Abstract
Reversion mosaicism has been reported in an increasing number of genetic disorders including primary immunodeficiency diseases. Several mechanisms can mediate somatic reversion of inherited mutations. Back mutations restore wild-type sequences, whereas second-site mutations result in compensatory changes. In addition, intragenic recombination, chromosomal deletions, and copy-neutral loss of heterozygosity have been demonstrated in mosaic individuals. Revertant cells that have regained wild-type function may be associated with milder disease phenotypes in some immunodeficient patients with reversion mosaicism. Revertant cells can also be responsible for immune dysregulation. Studies identifying a large variety of genetic changes in the same individual further support a frequent occurrence of reversion mosaicism in primary immunodeficiency diseases. This phenomenon also provides unique opportunities to evaluate the biological effects of restored gene expression in different cell lineages. In this paper, we review the recent findings of reversion mosaicism in primary immunodeficiency diseases and discuss its clinical implications.
Highlights
Genetic mosaicism refers to an individual who has developed from a unique zygote but carries two or more cell types with different genotypes [1]
Reversion Mosaicism in Primary immunodeficiency diseases (PIDs) second-site mutation, which occurs at a different site from the germline mutation but within the coding or noncoding regions of the same gene, and results in a compensatory change that abrogates the deleterious effect of the germline mutation [3] (Figure 1C)
Actin-related protein 2/3 complex subunit 1B (ARPC1B)+ revertant CD8+ T-cells displayed an improvement in T-cell migration. These findings suggested that reversion mutations in ARPC1B provide a preferential advantage in CD8+ cytotoxic T-cells and natural killer (NK) cells, which is consistent with the fact that the absence of ARPC1B disrupts the proliferation capacity of cytotoxic T-cells [93]
Summary
Reversion mosaicism has been reported in an increasing number of genetic disorders including primary immunodeficiency diseases. Back mutations restore wild-type sequences, whereas second-site mutations result in compensatory changes. Revertant cells that have regained wild-type function may be associated with milder disease phenotypes in some immunodeficient patients with reversion mosaicism. Studies identifying a large variety of genetic changes in the same individual further support a frequent occurrence of reversion mosaicism in primary immunodeficiency diseases. This phenomenon provides unique opportunities to evaluate the biological effects of restored gene expression in different cell lineages. We review the recent findings of reversion mosaicism in primary immunodeficiency diseases and discuss its clinical implications
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