Aging and health among migrants in a European perspective

Kristiansen M, Razum O, Tezcan-Güntekin H, Krasnik A. Aging and health among migrants in a European perspective. Public Health Reviews. 2016;37(1): 20

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 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

The ichq mutant mouse, a model for the human skin disorder harlequin ichthyosis: mapping, keratinocyte culture, and consideration of candidate genes involved in epidermal growth regulation.

Harlequin ichthyosis (HI) is a rare and usually fatal scaling skin disorder. The HI mutant mouse (ichq/ichq) has many similarities to the human disorder and provides an important model to identify candidate genes. In this study, we report refined mapping of the mouse ichq locus and consideration of the candidate genes: calpain 1 (Capn1), phospholipase C beta 3 (Plcb3), and Rela and Ikka/Chuk that encode components of the nuclear factor-kappa B (NF-kappaB) pathway. Each are strong candidates because of epidermal expression and/or changes in expression in human HI. All candidates are linked to the ichq locus on mouse Chromosome 19, although Ikka is located more distally. Genetic mapping in mouse has narrowed the ichq critical region to 4 cM. Keratinocytes from skin of +/+, +/ichq and ichq/ichq mice were cultured; all genotypes had similar expression of epidermal differentiation markers. RT-PCR amplification and sequence analysis of each candidate gene did not reveal any mutations in the ichq mouse. Mutational screening of CAPN1 cDNA from different human HI cases revealed a R433P change, but analysis of 50 normal samples demonstrated that this was an apparent polymorphism. Sequence of RELA in five unrelated human HI cases was normal. The results provide compelling evidence that none of these genes are the primary defect in the ichq mouse and that CAPN1 and RELA are not mutated in the human disorder

The impact of onychomycosis on quality of life: development of an international onychomycosis-specific questionnaire to measure patient quality of life.

Onychomycosis is a widespread refractory disease deleteriously affecting quality of life via social stigma and disrupting daily activities. Many physicians perceive onychomycosis as a cosmetic rather than a medical problem.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming.

Loss-of-function mutations in the FLG (filaggrin) gene cause the semidominant keratinizing disorder ichthyosis vulgaris and convey major genetic risk for atopic dermatitis (eczema), eczema-associated asthma and other allergic phenotypes. Several low-frequency FLG null alleles occur in Europeans and Asians, with a cumulative frequency of approximately 9% in Europe. Here we report a 1-bp deletion mutation, 5303delA, analogous to common human FLG mutations, within the murine Flg gene in the spontaneous mouse mutant flaky tail (ft). We demonstrate that topical application of allergen to mice homozygous for this mutation results in cutaneous inflammatory infiltrates and enhanced cutaneous allergen priming with development of allergen-specific antibody responses. These data validate flaky tail as a useful model of filaggrin deficiency and provide experimental evidence for the hypothesis that antigen transfer through a defective epidermal barrier is a key mechanism underlying elevated IgE sensitization and initiation of cutaneous inflammation in humans with filaggrin-related atopic disease