60 research outputs found
Deletion of LCE3C and LCE3B genes at PSORS4 does not contribute to susceptibility to psoriatic arthritis in German patients
A Mutational Hotspot in the 2B Domain of Human Hair Basic Keratin 6 (hHb6) in Monilethrix Patients
Monilethrix is an inherited hair dystrophy in which affected, fragile, hairs have an unique beaded morphology. Ultrastructural studies suggest a defect in filament structure in the cortex of the hair, and the hard keratins of hair and nail are thus candidate genes. In several families with autosomal dominant monilethrix, the disorder has been linked to the type II keratin gene cluster at chromosome 12q13. Recently, causative mutations in the critical helix termination motif in the 2B domain of the human hair basic keratin 6 (hHb6) have been identified. We now report the results of sequencing this domain in 13 unrelated families or cases with monilethrix. Five of the 13 had the same mutation as previously found, a G to A transversion leading to a lysine for glutamic acid substitution (E413K) in the 2B domain (residue 117 of the 2B helix) of hHb6. The mutation was confirmed by a restriction fragment length polymorphism assay developed for this purpose, and, as this mutation is evidently a common cause of the syndrome, for use in screening other cases. In eight families or cases, however, including three in whom linkage data are consistent with a defect at the type II keratin locus, no mutation was found in this domain of hHb6
Vitamin D Status in Distinct Types of Ichthyosis: Importance of Genetic Type and Severity of Scaling
Data on vitamin D status of patients with inherited ichthyosis in Europe is scarce and unspecific concerning the genetic subtype. This study determined serum levels of 25-hydroxyvitamin D3 (25(OH)D3) in 87 patients with ichthyosis; 69 patients were additionally analysed for parathyroid hormone. Vitamin D deficiency was pronounced in keratinopathic ichthyosis (n = 17; median 25(OH)D3: 10.5 ng/ml), harlequin ichthyosis (n = 2;7.0 ng/ml) and rare syndromic subtypes (n = 3; 7.0 ng/ml). Vitamin D levels were reduced in TG1-proficient lamellar ichthyosis (n = 15; 8.9 ng/ml), TG1-deficient lamellar ichthyosis (n = 12; 11.7 ng/ml), congenital ichthyosiform erythroderma (n = 13; 12.4 ng/ml), Netherton syndrome (n = 7; 10.7 ng/ml) and X-linked ichthyosis (n = 8; 13.9 ng/ml). In ichthyosis vulgaris 25(OH)D3 levels were higher (n = 10; 19.7 ng/ml). Parathyroid hormone was elevated in 12 patients. Low 25(OH)D3 levels were associated with high severity of scaling (p = 0.03) implicating scaling as a risk factor for vitamin D deficiency. Thus, this study supports our recent guidelines for ichthyoses, which recommend screening for and substituting of vitamin D deficiency
Tumor necrosis factor polymorphisms in psoriatic arthritis : association with the promoter polymorphism TNF-857 independent of the PSORS1 risk allele
Poster presentation Background Single nucleotide polymorphisms (SNPs) of the TNF gene at positions -238 and -308 have earlier been associated with psoriasis vulgaris and psoriatic arthritis (PsA). However, a strong linkage disequilibrium at the chromosomal region 6p21 renders the interpretation of these findings difficult since also other risk factors for psoriasis (PSORS1) than SNPs of the TNF gene have bee mapped to that particular region. Therefore, in this study several SNPs of the TNF gene and of its neighbouring lymphotoxin alpha (LTA) gene were analysed independently and dependently on carrying the PSORS1 risk allele. Methods SNPs in the promoter of the TNF gene (-238G/A, -308G/A, -857C/T, -1031T/C), and one SNP of the LTA gene (+252A/G), of the TNLFRSF1A gene (+36A/G) and of the TNLFRSF1B gene (+676T/G), respectively, were genotyped in 375 psoriasis patients, 375 PsA patients, and 376 controls. The tryptophan–tryptophan–cysteine–cysteine haplotype of the CCHCR1 gene (CCHCR1*WWCC) was used to estimate the genetic impact of the PSORS1 risk allele. Results Whereas an earlier-described association of allele TNF*-238A with psoriasis could be confirmed, our study revealed that this association was completely dependent on concomitant carriage of the PSORS1 risk allele. For PsA, but not psoriasis vulgaris without joint manifestations, strong association with the allele TNF*-857T was detected (OR = 1.956; P value corrected for multiple testing, Pcorr = 0.0025) also in patients negative for the PSORS1 risk allele. Conclusion Our results indicate genetic differences between psoriasis vulgaris patients with and without joint manifestation. While the previously reported association between TNF*-238A and psoriasis seems to primarily reflect linkage disequilibrium with PSORS1, TNF*-857T may represent a risk factor for PsA independent of PSORS1. A potential pathophysiologic relevance of the elucidated genetic association is further suggested by previously reported experimental evidence for a functional impact of the respective TNF polymorphism on TNFalpha expression levels
Themenheft 11 "Schuppenflechte"
Die Schuppenflechte (Psoriasis) ist eine chronisch entzündliche Hauterkrankung, die schätzungsweise 2 Millionen Menschen in Deutschland betrifft. Epidemiologische Studien sprechen dafür, dass Männer und Frauen gleich häufig betroffen sind. Innerhalb des Spektrums der Psoriasis werden die Hauptformen der Psoriasis vulgaris oder gewöhnliche Schuppenflechte, die mit Eiterbläschen einhergehende Psoriasis pustulosa und die Psoriasis-Arthritis oder Gelenk-Psoriasis unterschieden
