Recombination-induced revertant mosaicism in ichthyosis with confetti and loricrin keratoderma.

J Dermatol Sci

Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan. Electronic address:

Published: February 2020

AI Article Synopsis

  • Revertant mosaicism is when harmful genetic mutations in germline cells are spontaneously corrected in somatic cells, leading to a mix of different cell types from one fertilized egg, which can result in healthier tissue in conditions like genetic skin diseases.
  • This phenomenon can lead to milder symptoms in patients, with examples including small patches of healthy skin in diseases like ichthyosis with confetti (IWC) and loricrin keratoderma (LK), both of which show these revertant patches.
  • The mechanism behind this reversion is primarily through homologous recombination, suggesting that understanding how this works could lead to new therapeutic strategies for IWC, LK, and other genetic disorders.

Article Abstract

Revertant mosaicism refers to a condition in which a pathogenic germline mutation is spontaneously corrected in somatic cells, resulting in the presence of two or more cell populations with different genotypes in an organism arising from a single fertilized egg. If the revertant cells are clonally expanded due to a survival advantage over the surrounding mutant cells, patients benefit from this self-healing phenomenon which leads to the development of milder-than-expected clinical phenotypes; in genetic skin diseases, patients with revertant mosaicism present with small islands of healthy skin. To date, revertant mosaicism has been reported in ∼50 genetic diseases involving the skin, blood, liver, muscle, and brain. In this review, I briefly summarize current knowledge on revertant mosaicism in two particular skin diseases, ichthyosis with confetti (IWC) and loricrin keratoderma (LK), both of which develop numerous revertant skin patches. Notably, homologous recombination (HR) is the only mechanism underlying the reversion of pathogenic mutations in IWC and LK, and this was identified following the analysis of ∼50 revertant epidermis samples. All the samples showed long-tract loss of heterozygosity (LOH) that originated at regions centromeric to pathogenic mutations and extended to the telomere of the mutation-harboring chromosomes. Elucidating the molecular mechanisms underlying revertant mosaicism in IWC and LK-especially how mutant proteins induce long-tract LOH-would potentially expand the possibility of manipulating HR to induce the reversion of disease-causing mutations and help devising novel therapies not only for IWC and LK but also for other intractable genetic diseases.

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http://dx.doi.org/10.1016/j.jdermsci.2019.12.013DOI Listing

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