Christina Seebode
University of Göttingen
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Featured researches published by Christina Seebode.
Journal Der Deutschen Dermatologischen Gesellschaft | 2014
Stina Schiller; Christina Seebode; Hans Christian Hennies; Kathrin A. Giehl; Steffen Emmert
Palmoplantar keratodermas (PPK) comprise a heterogeneous group of keratinization disorders with hyperkeratotic thickening of palms and soles. Sporadic or acquired forms of PPKs and genetic or hereditary forms exist. Differentiation between acquired and hereditary forms is essential for adequate treatment and patient counseling. Acquired forms of PPK have many causes. A plethora of mutations in many genes can cause hereditary PPK. In recent years several new causative genes have been identified. Individual PPK may be quite heterogeneous with respect to presentation and associated symptoms. Since the various hereditary PPK – like many other monogenic diseases – exhibit a very low prevalence, making of the correct diagnosis is challenging and often requires a molecular genetic analysis. Knowledge about the large but quite heterogeneous group of hereditary PPK is also important to dissect the molecular mechanisms of epidermal differentiation on palms and soles, ultimately leading to targeted corrective therapies in the future.
Experimental Dermatology | 2013
Annika Schäfer; Alexei Gratchev; Christina Seebode; Lars Hofmann; Steffen Schubert; Petra Laspe; Antje Apel; Andreas Ohlenbusch; Mladen Tzvetkov; Carsten Weishaupt; Vinzenz Oji; Michael P. Schön; Steffen Emmert
The xeroderma pigmentosum (XP) group D protein is involved in nucleotide excision repair (NER) as well as in basal transcription. Determined by the type of XPD mutation, six different clinical entities have been distinguished: XP, XP with neurological symptoms, trichothiodystrophy (TTD), XP⁄TTD complex, XP⁄Cockayne syndrome (CS) complex or the cerebro‐oculo‐facio‐skeletal syndrome (COFS). We identified nine new XPD‐deficient patients. Their fibroblasts showed reduced post‐UV cell survival, reduced NER capacity, normal XPD mRNA expression and partly reduced XPD protein expression. Six patients exhibited a XP phenotype in accordance with established XP‐causing mutations (c.2079G>A, p.R683Q; c.2078G>T, p.R683W; c.1833G>T, p.R601L; c.1878G>C, p.R616P; c.1878G>A, p.R616Q). One TTD patient was homozygous for the known TTD‐causing mutation p.R722W (c.2195C>T). Two patients were compound heterozygous for a TTD‐causing mutation (c.366G>A, p.R112H) and a novel p.D681H (c.2072G>C) amino acid exchange, but exhibited different TTD and XP/CS complex phenotypes, respectively. Interestingly, the XP/CS patients cells exhibited a reduced but well detectable XPD protein expression compared with hardly detectable XPD expression of the TTD patients cells. Same mutations with different clinical outcomes in NER‐defective patients demonstrate the complexity of phenotype–genotype correlations, for example relating to additional genetic variations (parental consanguinity), different allelic expression due to SNPs or differences in the methylation status.
Cellular and Molecular Life Sciences | 2017
Janin Lehmann; Christina Seebode; Sabine Smolorz; Steffen Schubert; Steffen Emmert
The XPF/ERCC1 heterodimeric complex is essentially involved in nucleotide excision repair (NER), interstrand crosslink (ICL), and double-strand break repair. Defects in XPF lead to severe diseases like xeroderma pigmentosum (XP). Up until now, XP-F patient cells have been utilized for functional analyses. Due to the multiple roles of the XPF/ERCC1 complex, these patient cells retain at least one full-length allele and residual repair capabilities. Despite the essential function of the XPF/ERCC1 complex for the human organism, we successfully generated a viable immortalised human XPF knockout cell line with complete loss of XPF using the CRISPR/Cas9 technique in fetal lung fibroblasts (MRC5Vi cells). These cells showed a markedly increased sensitivity to UVC, cisplatin, and psoralen activated by UVA as well as reduced repair capabilities for NER and ICL repair as assessed by reporter gene assays. Using the newly generated knockout cells, we could show that human XPF is markedly involved in homologous recombination repair (HRR) but dispensable for non-homologous end-joining (NHEJ). Notably, ERCC1 was not detectable in the nucleus of the XPF knockout cells indicating the necessity of a functional XPF/ERCC1 heterodimer to allow ERCC1 to enter the nucleus. Overexpression of wild-type XPF could reverse this effect as well as the repair deficiencies.
