160 results on '"Ingrid Hausser"'
Search Results
2. pdx1 Knockout Leads to a Diabetic Nephropathy– Like Phenotype in Zebrafish and Identifies Phosphatidylethanolamine as Metabolite Promoting Early Diabetic Kidney Damage
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Lucas M. Wiggenhauser, Lena Metzger, Katrin Bennewitz, Silas Soleymani, Mike Boger, Christoph T. Tabler, Ingrid Hausser, Carsten Sticht, Paulus Wohlfart, Nadine Volk, Elena Heidenreich, Michael Buettner, Hans-Peter Hammes, and Jens Kroll
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Male ,endocrine system ,endocrine system diseases ,Podocytes ,Phosphatidylethanolamines ,Endocrinology, Diabetes and Metabolism ,Hypertrophy ,digestive system ,Phenotype ,Glomerular Basement Membrane ,Diabetes Mellitus ,Internal Medicine ,Animals ,Humans ,Diabetic Nephropathies ,Female ,Zebrafish - Abstract
The pdx1−/− zebrafish mutant was recently established as a novel animal model of diabetic retinopathy. In this study, we investigate whether knockout of pdx1 also leads to diabetic kidney disease (DKD). pdx1−/− larvae exhibit several signs of early DKD, such as glomerular hypertrophy, impairments in the filtration barrier corresponding to microalbuminuria, and glomerular basement membrane (GBM) thickening. Adult pdx1−/− mutants show progressive GBM thickening in comparison with the larval state. Heterozygous pdx1 knockout also leads to glomerular hypertrophy as initial establishment of DKD similar to the pdx1−/− larvae. RNA sequencing of adult pdx1+/− kidneys uncovered regulations in multiple expected diabetic pathways related to podocyte disruption and hinting at early vascular dysregulation without obvious morphological alterations. Metabolome analysis and pharmacological intervention experiments revealed the contribution of phosphatidylethanolamine in the early establishment of kidney damage. In conclusion, this study identified the pdx1 mutant as a novel model for the study of DKD, showing signs of the early disease progression already in the larval stage and several selective features of later DKD in adult mutants.
- Published
- 2022
3. Caffey disease is associated with distinct arginine to cysteine substitutions in the proα1(I) chain of type I procollagen
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Delfien Syx, Geert Mortier, Sofie Symoens, Peter H. Byers, Trinh Hermanns-Lê, Ingrid Hausser, Tibbe Dhooge, Jonathan Zonana, and Fransiska Malfait
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Arginine ,Infantile cortical hyperostosis ,Inflammation ,Biology ,medicine.disease ,Molecular biology ,Collagen Type I ,Hyperostosis, Cortical, Congenital ,Collagen Type I, alpha 1 Chain ,Procollagen peptidase ,medicine.anatomical_structure ,Dermis ,Ehlers–Danlos syndrome ,Child, Preschool ,Mutation ,medicine ,Humans ,Allelic heterogeneity ,Cysteine ,Human medicine ,medicine.symptom ,Procollagen ,Genetics (clinical) - Abstract
Purpose Infantile Caffey disease is a rare disorder characterized by acute inflammation with subperiosteal new bone formation, associated with fever, pain, and swelling of the overlying soft tissue. Symptoms arise within the first weeks after birth and spontaneously resolve before the age of two years. Many, but not all, affected individuals carry the heterozygous pathogenic COL1A1 variant (c.3040C>T, p.(Arg1014Cys)). Methods We sequenced COL1A1 in 28 families with a suspicion of Caffey disease and performed ultrastructural, immunocytochemical, and biochemical collagen studies on patient skin biopsies. Results We identified the p.(Arg1014Cys) variant in 23 families and discovered a novel heterozygous pathogenic COL1A1 variant (c.2752C>T, p.(Arg918Cys)) in five. Both arginine to cysteine substitutions are located in the triple helical domain of the pro alpha 1(I) procollagen chain. Dermal fibroblasts (one patient with p.(Arg1014Cys) and one with p.(Arg918Cys)) produced molecules with disulfide-linked pro alpha 1(I) chains, which were secreted only with p.(Arg1014Cys). No intracellular accumulation of type I procollagen was detected. The dermis revealed mild ultrastructural abnormalities in collagen fibril diameter and packing. Conclusion The discovery of this novel pathogenic variant expands the limited spectrum of arginine to cysteine substitutions in type I procollagen. Furthermore, it confirms allelic heterogeneity in Caffey disease and impacts its molecular confirmation.
