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  • 1
    Abstract: Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of monogenic genodermatoses that encompasses non-syndromic disorders of keratinization. The pathophysiology of ARCI has been linked to a disturbance in epidermal lipid metabolism that impaired the stratum corneum function, leading to permeability barrier defects. Functional characterization of some genes involved in ARCI contributed to the identification of molecular actors involved in epidermal lipid synthesis, transport or processing. Recently, PNPLA1 has been identified as a gene causing ARCI. While other members of PNPLA family are key elements in lipid metabolism, the function of PNPLA1 remained unclear. We identified 5 novel PNPLA1 mutations in ARCI patients, mainly localized in the putative active enzymatic domain of PNPLA1. To investigate Pnpla1 biological role, we analysed Pnpla1-deficient mice. KO mice died soon after birth from severe epidermal permeability defects. Pnpla1-deficient skin presented an important impairment in the composition and organization of the epidermal lipids. Quantification of epidermal ceramide species highlighted a blockade in the production of omega-O-acylceramides with a concomitant accumulation of their precursors in the KO. The virtually loss of omega-O-acylceramides in the stratum corneum was linked to a defective lipid coverage of the resistant pericellular shell encapsulating corneocytes, the so-called cornified envelope, and most probably disorganized the extracellular lipid matrix. Finally, these defects in omega-O-acylceramides synthesis and cornified envelope formation were also evidenced in the stratum corneum from PNPLA1-mutated patients. Overall, our data support that PNPLA1/Pnpla1 is a key player in the formation of omega-O-acylceramide, a crucial process for the epidermal permeability barrier function.
    Type of Publication: Journal article published
    PubMed ID: 28369476
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  • 2
    Keywords: EXPRESSION ; AGENTS ; human ; GENE ; PROTEIN ; DIFFERENTIATION ; TISSUE ; MICE ; MECHANISM ; INDUCTION ; TISSUES ; KERATINOCYTES ; mechanisms ; SKIN ; SEQUENCE ; SEQUENCES ; STAGE ; TRANSGENIC MICE ; IDENTIFICATION ; PROMOTER ; transgenic ; REGION ; FRANCE ; hyperproliferation ; epidermis ; TERMINAL DIFFERENTIATION ; LAYER ; MAMMALIAN-TISSUES ; HASSALLS CORPUSCLES ; FOLLICLE ; HAIR-FOLLICLES ; HUMAN TISSUES ; INNER-ROOT-SHEATH ; AGENT ; PATTERN ; HAIR FOLLICLE ; corneodesmosin ; CORNIFIED EPITHELIA ; GENE PROMOTER ; hyperkeratosis ; KERATINOCYTE DIFFERENTIATION ; promoter regions ; PSORIASIS SUSCEPTIBILITY ; REPORTER GENE ; S GENE ; STRATUM-CORNEUM
    Abstract: Corneodesmosin (CDSN) is a desmosomal protein expressed in the epidermis during the late stages of differentiation and in the inner root sheath of hair follicles. The homophilic adhesive properties of the protein suggest that it reinforces keratinocyte cohesion in the upper layers of the epidermis (stratum granulosum and stratum corneum). In this study, we analyzed the expression of the CDSN gene in 16 human tissues. We confirmed the closely restricted expression pattern of CSDN. Indeed, apart from the skin, the mRNA was significantly detected only in the placenta and the thymus. As a step in elucidating the mechanisms of tissue-specific expression, transgenic mice bearing a 4.2 kb fragment of the human CSDN gene promoter linked to the LacZ gene were generated. The reporter-gene expression was detected in special areas of the inner root sheath of the hair follicles and the hair medulla but not in the epidermis. Induction of epidermis hyperproliferation however either by pharmacological agents or by wounding led to strong expression of the reporter gene in the keratinocytes of the stratum granulosum and the parakeratotic corneocytes of the stratum corneum. The data suggest that the genomic sequences and/or regulating factors responsible for the cell-specific expression of the human CDSN gene in the normal hair follicle as well as in the hyperproliferative epidermis are different from those necessary for expression in the normal epidermis
    Type of Publication: Journal article published
    PubMed ID: 15086560
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  • 3