Experimental Dermatology | 2016
Stina Schiller; Christina Seebode; Georg L. Wieser; Sandra Goebbels; Torben Ruhwedel; Mia Horowitz; Debora Rapaport; Ofer Sarig; Eli Sprecher; Steffen Emmert
melanin through the regulation of signalling molecules associated with the melanogenesis both in vitro and in vivo model systems. Experimental design A detailed description of the materials and methods is provided in the supplementary section, see Data S1. Results The cytotoxicity of AA (Fig. 1a) in the melan-a murine melanocytes was determined. AA did not exhibit a significant cytotoxicity (% survival >86%, Figure S1a) and a morphological change (Figure S1b) when treated with up to 20 lM AA. However, as depicted in Fig. 1b, the numbers of pigmented cells was markedly reduced in AA-treated cells. Therefore, further mechanistic studies were performed with the test concentrations of AA up to 20 lM in cultured cells. When primarily determined the tyrosinase inhibition by AA using a mushroom TYR in a cell-free system, AA slightly inhibited the enzyme activity (Fig. 1c). However, AA significantly inhibited the melanin synthesis in a concentration-dependent manner with the IC50 value of 11.5 lM (Fig. 1d, e) in melan-a cells, and the inhibitory activity was comparable to that of a-arbutin, a well-known skin-whitening agent. We next elucidated the mechanism of action in the inhibition of melanin synthesis by AA with the analysis of melanogenesisassociated biomarkers in melanocytes. AA effectively downregulated the melanogenesis-related mRNA expressions of MITF (Figure S2a) and TYR (Figure S2b) compared to those of control cells. AA also significantly suppressed the protein levels of TYR, TRP-1 and TRP-2 expressions (Fig. 2a). The expressions of c-Kit, a relevant upstream regulator of MITF, and a transcription factor SOX10 which acts on promoter region of MITF, were also downregulated by AA (Fig. 2b). The expressions of MITF, TYR and TRP-1 were also suppressed by AA with time exposure until 8 h (Figure S2c). The downregulation of MITF by AA was further confirmed using an immunocytochemical analysis (Fig. 2c). The expressions of MEK1/2 and ERK which involved in melanogenesis pathway (7), and p21, a cofactor of MITF in melanoma cells (8) and also downstream target of MITF (9), were also suppressed by AA (Figure S2d). AA also significantly inhibited the promoter activities of both MITF and TYR (Fig. 2d, e), suggesting that AA affects both the expression and activity of MITF in the melanogenesis. The antimelanogenesis activity of AA was further confirmed in in vivo zebrafish embryo model systems (Fig. 2f). Conclusions In this study, americanin A, a natural lignan, was identified as an effective inhibitor of melanin synthesis by the downregulation of MITF and TYR expressions without affecting the cytotoxicity in melanocytes. Taken together, these findings suggest that the antimelanogenic activity of AA may be attributable to serve as a plausible candidate for a skin-whitening agent through the regulation of MITF signalling pathway. Acknowledgements The wild-type zebrafishes were kindly provided by Dr. Kyu-Won Kim and Dr. Jae-Hak Park (Seoul National University), and this study was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant Number: HN14C0088). Author contributions Y. S., H. J. P., J.-Y. H., S. S. K. and S. K. L. conceived and designed the study. Y. S. and E. J. J. performed the experiments. Y. S. and S. K. L. wrote and revised the manuscript. All authors read and approved the final version of the manuscript. Conflict of interests The authors have declared no conflicting interest. Supporting Information
Hautarzt | 2014
Christina Seebode; Stina Schiller; Steffen Emmert; Kathrin A. Giehl
