Filaggrin Deficiency Research Articles

No Impact of Filaggrin Deficiency on Epit Efficacy in a Murine Model

No Impact of Filaggrin Deficiency on Epit Efficacy in a Murine Model

Filaggrin genotype does not determine the skin's threshold to UV-induced erythema

Filaggrin genotype does not determine the skin's threshold to UV-induced erythema

Filaggrin and Skin Barrier Function.

The skin barrier function is greatly dependent on the structure and composition of the uppermost layer of the epidermis, the stratum corneum (SC), which is made up of flattened anucleated cells surrounded by highly organized and continuous lipid matrix. The interior of the corneocytes consists mainly of keratin filaments aggregated by filaggrin (FLG) protein. Next, together with several other proteins, FLG is cross-linked into a mechanically robust cornified cell envelope providing a scaffold for the extracellular lipid matrix. In addition to its role for the SC structural and mechanical integrity, FLG degradation products account in part for the water-holding capacity and maintenance of acidic pH of the SC, both crucial for the epidermal barrier homoeostasis by regulating activity of multiple enzymes that control desquamation, lipid synthesis and inflammation. The major determinant of FLG expression in the skin are loss-of-function mutations in FLG, the strongest genetic risk factor for atopic dermatitis (AD), an inflammatory skin disease characterized by a reduced skin barrier function. The prevalence of FLG mutations varies greatly among different populations and ranges from about 10% in Northern Europeans to less than 1% in the African populations. An impaired skin barrier facilitates absorption of potentially hazardous chemicals, which might cause adverse effects in the skin, such as contact dermatitis, or systemic toxicity after their passage into blood. In another direction, a leaky epidermal barrier will lead to enhanced loss of water from the skin. A recent study has shown that even subtle increase in epidermal water loss in newborns increases the risk for AD. Although there are multiple modes of action by which FLG might affect skin barrier it is still unclear whether and how FLG deficiency leads to the reduced skin barrier function. This chapter summarizes the current knowledge in this field obtained from clinical studies, and animal and in vitro models of FLG deficiency.

Influence of Th2 Cytokines on the Cornified Envelope, Tight Junction Proteins, and β-Defensins in Filaggrin-Deficient Skin Equivalents

Atopic dermatitis is a chronic skin condition with complex etiology. It is characterized by skin barrier defects and T helper type 2 (Th2)-polarized inflammation. Although mutations in the filaggrin gene are known to be prominent genetic risk factors for the development of atopic dermatitis, the interdependency between these and an altered cytokine milieu is not fully understood. In this study, we evaluated the direct effects of filaggrin deficiency on the cornified envelope, tight junction proteins, and innate immune response, and report the effects of Th2 cytokines in normal and filaggrin-deficient skin equivalents. Supplementation with IL-4 and IL-13 led to distinct histologic changes and significantly increased skin surface pH, both of which were enhanced in filaggrin knockdown skin equivalents. We detected a compensatory up-regulation of involucrin and occludin in filaggrin-deficient skin that was dramatically disturbed when simultaneous inflammation occurred. Furthermore, we found that a lack of filaggrin triggered an up-regulation of human ?-defensin 2 via an unknown mechanism, which was abolished by Th2 cytokine supplementation. Taken together, these results indicate that defects in the epidermal barrier, skin permeability, and cutaneous innate immune response are not primarily linked to filaggrin deficiency but are rather secondarily induced by Th2 inflammation.

Xerosis is associated with asthma in men independent of atopic dermatitis and filaggrin gene mutations.

Epidermal filaggrin deficiency due to common filaggrin gene (FLG) mutations causes xerosis and strongly increases the risk of atopic dermatitis and even asthma. However, it is unknown whether xerosis independent of FLG mutations could also increase the risk of asthma. To evaluate whether generalized xerosis was associated with asthma, independent of atopic dermatitis and common FLG mutations in a cross-sectional study on adult Danes. A total of 3396 adults from the general population participated in a health examination. Lung function and serum-specific IgE levels to inhalant allergens were measured and information on xerosis and atopic diseases was obtained by means of a questionnaire. Participants were genotypes for the three most common FLG mutations in Northern Europeans: R501X, 2282del4 and R2447X. Fully adjusted logistic regression analyses showed that asthma (either current or at some point in life) was significantly associated with reporting generalized xerosis (OR 1.32; 95% CI 1.02-1.72). The association was stronger in men (OR 1.79; 95% CI 1.13-2.84) when compared to women (OR 1.18; 95% CI 0.86-1.62). Furthermore, a significant association was observed between xerosis and 'allergic asthma' in men (OR 2.13; 95% CI 1.08-4.19). Our findings indicate an association between xerosis and asthma in men independent of atopic dermatitis and FLG mutations. Both facilitated allergen sensitization and secondary degradation of filaggrin following T-helper cell 2 inflammation might be key elements to understanding this relationship.

