Revertant mosaicism (RM) occurs from spontaneous, somatic correction of pathogenic mutation, giving rise to areas of normal tissue. Ichthyosis with confetti (IWC), an autosomal dominant skin disorder caused by mutations affecting the tail domains of keratin 10 (K10) and keratin 1 (K1), is remarkable for its high frequency of RM, as patients develop hundreds to thousands of revertant islands of normal skin beginning in childhood. Interestingly, each revertant clone arises from independent copy-neutral loss-of-heterozygosity (CN-LOH), likely via homologous recombination (HR) of the mutant haplotype. Furthermore, the revertant macules are observed to grow in size and number over time, suggesting intercellular competition favoring the selection and expansion of revertant clones over their mutant neighbors. We have successfully demonstrated that expression of IWC mutant keratins uniquely increase the rate of HR, while inducing the formation of DNA double- strand breaks (DSBs). Furthermore, we have developed a conditional knock-in model of IWC, which clinically and histologically recapitulates disease including revertant mosaicism via CN-LOH, and demonstrates expansion of revertant, wild type clones. We now propose to systematically identify and interrogate the mechanisms and mediators governing IWC keratin-induced HR and cellular competition. We will investigate which DNA damage response (DDR) components are recruited to sites of keratin-induced DSBs, characterize the kinetics of DSB formation and resolution, and pinpoint the stage in the cell cycle at which damage occurs. We propose to utilize intravital live-imaging to explore, at the cellular level, whether altered rates of mitosis, apoptosis, or differentiation/delamination underlie the intercellular competition in IWC. Finally, we will perform single-cell RNA sequencing and CRISPR knockout screens, to identify mediators of intercellular competition and determinants or modifiers of HR in IWC. We will further examine compelling candidates in IWC patient and murine tissue and cells. Elucidating the previse mechanisms of genetic reversion and intercellular competition in IWC has the potential to identify pathways which may enable therapeutic recombination to treat inherited and acquired dominant genetic disorders.

Public Health Relevance

Genetic self-correction is vanishingly rare in human disease, yet in the severe rare skin disorder ichthyosis with confetti (IWC), affected individuals develop hundreds to thousands of spots of self- corrected normal skin. We have found that mutations in KRT1 and KRT10 that cause IWC lead to DNA damage favoring self-correction via copy neutral loss of heterozygosity while also providing a selective advantage to corrected clones, permitting their expansion. Our experiments will identify the specific cellular pathways which are required for genetic self-correction and normal clone expansion; by identifying these pathways, it may become possible to develop tools to enhance self-correction not only in IWC, but also in any genetic disorder resulting from one copy of a mutant gene.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Therapeutic Approaches to Genetic Diseases Study Section (TAG)
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Tseng, Hung H
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Yale University
Schools of Medicine
New Haven
United States
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Lim, Young H; Fisher, Jonathan M; Choate, Keith A (2017) Revertant mosaicism in genodermatoses. Cell Mol Life Sci 74:2229-2238
Lim, Young H; Moscato, Zoe; Choate, Keith A (2017) Mosaicism in Cutaneous Disorders. Annu Rev Genet 51:123-141
Lim, Young H; Choate, Keith A (2016) Expanding the Mutation Spectrum of Ichthyosis with Confetti. J Invest Dermatol 136:1941-1943
Lim, Young H; Qiu, Jingyao; Saraceni, Corey et al. (2016) Genetic Reversion via Mitotic Recombination in Ichthyosis with Confetti due to a KRT10 Polyalanine Frameshift Mutation. J Invest Dermatol 136:1725-1728
Choate, Keith A; Lu, Yin; Zhou, Jing et al. (2015) Frequent somatic reversion of KRT1 mutations in ichthyosis with confetti. J Clin Invest 125:1703-7
Choate, Keith A; Milstone, Leonard M (2015) Phenotypic expansion in ichthyosis with confetti. JAMA Dermatol 151:15-6