Somatic recombination underlies frequent revertant mosaicism in loricrin keratoderma

Suzuki, Shotaro; Nomura, Toshifumi; Miyauchi, Takashi; Takeda, Mahito; Fujita, Yasuyuki; Nishie, Wataru; Akiyama, Masashi; Ishida‐Yamamoto, Akemi; Shimizu, Hiroshi

doi:10.26508/lsa.201800284

Cited by 14 publications

(16 citation statements)

References 23 publications

(41 reference statements)

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“…Recent advances in analytical methods have revealed the progressive accumulation of cells with genomic damage, including homologous recombination, in humans (Abyzov et al, 2012;Abyzov et al, 2017;Forsberg et al, 2017;Laurie et al, 2012;Wang et al, 2018). Disseminated epidermal homologous recombinations have been found in patients with ichthyosis with confetti (OMIM 609165) and loricrin keratoderma (OMIM 604117); revertant cells that have lost the disease-causing mutation via homologous recombination form normal-looking patches on affected skin (Choate et al, 2010;Choate et al, 2015;Suzuki et al, 2019). DSAP is almost a mirror image of such diseases.…”

Section: Discussionmentioning

confidence: 99%

Clonal Expansion of Second-Hit Cells with Somatic Recombinations or C>T Transitions Form Porokeratosis in MVD or MVK Mutant Heterozygotes

Kubo

Sasaki

Suzuki

et al. 2019

Journal of Investigative Dermatology

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Patients with disseminated superficial actinic porokeratosis (DSAP) and linear porokeratosis (LP) exhibit monoallelic germline mutations in genes encoding mevalonate pathway enzymes, such as MVD or MVK. Here, we showed that each skin lesion of DSAP exhibited an individual second hit genetic change in the wild-type allele of the corresponding gene specifically in the epidermis, indicating that a postnatal second hit triggering biallelic deficiency of the gene is required for porokeratosis to develop. Most skin lesions exhibited one of two principal second hits, either somatic homologous recombinations rendering the monoallelic mutation biallelic or C>T transition mutations in the wild-type allele. The second hits differed among DSAP lesions but were identical in those of congenital LP, suggesting that DSAP is attributable to sporadic postnatal second hits and congenital LP to a single second hit in the embryonic period. In the characteristic annular skin lesions of DSAP, the central epidermis featured mostly second hit keratinocytes, and that of the annular ring featured a mixture of such cells and naïve keratinocytes, implying that each lesion reflects the clonal expansion of single second hit keratinocytes. DSAP is therefore a benign intraepidermal neoplasia, which can be included in the genetic tumor disorders explicable by Knudson's two-hit hypothesis.

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Section: Discussionmentioning

confidence: 99%

Clonal Expansion of Second-Hit Cells with Somatic Recombinations or C>T Transitions Form Porokeratosis in MVD or MVK Mutant Heterozygotes

Kubo

Sasaki

Suzuki

et al. 2019

Journal of Investigative Dermatology

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“…Therefore, to our knowledge, this study is the first to provide evidence indicating the potential contribution of BIR to RM. Notably, similar long-tract LOH has also been frequently observed in other skin diseases such as ichthyosis with confetti and loricrin keratoderma where dozens to thousands of HR-driven revertant skin spots arise in each patient [14][15][16][17][18] .…”

Section: Discussionmentioning

confidence: 53%

Curing genetic skin disease through altered replication stress response

Miyauchi¹,

Suzuki²,

Takeda³

et al. 2020

Preprint

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Revertant mosaicism, or "natural gene therapy", refers to the spontaneous in vivo reversion of an inherited mutation in a somatic cell. Only ~50 human genetic disorders exhibit revertant mosaicism, implicating a distinctive role played by mutant proteins in somatic correction of a pathogenic germline mutation. However, the process by which mutant proteins induce somatic genetic reversion in these diseases remains unknown. Here we show that heterozygous pathogenic CARD14 mutations causing autoinflammatory skin diseases, including psoriasis and pityriasis rubra pilaris, are repaired mainly via homologous recombination. Rather than altering the DNA damage response to exogenous stimuli such as X-irradiation or etoposide treatment, mutant CARD14 increased DNA double-strand breaks under conditions of replication stress. Furthermore, mutant CARD14 suppressed new origin firings without promoting crossover events in the replication stress state. Together, these results suggest that mutant CARD14 alters the replication stress response and preferentially drives break-induced replication (BIR), which is generally suppressed in eukaryotes. Our results highlight the involvement of BIR in reversion events, thus revealing a previously undescribed role of BIR that could potentially be exploited to develop therapeutics for currently intractable genetic diseases.

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“…6B) (83). Similar examples of spontaneous revertants in the skin have been described in epidermolysis bullosa (84), ichthyosis with confetti (85) and loricrin keratoderma (86). This makes drug enhancement of revertance ("natural gene therapy") an interesting possibility for dominant negative genodermatoses (87,88).…”

Section: Clinical Examination and Serendipity As Research Toolsmentioning

confidence: 67%

Ichthyosis: A Road Model for Skin Research

Vahlquist¹,

Törmä²

2020

Acta Derm Venerol

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Ichthyosis refers to skin diseases with scaling somewhat reminiscent of fish scales (Greek: ichthus=fish). There are more than 50 genetic types of, mostly non-syndromic, ichthyosis, ranging in severity and frequency from mild and common (prevalence < 1%) to severe and rare (< 0.001%). In the latter case, babies are often born with a thick horny layer (collodion), dermal inflammation and impaired skin barrier function, requiring intensive medical care. Nearly all patients with ichthyosis require daily applications of cream, sometimes complemented with retinoid tablets. This review highlights recent progress in the understanding of the causes and consequences of ichthyosis, which may lead to better care and treatments. The understanding of monogenetic disorders of cornification, including the group of diseases called ichthyoses, has expanded greatly in recent years. Studies of the aetiology of more than 50 types of ichthyosis have almost invariably uncovered errors in the biosynthesis of epidermal lipids or structural proteins essential for normal skin barrier function. The barrier abnormality per se may elicit epidermal inflammation, hyperproliferation and hyperkeratosis, potentially contributing to the patient's skin symptoms. Despite this and other new knowledge about pathomechanisms, treatment of ichthyosis often remains unsatisfactory. This review highlights a series of approaches used to elucidate the pathobiology and clinical consequences of different types of ichthyosis, and related diseases with the ultimate goal of finding new and better treatments.

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Somatic recombination underlies frequent revertant mosaicism in loricrin keratoderma

Abstract: We demonstrate that revertant mosaicism frequently occurs in loricrin keratoderma and that somatic recombination is the major mechanism underlying this therapeutically important phenomenon.

Cited by 14 publications

References 23 publications

Clonal Expansion of Second-Hit Cells with Somatic Recombinations or C>T Transitions Form Porokeratosis in MVD or MVK Mutant Heterozygotes

Clonal Expansion of Second-Hit Cells with Somatic Recombinations or C>T Transitions Form Porokeratosis in MVD or MVK Mutant Heterozygotes

Curing genetic skin disease through altered replication stress response

Ichthyosis: A Road Model for Skin Research

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