Genetic Reversion via Mitotic Recombination in Ichthyosis with Confetti due to a KRT10 Polyalanine Frameshift Mutation

Lim, Young Hee; Qiu, Jingyao; Saraceni, Corey; Burrall, Barbara A; Choate, Keith

doi:10.1016/j.jid.2016.04.023

Cited by 12 publications

(25 citation statements)

References 15 publications

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“…All mutations identified in IWC to date are de novo frameshift mutations with dominant inheritance affecting the carboxyl tail domain of keratin-10 ( KRT10 ) or keratin-1 ( KRT1 ), causing Type I IWC (IWC-I) and Type II IWC (IWC-II), respectively [21–23,45,46]. KRT10 and KRT1 interact via their rod domains to form obligate heteropolymers that serve as the major intermediate filament protein of the suprabasal layer of the epidermis.…”

Section: Reversion In Ichthyosis With Confettimentioning

confidence: 99%

“…As polyarginated peptides are known to bind ribosomal proteins, the arginine repeats in the mutant tail were postulated to be critical for nucleolar mislocalization as well as genetic reversion; however, subsequent identification of alternate frameshift mutations leading to a polyalanine tail in KRT10 , also featuring nucleolar aggregates and reversion, suggests that loss of the endogenous glycine-rich tail may underlie the pathobiology of IWC-I [23,45]. Likewise, in IWC-II, both a mutation leading to KRT1 with a polyarginine tail [46], as well as a mutation replacing the final 22 amino acids with a new 30 amino acid sequence [22], have been reported.…”

Section: Reversion In Ichthyosis With Confettimentioning

confidence: 99%

“…Further, multiple independent events of reversion within one patient is not uncommon, and each independent event may be the result of one [21–23] or more [19,24] distinct corrective mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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Revertant mosaicism in genodermatoses

Lim

Fisher

Choate

2017

Cell. Mol. Life Sci.

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Inherited monogenic skin disorders include blistering disorders, inflammatory disorders, and disorders of differentiation or development. In most cases, the skin is broadly involved throughout the affected individual’s lifetime, but rarely, appearance of normal skin clones has been described. In these cases of revertant mosaicism, cells undergo spontaneous correction to ameliorate the effects of genetic mutation. While targeted reversion of genetic mutation would have tremendous therapeutic value, the mechanisms of reversion in the skin are poorly understood. In this review, we provide an overview of genodermatoses that demonstrate widespread reversion and their corrective mechanisms, as well as the current research aimed to understand this “natural gene therapy”.

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Section: Reversion In Ichthyosis With Confettimentioning

confidence: 99%

Section: Reversion In Ichthyosis With Confettimentioning

confidence: 99%

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Revertant mosaicism in genodermatoses

Lim

Fisher

Choate

2017

Cell. Mol. Life Sci.

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“…Although patients are born with features shared among other ichthyoses, including erythema, scaling, and palmoplantar keratoderma, thousands of confetti-like white spots appear over the body by late childhood or puberty. These increase in number and size over time, representing independent clones of keratinocytes that are genotypically wild type (Choate et al, 2010, 2015; Lim et al, 2016; Suzuki et al., 2016). Although the red, diseased skin exhibits histopathologic evidence of perinuclear vacuolization and parakeratotic hyperkeratosis, the white macules show normal histology and keratinocyte differentiation (Choate et al, 2010, 2015).…”

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confidence: 99%

“…In 42 cases of IWC-I reported to date, most frameshift mutations replace the endogenous glycine-serine–rich tail of KRT10 with one that is rich in arginine, leading to mislocalization of KRT10, from the cytosol to the nucleus and nucleolus (Guerra et al, 2015; Hotz et al, 2016; Lim et al, 2016). Cases of IWC-II are much rarer: Suzuki et al (2016) identified the second kindred to date, harboring a novel c.1758_1759insT (p.Tyr587LeufsTer67) mutation in KRT1 , leading to expression of KRT1 with a polyarginine tail and affecting three generations (Suzuki et al, 2016).…”