Sebaceous Gland, Hair Shaft, and Epidermal Barrier Abnormalities in Keratosis Pilaris with and without Filaggrin Deficiency

Although keratosis pilaris (KP) is common, its etiopathogenesis remains unknown. KP is associated clinically with ichthyosis vulgaris and atopic dermatitis and molecular genetically with filaggrin-null mutations. In 20 KP patients and 20 matched controls, we assessed the filaggrin and claudin 1 genotypes, the phenotypes by dermatoscopy, and the morphology by light and transmission electron microscopy. Thirty-five percent of KP patients displayed filaggrin mutations, demonstrating that filaggrin mutations only partially account for the KP phenotype. Major histologic and dermatoscopic findings of KP were hyperkeratosis, hypergranulosis, mild T helper cell type 1-dominant lymphocytic inflammation, plugging of follicular orifices, striking absence of sebaceous glands, and hair shaft abnormalities in KP lesions but not in unaffected skin sites. Changes in barrier function and abnormal paracellular permeability were found in both interfollicular and follicular stratum corneum of lesional KP, which correlated ultrastructurally with impaired extracellular lamellar bilayer maturation and organization. All these features were independent of filaggrin genotype. Moreover, ultrastructure of corneodesmosomes and tight junctions appeared normal, immunohistochemistry for claudin 1 showed no reduction in protein amounts, and molecular analysis of claudin 1 was unremarkable. Our findings suggest that absence of sebaceous glands is an early step in KP pathogenesis, resulting in downstream hair shaft and epithelial barrier abnormalities.

Filaggrin deficiency promotes the dissemination of cutaneously inoculated vaccinia virus

Eczema vaccinatum is a life-threatening complication of smallpox vaccination in patients with atopic dermatitis (AD) characterized by dissemination of vaccinia virus (VV) in the skin and internal organs. Mutations in the filaggrin (FLG) gene, the most common genetic risk factor for AD, confer a greater risk for eczema herpeticum in patients with AD, suggesting that it impairs the response to cutaneous viral infections. We sought to determine the effects of FLG deficiency on the response of mice to cutaneous VV inoculation. VV was inoculated by means of scarification of unsensitized skin or skin topically sensitized with ovalbumin in FLG-deficient flaky tail (ft/ft) mice or wild-type (WT) control mice. The sizes of primary and satellite skin lesions were measured, and hematoxylin and eosin staining was performed. VV genome copy numbers and cytokine mRNA levels were measured by using quantitative PCR. VV inoculation in unsensitized skin of ft/ft mice, independent of the matted hair mutation, resulted in larger primary lesions, more abundant satellite lesions, heavier viral loads in internal organs, greater epidermal thickness, dermal cellular infiltration, and higher local Il17a, Il4, Il13, and Ifng mRNA levels than in WT control mice. VV inoculation at sites of topical ovalbumin application amplified all of these features in ft/ft mice but had no detectable effect in WT control mice. The number of satellite lesions and the viral loads in internal organs after cutaneous VV inoculation were significantly reduced in both unsensitized and topically sensitized ft/ftxIl17a(-/-) mice. FLG deficiency predisposes to eczema vaccinatum. This is mediated primarily through production of IL-17A.

The Role of Filaggrin in the Skin Barrier and Disease Development

Filaggrin is a structural protein that is fundamental in the development and maintenance of the skin barrier. The function of filaggrin and its involvement in various cutaneous and extracutaneous disorders has been the subject of considerable research in recent years. Mutations in FLG, the gene that encodes filaggrin, have been shown to cause ichthyosis vulgaris, increase the risk of atopic dermatitis and other atopic diseases, and exacerbate certain conditions. The present article reviews the current knowledge on the role of filaggrin in the skin barrier, FLG mutations, and the consequences of filaggrin deficiency.