    Abstract: Omega-O-acylceramides are epidermis-specific ceramides that play a crucial role in establishment and maintenance of skin permeability barrier. Recent advances elucidated several molecular actors involved in the multistep catalytic process resulting in omega-O-acylceramides. However, the acyltransferase which catalyzes final incorporation of linoleic acid into omega-hydroxyceramides remained unknown. PNPLA1 has recently been identified as a gene causing Autosomal Recessive Congenital Ichthyosis (ARCI), a subgroup of ichthyoses. Using a next generation sequencing approach, we identified 5 novel mutations in heterozygous composite patients from 3 non-consanguineous families. Invalidation of Pnpla1 in mice induced death soon after birth from severe epidermal barrier defects. KO skin presented an important impairment in the composition and organization of the epidermal lipids. More particularly, the production of omega-O-acylceramides and subsequently of protein-bound ceramides of the cornified lipid envelope was blocked in the absence of Pnpla1. These alterations in stratum corneum lipids were evidenced in epidermis from PNPLA1-mutated patients. Overall, our data sustain that PNPLA1/Pnpla1 is most probably the previously unknown acyltransferase which catalyzes the esterification of omega-hydroxyceramides with linoleic acid to form omega-O-acylceramides, a crucial lipid species required for proper barrier function. This finding brings new insights into the metabolism of stratum corneum lipids in normal epidermis and enhances our understanding of the pathophysiology of ARCI.
    Type of Publication: Meeting abstract published
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  • 4
    ISSN: 0531-5565
    Keywords: cell aging ; cytogerontology ; ionizing radiation ; radiation of cells
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Over the past 8 years, we have followed a child born as a harlequin baby, who survived due to treatment with retinoids. His condition evolved clinically towards the erythrodermic form of lamellar ichthyosis (non-bullous congenital ichthyosiform erythroderma, NBCIE). According to ultrastructural and biochemical criteria, our patient originally presented with type II harlequin ichthyosis. Investigations showed an abnormal keratinosome structure and extrusion, a keratin pattern characteristic for epidermal hyperproliferation, and an absence of conversion of profilaggrin to filaggrin. Persisting keratinocyte hyperproliferation, associated with the presence of a dermal infiltrate, is in agreement with the present clinical picture of severe NBCIE. However, abnormal lamellar body production and defective filaggrin processing, which is not one of the diagnostic criteria of NBCIE, persist in the patient's skin. Further studies of the epidermal lipid composition, and of possible mutations of the keratinocyte transglutaminase gene performed on epidermal cell cultures of harlequin ichthyosis, will be necessary before type II harlequin ichthyosis can be accepted as an extremely severe form of NBCIE.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The stratum corneum (SC) has long been considered as a sort of inert membrane destined to be shed at the surface of the epidermis. During the last two decades, however, several lines of evidence have been reported, suggesting that active physical and chemical changes take place in the horny layer despite the absence of intracytoplasmic organelles. In particular, processing of filaggrin, replacement of the plasma membrane by a ceramide envelope and constant, progressive modification of extracellular lipid multilayers have been put forward. Recently, attention has focused on the intercellular junctions, which may be involved in the regulation of SC desquamation. Corneodesmosin, a newly discovered protein of SC desmosomes (corneodesmosomes), is synthesized at the latest stages of keratinocyte differentiation and persists between the horny cells until desquamation occurs. In the present study, we performed immunohistochemical and immuno-ultrastructural investigations on corneodesmosin expression in various skin lesions characterized by abnormal production and/or retention of the horny layer. Our results suggest that corneodesmosin expression is independent from profilaggrin synthesis. We found corneodesmosin in almost all morphologically recognizable corneodesmosomal structures and specifically those which persisted up to the SC surface. Hyperkeratotic lesions which are characterized by an increased number of junctions showed intense immunoreactivity with anticorneodesmosin antibody. A complete absence of corneodesmosin was not observed in any disease. This finding, together with our previous biochemical studies, suggests that corneodesmosin may exert a protective function against proteolytic degradation of corneodesmosomes both in normal skin and in the pathological horny layer.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-069X
