Summary
Background
Peeling skin syndrome type 1 (PSS1) is a rare and severe autosomal recessive form of congenital ichthyosis. Patients are affected by pronounced erythroderma accompanied by pruritus ...and superficial generalized peeling of the skin. The disease is caused by nonsense mutations or complete deletion of the CDSN gene encoding for corneodesmosin (CDSN). PSS1 severely impairs quality of life and therapeutic approaches are totally unsatisfactory.
Objectives
The objective of this study was to develop the first steps towards a specific protein replacement therapy for CDSN deficiency. Using this approach, we aimed to restore the lack of CDSN and improve cell–cell cohesion in the transition area of the stratum granulosum (SG) to the stratum corneum.
Methods
Human CDSN was recombinantly expressed in Escherichia coli. A liposome‐based carrier system, prepared with a cationic lipopeptide to mediate the transport to the outer membrane of keratinocytes, was developed. This formulation was chosen for CDSN delivery into the skin. The liposomal carrier system was characterized with respect to size, stability and toxicity. Furthermore, the interaction with primary keratinocytes and human epidermal equivalents was investigated.
Results
The liposomes showed an accumulation at the membranes of keratinocytes. CDSN‐deficient epidermal equivalents that were treated with liposomal encapsulated CDSN demonstrated presence of CDSN in the SG. Finally, the penetration assay and histological examinations revealed an improved epidermal integrity for CDSN‐deficient epidermal equivalents, if they were treated with liposomal encapsulated CDSN.
Conclusions
This study presents the first preclinical in vitro experiments for a future specific protein replacement therapy for patients affected by PSS1.
What is already known about this topic?
Peeling skin syndrome type 1 (PSS1) refers to Mendelian disorders of cornification and is characterized by pruritus, pronounced erythroderma with skin abnormalities and lifelong patchy peeling of the skin.
The disease is caused by autosomal recessive nonsense mutations in the gene encoding corneodesmosin (CDSN). Histopathologically, the absence of CDSN is characterized by subcorneal splitting and enhanced detachment of corneocytes.
What does this study add?
We present a liposomal formulation, which can be used for topical delivery of recombinant CDSN.
Our in vitro study shows that the impaired barrier of CDSN‐deficient human epidermal equivalents can be improved when treated with liposomal human CDSN.
What is the translational message?
This study presents, for the first time, preclinical in vitro experiments for a specific protein replacement therapy in patients with PSS1.
Linked Comment: Schmuth. Br J Dermatol 2021; 184:998–999.
Summary
Background
Transglutaminase (TG)1 plays a key role in the formation of the cornified envelope and thus in the maintenance of the epidermal barrier. Patients with Netherton syndrome (LEKTI ...deficiency) have increased activity of both TG1 and serin proteases.
Objectives
To determine whether there is a functional biochemical link between TG1 and LEKTI and whether LEKTI domains could possibly serve as substrates for TG1.
Methods
We analysed the protein sequence of LEKTI for possible TG1 recognition sites using bioinformatics. Synthetic peptides and recombinant LEKTI domains D6, D7 and D8+9 were examined in vitro and in situ for possible substrate specificity. The recombinant LEKTI domains were studied for inhibitory activity in a kallikrein (KLK)5 activity test.
Results
We identified possible TG1 consensus sequences in LEKTI domains D6, D7 and D8+9, pointing to a novel biological link between these two proteins. Indeed, synthesized short peptides from these consensus sequences were incorporated into the TG1 activity zone of the epidermis. In vitro the entire recombinant domains of LEKTI showed substrate specificity for TG1, which was again confirmed in situ. The inhibitory activity of the recombinant LEKTI domains was confirmed by a KLK5 inhibition test. The strongest inhibition was observed for domains D8+9.
Conclusions
There are specific domains of LEKTI that are recognized and processed by TG1. LEKTI domains D6, D7 and D8+9 contribute to the formation and protection of the cornified envelope. These results impact the development of protein replacement therapy approaches for Netherton syndrome.
What's already known about this topic?
LEKTI and transglutaminase (TG)1 are key proteins involved in the terminal differentiation of the epidermis.
Lack of LEKTI causes Netherton syndrome; TG1 deficiency causes lamellar ichthyosis.
The serine protease inhibitor LEKTI is processed into different functional units.
Among different target proteases, kallikrein (KLK)5 appears to be a key player in disease pathology.
It has been demonstrated that LEKTI domain 6 inhibits KLK5 and KLK7; LEKTI domains 8–11 also inhibit KLK14.
What does this study add?
The single LEKTI domains 6, 7 and the functional unit of domains 8 and 9 contain recognition motifs for TG1.