Epidermal tight junction barrier function is altered by skin inflammation, but not by filaggrin-deficient stratum corneum

BackgroundThe tight junction (TJ) barrier is located in the granular layer of the epidermis. Filaggrin deficiency predisposes patients to atopic dermatitis (AD) by impairing stratum corneum (SC) barrier function. Altered TJ barrier function has been observed in the skin of patients with AD; however, it remains unclear whether TJ function is influenced by filaggrin deficiency directly or secondarily via skin inflammation. ObjectiveTo investigate the in vivo effects of filaggrin deficiency and skin inflammation on epidermal TJ function. MethodsMorphological changes in the TJ were investigated in filaggrin knockout mice and mice with hapten-induced dermatitis using en face visualization of epidermal sheets, and functional changes in the TJ were assessed with an in vivo permeation assay using tracers of various sizes. ResultsIn filaggrin knockout mice, there was no apparent change in the honeycomb morphology of the TJ, TJ component mRNA expression, or TJ barrier function in neonates and adults, indicating that filaggrin-deficiency had no direct effects on the TJ. By contrast, in mice with hapten-induced dermatitis, the mRNA expression of TJ components was decreased markedly and the TJ barrier function was size-dependently impaired: the TJ leaked small tracers (<5kDa), but not large tracers (>30kDa). ConclusionFilaggrin deficiency did not affect the epidermal TJ barrier directly, but once dermatitis occurred, the skin inflammation induced TJ dysfunction. Since TJ dysfunction induces the SC barrier impairment, skin inflammation will enhance skin permeability to external antigens and result in a vicious cycle of barrier dysfunction and skin inflammation.

Atopic dermatitis: the updated practice parameter and beyond.

An update to the atopic dermatitis (AD) practice parameter was published in 2013 using an established grading system for determining category of evidence and strength of recommendation. Since the previous update in 2004, a number of seminal observations regarding skin barrier and immune dysregulation in AD have been made with important therapeutic implications. A key addition to the treatment algorithm based on our understanding that normal-appearing skin in patients with AD is not normal is proactive therapy. Studies with both topical steroids and a topical calcineurin inhibitor have shown that in patients with relapsing AD, if they are able to clear or almost clear their eczema, then twice-weekly proactive treatment of normal-appearing skin that tends to flare leads to better disease control. For difficult-to-manage patients, the value of wet wrap therapy is reaffirmed in the practice parameter update. In addition, allergen immunotherapy is now a consideration in select patients with AD and aeroallergen sensitivity. Beyond the practice parameter, novel approaches to filaggrin deficiency are being evaluated. With respect to immune dysregulation, dupilumab, a fully human monoclonal antibody directed at the IL-4 receptor alpha subunit was recently shown to be effective in treating adults with moderate-to-severe AD.

The skin microbiome of caspase-14-deficient mice shows mild dysbiosis.

Caspase-14, an important proteinase involved in filaggrin catabolism, is mainly active in terminally differentiating keratinocytes, where it is required for the generation of skin natural moisturizing factors (NMFs). Consequently, caspase-14 deficient epidermis is characterized by reduced levels of NMFs such as urocanic acid and 2-pyrrolidone-5-carboxylic acid. Patients suffering from filaggrin deficiency are prone to develop atopic dermatitis, which is accompanied with increased microbial burden. Among several reasons, this effect could be due to a decrease in filaggrin breakdown products. In this study, we found that caspase-14(-/-) mice show enhanced antibacterial response compared to wild-type mice when challenged with bacteria. Therefore, we compared the microbial communities between wild-type and caspase-14(-/-) mice by sequencing of bacterial 16S ribosomal RNA genes. We observed that caspase-14 ablation leads to an increase in bacterial richness and diversity during steady-state conditions. Although both wild-type and caspase-14(-/-) skin were dominated by the Firmicutes phylum, the Staphylococcaceae family was reduced in caspase-14(-/-) mice. Altogether, our data demonstrated that caspase-14 deficiency causes the imbalance of the skin-resident bacterial communities.

