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Bathing suit ichthyosis is caused by transglutaminase-1 deficiency: evidence for a temperaturesensitive phenotype. Hum Mol Genet 15: 3083-97 Persikov AV, Pillitteri RJ, Amin P et al. (2004) Stability related bias in residues replacing glycines within the collagen triple helix (Gly-Xaa-Yaa) in inherited connective tissue disorders. Hum Mutat 24:330-7 Xu K, Nowak I, Kirchner M et al. (2008) Recombinant collagen studies link the severe conformational changes induced by osteo-genesis imperfecta mutations to the disruption of a set of interchain salt bridges. J Biol Chem 283:34337-44 Woodley DT, Hou Y, Martin S et al. (2008) Characterization of molecular mechanisms underlying mutations in dystrophic epidermolysis bullosa using site-directed mutagenesis.

Ceramides (CERs) in human stratum corneum (SC) play physicochemical roles in determining barrier and waterholding functions of the skin, and specific species might be closely related to the regulation of keratinization, together with other CER-related lipids. Structures of those diverse CER species, however, have not been comprehensively revealed. The aim of this study was to characterize overall CER species in the SC. First, we constructed 3D multi-mass chromatograms of the overall CER species, based on normalphase liquid chromatography (NPLC) connected to electrospray ionization-mass spectrometry (ESI-MS) using a gradient elution system and a postcolumn addition of a volatile saltcontaining polar solvent. The CERs targeted from the 3D chromatograms were structurally analyzed using NPLC-ESItandem mass spectrometry (MS/MS), which resulted in the identification of 342 CER species in the inner forearm SC. This led to the discovery of a new CER class consisting of ahydroxy fatty acid and dihydrosphingosine moieties, in addition to the 10 classes generally known. The results also revealed that those CERs contain long-chain (more than C 18 )-containing sphingoids and a great number of isobaric species. These novel results will contribute not only to physiochemical research on CERs in the SC but also to lipidomics approaches to CERs in the skin.-Masukawa, Y

Mammalian epidermis produces and delivers large quantities of glucosylceramide and sphingomyelin precursors to stratum corneum extracellular domains, where they are hydrolyzed to corresponding ceramide species. This cycle of lipid precursor formation and subsequent hydrolysis represents a mechanism that protects the epidermis against potentially harmful effects of ceramide accumulation within nucleated cell layers. Prominent skin disorders, such as psoriasis and atopic dermatitis, have diminished epidermal ceramide levels, reflecting altered sphingolipid metabolism, that may contribute to disease severity/ progression. Enzymatic processes in the hydrolysis of glucosylceramide and sphingomyelin, and the roles of sphingolipids in skin diseases, are the focus of this review. Keywords: ABCA12; Barrier; Ceramide; Dermis; Epidermis; Gaucher; Glucocerebrosidase; Glucosylceramides; Ichthyosis; Niemann-Pick; Prosaposin; Saposins; Sphingolipid; Sphingomyelin; Sphingomyelinase; Stratum corneum Sphingolipids in the structure and function of mammalian epidermisMammalian skin is composed of two distinct layers divided by a basement membrane zone: (1) the underlying dermis containing primarily fibroblasts embedded in an acellular collagen/elastin matrix that accounts for the majority of skin thickness; and (2) the overlying epidermis, responsible for formation and maintenance of the skin barrier to both desiccation and penetration of xenobiotics. The function of this barrier resides primarily in the extracellular lipid domains between the outermost, enucleated cells, called corneocytes, of the stratum corneum (SC). Mammalian SC contains extensive quantities of lipids, localized to these extracellular domains (interstices), comprised of nearly equimolar quantities of ceramides (Cer), cholesterol, and free fatty acids, a ratio that is imperative for normal organization into the lamellar membrane structures primarily responsible for epidermal barrier homeostasis [1,2]. Cer species comprise approximately half of the total intercellular lipid content by weight, and are critical for these lamellar membrane structures [3,4]. The specific roles for Cer in epidermal function have been revealed in studies with both normal and diseased human skin, as well as animal models and model membranes in vitro [5,6]. For example, the Cer content is altered in patients with both atopic dermatitis [7][8][9] and psoriasis [10,11] (discussed further below). Likewise, cholesterol as well as both essential and non-essential free fatty acids play separate, critical roles in epidermal barrier homeostasis.Given that human SC contains at least nine major Cer fractions (see Fig. 1), many of which are unique to the epidermis, including omega(x)-hydroxylated and x-acylated forms, as well as x-hydroxy-Cer species that are covalently attached via the x-hydroxyl of the N-acyl fatty acid to cornified envelope proteins of the enucleate stratum corneum cells (i.e., corneocytes), the metabolism of these unique sphingolipids is of significant interest. It is ...

The stratum corneum of the skin of patients with atopic dermatitis is highly susceptible to colonization by various bacteria, including Staphylococcus aureus. The defense system of the skin against bacterial invasion appears to be significantly disrupted in atopic dermatitis skin, but little is known about the defense mechanism(s) involved. As one sphingolipid metabolite, sphingosine is known to exert a potent antimicrobial effect on S. aureus at physiologic levels, and it may play a significant role in bacterial defense mechanisms of healthy normal skin. Because of the altered ceramide metabolism in atopic dermatitis, the possible alteration of sphingosine metabolism might be associated with the acquired vulnerability to colonization by S. aureus in patients with atopic dermatitis. In this study, we measured the levels of sphingosine in the upper stratum corneum from patients with atopic dermatitis, and then compared that with the colonization levels of bacteria in the same subjects. Levels of sphingosine were significantly downregulated in uninvolved and in involved stratum corneum of patients with atopic dermatitis compared with healthy controls. This decreased level of sphingosine was relevant to the increased numbers of bacteria including S. aureus present in the upper stratum corneum from the same subjects. This suggests the possibility that the increased colonization of bacteria found in patients with atopic dermatitis may result from a deficiency of sphingosine as a natural antimicrobial agent. As for the mechanism involved in the decreased production of sphingosine in atopic dermatitis, analysis of the activities of ceramidases, major sphingosine-producing enzymes, revealed that, whereas the activity of alkaline ceramidase did not differ between patients with atopic dermatitis and healthy controls, the activity of acid ceramidase was significantly reduced in patients with atopic dermatitis and this had obvious relevance to the increased colonization of bacteria in those subjects. Further, there was a close correlation between the level of sphingosines and acid ceramidase (r = 0.65, p < 0.01) or ceramides (r = 0.70, p < 0.01) in the upper stratum corneum from the same patients with atopic dermatitis. Collectively, our results suggest the possibility that vulnerability to bacterial colonization in the skin of patients with atopic dermatitis is associated with reduced levels of a natural antimicrobial agent, sphingosine, which results from decreased levels of ceramides as a substrate and from diminished activities of its metabolic enzyme, acid ceramidase.