Evidence for novel functions of the keratin tail emerging from a mutation causing ichthyosis hystrix

Unraveling the molecular basis of inherited disorders of epithelial fragili ty has led to understanding of the complex structure and function of kerati n intermediate filaments. Keratins are organized as a central alpha -helica l rod domain flanked by nonhelical, variable end domains. Pathogenic mutati ons in 19 different keratin genes have been identified in sequences corresp onding to conserved regions at the beginning and end of the rod. These area s 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 muc ous 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 fi rst 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 f rom the nucleus, and failed translocation of loricrin to the desmosomal pla ques. These data provide the first in vivo evidence for the crucial role of a keratin tail domain in supramolecular keratin intermediate filament orga nization and barrier formation.