We show that these domains and unit are crosslinked into the epidermis by TG1.
Functional analyses of the recombinant LEKTI domains revealed that LEKTI D8+9 has the strongest inhibitory effect on KLK5.
What is the translational message?
The novel functional link between LEKTI and TG1 should be taken into account when considering the development of a targeted topical protein therapy for Netherton syndrome.
The unit of domains D8+9 may be sufficient for this purpose.
Respond to this article
Background
Ichthyosis vulgaris (IV) is caused by loss‐of‐function mutations in the profilaggrin (FLG) gene. Filaggrin drives complex interrelated functions, with strategic roles in establishing ...structural and chemical barrier function, hydration of the skin and maintaining epidermal homeostasis. Data on the effect of FLG mutations on epidermal barrier function in IV are very scarce.
Objectives
A primary aim of this study was to determine in vivo characteristics of epidermal permeability barrier function such as transepidermal water loss (TEWL), skin hydration and skin surface pH in homozygous or compound heterozygous (FLG−/−) and heterozygous (FLG+/−) subjects with IV.
Methods
We evaluated a cohort of 15 patients with IV, analysed epidermal ultrastructure and investigated epidermal barrier function by measurement of TEWL, skin surface pH and skin hydration. Mutations were screened by restriction enzyme analysis and/or complete sequencing. Ten patients were homozygous or compound heterozygous (FLG−/−), while five patients were heterozygous (FLG+/−). Twenty healthy individuals served as controls.
Results
In FLG−/− subjects, a moderate increase of TEWL from 5.41 ± 0.32–7.54 ± 0.90 g/m2h (P < 0.03) and a moderate decrease of skin hydration from 29.20 ± 1.96 to 20.17 ± 3.60 (P < 0.05) in comparison with the control group were observed. Changes in skin surface pH were not significant. FLG+/− subjects did not suffer from significant changes in all variables.
Conclusions
A complete, but not a partial deficiency is associated with moderate changes in TEWL and skin hydration, revealing surprisingly only a mild disturbance of the epidermal permeability barrier function.
Peeling skin syndromes (PSS) refer to a heterogeneous group of generalized and/or palmoplantar disorders. Inflammatory peeling skin disease (PSD) refers to PSS type B MIM 270300 (1) and is an ...ichthyosiform erythroderma characterized by recurrent patchy peeling of the skin with accompanying pruritus. The disease persists throughout life, is accompanied by significant atopic manifestations, and can be reminiscent of Netherton syndrome (NTS).
Common Futures Schismenos, Alexandros; Tarinski, Yavor
2020, 2020-11-01
eBook
What does the future hold? Is the desertification of the planet, driven by state and corporate authority, the final horizon of history? Is the dystopian future implied by the systemic degradation of ...nature and society inescapable? From marginal activist groups to governments and interstate organizations, all appear to be concerned with what the future of our shared world will look like. Yet even amid the ongoing global crisis caused by capitalism, the potential of a different, radically rooted future has also appeared. Common Futures explores the global emergence of twenty-first-century social movements, opposed to capitalism and state authority. These movements, Yavor Tarinski and Alexandros Schismenos show, transcend traditional political forms of organization and try to form autonomous networks premised on direct democracy and solidarity. The authors identify the importance of grassroots movements, which can bring radical change and create a more democratic and ecological future.Common Futures examines the social and political roots of the environmental crisis and the relationship between ecology and direct democracy. But Tarinski and Schismenos go beyond the analysis of crises, contemporary struggles, and social movements: Common Futures also clarifies the conditions for the re-creation of free public time and space and point to practical steps that we can take to alleviate the problems of our future.
Generalized peeling skin disease is an autosomal-recessive ichthyosiform erythroderma characterized by lifelong patchy peeling of the skin. After genome-wide linkage analysis, we have identified a ...homozygous nonsense mutation in
CDSN in a large consanguineous family with generalized peeling skin, pruritus, and food allergies, which leads to a complete loss of corneodesmosin. In contrast to hypotrichosis simplex, which can be associated with specific dominant
CDSN mutations, peeling skin disease is characterized by a complete loss of
CDSN expression. The skin phenotype is consistent with a recent murine
Cdsn knockout model. Using three-dimensional human skin models, we demonstrate that lack of corneodesmosin causes an epidermal barrier defect supposed to account for the predisposition to atopic diseases, and we confirm the role of corneodesmosin as a decisive epidermal adhesion molecule. Therefore, peeling skin disease will represent a new model disorder for atopic diseases, similarly to Netherton syndrome and ichthyosis vulgaris in the recent past.
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