    Keywords: Corneodesmosin ; Desmosomes ; Cornification ; Stratum corneum ; Desquamation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Corneodesmosin, defined as the protein recognized by the monoclonal antibody G36-19, is a recently described late differentiation protein of human cornified epithelium. In the stratum corneum it is localized in the extracellular parts of modified desmosomes (corneodesmosomes) and adjacent parts of the cornified cell envelope. The aim of the present study was to investigate whether corneodesmosin undergoes changes in the stratum corneum which can be related to the cohesive state of the tissue and to desquamation. Extracts of plantar stratum corneum from various tissue levels and tape-stripped non-palmoplantar stratum corneum were analysed by immunoblotting with G36-19. In addition, the fate of corneodesmosin during shedding of surface cells in a recently described in vitro model of desquamation in plantar stratum corneum was investigated and compared with the degradation of the desmosomal protein desmoglein I in this system. The apparent molecular weights of the major G36-19-positive components in plantar stratum corneum ranged between 33 and 48 kDa. The components with the highest molecular weights were predominant in the deepest tissue layers. In the intermediate tissue layers G36-19-positive components of molecular weight 33–36, 39 and 44–48 kDa were found. There seemed to be a further degradation of the 33 to 36-kDa components in the most superficial parts of the tissue. In surface cells dissociated in vivo as well as in vitro no G36-19-positive components with molecular weights above 36 kDa were detected. Results from analyses of nonpalmoplantar stratum corneum suggested that corneodesmosin is degraded in this tissue in a way that may be similar to that in plantar stratum corneum. In the in vitro system, EDTA caused a marked stimulation of the further degradation of the 33 to 36-kDa G36-19-positive components, but appeared not to affect the degradation of desmoglein I. The results are compatible with a role of corneodesmosin in stratum corneum cell cohesion. The degradation of this protein may be one of the biochemical changes in the stratum corneum which ultimately leads to desquamation.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1573-8221
    Keywords: immunohistochemistry ; monoclonal antibodies ; reserve cells ; cervix uteri
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 0047-6374
    Keywords: Aging ; Catalase ; Glutathione peroxidase ; Paramecium tetraurelia ; Superoxidismutase
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1573-6822
    Keywords: 4,4′-bipyridyl ; cell toxicity ; epidermal differentiation ; keratinocytes ; precursor of paraquat ; reconstructed skin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Recent epidemiological studies have brought to light a possible link between premalignant or neoplastic skin lesions (Bowen disease, squamous carcinoma) and occupational exposure to 4,4′-bipyridyl (4,4′B), a precursor in the synthesis of paraquat herbicide. The present study used a serum-free cell culture of normal human keratinocytes (NHK) and two skin-equivalent models to test the effects of exposure to different concentrations of 4,4′B. Cytotoxicity of 4,4′B on NHK was measured by neutral red release assay. Superoxide dismutase (SOD) activity and cell cycle were analyzed in exposed and nonexposed NHK cultures. Histological and immunohistological tests enabled evaluation of differentiation and proliferation effects in reconstructed-skin models. Results showed that significant cytotoxicity occurred after 5 to 11 days' exposure to 4,4′B concentrations of 10-6-10-3 mol/L (IC50 between 10-3 and 10-4 mol/L 4,4′B after 11 days). Parallel modifications of SOD activity were recorded. Histological and immunohistological analysis revealed dose-related 4,4′B effects in reconstructed skin models. This involved abnormal terminal differentiation, connected with filaggrin expression, observed in skin models exposed to 10-7 and 10-6 mol/L 4,4′B. However, no modification of cell cycle or dysplasia was detected as a result of exposure to 4,4′B. Thus, 4,4′B appears to be cytotoxic for NHK, but as an isolated contaminant, and is unable to induce keratinocyte dysplasia in vitro. These preliminary results do not exclude a cocarcinogenic action of 4,4′B (with UVB for example).
    Type of Medium: Electronic Resource
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