Expanding the Clinical and Genetic Spectrum of KRT1, KRT2 and KRT10 Mutations in Keratinopathic Ichthyosis

Abstract

Twenty-six families with keratinopathic ichthyoses (epidermolytic ichthyosis, superficial epidermolytic ichthyosis or congenital reticular ichthyosiform erythroderma) were studied. Epidermolytic ichthyosis is caused by mutations in the genes KRT1 or KRT10, mutations in the gene KRT2 lead to superficial epidermolytic ichthyosis, and congenital reticular ichthyosiform erythroderma is caused by frameshift mutations in the genes KRT10 or KRT1, which lead to the phenomenon of revertant mosaicism. In this study mutations were found in KRT1, KRT2 and KRT10, including 8 mutations that are novel pathogenic variants. We report here the first case of a patient with congenital reticular ichthyosiform erythroderma carrying a mutation in KRT10 that does not lead to an arginine-rich reading frame. Novel clinical features found in patients with congenital reticular ichthyosiform erythroderma are described, such as mental retardation, spasticity, facial dysmorphisms, symblepharon and malposition of the 4th toe.

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

“…Most IWC KRT10 mutations reported thus far lead to a mutant polyarginine tail and this is the second report of a KRT10 mutation encoding a mutant polyalanine tail (Hotz et al , 2015), though the prior report neither investigated localization of the mutant protein nor mechanism of reversion.…”

Large Intragenic KRT1 Deletion Underlying Atypical Autosomal Dominant Keratinopathic Ichthyosis

“…Mutations in KRT1 (keratin 1) or KRT10 (keratin 10) underlie a spectrum of diseases known as keratinopathic ichthyoses (Oji et al, 2010;Hotz et al, 2016). Most commonly, heterozygous missense mutations within the head/tail domains result in autosomal dominant epidermolytic ichthyosis (EI), although a spectrum of mutations (some of which may be recessive) underlie a diverse collection of phenotypes that include generalized, annular, superficial (occasionally; mostly keratin 2) and nevoid forms of EI, as well as palmoplantar keratoderma (diffuse, focal, striate), severe variants such as Curth-Macklin ichthyosis, and most recently, ichthyosis with confetti (IWC) (for review on keratin diseases, see Knöbel et al, 2015).…”

Revertant mosaicism in genodermatoses

“…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.…”

“…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.…”