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  • 1
    Abstract: The genetic basis of epidermolysis bullosa, a group of genetic disorders characterized by the mechanically induced formation of skin blisters, is largely known, but a number of cases still remain genetically unsolved. Here, we used whole-exome and targeted sequencing to identify monoallelic mutations, c.1A〉G and c.2T〉C, in the translation initiation codon of the gene encoding kelch-like protein 24 (KLHL24) in 14 individuals with a distinct skin-fragility phenotype and skin cleavage within basal keratinocytes. Remarkably, mutation c.1A〉G occurred de novo and was recurrent in families originating from different countries. The striking similarities of the clinical features of the affected individuals point to a unique and very specific pathomechanism. We showed that mutations in the translation initiation codon of KLHL24 lead to the usage of a downstream translation initiation site with the same reading frame and formation of a truncated polypeptide. The pathobiology was examined in keratinocytes and fibroblasts of the affected individuals and via expression of mutant KLHL24, and we found mutant KLHL24 to be associated with abnormalities of intermediate filaments in keratinocytes and fibroblasts. In particular, KLHL24 mutations were associated with irregular and fragmented keratin 14. Recombinant overexpression of normal KLHL24 promoted keratin 14 degradation, whereas mutant KLHL24 showed less activity than the normal molecule. These findings identify KLHL24 mutations as a cause of skin fragility and identify a role for KLHL24 in maintaining the balance between intermediate filament stability and degradation required for skin integrity.
    Type of Publication: Journal article published
    PubMed ID: 27889062
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 408 (1986), S. 527-540 
    ISSN: 1432-2307
    Keywords: Involucrin ; Adnexal skin tumours
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The expression of involucrin was studied in a group of skin neoplasms, mostly of adnexal origin. As happens with other types of epithelial tumours, involucrin was detected in the most differentiated areas (presenting a squamoid or ductal differentiation). No reactivity was observed in non-epithelial skin tumours. These results suggest that involucrin is a specific marker for epithelial and adnexal differentiation of skin tumours and may thus be a useful aid in histopathologic diagnosis and classification of neoplasms.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-069X
    Keywords: Dermal ; Epidermal junction ; Basement membrane ; Skin ; NU-T2 antibody ; Bullous dermatoses
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract NU-T2 is a mouse monoclonal IgG1 antibody to the CD1b molecule, (cross-)reacting with an antigen of the dermal-epidermal junction (NU-T2 DEJ AG). Further immunohistochemical characterization of the NU-T2 DEJ AG showed it to display unique properties that differentiate it from other known antigens of the dermal-epidermal junction. Indeed, the NU-T2 DEJ AG is primate-specific and present only in epithelial basement membranes. In normal human skin it is expressed within the lowermost lamina lucida of the dermal-epidermal junction but not in the deep part of epidermal appendages nor in the deep part of epidermal appendages nor in the basement membrane of dermal vessels, smooth muscles or nerves. In diseases with intraepidermal or intradermal cleavage, NU-T2 reactivity was observed at the floor of the blister. In various skin specimens with a cleavage through the lamina lucida (NaCl — or dispase-split skin, bullous pemphigoid, junctional epidermolysis bullosa), NU-T2 immunoreactivity seemed reduced, being localized at the dermal side of the cleavage. These results suggest that the antigen recognized by NU-T2 is a novel component of the lamina lucida of the dermal-epidermal junction, that seems to be important for dermal-epidermal adhesion.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The very late antigens, or VLA proteins, are a family of cell surface heterodimers (α1–6β1) that mediate cell adhesion to specific components of the extracellular matrix (collagens, fibronectin, laminin). In normal human epidermis, the common VLA β1 subunit is expressed on basal keratinocytes (BK). Langerhans cells (LC) and melanocytes. By means of light and electron microscopic immunostaining procedures, we have investigated the distribution of VLA α1,2,3,4,6 subunits on normal human adult and foetal epidermal cells, α1 antigen expression was not observed on any epidermal cell type. Both during foetal development and in adult epidermis, α2 and α3 were strongly expressed on the cell membrane of BK, while α6 was mainly expressed at their dermal pole. These different patterns of distribution suggest that the α6 subunit may mediate BK anchorage to the basement membrane zone, while the α2 and α3 subunits may also be involved in intercellular adhesion. Moreover, with immunoelectron microscopy, LC were seen to be weakly α4 and α6 positive and melanocytes were α3 and α6 positive. Thus, VLA proteins are expressed by epidermal cells in a cell-type-specific pattern that could be related to particular functional roles of these proteins.