title: Evidence for novel functions of the keratin tail emerging from a mutation causing ichthyosis hystrix.
abstract: Unraveling the molecular basis of inherited disorders of epithelial fragility has led to understanding of the complex structure and function of keratin intermediate filaments. Keratins are organized as a central alpha-helical rod domain flanked by nonhelical, variable end domains. Pathogenic mutations in 19 different keratin genes have been identified in sequences corresponding to conserved regions at the beginning and end of the rod. These areas have been recognized as zones of overlap between aligned keratin proteins and are thought to be crucial for proper assembly of keratin intermediate filaments. Consequently, all keratin disorders of skin, hair, nail, and mucous membranes caused by mutations in rod domain sequences are characterized by perinuclear clumping of fragmented keratin intermediate filaments, thus compromising mechanical strength and cell integrity. We report here the first mutation in a keratin gene (KRT1) that affects the variable tail domain (V2) and results in a profoundly different abnormality of the cytoskeletal architecture leading to a severe form of epidermal hyperkeratosis known as ichthyosis hystrix Curth-Macklin. Structural analyses disclosed a failure in keratin intermediate filament bundling, retraction of the cytoskeleton from the nucleus, and failed translocation of loricrin to the desmosomal plaques. These data provide the first in vivo evidence for the crucial role of a keratin tail domain in supramolecular keratin intermediate filament organization and barrier formation.
authors: Department of Dermatology and Cutaneous Biology and the Jefferson Institute of Molecular Medicine, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
authors: E
authors: E
authors: Sprecher
authors: A
authors: A
authors: Ishida-Yamamoto
authors: O M
authors: OM
authors: Becker
authors: L
authors: L
authors: Marekov
authors: C J
authors: CJ
authors: Miller
authors: P M
authors: PM
authors: Steinert
authors: K
authors: K
authors: Neldner
authors: G
authors: G
authors: Richard
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D001483:Base Sequence / Q000235:genetics; D003593:Cytoplasm / Q000378:metabolism; D016368:Frameshift Mutation / Q000502:physiology*; D006579:Heterozygote; D006801:Humans; D007057:Ichthyosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D007382:Intermediate Filaments / Q000502:physiology / Q000648:ultrastructure; D007633:Keratins / Q000235:genetics* / Q000502:physiology*; D007645:Keratoderma, Palmoplantar / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D010375:Pedigree; D020033:Protein Isoforms / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D014018:Tissue Distribution
chemical_list: D008565:Membrane Proteins; D020033:Protein Isoforms; C064554:loricrin; D007633:Keratins