ZusammenfassungHintergrundErkrankungen der Hände und Füße kommen häufig vor. Dabei sind nicht nur funktionelle Einschränkungen stark belastend, sondern auch die sichtbaren Hautveränderungen stigmatisierend. Zumeist gehen derartige Erkrankungen mit einer Hyperkeratose an den Handflächen und Fußsohlen einher. Grundsätzlich können palmoplantare Keratosen (PPKs) in erworbene, sporadische und genetisch bedingte PPKs eingeteilt werden.FragestellungEin nicht unerheblicher Anteil der PPKs entsteht aufgrund genetisch bedingter Ursachen. Da es sich um eine sehr heterogene Gruppe einzelner Entitäten handelt, ist es für den behandelnden Arzt wichtig zu wissen, wann an genetisch bedingte PPKs und an welche Gene gedacht werden muss.Material und MethodeWir stellen die häufigsten Ursachen erworbener und genetisch bedingter PPKs anhand einer aktuellen Literaturübersicht dar.ErgebnisseDie häufigsten Ursachen erworbener PPKs liegen in entzündlichen Dermatosen wie Psoriasis, Lichen ruber planus oder Hand- und Fußekzemen. Aber auch irritativ toxische PPKs (Vergiftungen mit Arsen oder chlorierten Kohlenwasserstoffen) und infektiöse PPKs (humane Papillomviren, Syphilis, Skabies, Tuberkulose, Lepra und Mykosen) sind nicht selten. Genetisch bedingte PPKs können isoliert, im Rahmen eines Syndroms oder paraneoplastisch auftreten. Die klinische/histologische Klassifikation unterscheidet diffus/flächige, fokal/herdförmige oder punktierte PPKs mit/ohne Epidermolyse. Die Klassifikation nach den zugrunde liegenden Gendefekten löst mehr und mehr die klinische Klassifikation ab.SchlussfolgerungenKenntnisse über die große, jedoch heterogene Gruppe genetisch bedingter PPKs ist wichtig, um den Patienten und seine Familie fundiert beraten und adäquat behandeln zu können.AbstractBackgroundPalmoplantar dermatoses are common. They can be both functionally debilitating and markedly stigmatize the patient because they are so visible. Dermatoses on the hands and feet often go along with palmoplantar hyperkeratosis. Such palmoplantar keratoses (PPK) can be classified into acquired (non-hereditary) and hereditary (monogenetic) PPK.ObjectivesA considerable proportion of PPK develop on the grounds of gene defects. As these diseases constitute a heterogeneous group of quite uncommon single entities, the treating physician must know when to entertain the diagnosis of a hereditary PPK and which causative genes should be considered.MethodsWe summarize the common causes of acquired and hereditary PPK based on a review of the latest literature.ResultsThe most common causes of acquired PPK are inflammatory dermatoses like psoriasis, lichen planus, or hand and feet eczema. Also irritative-toxic (arsenic poisoning, polycyclic aromatic hydrocarbons) and infectious causes of PPK (human papilloma viruses, syphilis, scabies, tuberculosis, mycoses) are not uncommon. Genetically caused PPK may occur isolated, within syndromes or as a paraneoplastic marker. The clinical/histological classification discerns diffuse, focal, or punctuate forms of PPK with and without epidermolysis. A new classification based on the causative gene defect is starting to replace the traditional clinical classification.ConclusionsKnowledge about the large, but heterogeneous group of hereditary PPK is important to adequately counsel and treat patients and their families.BACKGROUND Palmoplantar dermatoses are common. They can be both functionally debilitating and markedly stigmatize the patient because they are so visible. Dermatoses on the hands and feet often go along with palmoplantar hyperkeratosis. Such palmoplantar keratoses (PPK) can be classified into acquired (non-hereditary) and hereditary (monogenetic) PPK. OBJECTIVES A considerable proportion of PPK develop on the grounds of gene defects. As these diseases constitute a heterogeneous group of quite uncommon single entities, the treating physician must know when to entertain the diagnosis of a hereditary PPK and which causative genes should be considered. METHODS We summarize the common causes of acquired and hereditary PPK based on a review of the latest literature. RESULTS The most common causes of acquired PPK are inflammatory dermatoses like psoriasis, lichen planus, or hand and feet eczema. Also irritative-toxic (arsenic poisoning, polycyclic aromatic hydrocarbons) and infectious causes of PPK (human papilloma viruses, syphilis, scabies, tuberculosis, mycoses) are not uncommon. Genetically caused PPK may occur isolated, within syndromes or as a paraneoplastic marker. The clinical/histological classification discerns diffuse, focal, or punctuate forms of PPK with and without epidermolysis. A new classification based on the causative gene defect is starting to replace the traditional clinical classification. CONCLUSIONS Knowledge about the large, but heterogeneous group of hereditary PPK is important to adequately counsel and treat patients and their families.