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background  The NC16A immunodominant region of the bullous pemphigoid (BP) antigen BP180 has been used to develop several enzyme-linked immunosorbent assays (ELISAs) as diagnostic tools for BP autoantibody detection.Objectives  Because BP180 autoantibody reactivity is not restricted to NC16A, we have investigated the possibility of developing an ELISA based on selected epitopes additional to this immunodominant region.Methods  Initially 78 BP sera were tested using an NC16A ELISA and IgG reactivity was detected in 64 BP sera (82%). The 14 NC16A-negative BP sera were then analysed by immunological screening against seven BP180-specific epitopes. Recombinant phages displaying BP180 epitopes were grown as plaques, blotted onto a nitrocellulose filter and incubated with BP sera.Results  Three and five NC16A-negative BP sera reacted with epitopes AA 1080–1107 and AA 1331–1404 of the BP180 ectodomain, respectively. Thus, a novel ELISA with GST-1080 and GST-1331 (GST-1080/1331) was developed: 32 of 78 BP sera (41%) proved positive by this assay. The combined use of ELISAs with GST-NC16A and GST-1080/1331 detected IgG reactivity in 72 of 78 BP sera, increasing the sensitivity from 82% to 92%. In addition, autoreactivity against the three extracellular epitopes appeared to be related to the presence of both skin and mucosal involvement as assessed by Fisher's exact probability test.Conclusions  Our findings further characterize the autoimmune response in BP by identifying a subgroup of NC16A-negative patients who react with different BP180 extracellular epitopes. The developed ELISA system appears more sensitive than the ELISA based on NC16A alone and also informative about the epitope profile of BP patients.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background  Disseminated superficial actinic porokeratosis (DSAP) is the most common porokeratosis and is characterized by multiple keratotic lesions which tend to occur at sun-exposed sites. A mild hypersensitivity to X-rays has been reported for DSAP-derived fibroblasts and frequent over-expression of p53 has been found in lesional epidermis.Objectives  In order to clarify whether genome maintenance mechanisms might be compromised in this disease the following approaches were undertaken: (i) primary cultured keratinocytes and fibroblasts from DSAP patients were characterized for ultraviolet (UV) B and X-ray response; (ii) 15 lesions were studied for p53 mutations, and (iii) the differentiation status of DSAP-derived keratinocytes was evaluated.Methods  Primary cultures of keratinocytes and fibroblasts were established from lesional and nonlesional skin biopsies of two subjects with DSAP. p53 mutations were analysed by DNA sequencing of the conserved region of the TP53 gene. Differentiation was evaluated both in stratified epithelial sheets from confluent keratinocyte cultures and in organotypic skin cultures.Results  The cytotoxic and apoptotic response to UVB or X-irradiation was similar in DSAP-derived keratinocytes and fibroblasts when compared with normal cells. Two of 15 lesions examined presented p53 mutations located at nondipyrimidine sites. A strikingly decreased expression of filaggrin was observed both in reconstructed epidermis and in reconstructed skin.Conclusions  The UVB and X-ray response of DSAP-derived keratinocytes and fibroblasts indicates that the actinic character of this skin pathology is not due to radiation hypersensitivity. In agreement with this finding, mutations in the p53 gene, which are often associated with UV-related skin carcinogenesis, were rarely detected in DSAP lesions and were not UV-specific. Reconstructed epidermis and reconstructed skin models successfully reproduced the main features of this genodermatosis, showing that DSAP-derived keratinocytes bear an inherent defect in the terminal differentiation programme.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Summary Classic Kaposi's sarcoma, with primary bone lesions, is described in an HIV-seronegative man. The bone involvement, painful lytic lesions in the right leg and both feet, was shown by magnetic resonance and histology not to be contiguous with the skin lesions. Chemotherapy with vinblastine and doxorubicin. significantly reduced the skin and bone lesions, and pain also improved.