Individuals with complete filaggrin deficiency may have an increased risk of squamous cell carcinoma

British Journal of DermatologyVolume 170, Issue 6 p. 1380-1381 Correspondence Individuals with complete filaggrin deficiency may have an increased risk of squamous cell carcinoma J. Kaae, J. Kaae jkaae@dadlnet.dk Department of Dermato-Allergology, Gentofte Hospital, University of Copenhagen, 2900-Hellerup, DenmarkSearch for more papers by this authorP.B. Szecsi, P.B. Szecsi Department of Clinical Biochemistry, Gentofte Hospital, University of Copenhagen, Hellerup, DenmarkSearch for more papers by this authorM. Meldgaard, M. Meldgaard Department of Clinical Biochemistry, Gentofte Hospital, University of Copenhagen, Hellerup, DenmarkSearch for more papers by this authorM.L.M. Espersen, M.L.M. Espersen Department of Pathology, Herlev Hospital, University of Copenhagen, Herlev, DenmarkSearch for more papers by this authorS. Stender, S. Stender Department of Clinical Biochemistry, Gentofte Hospital, University of Copenhagen, Hellerup, DenmarkSearch for more papers by this authorJ.D. Johansen, J.D. Johansen National Allergy Research Centre, Gentofte Hospital, University of Copenhagen, Hellerup, DenmarkSearch for more papers by this authorJ. Bandier, J. Bandier National Allergy Research Centre, Gentofte Hospital, University of Copenhagen, Hellerup, DenmarkSearch for more papers by this authorJ.P. Thyssen, J.P. Thyssen Department of Dermato-Allergology, Gentofte Hospital, University of Copenhagen, 2900-Hellerup, DenmarkSearch for more papers by this authorT. Menné, T. Menné Department of Dermato-Allergology, Gentofte Hospital, University of Copenhagen, 2900-Hellerup, DenmarkSearch for more papers by this authorS.L. Nielsen, S.L. Nielsen Department of Pathology, Herlev Hospital, University of Copenhagen, Herlev, DenmarkSearch for more papers by this authorE. Høgdall, E. Høgdall Department of Pathology, Herlev Hospital, University of Copenhagen, Herlev, DenmarkSearch for more papers by this authorE. Balslev, E. Balslev Department of Pathology, Herlev Hospital, University of Copenhagen, Herlev, DenmarkSearch for more papers by this authorL. Skov, L. Skov Department of Dermato-Allergology, Gentofte Hospital, University of Copenhagen, 2900-Hellerup, DenmarkSearch for more papers by this author J. Kaae, J. Kaae jkaae@dadlnet.dk Department of Dermato-Allergology, Gentofte Hospital, University of Copenhagen, 2900-Hellerup, DenmarkSearch for more papers by this authorP.B. Szecsi, P.B. Szecsi Department of Clinical Biochemistry, Gentofte Hospital, University of Copenhagen, Hellerup, DenmarkSearch for more papers by this authorM. Meldgaard, M. Meldgaard Department of Clinical Biochemistry, Gentofte Hospital, University of Copenhagen, Hellerup, DenmarkSearch for more papers by this authorM.L.M. Espersen, M.L.M. Espersen Department of Pathology, Herlev Hospital, University of Copenhagen, Herlev, DenmarkSearch for more papers by this authorS. Stender, S. Stender Department of Clinical Biochemistry, Gentofte Hospital, University of Copenhagen, Hellerup, DenmarkSearch for more papers by this authorJ.D. Johansen, J.D. Johansen National Allergy Research Centre, Gentofte Hospital, University of Copenhagen, Hellerup, DenmarkSearch for more papers by this authorJ. Bandier, J. Bandier National Allergy Research Centre, Gentofte Hospital, University of Copenhagen, Hellerup, DenmarkSearch for more papers by this authorJ.P. Thyssen, J.P. Thyssen Department of Dermato-Allergology, Gentofte Hospital, University of Copenhagen, 2900-Hellerup, DenmarkSearch for more papers by this authorT. Menné, T. Menné Department of Dermato-Allergology, Gentofte Hospital, University of Copenhagen, 2900-Hellerup, DenmarkSearch for more papers by this authorS.L. Nielsen, S.L. Nielsen Department of Pathology, Herlev Hospital, University of Copenhagen, Herlev, DenmarkSearch for more papers by this authorE. Høgdall, E. Høgdall Department of Pathology, Herlev Hospital, University of Copenhagen, Herlev, DenmarkSearch for more papers by this authorE. Balslev, E. Balslev Department of Pathology, Herlev Hospital, University of Copenhagen, Herlev, DenmarkSearch for more papers by this authorL. Skov, L. Skov Department of Dermato-Allergology, Gentofte Hospital, University of Copenhagen, 2900-Hellerup, DenmarkSearch for more papers by this author First published: 21 February 2014 https://doi.org/10.1111/bjd.12911Citations: 13 Funding sources: This work was supported by grants from the Aage Bangs Foundation, Aase Ejnar Danielsens Foundation and The Capital Region of Denmark, Foundation for Health Research. Conflicts of interest: none declared. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume170, Issue6June 2014Pages 1380-1381 RelatedInformation

Evidence That Loss-of-Function Filaggrin Gene Mutations Evolved in Northern Europeans to Favor Intracutaneous Vitamin D3 Production.