Ichthyoses—A Clinical and Pathological Spectrum from Heterogeneous Cornification Disorders to Inflammation
Ichthyoses are inborn keratinization disorders affecting the skin only (non-syndromic) or are associated with diseases of internal organs (syndromic). In newborns, they can be life-threatening. The identification of the gene defects resulted in reclassification and a better understanding of the pathophysiology. Histopathologic patterns include orthohyperkeratosis with a reduced or well-developed stratum granulosum, hyperkeratosis with ortho- and parakeratosis with preserved or prominent stratum granulosum, and epidermolytic ichthyosis. Another pattern features “perinuclear vacuoles and binucleated keratinocytes”, which is associated with keratin mutations. Some ichthyoses are histologically defined by psoriasis-like features, and distinct subtypes show follicular hyperkeratosis. In addition to histological and immunohistochemical methods, these patterns allow a better histopathologic diagnosis
Beta-Actin is a Target for Transglutaminase Activity at Synaptic Endings in Chicken Telencephalic Cell Cultures
Topical enzyme-replacement therapy restores transglutaminase 1 activity and corrects architecture of transglutaminase-1-deficient skin grafts
et al.Transglutaminase-1 (TG1)-deficient autosomal-recessive congenital ichthyosis (ARCI) is a rare and severe genetic skin disease caused by mutations in TGM1. It is characterized by collodion babies at birth, dramatically increased transepidermal water loss (TEWL), and lifelong pronounced scaling. The disease has a tremendous burden, including the problem of stigmatization. Currently, no therapy targeting the molecular cause is available, and the therapeutic situation is deplorable. In this study, we developed the basis for a causative therapy aiming at the delivery of the enzyme to the inner site of the keratinocytes’ plasma membrane. We prepared sterically stabilized liposomes with encapsulated recombinant human TG1 (rhTG1) and equipped with a highly cationic lipopeptide vector to mediate cellular uptake. The liposomes overcame the problems of insufficient cutaneous delivery and membrane penetration and provided excellent availability and activity of rhTG1 in primary keratinocytes. To demonstrate the general feasibility of this therapeutic approach in a humanized context, we used a skin-humanized mouse model. Treatment with rhTG1 liposomes resulted in considerable improvement of the ichthyosis phenotype and in normalization of the regenerated ARCI skin: in situ monitoring showed a restoration of TG1 activity, and cholesterol clefts vanished ultrastructurally. Measurement of TEWL revealed a restoration of epidermal barrier function. We regard this aspect as a major advance over available nonspecific approaches making use of, for example, retinoid creams. We conclude that this topical approach is a promising strategy for restoring epidermal integrity and barrier function and provides a causal cure for individuals with TG1 deficiency.This work was supported by the Bundesministerium für Bildung und Forschung as part of the Network for Ichthyosis and Related Keratinization Disorders (NIRK) (grants 01GM0901 and 01GM0902), the Foundation for Ichthyosis and Related Skin Types, and the Selbsthilfe Ichthyose e.V. F.L. was supported in part by the Instituto de Salud Carlos III (grant PI11/1225) and by grant S2010/BMD-2359 from C.M. M.D.R. was supported by the Ministerio de Ciencia y Innovación (grant SAF2010-16976). The work of M.D. was partially supported by Deutsche Forschungsgemeinschaft (grant DA 324/9-1).Peer reviewe
Transglutaminases in autoimmune and inherited skin diseases: The phenomena of epitope spreading and functional compensation
Transglutaminases (TGs) are structurally and functionally related enzymes that modify the post-translational structure and activity of proteins or peptides, and thus are able to turn on or switch off their function. Depending on location and activities, TGs are able to modify the signalling, the function and the fate of cells and extracellular connective tissues. Besides mouse models, human diseases enable us to appreciate the function of various TGs. In this study, skin diseases induced by genetic damages or autoimmune targeting of these enzymes will be discussed. TG1, TG3 and TG5 contribute to the cutaneous barrier and thus to the integrity and function of epidermis. TGM1 mutations related to autosomal recessive ichthyosis subtypes, TGM5 mutations to a mild epidermolysis bullosa phenotype and as novelty TGM3 mutation to uncombable hair syndrome will be discussed. Autoimmunity to TG2, TG3 and TG6 may develop in a few of those genetically determined individuals who lost tolerance to gluten, and manifest as coeliac disease, dermatitis herpetiformis or gluten-dependent neurological symptoms, respectively. These gluten responder diseases commonly occur in combination. In autoimmune diseases, the epitope spreading is remarkable, while in some inherited pathologies, a unique compensation of the lost enzyme function is noted
A functional analysis of pathogenic variants in NIPAL4 in patients with congenital ichthyosis
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