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: We have studied the expression of involucrin in a variety of keratinization disorders, mostly of genetic origin using an avidin-biotin-peroxidase technique. In normal human epidermis 25% of the living epidermis was labelled. The diseases studied fell into two groups. Diseases with greatly increased involucrin staining including collodion baby (38%), Darier's disease (49%), Flegel's disease (56%), erythrokeratoderma variabilis (6o%), epidermal naevus with epidermolytic hyperkeratosis (45%) and congential bullous (58%) and non-bullous (44%) ichythyosiform erythroderma; and diseases with normal or slightly increased staining, including ichthyosis vulgaris (27%), X-linked ichthyosis (25%), confluent and reticulate papillomatosis (27%) and simple epidermal naevus (28%). These results demonstrate that involucrin exression is altered in some keratinization disorders and suggest that in such conditions cellular functions other than keratin metabolism are also affected.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background  Junctional epidermolysis bullosa with pyloric atresia (PA-JEB) is a rare autosomal recessive genodermatosis that manifests with neonatal mucocutaneous blistering and gastric outlet obstruction. The disease, which is caused by mutations in the α6β4 integrin genes (ITGA6, ITGB4), is usually lethal. However, nonlethal cases have also been reported. Mutation database analysis has suggested that premature termination codons predominantly result in lethal forms while missense mutations frequently associate with nonlethal variants. Nevertheless, it is becoming more and more evident that the disease phenotype is also influenced by the position of the mutation in the protein functional domains.Objective  To investigate the molecular basis of a novel PA-JEB lethal case.Methods  Reverse transcriptase–polymerase chain reaction and direct sequencing-based mutation screening were performed. Mutation consequences in the patient's keratinocytes were then analysed by Northern blot and immunoprecipitation. Immunofluorescence analysis of cultured keratinocytes treated with protein intracellular degradation pathway inhibitors was also carried out.Results  The phenotype was caused by the presence, in the homozygous state, of a novel 33 bp in-frame deletion (nucleotides 175–207) in the ITGB4 coding sequence. Despite the normal steady-state level of integrin β4 mRNA, the mutation, designated ΔR59-A69, results in the almost complete absence of α6β4 integrin in the patient's skin and cultured keratinocytes. Exposure of the patient's keratinocytes to the proteasomal inhibitor clasto-lactacystin β-lactone increased the expression of the mutated β4 integrin chains indicating that the proteasome complex is involved in the degradation of the internally deleted β4 polypeptides.Conclusions  We report for the first time a homozygous in-frame deletion in the ITGB4 gene. Our results suggest that the deletion of amino acids R59-A69 interferes with the biosynthetic folding of the protein, leading to a rapid degradation of the mutated β4 chains. These findings provide new insight into the pathogenic effects of mutations affecting different functional domains of the β4 integrin molecule and their prognostic implications in PA-JEB patients.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background Dystrophic epidermolysis bullosa (DEB) is a bullous skin disease caused by mutations in the type VII collagen gene (COL7A1). Objectives To elucidate the mutations shown by two patients with DEB and understand the clinical phenotypes that they displayed. Methods We have characterized two patients, one affected by the severe recessive Hallopeau–Siemens variant of DEB (HS-RDEB) and the other by a milder recessive DEB form. Results In both patients we identified the R2063W missense mutation. The second mutation, in the HS-RDEB patient, was a novel 344insG, leading to a premature termination codon of translation (PTC) in exon 3, while, in the other patient, it was a novel 4965C→T transition, which creates a new donor splice site in exon 53. The effect of this anomalous splice site leads to the maturation of a 17-nucleotides-deleted mRNA containing a PTC. In addition to this aberrant transcript, a certain amount of full-length mRNA is also generated from the mutated pre-mRNA through splicing at the canonical site. Conclusions In these patients therefore the severity of the phenotype depends on the second mutation. In the patient with the 344insG mutation, leading to a PTC, type VII collagen (COLVII) molecules are exclusively composed of chains containing the R2063W substitution; as a consequence, all anchoring fibrils (AF) are abnormal and the phenotype is severe. In the other patient, the 4965C→T splicing mutation allows the synthesis of a certain quantity of normal chains and the consequent assembly of partially functional COLVII molecules and AF, thus explaining the mild phenotype.
    Type of Medium: Electronic Resource
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