Management of Plantar Keratodermas.

Plantar keratodermas can arise due to a variety of genetically inherited mutations. The need to distinguish between different plantar keratoderma disorders is becoming increasingly apparent because there is evidence that they do not respond identically to treatment. Diagnosis can be aided by observation of other clinical manifestations, such as palmar keratoderma, more widespread hyperkeratosis of the epidermis, hair and nail dystrophies, or erythroderma.

In vivo response of GsdmA3(Dfl)/+ mice to topically applied fish oil - effects on cellular markers and macrophages.

Psoriasis is an incurable autoimmune disease characterized by patches of abnormal red, itchy and scaly skin. This work examined the modulation of inflammation, hyperproliferation and immune cell markers following topical application of fish oil (FO) in comparison to the antipsoriatic agents, betamethasone dipropionate (BD) and salicylic acid (SA), to GsdmA3(Dfl)/+ mice, a hair loss mutant which also exhibits epidermal hyperproliferation akin to psoriasis. The mice were dosed with 100 mg of the test formulation and after 10 days, the mice were sacrificed, skin sections excised and subjected to immunohistochemical determination of COX-2, K17 and MAC-1; and immunofluorescence of Ki-67.

Evidence and conjecture about mechanisms of cutaneous disease in photodermatology.

Photosensitivity disorders are caused by a variety of mechanisms. Three common themes are as follows: excess chromophore allowing visible light energy to cause photodynamic damage, reduced DNA repair capacity to UV-induced DNA damage, and enhanced sensitivity to light-induced allergens mediated immunologically. Although the cause of each condition may be known, the precise pathogenesis underlying the photosensitivity has taken longer to understand.

Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in human subjects.

Background: Atopic dermatitis (AD) is a major inflammatory condition of the skin caused by inherited skin barrier deficiency, with mutations in the filaggrin gene predisposing to development of AD. Support for barrier deficiency initiating AD came from flaky tail mice, which have a frameshift mutation in Flg and also carry an unknown gene, matted, causing a matted hair phenotype.

Objective: We sought to identify the matted mutant gene in mice and further define whether mutations in the human gene were associated with AD.

Intense pulsed light enhances transforming growth factor beta1/Smad3 signaling in acne-prone skin.

Background: Recently, much interest has been generated in the use of intense pulsed light (IPL) sources in the treatment of various skin conditions. However, the underlying mechanism for its therapeutic action has not been elucidated.

Objective: To investigate the effect of IPL on the in vivo expression of transforming growth factor beta1 (TGF-β1) and on the immunolocalization of Smad3 in biopsies obtained from perilesional skin in patients with mild-to-moderate inflammatory acne vulgaris.

In vivo response of GsdmA3Dfl/+ mice to topically applied anti-psoriatic agents: effects on epidermal thickness, as determined by optical coherence tomography and H&E staining.

This study evaluated in vivo the potential of optical coherence tomography (OCT) to determine changes in thickness of the epidermis in response to the topically applied anti-psoriatics betamethasone dipropionate (BD), salicylic acid (SA) and also fish oil (FO). GsdmA3Dfl/+ mice have an inflammatory hair loss phenotype that includes hyperproliferation and epidermal thickening, hence a potential psoriasis model. Changes in epidermal thickness were evaluated over a period of 10 days, with the mice treated with combined BD + SA, FO + SA and BD + FO + SA.

Delineating immune-mediated mechanisms underlying hair follicle destruction in the mouse mutant defolliculated.

Defolliculated (Gsdma3(Dfl)/+) mice have a hair loss phenotype that involves an aberrant hair cycle, altered sebaceous gland differentiation with reduced sebum production, chronic inflammation, and ultimately the loss of the hair follicle. Hair loss in these mice is similar to that seen in primary cicatricial, or scarring alopecias in which immune targeting of hair follicle stem cells has been proposed as a key factor resulting in permanent hair follicle destruction. In this study we examine the mechanism of hair loss in GsdmA3(Dfl)/+ mice.

Palmitoylation regulates epidermal homeostasis and hair follicle differentiation.