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confidence: 99%

Expanding the Mutation Spectrum of Ichthyosis with Confetti

Lim

Choate

2016

Journal of Investigative Dermatology

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Ichthyosis with confetti is a rare, autosomal dominant disorder caused by frameshift mutations in KRT10 or KRT1 and characterized by the development of white, genetically revertant macules in red, diseased skin. All cases result from mutations affecting the tail domains of keratin-10 or keratin-1, and Suzuki et al. expand the mutation spectrum for ichthyosis with confetti caused by mutations in KRT1, showing that a polyarginine frameshift in the keratin-1 tail can also cause this disorder.Spontaneous correction of pathogenic mutations can occur rarely in somatic cells, leading to genetic reversion . This "natural gene therapy" can easily be visualized in skin disorders, as populations of revertant cells give rise to areas of healthyappearing wild-type epidermis, surrounded by adjacent diseased skin. Ichthyosis with confetti (IWC) is a rare disorder of keratinization that displays a dramatic example of genetic reversion. Although patients are born with features shared among other ichthyoses, including erythema, scaling, and palmoplantar keratoderma, thousands of confetti-like white spots appear over the body by late childhood or puberty. These increase in number and size over time, representing independent clones of keratinocytes that are genotypically wild type (Choate et al., 2010(Choate et al., , 2015Lim et al., 2016;Suzuki et al., 2016). Although the red, diseased skin exhibits histopathologic evidence of perinuclear vacuolization and parakeratotic hyperkeratosis, the white macules show normal histology and keratinocyte differentiation (Choate et al., 2010(Choate et al., , 2015.

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Coexistence of mutations in keratin 10 (KRT10) and the mitochondrial genome in a patient with ichthyosis with confetti and Leber's hereditary optic neuropathy

Kalińska-Bienias

Pollak

Kowaléwski

et al. 2017

American J of Med Genetics Pt A

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Ichthyosis with confetti (IWC) is a severe congenital genodermatosis characterized by ichthyosiform erythroderma since birth and confetti-like spots of normal skin appearing in childhood as a results of revertant mosaicism. This disorder is caused by mutations in KRT10 or KRT1 genes. We report a 16-year-old boy who presented ichthyosiform erythroderma with severe desquamation since birth and gradually worsening psycho-neurological symptoms (mental retardation, ataxia, dystonia, hypoacusis). The patient conspicuously lacked typical confetti-like spots at the age of 16. The molecular diagnostics by the whole exome sequencing showed a novel de novo (c.1374-2A>C) mutation in the KRT10 gene responsible for the development of IWC (KRT10 defect was confirmed by immunofluorescent study). Concurrently, the m.14484T>C mutation in mitochondrial MTND6 gene (characteristic for Leber's hereditary optic neuropathy or LHON) was detected in patient, his mother and brother. LHON causes frequent inherited blindness typically appearing during young adult life whose expression can be triggered by additional factors such as smoking or alcohol exposure. We speculate the effects of KRT10 and LHON mutations influence each other-skin inflammatory reaction due to severe ichthyosis might trigger the development of psychoneurological abnormalities whereas the mitochondrial mutation may reduce revertant mosaicism phenomenon resulting in the lack of confetti-like spots characteristic for IWC. However, based on a single case we should be cautious about attributing phenotypes to digenic mechanisms without functional data.

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Genetic Reversion via Mitotic Recombination in Ichthyosis with Confetti due to a KRT10 Polyalanine Frameshift Mutation

Cited by 12 publications

References 15 publications

Revertant mosaicism in genodermatoses

Revertant mosaicism in genodermatoses

Expanding the Mutation Spectrum of Ichthyosis with Confetti

Coexistence of mutations in keratin 10 (KRT10) and the mitochondrial genome in a patient with ichthyosis with confetti and Leber's hereditary optic neuropathy

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