title: Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients: genetic and functional analyses.
abstract: Previously we demonstrated that transgenic mice expressing mutant basal epidermal keratin genes exhibited a phenotype resembling a group of autosomal dominant human skin disorders known as epidermolysis bullosa simplex (EBS). EBS diseases affect approximately 1: 50,000 and are of unknown etiology, although all subtypes exhibit blistering arising from basal cell cytolysis. We now demonstrate that two patients with spontaneous cases of Dowling-Meara EBS have point mutations in a critical region in one (K14) of two basal keratin genes. To demonstrate function, we engineered one of these point mutations in a cloned human K14 cDNA, and showed that a K14 with an Arg-125----Cys mutation disrupted keratin network formation in transfected keratinocytes and perturbed filament assembly in vitro. Since we had previously shown that keratin network perturbation is an essential component of EBS diseases, these data suggest that the basis for the phenotype in this patient resides in this point mutation.
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Genetics and Cell Biology, University of Chicago, Illinois 60637.
authors.forename: P A
authors.initials: PA
authors.lastname: Coulombe
authors.forename: M E
authors.initials: ME
authors.lastname: Hutton
authors.forename: A
authors.initials: A
authors.lastname: Letai
authors.forename: A
authors.initials: A
authors.lastname: Hebert
authors.forename: A S
authors.initials: AS
authors.lastname: Paller
authors.forename: E
authors.initials: E
authors.lastname: Fuchs
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D004252:DNA Mutational Analysis; D016110:Epidermolysis Bullosa Simplex / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D007382:Intermediate Filaments / Q000648:ultrastructure; D007633:Keratins / Q000235:genetics* / Q000502:physiology; D008969:Molecular Sequence Data; D009154:Mutation; D009841:Oligonucleotides / Q000737:chemistry; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins; D013329:Structure-Activity Relationship
chemical_list: D009841:Oligonucleotides; D012333:RNA, Messenger; D011994:Recombinant Proteins; D007633:Keratins