Hautarzt | 2014
Christina Seebode; Stina Schiller; Steffen Emmert; Kathrin A. Giehl
ZusammenfassungHintergrundErkrankungen der Hände und Füße kommen häufig vor. Dabei sind nicht nur funktionelle Einschränkungen stark belastend, sondern auch die sichtbaren Hautveränderungen stigmatisierend. Zumeist gehen derartige Erkrankungen mit einer Hyperkeratose an den Handflächen und Fußsohlen einher. Grundsätzlich können palmoplantare Keratosen (PPKs) in erworbene, sporadische und genetisch bedingte PPKs eingeteilt werden.FragestellungEin nicht unerheblicher Anteil der PPKs entsteht aufgrund genetisch bedingter Ursachen. Da es sich um eine sehr heterogene Gruppe einzelner Entitäten handelt, ist es für den behandelnden Arzt wichtig zu wissen, wann an genetisch bedingte PPKs und an welche Gene gedacht werden muss.Material und MethodeWir stellen die häufigsten Ursachen erworbener und genetisch bedingter PPKs anhand einer aktuellen Literaturübersicht dar.ErgebnisseDie häufigsten Ursachen erworbener PPKs liegen in entzündlichen Dermatosen wie Psoriasis, Lichen ruber planus oder Hand- und Fußekzemen. Aber auch irritativ toxische PPKs (Vergiftungen mit Arsen oder chlorierten Kohlenwasserstoffen) und infektiöse PPKs (humane Papillomviren, Syphilis, Skabies, Tuberkulose, Lepra und Mykosen) sind nicht selten. Genetisch bedingte PPKs können isoliert, im Rahmen eines Syndroms oder paraneoplastisch auftreten. Die klinische/histologische Klassifikation unterscheidet diffus/flächige, fokal/herdförmige oder punktierte PPKs mit/ohne Epidermolyse. Die Klassifikation nach den zugrunde liegenden Gendefekten löst mehr und mehr die klinische Klassifikation ab.SchlussfolgerungenKenntnisse über die große, jedoch heterogene Gruppe genetisch bedingter PPKs ist wichtig, um den Patienten und seine Familie fundiert beraten und adäquat behandeln zu können.AbstractBackgroundPalmoplantar dermatoses are common. They can be both functionally debilitating and markedly stigmatize the patient because they are so visible. Dermatoses on the hands and feet often go along with palmoplantar hyperkeratosis. Such palmoplantar keratoses (PPK) can be classified into acquired (non-hereditary) and hereditary (monogenetic) PPK.ObjectivesA considerable proportion of PPK develop on the grounds of gene defects. As these diseases constitute a heterogeneous group of quite uncommon single entities, the treating physician must know when to entertain the diagnosis of a hereditary PPK and which causative genes should be considered.MethodsWe summarize the common causes of acquired and hereditary PPK based on a review of the latest literature.ResultsThe most common causes of acquired PPK are inflammatory dermatoses like psoriasis, lichen planus, or hand and feet eczema. Also irritative-toxic (arsenic poisoning, polycyclic aromatic hydrocarbons) and infectious causes of PPK (human papilloma viruses, syphilis, scabies, tuberculosis, mycoses) are not uncommon. Genetically caused PPK may occur isolated, within syndromes or as a paraneoplastic marker. The clinical/histological classification discerns diffuse, focal, or punctuate forms of PPK with and without epidermolysis. A new classification based on the causative gene defect is starting to replace the traditional clinical classification.ConclusionsKnowledge about the large, but heterogeneous group of hereditary PPK is important to adequately counsel and treat patients and their families.BACKGROUND Palmoplantar dermatoses are common. They can be both functionally debilitating and markedly stigmatize the patient because they are so visible. Dermatoses on the hands and feet often go along with palmoplantar hyperkeratosis. Such palmoplantar keratoses (PPK) can be classified into acquired (non-hereditary) and hereditary (monogenetic) PPK. OBJECTIVES A considerable proportion of PPK develop on the grounds of gene defects. As these diseases constitute a heterogeneous group of quite uncommon single entities, the treating physician must know when to entertain the diagnosis of a hereditary PPK and which causative genes should be considered. METHODS We summarize the common causes of acquired and hereditary PPK based on a review of the latest literature. RESULTS The most common causes of acquired PPK are inflammatory dermatoses like psoriasis, lichen planus, or hand and feet eczema. Also irritative-toxic (arsenic poisoning, polycyclic aromatic hydrocarbons) and infectious causes of PPK (human papilloma viruses, syphilis, scabies, tuberculosis, mycoses) are not uncommon. Genetically caused PPK may occur isolated, within syndromes or as a paraneoplastic marker. The clinical/histological classification discerns diffuse, focal, or punctuate forms of PPK with and without epidermolysis. A new classification based on the causative gene defect is starting to replace the traditional clinical classification. CONCLUSIONS Knowledge about the large, but heterogeneous group of hereditary PPK is important to adequately counsel and treat patients and their families.
