title: A functional "knockout" of human keratin 14.
abstract: The importance of keratins and other intermediate filaments in the maintenance of tissue structure is emphasized by the discovery that many hereditary skin-blistering diseases are caused by mutations in keratin genes. Here, we describe a situation in which keratin 14 (K14) is missing altogether in the epidermis: A homozygous 2-nucleotide deletion in exon I of the K14 gene causes premature termination of the mRNA transcripts upstream from the start of the rod domain and results in a K14 null phenotype. In this individual no keratin intermediate filaments are visible in basal epidermal cells, although filaments are present in the upper layers of the epidermis. No compensating keratin expression is detected in vivo, and K14 mRNA is down-regulated. The individual, diagnosed as Köbner (generalized) EBS, suffers from severe widespread keratinocyte fragility and blistering at many body sites, but although the phenotype is severe, it is not lethal. This K14-/- phenotype confirms that only one K14 gene is expressed in human epidermis and provides an important model system for examining the interdependence of different keratin filament systems and their associated structures in the skin.
authors.affiliation: Department of Anatomy, University of Dundee, UK.
authors.forename: E L
authors.initials: EL
authors.lastname: Rugg
authors.forename: W H
authors.initials: WH
authors.lastname: McLean
authors.forename: E B
authors.initials: EB
authors.lastname: Lane
authors.forename: R
authors.initials: R
authors.lastname: Pitera
authors.forename: J R
authors.initials: JR
authors.lastname: McMillan
authors.forename: P J
authors.initials: PJ
authors.lastname: Dopping-Hepenstal
authors.forename: H A
authors.initials: HA
authors.lastname: Navsaria
authors.forename: I M
authors.initials: IM
authors.lastname: Leigh
authors.forename: R A
authors.initials: RA
authors.lastname: Eady
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001706:Biopsy; D002478:Cells, Cultured; D003241:Consanguinity; D017931:DNA Primers; D016110:Epidermolysis Bullosa Simplex / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006720:Homozygote; D006801:Humans; D017403:In Situ Hybridization; D007223:Infant; D015603:Keratinocytes / Q000473:pathology; D007633:Keratins / Q000096:biosynthesis / Q000235:genetics* / Q000302:isolation & purification; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D017384:Sequence Deletion; D012867:Skin / Q000378:metabolism / Q000473:pathology; D012871:Skin Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; D007633:Keratins