Loss of Normal Profilaggrin and Filaggrin in Flaky Tail (ft/ft) Mice: an Animal Model for the Filaggrin-Deficient Skin Disease Ichthyosis Vulgaris

Abstract

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 the neonatal period. Previous studies demonstrated that the ft mutation maps to the central region of mouse chromosome 3, in the vicinity of the epidermal differentiation complex, a gene locus that includes many nonkeratin genes expressed in epidermis. In this study we report a detailed characterization of the flaky tail mouse. Affected homozygous ft/ft mice exhibit large, disorganized scales on tail and paw skin, marked attenuation of the epidermal granular layer, mild acanthosis, and orthokeratotic hyperkeratosis. Biochemical analysis demonstrated that ft/ft mice lacked normal high molecular profilaggrin (approximately 500 kDa), and instead expressed a lower molecular weight form of profilaggrin (220 kDa) that is not proteolytically processed to profilaggrin intermediates or filaggrin. Mutant mice lacked the large, irregular F-type keratohyalin granules that contain profilaggrin, and filaggrin was absent from the cornified layers of ft/ft epidermis. The expression of epidermal keratins was unchanged, whereas the cornified envelope proteins involucrin and loricrin were increased in ft/ft epidermis. Cultured ft/ft keratinocytes also synthesized reduced amounts of profilaggrin mRNA and protein, demonstrating that the defect in profilaggrin expression is intrinsic to epidermal cells. These findings demonstrate that flaky tail mice express an abnormal profilaggrin polypeptide that does not form normal keratohyalin F-granules and is not proteolytically processed to filaggrin. We propose that the absence of filaggrin, and in particular the hygroscopic, filaggrin-derived amino acids that are thought to function in epidermal hydration, underlies the dry, scaly skin characteristic of ft/ft mice. This animal 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. J Invest Dermatol 115:1072-1081 2000

Linkage analysis suggests a locus of ichthyosis vulgaris on 1q22

“…Recently, two multigenerational families with affected individuals showing clinical features of IV but distinct histological features were studied by gene linkage, and the results suggested the epidermal differentiation complex on chromosome 1 might be involved (Compton et al 2002). Furthermore, strong evidence revealed the crucial importance of filaggrin (encoded by FLG) in normal epidermal function and the molecular basis of IV (Nirunsuksiri et al1995;Presland et al 2000). But as far as we know, no mutation of FLG has been found in IV patient.…”

Flaky Tail Mouse as a Novel Animal Model of Atopic Dermatitis: Possible Roles of Filaggrin in the Development of Atopic Dermatitis

“…Flaky tail mice (Flg ft ), first introduced in 1958, are spontaneously mutated mice with smaller ears, tail constrictions, and a flaking tail skin appearance (Lane, 1972). Flg ft mice were outcrossed onto B6 mice at Jackson Laboratory (Bar Harbor, ME, USA) (Lane, 1972, Presland, et al, 2000 (Note: Although this strain was crossed with B6, it is not a B6 congenic strain but rather a hybrid stock that is probably semi-inbred). Homozygous Flg ft mice have dry, flaky skin which expresses reduced amounts of profilaggrin mRNA and abnormal profilaggrin protein that is not processed to filaggrin monomers (Fallon, et al, 2009, Presland, et al, 2000.…”

Skin Diseases in Laboratory Mice: Approaches to Drug Target Identification and Efficacy Screening

“…If the drug works in one model but not another and the gene is known, this can focus on the best homologous human disease to target. [27,23] If the target is known, for example as with filaggrin (Flg) or the closely linked transmembrane protein 79 (Tmem79), which are risk factors for atopic dermatitis [28][29][30][31][32][33][34][35][36][37][38][39], then a mouse with double mutations in Flg and Tmem79, such as the flaky tail-matted mutant mouse (Flg ft Tmem79 ma ) can be used for testing targeted drugs [40,41].…”