Skin pigmentation lightened progressively to a variable extent, as modern humans emigrated out of Africa, but extreme lightening occurred only in northern Europeans. Yet, loss of pigmentation alone cannot suffice to sustain cutaneous vitamin D3 (VD3) formation at the high latitudes of northern Europe. We hypothesized that loss-of-function mutations in the epidermal structural protein, filaggrin (FLG), could have evolved to sustain adequate VD3 status. Loss of FLG results in reduced generation of trans-urocanic acid, the principal endogenous ultraviolet-B (UV-B) filter in lightly-pigmented individuals. Accordingly, we identified a higher prevalence of FLG mutations in northern European populations when compared to more southern European, Asian and African populations that correlates significantly with differences in circulating 25-OH-VD3 levels in these same populations. By allowing additional UV-B penetration and intracutaneous VD3 formation, the latitude-dependent gradient in FLG mutations, likely together with other concurrent mutations in VD3 metabolic pathways, provide a non-pigment-based mechanism that sustains higher levels of circulating VD3 in northern Europeans. At the time that FLG mutations evolved, xerosis due to FLG deficiency was a lesser price to pay for enhanced VD3 production. Yet, the increase in FLG mutations has inadvertently contributed to an epidemic of atopic diseases that has emerged in recent decades.

Increased epidermal filaggrin in chronic idiopathic urticaria is associated with severity of urticaria

BackgroundChronic idiopathic urticaria (CIU) and atopic dermatitis (AD) are common allergic skin diseases associated with severe pruritus. AD skin is characterized by filaggrin deficiency, but it has not been studied in CIU. ObjectiveTo compare the expression of filaggrin in skin from patients with CIU, patients with AD, and normal controls and to investigate whether altered filaggrin expression is associated with CIU severity. MethodsSkin biopsies were obtained from 16 patients with CIU, 11 patients with AD, and 14 normal controls. Filaggrin expression was evaluated using real-time reverse transcriptase polymerase chain reaction and immunostaining. Urticaria activity score, transepidermal water loss, and skin pH were measured. ResultsFLG gene expression was significantly greater in lesional CIU skin compared with lesional AD skin (P < .01). The staining intensity of filaggrin was significantly increased in lesional CIU skin compared with skin from normal controls (P < .01) and lesional AD skin (P < .001). A significant correlation was observed between filaggrin staining intensity and urticaria activity score in patients with CIU (r = 0.538, P < .05). Transepidermal water loss was significantly increased in lesional skin of patients with AD compared with skin from normal controls (P < .01) and lesional skin from patients with CIU (P < .01). Skin pH was significantly decreased in lesional skin from patients with CIU compared with skin from normal controls (P < .01) and patients with AD (P < .001). ConclusionFilaggrin is overexpressed in lesional CIU skin, and increased filaggrin expression is positively correlated with urticaria severity in CIU. Altered filaggrin expression has physiologic effects on transepidermal water loss and pH in the skin of patients with CIU, suggesting increased barrier function compared with skin from patients with AD.

Filagrina: papel en la barrera cutánea y en el desarrollo de patología

Filaggrin is a structural protein that is fundamental in the development and maintenance of the skin barrier. The function of filaggrin and its involvement in various cutaneous and extracutaneous disorders has been the subject of considerable research in recent years. Mutations in FLG, the gene that encodes filaggrin, have been shown to cause ichthyosis vulgaris, increase the risk of atopic dermatitis and other atopic diseases, and exacerbate certain conditions. The present article reviews the current knowledge on the role of filaggrin in the skin barrier, FLG mutations, and the consequences of filaggrin deficiency.

