1. Department of Dermatology and Cutaneous Biology and the Jefferson Institute of Molecular Medicine, Jefferson Medical College, Philadelphia, Pennsylvania, U.S.A.;
2. ^*Department of Dermatology, Asahikawa Medical College, Asahikawa, Japan;
3. ^†School of Chemistry, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel;
4. ^‡Laboratory of Skin Biology, NIAMS, NIH, Bethesda, Maryland, U.S.A.;
5. ^§Department of Dermatology, Texas Tech University, Lubbock, Texas, U.S.A.

Correspondence: Dr Gabriele Richard, Department of Dermatology and Cutaneous Biology and the Jefferson Institute of Molecular Medicine, Jefferson Medical College, Philadelphia, 233 S 10th Street, BLSB Suite 409, Philadelphia, PA 19107, U.S.A. Email: Gabriele.Richard@mail.tju.edu

Received 16 November 2000; Revised 20 December 2000; Accepted 29 December 2000.

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 -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.