Mitotic Recombination in Patients with Ichthyosis Causes Reversion of Dominant Mutations in KRT10

Department of Dermatology, Yale University School of Medicine, New Haven, CT 06510, USA.
Science (Impact Factor: 33.61). 10/2010; 330(6000):94-7. DOI: 10.1126/science.1192280
Source: PubMed


Somatic loss of wild-type alleles can produce disease traits such as neoplasia. Conversely, somatic loss of disease-causing
mutations can revert phenotypes; however, these events are infrequently observed. Here we show that ichthyosis with confetti,
a severe, sporadic skin disease in humans, is associated with thousands of revertant clones of normal skin that arise from
loss of heterozygosity on chromosome 17q via mitotic recombination. This allowed us to map and identify disease-causing mutations
in the gene encoding keratin 10 (KRT10); all result in frameshifts into the same alternative reading frame, producing an arginine-rich C-terminal peptide that redirects
keratin 10 from the cytokeratin filament network to the nucleolus. The high frequency of somatic reversion in ichthyosis with
confetti suggests that revertant stem cell clones are under strong positive selection and/or that the rate of mitotic recombination
is elevated in individuals with this disorder.

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Available from: Keith A Choate, Sep 19, 2014
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    • "In some instances, the revertants' expansion is so efficient that selective advantage has been proposed (Choate et al., 2010). Intriguingly, ichthyosis with confetti, a skin disease characterized by confetti-like appearance of revertant skin spots, is associated with a mutation in Keratin 10 (Choate et al., 2010), which, due to its nucleolar mislocalization, could affect ribosome production similar to M À/+ mutants. Thus, based on our findings, it is tentative to speculate that selective advantage in mosaic revertants could in some cases be driven by cell competition. "
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    • "In skin, every distinct revertant spot or patch has arisen from one single reversion event. The reversion mechanism for KRT10 in ichthyosis with confetti seems to be mitotic recombination (Choate et al., 2010; Burger et al., 2012). The cause for the same mechanism in each revertant spot was thought to be the result of mutant keratin 10 protein forming aggregates in the nucleus, and it was predicted that this mis-localization contributed to the high frequency of reversion seen in the patients. "
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    ABSTRACT: Revertant mosaicism (RM) refers to the co-existence of cells carrying disease-causing mutations with cells in which the inherited mutation is genetically corrected by a spontaneous event. It has been discovered in an increasing number of heritable skin diseases: ichthyosis with confetti and different subtypes of epidermolysis bullosa. This "natural gene therapy" phenomenon manifests as normal appearing skin areas surrounded by affected skin. Although initially thought to be rare, RM is now considered relatively common in genetic skin diseases. To address the issues relevant to RM, we here discuss the following questions: 1) What is the incidence of RM in heritable skin diseases? 2) What are the repair mechanisms in RM? 3) When do the revertant mutations occur? 4) How do you recognize revertant skin? 5) Do the areas of RM change in size? The answers to these questions allow us to acquire knowledge on these reverted cells, the mechanisms of RM, and utility of the reverted cells to the advantage of the patient. The revertant skin could potentially be used to treat the patient's own affected skin.
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    • "Another group showed that ichthyosis with confetti, a severe, sporadic skin disease in humans, is associated with thousands of revertant clones of normal skin that arose from spontaneous loss via mitotic recombination of a region on chromosome 17q containing disease-causing mutations in the gene encoding keratin 10 (KRT10). They further suggested that either the revertant stem cell clones are under strong positive selection and/or that the rate of mitotic recombination is elevated in individuals with this disorder [54]. To complicate matters further, another group showed that retrotransposition of long interspersed nuclear elements-1 (LINE-1 or L1s), which are abundant retrotransposons that comprise approximately 20% of mammalian genomes, during brain development can have an impact on gene expression and neuronal function, thereby increasing brain-specific genetic mosaicism. "
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