Loss of normal profilaggrin and filaggrin in flaky tail (ft/ft) mice: an animal model for the filaggrin-deficient skin disease ichthyosis vulgaris

Flaky tail (gene symbol ft) is an autosomal recessive mutation in mice that results in a dry, flaky skin, and annular tail and paw constrictions in th e neonatal period. Previous studies demonstrated that the ft mutation maps to the central region of mouse chromosome 3, in the vicinity of the epiderm al differentiation complex, a gene locus that includes many nonkeratin gene s expressed in epidermis. In this study we report a detailed characterizati on of the flaky tail mouse. Affected homozygous ft/ft mice exhibit large, d isorganized scales on tail and paw skin, marked attenuation of the epiderma l granular layer, mild acanthosis, and orthokeratotic hyperkeratosis. Bioch emical analysis demonstrated that ft/ft mice lacked normal high molecular p rofilaggrin (approximate to 500 kDa), and instead expressed a lower molecul ar weight form of profilaggrin (220 kDa) that is not proteolytically proces sed to profilaggrin intermediates or filaggrin. Mutant mice lacked the larg e, irregular F-type keratohyalin granules that contain profilaggrin, and fi laggrin was absent from the cornified layers of ft/ft epidermis. The expres sion of epidermal keratins was unchanged, whereas the cornified envelope pr oteins involucrin and loricrin were increased in ft/ft epidermis. Cultured ft/ft keratinocytes also synthesized reduced amounts of profilaggrin mRNA a nd protein, demonstrating that the defect in profilaggrin expression is int rinsic to epidermal cells. These findings demonstrate that flaky tail mice express an abnormal profilaggrin polypeptide that does not form normal kera tohyalin F-granules and is not proteolytically processed to filaggrin. We p ropose that the absence of filaggrin, and in particular the hygroscopic, fi laggrin-derived amino acids that are thought to function in epidermal hydra tion, underlies the dry, scaly skin characteristic of ft/ft mice. This anim al model provides a tool for understanding the role of filaggrin in normal epidermal function and may provide insight into the molecular basis of the filaggrin-deficient human skin disorder ichthyosis vulgaris.