title: Frequent somatic reversion of KRT1 mutations in ichthyosis with confetti.
abstract: Widespread reversion of genetic disease is rare; however, such events are particularly evident in some skin disorders in which normal clones develop on a background of affected skin. We previously demonstrated that mutations in keratin 10 (KRT10) cause ichthyosis with confetti (IWC), a severe dominant disorder that is characterized by progressive development of hundreds of normal skin spots via revertant mosaicism. Here, we report on a clinical and histological IWC subtype in which affected subjects have red, scaly skin at birth, experience worsening palmoplantar keratoderma in childhood, and develop hundreds of normal skin spots, beginning at around 20 years of age, that increase in size and number over time. We identified a causal de novo mutation in keratin 1 (KRT1). Similar to IWC-causing KRT10 mutations, this mutation in KRT1 resulted in a C-terminal frameshift, replacing 22 C-terminal amino acids with an alternate 30-residue peptide. Mutant KRT1 caused partial collapse of the cytoplasmic intermediate filament network and mislocalized to the nucleus. As with KRT10 mutations causing IWC, reversion of KRT1 mutations occurred via mitotic recombination. Because reversion is not observed with other disease-causing keratin mutations, the results of this study implicate KRT1 and KRT10 C-terminal frameshift mutations in the high frequency of revertant mosaicism in IWC.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Choate
authors.forename: Yin
authors.initials: Y
authors.lastname: Lu
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
authors.forename: Samir
authors.initials: S
authors.lastname: Zaidi
authors.forename: Amy S
authors.initials: AS
authors.lastname: Paller
authors.forename: Anita
authors.initials: A
authors.lastname: Farhi
authors.forename: Carol
authors.initials: C
authors.lastname: Nelson-Williams
authors.forename: Debra
authors.initials: D
authors.lastname: Crumrine
authors.forename: Leonard M
authors.initials: LM
authors.lastname: Milstone
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
mesh_terms: D000328:Adult; D017668:Age of Onset; D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D003599:Cytoskeleton / Q000648:ultrastructure; D016368:Frameshift Mutation; D006801:Humans; D007057:Ichthyosis / Q000235:genetics* / Q000473:pathology; D007382:Intermediate Filaments / Q000378:metabolism; D053556:Keratin-1 / Q000235:genetics* / Q000502:physiology; D015603:Keratinocytes / Q000473:pathology; D019656:Loss of Heterozygosity; D008297:Male; D008969:Molecular Sequence Data; D009030:Mosaicism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D021381:Protein Transport; D014162:Transfection
chemical_list: C491616:KRT1 protein, human; D053556:Keratin-1