected somatic cell or cells to a wild-type phenotype [4]. It is not uncommon, occurring in up to 11% (30/272 cases) of patients with Wiskott-Aldrich syndrome [5], 18% (5/28 cases) of individuals with Fanconi's anemia [6] and 35% (7/20 cases) of subjects with nonHerlitz junctional EB [4]. The reasons for the relatively high frequency are unclear and could reflect a selective advantage of the revertant cell over its mutant counterpart, as well as high mutation rates and DNA polymerase errors [7]. With regards to revertant phenotypes, the skin provides a unique opportunity to investigate clinical patterns of disease expression such as mosaicism. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. For diseases such as EB, the key proteins underlying skin blistering and in which revertant mosaicism has been implicated are shown in Figure 1. Revertant mosaicism can occur in the germline or in somatic cells. Germline revertant mosaicism has previously been described in myotonic dystrophy wherein the size of the CTG repeats in two unrelated healthy individuals, born to clinically affected parents, was normal despite having inherited the myotonic dystrophy DNA-marker haplotype [8]. Somatic revertant mosaicism occurs secondarily to a...

Concise Review: Transplantation of Human Hematopoietic Cells for Extracellular Matrix Protein Deficiency in Epidermolysis Bullosa

“…That such stem cell gene therapy will be effective in a nonhematopoietic disorder, and specifically in EB, is supported by the observations that a minority of individuals with EB develop self-correcting mutations in one of the genes underlying the EB pathology and that when such somatic mutations occur, the gene self-corrected skin is resistant to trauma [50][51][52]. In contrast to other conditions with prominent mosaicism, such as BM failure syndrome Fanconi anemia, where a self-correcting somatic mutation occurring in a single stem cell is capable of restoring normal hematopoiesis [53], the mosaicism in EB remains confined to small area of skin.…”

Molecular pathogenesis and clinical management of Fanconi anemia

“…The revertant FA stem cells could, in principle, be isolated, expanded in vitro, and grafted back to the patient as an autologous transplant (Table 2). Successful attempts have been made to transplant revertant keratinocytes as a treatment for skin disorders (110,111). However, questions remain about the ability of corrected cells to sustain the hematopoietic functionality in the long term.…”

Natural Gene Therapy in Dystrophic Epidermolysis Bullosa

“…The patient described herein displays a novel correction mechanism in the COL7A1 gene. Hence, different correcting mechanisms occur in COL7A1, as in COL17A1 and LAMB3, 5 whereas in patients with ichthyosis with confetti due to dominant KRT10 mutations, the same correction mechanism of mitotic recombination occurs in each revertant skin spot in each patient. 19 In our patient, a somatic nucleotide change in the germline mutated codon rescues the mutant phenotype by reverting the nonsense codon to a tyrosine (p.X2170Tyr), which leads to the restoration of functionalproteinproduction.Theresultantmissensechange p.Gln2170Tyr has been described neither as a neutral polymorphism (dbSNP, http://www.ncbi.nlm.nih.gov/projects /SNP/) nor as a pathogenic mutation in patients with RDEB (International Dystrophic Epidermolysis Bullosa Patient Registry, www.deb-central.org, accessed on June 30, 2011).…”