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- 2021
4. Loss of glyoxalase 2 alters the glucose metabolism in zebrafish
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Christoph Tobias Tabler, Elisabeth Lodd, Katrin Bennewitz, Chiara Simone Middel, Vanessa Erben, Hannes Ott, Tanja Poth, Thomas Fleming, Jakob Morgenstern, Ingrid Hausser, Carsten Sticht, Gernot Poschet, Julia Szendroedi, Peter Paul Nawroth, and Jens Kroll
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Organic Chemistry ,Clinical Biochemistry ,Biochemistry - Abstract
Glyoxalase 2 is the second enzyme of the glyoxalase system, catalyzing the detoxification of methylglyoxal to d-lactate via SD-Lactoylglutathione. Recent in vitro studies have suggested Glo2 as a regulator of glycolysis, but if Glo2 regulates glucose homeostasis and related organ specific functions in vivo has not yet been evaluated. Therefore, a CRISPR-Cas9 knockout of glo2 in zebrafish was created and analyzed. Consistent with its function in methylglyoxal detoxification, SD-Lactoylglutathione, but not methylglyoxal accumulated in glo2
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- 2022
5. The role of cutaneous manifestations in the diagnosis of the Ehlers‐Danlos syndromes
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Natasha Stembridge, Brent J. Doolan, Mark E. Lavallee, Ingrid Hausser, F. Michael Pope, Suranjith L. Seneviratne, Ingrid M. Winship, and Nigel P. Burrows
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General Medicine - Published
- 2022
6. Comparative Morphological, Metabolic and Transcriptome Analyses in elmo1−/−, elmo2−/−, and elmo3−/− Zebrafish Mutants Identified a Functional Non-Redundancy of the Elmo Proteins
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Mike Boger, Katrin Bennewitz, David Philipp Wohlfart, Ingrid Hausser, Carsten Sticht, Gernot Poschet, and Jens Kroll
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Cell Biology ,Developmental Biology - Abstract
The ELMO protein family consists of the homologues ELMO1, ELMO2 and ELMO3. Several studies have shown that the individual ELMO proteins are involved in a variety of cellular and developmental processes. However, it has poorly been understood whether the Elmo proteins show similar functions and act redundantly. To address this question, elmo1−/−, elmo2−/− and elmo3−/− zebrafish were generated and a comprehensive comparison of the phenotypic changes in organ morphology, transcriptome and metabolome was performed in these mutants. The results showed decreased fasting and increased postprandial blood glucose levels in adult elmo1−/−, as well as a decreased vascular formation in the adult retina in elmo1−/−, but an increased vascular formation in the adult elmo3−/− retina. The phenotypical comparison provided few similarities, as increased Bowman space areas in adult elmo1−/− and elmo2−/− kidneys, an increased hyaloid vessel diameter in elmo1−/− and elmo3−/− and a transcriptional downregulation of the vascular development in elmo1−/−, elmo2−/−, and elmo3−/− zebrafish larvae. Besides this, elmo1−/−, elmo2−/−, and elmo3−/− zebrafish exhibited several distinct changes in the vascular and glomerular structure and in the metabolome and the transcriptome. Especially, elmo3−/− zebrafish showed extensive differences in the larval transcriptome and an impaired survivability. Together, the data demonstrated that the three zebrafish Elmo proteins regulate not only similar but also divergent biological processes and mechanisms and show a low functional redundancy.
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- 2022
7. Methylglyoxal Induces Endothelial Dysfunction via a Stunning-like Phenotype
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Thomas Fleming, Bastian von Nettelbladt, Jakob Morgenstern, Marta Campos, Maxime Le Marois, Maria Bartosova, Ingrid Hausser, Constantin Schwab, Andreas Fischer, Peter P. Nawroth, Julia Szendrödi, and Stephan Herzig
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- 2022
8. Comparative Morphological, Metabolic and Transcriptome Analyses in
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Mike, Boger, Katrin, Bennewitz, David Philipp, Wohlfart, Ingrid, Hausser, Carsten, Sticht, Gernot, Poschet, and Jens, Kroll
- Abstract
The ELMO protein family consists of the homologues ELMO1, ELMO2 and ELMO3. Several studies have shown that the individual ELMO proteins are involved in a variety of cellular and developmental processes. However, it has poorly been understood whether the Elmo proteins show similar functions and act redundantly. To address this question
- Published
- 2022
9. Inter-Laboratory Comparison of Extracellular Vesicle Isolation Based on Ultracentrifugation
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Ingrid Hausser, Katja Nitschke, Karen Bieback, Michael Karremann, Fabia Fricke, Adriana Torres Crigna, Dominik Buschmann, Christine Tucher, Thomas Stefan Worst, Martin Schiller, Ulrike Erb, Johannes Gebert, and Susanne Elvers-Hornung
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medicine.diagnostic_test ,Chemistry ,Nanoparticle tracking analysis ,Hematology ,Extracellular vesicle ,030204 cardiovascular system & hematology ,Cell sorting ,Isolation (microbiology) ,Microvesicles ,ddc ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,Biochemistry ,medicine ,Immunology and Allergy ,Centrifugation ,Ultracentrifuge ,Research Article ,030215 immunology - Abstract