Palmitoylation is a key post-translational modification mediated by a family of DHHC-containing palmitoyl acyl-transferases (PATs). Unlike other lipid modifications, palmitoylation is reversible and thus often regulates dynamic protein interactions. We find that the mouse hair loss mutant, depilated, (dep) is due to a single amino acid deletion in the PAT, Zdhhc21, resulting in protein mislocalization and loss of palmitoylation activity.

The new keratin nomenclature.

When the first nomenclature of the keratin protein family was published over 20 years ago, only 19 keratins were thought to exist. Sequencing of the human genome has now revealed that there are 54 keratin genes. As a consequence, the nomenclature needed revision to apply a logical numbering system that includes the more recently identified keratins of the hair follicle.

Mutations in gasdermin 3 cause aberrant differentiation of the hair follicle and sebaceous gland.

Defolliculated (Dfl) is a spontaneous mouse mutant with a hair-loss phenotype that includes altered sebaceous gland differentiation, short hair shafts, aberrant catagen stage of the hair cycle, and eventual loss of the hair follicle. Recently a similar mutant, finnegan (Fgn), with an identical phenotype was discovered during a phenotypic screen for mutations induced by chemical mutagenesis. The gene underlying the phenotype of both finnegan and defolliculated has been mapped to chromosome 11 and here we show that both mice harbor mutations in gasdermin 3 (Gsdm3), a gene of unknown function.

The lanceolate hair rat phenotype results from a missense mutation in a calcium coordinating site of the desmoglein 4 gene.

Desmosomal cadherins are essential cell adhesion molecules present throughout the epidermis and other organs, whose major function is to provide mechanical integrity and stability to epithelial cells in a wide variety of tissues. We recently identified a novel desmoglein family member, Desmoglein 4 (Dsg4), using a positional cloning approach in two families with localized autosomal recessive hypotrichosis (LAH) and in the lanceolate hair (lah) mouse. In this study, we report cloning and identification of the rat Dsg4 gene, in which we discovered a missense mutation in a naturally occurring lanceolate hair (lah) rat mutant.

Phenotypes, genotypes and their contribution to understanding keratin function.

A large number of mutations in keratin genes underlie inherited tissue fragility disorders of epithelia. The genotype-phenotype correlations emerging from these studies provide a rich source of information about the function of keratins that would have taken decades to achieve by a purely transgenic approach. Human disease studies are being supplemented by engineered mouse mutant studies, which give access to the effects of genetic alterations unlikely to occur naturally.

Mouse models for human hair loss disorders.

The outer surface of the hand, limb and body is covered by the epidermis, which is elaborated into a number of specialized appendages, evolved not only to protect and reinforce the skin but also for social signalling. The most prominent of these appendages is the hair follicle. Hair follicles are remarkable because of their prolific growth characteristics and their complexity of differentiation.

Cloning of human, murine, and marsupial keratin 7 and a survey of K7 expression in the mouse.

Keratins are cytoplasmic intermediate filament proteins expressed by epithelial cells. Keratin 7 (K7) is expressed in a wide range of epithelial structures in humans. We have cloned and fully sequenced the human and mouse K7 genes and mRNAs, and the K7 mRNA from the marsupial Potorous tridactylis, from which the widely used simple epithelial cell lines PtK1 and PtK2 are derived.

Defolliculated (dfl): a dominant mouse mutation leading to poor sebaceous gland differentiation and total elimination of pelage follicles.

Defolliculated is a novel spontaneous mouse mutation that maps to chromosome 11 close to the type I keratin locus. Histology shows abnormal differentiation of the sebaceous gland, with the sebocytes producing little or no sebum and undergoing abnormal cornification. The hair follicles fail to regress during catagen leading to abnormally long follicles.

Characterization of early assembly intermediates of recombinant human keratins.

The intermediate filaments (IFs) form major structural elements of the cytoskeleton. In vitro analyses of these fibrous proteins reveal very different assembly properties for the nuclear and cytoplasmic IF proteins. However, keratins in particular, the largest and most heterogenous group of cytoplasmic IF proteins, have been difficult to analyze due to their rapid assembly dynamics under the near-physiological conditions used for other IF proteins.