Severe skin inflammation and filaggrin mutation similarly alter the skin barrier in patients with atopic dermatitis

Filaggrin (FLG) deficiency is a well-known predisposing factor for the development of atopic dermatitis (AD). Decreased FLG expression can be the result of haploinsufficiency or severe inflammation, which can cause acquired FLG alterations. FLG mutations are related to several clinical and laboratory parameters of AD; however, some recent data seem to contradict these associations. Our aim was to determine which clinical and biochemical parameters are connected to FLG haploinsufficiency and which ones are also associated with acquired FLG alterations due to severe skin symptoms in patients with AD. We introduced a novel classification of patients with AD, based on FLG mutations and SCORAD (SCORing Atopic Dermatitis). Based on these parameters, we created three groups of patients with AD: mild-to-moderate wild-type (A), severe wild-type (B) and severe mutant (C). In all groups, we assessed laboratory and clinical parameters and performed immunohistochemical analyses. Groups B and C contained patients with equally severe symptoms based on the SCORAD. The two severe groups did not differ significantly with respect to barrier-specific parameters, whereas group A had significantly better results for the barrier function measurements. However, significant differences were detected between groups B and C with respect to the allergic sensitization-specific parameters. These findings suggest that skin barrier function correlates with the severity of skin inflammation and can be equally impaired in patients with FLG mutant- and wild-type AD with severe symptoms. Nevertheless, our results also suggest that patients with FLG mutant-type AD may have a higher risk of allergic sensitization compared with patients with the wild-type.

Filaggrin Deficiency Leads to Impaired Lipid Profile and Altered Acidification Pathways in a 3D Skin Construct

Mutations in the filaggrin (FLG) gene are strongly associated with common dermatological disorders such as atopic dermatitis. However, the exact underlying pathomechanism is still ambiguous. Here, we investigated the impact of FLG on skin lipid composition, organization, and skin acidification using a FLG knockdown (FLG-) skin construct. Initially, sodium/hydrogen antiporter (NHE-1) activity was sufficient to maintain the acidic pH (5.5) of the reconstructed skin. At day 7, the FLG degradation products urocanic (UCA) and pyrrolidone-5-carboxylic acid (PCA) were significantly decreased in FLG- constructs, but the skin surface pH was still physiological owing to an upregulation of NHE-1. At day 14, secretory phospholipase A2 (sPLA2) IIA, which converts phospholipids to fatty acids, was significantly more activated in FLG- than in FLG+. Although NHE-1 and sPLA2 were able to compensate the FLG deficiency, maintain the skin surface pH, and ensured ceramide processing (no differences detected), an accumulation of free fatty acids (2-fold increase) led to less ordered intercellular lipid lamellae and higher permeability of the FLG- constructs. The interplay of the UCA/PCA and the sPLA2/NHE-1 acidification pathways of the skin and the impact of FLG insufficiency on skin lipid composition and organization in reconstructed skin are described.

A Lipid Plant Extract From Chamaecyparis Obtusa Induces Filaggrin and Human Beta-Defensin -3

Patients with atopic dermatitis suffer from skin barrier defects and recurrent skin infections due to filaggrin (FLG) deficiency and reduced antimicrobial peptide expression. Anecdotal reports suggest that plant extracts from Chamaecyparis Obtusa have beneficial effects on skin health. However, it has not been reported whether they modulate FLG and human beta defensin (HBD)-3. Therefore, we investigated whether a lipid plant extract from Chamaecyparis Obtusa induces FLG and HBD-3.

Use of emollients in atopic dermatitis: a questionnaire survey study.

Use of emollients in atopic dermatitis: a questionnaire survey study.

Distinguishing Ichthyoses by Protein Profiling

To explore the usefulness of protein profiling for characterization of ichthyoses, we here determined the profile of human epidermal stratum corneum by shotgun proteomics. Samples were analyzed after collection on tape circles from six anatomic sites (forearm, palm, lower leg, forehead, abdomen, upper back), demonstrating site-specific differences in profiles. Additional samples were collected from the forearms of subjects with ichthyosis vulgaris (filaggrin (FLG) deficiency), recessive X-linked ichthyosis (steroid sulfatase (STS) deficiency) and autosomal recessive congenital ichthyosis type lamellar ichthyosis (transglutaminase 1 (TGM1) deficiency). The ichthyosis protein expression patterns were readily distinguishable from each other and from phenotypically normal epidermis. In general, the degree of departure from normal was lower from ichthyosis vulgaris than from lamellar ichthyosis, parallel to the severity of the phenotype. Analysis of samples from families with ichthyosis vulgaris and concomitant modifying gene mutations (STS deficiency, GJB2 deficiency) permitted correlation of alterations in protein profile with more complex genetic constellations.