Plasminogen activator inhibitor-2 is expressed in different types of congenital ichthyosis: In vivo evidence for its cross-linking into the cornified cell envelope by transglutaminase-1

10.1111/j.1365-2133.2005.07109.xBritish Journal of Dermatology1545860-867BJDE

Bathing suit ichthyosis is caused by transglutaminase-1 deficiency: evidence for a temperature-sensitive phenotype

Bathing suit ichthyosis (BSI) is a striking and unique clinical form of autosomal recessive congenital ichthyosis characterized by pronounced scaling on the bathing suit areas but sparing of the extremities and the central face. Here we report on a series of ten BSI patients. Our genetic, ultrastructural and biochemical investigations show that BSI is caused by transglutaminase-1 (TGase-1) deficiency. Altogether we identified 13 mutations in TGM1 - among them seven novel missense mutations and one novel nonsense mutation. Structural modelling for the Tyr276Asn mutation reveals that the residue is buried in the hydrophobic interior of the enzyme and that the hydroxyl side chain of Tyr276 is exposed to solvent in a cavity of the enzyme. Cryosections of healthy skin areas demonstrated an almost normal TGase activity, in contrast to the affected BSI skin, which only showed a cytoplasmic and clearly reduced TGase-1 activity. The distribution of TGase-1 substrates in the epidermis of affected skin corresponded to the situation in TGase-1 deficiency. Interestingly, the expression of TGase-3 and cathepsin D was reduced. Digital thermography validated a striking correlation between warmer body areas and presence of scaling in patients suggesting a decisive influence of the skin temperature. In situ TGase testing in skin of BSI patients demonstrated a marked decrease of enzyme activity when the temperature was increased from 25 degrees C to 37 degrees C. We conclude that BSI is caused by TGase-1 deficiency and suggest that it is a temperature sensitive phenotype

Models for heritable skin diseases: correlation of morphological and molecular data

International audienceA number of genodermatoses are characterized by distinct morphological markers which have been and are used for classification and diagnosis as well as for identifying causative gene mutations and pathogenetic pathways. Various types of animal models and organotypic cell cultures have been established to provide further insight into disease mechanisms and treatment. Selected examples are: (i) a spontaneous rat model for dominant epidermolysis bullosa revealing similar variability of anchoring fibril expression as in human patients; (ii) PNPLA1 as a new gene involved in autosomal recessive congenital ichthyosis pathology identified from a Golden Retriever breed spontaneously affected by lamellar ichthyosis; (iii) knockout mice for lipoxygenases expressing differential skin barrier defects and compensatory hyperkeratosis; (iv) a long-term skin-humanized mouse model for transglutaminase 1-deficient lamellar ichthyosis, obviously in some respects advantageous to organotypic cell cultures and successfully having been used for enzyme substitution therapy; (v) Persian cat with classical Ehlers-Danlos syndrome. Investigation of such monogenetic disease models can help to understand causal correlations between pathology and clinical manifestations and provide insights towards developing and evaluating novel causal therapies

Interactions of Hyaluronic Acid with the Skin and Implications for the Dermal Delivery of Biomacromolecules

Hyaluronic acid (HA) hydrogels are interesting delivery systems for topical applications. Besides moisturizing the skin and improving wound healing, HA facilitates topical drug absorption and is highly compatible with labile biomacromolecules. Hence, in this study we investigated the influence of HA hydrogels with different molecular weights (5 kDa, 100 kDa, 1 MDa) on the skin absorption of the model protein bovine serum albumin (BSA) using fluorescence lifetime imaging microscopy (FLIM). To elucidate the interactions of HA with the stratum corneum and the skin absorption of HA itself, we combined FLIM and Fourier-transform infrared (FTIR) spectroscopy. Our results revealed distinct formulation and skin-dependent effects. In barrier deficient (tape-stripped) skin, BSA alone penetrated into dermal layers. When BSA and HA were applied together, however, penetration was restricted to the epidermis. In normal skin, penetration enhancement of BSA into the epidermis was observed when applying low molecular weight HA (5 kDa). Fluorescence resonance energy transfer analysis indicated close interactions between HA and BSA under these conditions. FTIR spectroscopic analysis of HA interactions with stratum corneum constituents showed an α-helix to β-sheet interconversion of keratin in the stratum corneum, increased skin hydration, and intense interactions between 100 kDa HA and the skin lipids resulting in a more disordered arrangement of the latter. In conclusion, HA hydrogels restricted the delivery of biomacromolecules to the stratum corneum and viable epidermis in barrier deficient skin, and therefore seem to be potential topical drug vehicles. In contrast, HA acted as an enhancer for delivery in normal skin, probably mediated by a combination of cotransport, increased skin hydration, and modifications of the stratum corneum properties

Revised nomenclature and classification of inherited ichthyoses:Results of the First Ichthyosis Consensus Conference in Sorze 2009

BACKGROUND: Inherited ichthyoses belong to a large, clinically and etiologically heterogeneous group of mendelian disorders of cornification, typically involving the entire integument. Over the recent years, much progress has been made defining their molecular causes. However, there is no internationally accepted classification and terminology. OBJECTIVE: We sought to establish a consensus for the nomenclature and classification of inherited ichthyoses. METHODS: The classification project started at the First World Conference on Ichthyosis in 2007. A large international network of expert clinicians, skin pathologists, and geneticists entertained an interactive dialogue over 2 years, eventually leading to the First Ichthyosis Consensus Conference held in Sorèze, France, on January 23 and 24, 2009, where subcommittees on different issues proposed terminology that was debated until consensus was reached. RESULTS: It was agreed that currently the nosology should remain clinically based. "Syndromic" versus "nonsyndromic" forms provide a useful major subdivision. Several clinical terms and controversial disease names have been redefined: eg, the group caused by keratin mutations is referred to by the umbrella term, "keratinopathic ichthyosis"-under which are included epidermolytic ichthyosis, superficial epidermolytic ichthyosis, and ichthyosis Curth-Macklin. "Autosomal recessive congenital ichthyosis" is proposed as an umbrella term for the harlequin ichthyosis, lamellar ichthyosis, and the congenital ichthyosiform erythroderma group. LIMITATIONS: As more becomes known about these diseases in the future, modifications will be needed. CONCLUSION: We have achieved an international consensus for the classification of inherited ichthyosis that should be useful for all clinicians and can serve as reference point for future research