Journal Der Deutschen Dermatologischen Gesellschaft | 2017
Janin Lehmann; Christina Seebode; Steffen Emmert
Genodermatoses comprise a clinically heterogeneous group of mostly devastating disorders affecting the skin. To date, treatment options have in general been limited to symptom relief. However, the recent technical evolution in genome editing has ushered in a new era in the development of causal therapies for rare monogenetic diseases such as genodermatoses. The present review revisits the advantages and drawbacks of engineered nuclease tools currently available: zinc finger nucleases (ZFNs), transcription activator‐like effector nucleases (TALENs), meganucleases, and – the most innovative – clustered regularly interspaced short palindromic repeats (CRISPR)‐associated (Cas) nuclease 9 (CRISPR/Cas9) system. A mechanistic overview of the different modes of action of these programmable nucleases as well as their significance for causal therapy of genodermatoses is presented. Remaining limitations and challenges such as efficient delivery and off‐target activity are critically discussed, highlighting both the past and future of gene therapy in dermatology.
Oncotarget | 2018
Janin Lehmann; Steffen Schubert; Christina Seebode; Antje Apel; Andreas Ohlenbusch; Steffen Emmert
The two endonucleases XPF and XPG are essentially involved in nucleotide excision repair (NER) and interstrand crosslink (ICL) repair. Defects in these two proteins result in severe diseases like xeroderma pigmentosum (XP). We applied our newly CRISPR/Cas9 generated human XPF knockout cell line with complete loss of XPF and primary fibroblasts from an XP-G patient (XP20BE) to analyze until now uncharacterized spontaneous mRNA splice variants of these two endonucleases. Functional analyses of these variants were performed using luciferase-based reporter gene assays. Two XPF and XPG splice variants with residual repair capabilities in NER, as well as ICL repair could be identified. Almost all variants are severely C-terminally truncated and lack important protein-protein interaction domains. Interestingly, XPF-202, differing to XPF-003 in the first 12 amino acids only, had no repair capability at all, suggesting an important role of this region during DNA repair, potentially concerning protein-protein interaction. We also identified splice variants of XPF and XPG exerting inhibitory effects on NER. Moreover, we showed that the XPF and XPG splice variants presented with different inter-individual expression patterns in healthy donors, as well as in various tissues. With regard to their residual repair capability and dominant-negative effects, functionally relevant spontaneous XPF and XPG splice variants present promising prognostic marker candidates for individual cancer risk, disease outcome, or therapeutic success. This merits further investigations, large association studies, and translational research within clinical trials in the future.
Journal Der Deutschen Dermatologischen Gesellschaft | 2017
Janin Lehmann; Christina Seebode; Steffen Emmert
Genodermatosen umfassen eine klinisch heterogene Krankheitsgruppe mit meist schwerwiegenden Auswirkungen auf die Haut. Bis heute beschränken sich die Behandlungsmöglichkeiten auf die Linderung der Symptome. Jüngste technische Fortschritte im Rahmen des Genome‐Editing leiten eine neue Ära in der Entwicklung kausaler Therapien seltener monogenetischer Erkrankungen wie Genodermatosen ein. Diese Übersichtsarbeit behandelt die Vor‐ und Nachteile der derzeit verfügbaren Nuklease‐basierten Methoden: Zinkfinger‐Nukleasen (ZFNs), transcription activator‐like effector nucleases (TALENs), Meganukleasen und das innovative clustered regularly interspaced short palindromic repeats (CRISPR)‐associated (Cas) nuclease 9 (CRISPR/Cas9) system. Ein mechanistischer Überblick über die verschiedenen Wirkmechanismen dieser programmierbaren Nukleasen, sowie deren Bedeutung für die Kausaltherapie von Genodermatosen wird vorgestellt. Fortbestehende Grenzen und Herausforderungen, wie das effiziente Eindringen und Off‐Target‐Aktivität, werden kritisch diskutiert, um die Vergangenheit und Zukunftsaussichten der Gentherapie in der Dermatologie deutlich zu machen.
Photodermatology, Photoimmunology and Photomedicine | 2016
Steffen Schubert; Petra Rieper; Andreas Ohlenbusch; Christina Seebode; Janin Lehmann; Alexei Gratchev; Steffen Emmert
The nucleotide excision repair (NER) pathway, defective in xeroderma pigmentosum (XP) patients, removes DNA photolesions in order to prevent carcinogenesis. Complementation group C (XP‐C) is the most frequent group of XP patients worldwide.