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

• Published in: Journal of dermatological science Vol. 97; no. 2; pp. 94 - 100
• Main Author: Nomura, Toshifumi
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2020
• Subjects: Homologous recombination; Ichthyosis with confetti; Loricrin keratoderma; Loss of heterozygosity; Revertant mosaicism; Loricrin keratoderma; LOH; Homologous recombination; HR; PPK; Ichthyosis with confetti; MIM; DSB; IWC; Loss of heterozygosity; Revertant mosaicism; EB; CIE; LK
• ISSN: 0923-1811; 1873-569X
• DOI: 10.1016/j.jdermsci.2019.12.013

•Somatic correction of a germline mutation is referred to as revertant mosaicism.•To date, revertant mosaicism has been documented in ∼50 genetic diseases.•Ichthyosis with confetti and loricrin keratoderma develop numerous revertant spots.•Homologous recombination underlies the mutation reversion in these diseases. 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.