Background/Aims: Extracellular vesicles (EVs), including microvesicles and exosomes, deliver bioactive cargo mediating intercellular communication in physiological and pathological conditions. EVs are increasingly investigated as therapeutic agents and targets, but also as disease biomarkers. However, a definite consensus regarding EV isolation methods is lacking, which makes it intricate to standardize research practices and eventually reach a desirable level of data comparability. In our study, we performed an inter-laboratory comparison of EV isolation based on a differential ultracentrifugation protocol carried out in 4 laboratories in 2 independent rounds of isolation. Methods: Conditioned medium of colorectal cancer cells was prepared and pooled by 1 person and distributed to each of the participating laboratories for isolation according to a pre-defined protocol. After EV isolation in each laboratory, quantification and characterization of isolated EVs was collectively done by 1 person having the highest expertise in the respective test method: Western blot, flow cytometry (fluorescence-activated cell sorting [FACS], nanoparticle tracking analysis (NTA), and transmission electron microscopy (TEM). Results: EVs were visualized with TEM, presenting similar cup-shaped and spherical morphology and sizes ranging from 30 to 150 nm. NTA results showed similar size ranges of particles in both isolation rounds. EV preparations showed high purity by the expression of EV marker proteins CD9, CD63, CD81, Alix, and TSG101, and the lack of calnexin. FACS analysis of EVs revealed intense staining for CD63 and CD81 but lower levels for CD9 and TSG101. Preparations from 1 laboratory presented significantly lower particle numbers (p < 0.0001), most probably related to increased processing time. However, even when standardizing processing time, particle yields still differed significantly between groups, indicating inter-laboratory differences in the efficiency of EV isolation. Importantly, no relation was observed between centrifugation speed/k-factor and EV yield. Conclusions: Our findings demonstrate that quantitative differences in EV yield might be due to equipment- and operator-dependent technical variability in ultracentrifugation-based EV isolation. Furthermore, our study emphasizes the need to standardize technical parameters such as the exact run speed and k-factor in order to transfer protocols between different laboratories. This hints at substantial inter-laboratory biases that should be assessed in multi-centric studies.
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- 2020
10. pdx1 Knockout Leads to a Diabetic Nephropathy-Like Phenotype in Zebrafish and Identifies Phosphatidylethanolamine as Metabolite Promoting Early Diabetic Kidney Damage
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Jens Kroll, Hans-Peter Hammes, Michael Buettner, Elena Heidenreich, Nadine Volk, Paulus Wohlfart, Carsten Sticht, Ingrid Hausser, Christoph T. Tabler, Mike Boger, Silas Soleymani, Katrin Bennewitz, Lena Metzger, and Lucas M. Wiggenhauser
- Abstract
The pdx1-/- zebrafish mutant was recently established as a novel animal model of diabetic retinopathy. Here, we investigate whether knockout of pdx1 also leads to diabetic kidney disease (DKD). pdx1-/- larvae exhibit several signs of early DKD such as glomerular hypertrophy, impairments in the filtration barrier corresponding to microalbuminuria and glomerular basement membrane (GBM) thickening. Adult pdx1-/- mutants show progressive GBM thickening in comparison to the larval state. Heterozygous pdx1 knockout also leads to glomerular hypertrophy as initial establishment of DKD similar to the pdx1-/- larvae. RNA sequencing (RNA-seq) of adult pdx1+/- kidneys uncovered regulations in multiple expected diabetic pathways related to podocyte disruption and hinting at early vascular dysregulation without obvious morphological alterations. Metabolome analysis and pharmacological intervention experiments revealed the contribution of phosphatidylethanolamine (PtdE) in the early establishment of kidney damage. In conclusion, this study identified the pdx1 mutant as a novel model for the study of DKD showing signs of the early disease progression already in larval stage and several selective features of later DKD in adult mutants.
- Published
- 2022
11. Accumulation of acetaldehyde in aldh2.1
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David Philipp, Wohlfart, Bowen, Lou, Chiara Simone, Middel, Jakob, Morgenstern, Thomas, Fleming, Carsten, Sticht, Ingrid, Hausser, Rüdiger, Hell, Hans-Peter, Hammes, Julia, Szendrödi, Peter Paul, Nawroth, and Jens, Kroll
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Glucose ,Aldehyde Dehydrogenase, Mitochondrial ,Animals ,Retinal Vessels ,Acetaldehyde ,Aldehyde Dehydrogenase ,Retinal Neovascularization ,Zebrafish - Abstract
Reactive carbonyl species (RCS) are spontaneously formed in the metabolism and modify and impair the function of DNA, proteins and lipids leading to several organ complications. In zebrafish, knockout of the RCS detoxifying enzymes glyoxalase 1 (Glo 1), aldehyde dehydrogenase 3a1 (Aldh3a1) and aldo-ketoreductase 1a1a (Akr1a1a) showed a signature of elevated RCS which specifically regulated glucose metabolism, hyperglycemia and diabetic organ damage. aldh2.1 was compensatory upregulated in glo1
- Published
- 2021
12. Fatal Neonatal DOLK-CDG as a Rare Form of Syndromic Ichthyosis
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Katalin Komlosi, Olivier Claris, Sophie Collardeau-Frachon, Julia Kopp, Ingrid Hausser, Juliette Mazereeuw-Hautier, Nathalie Jonca, Andreas D. Zimmer, Damien Sanlaville, Judith Fischer, University of Freiburg [Freiburg], Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Heidelberg University Hospital [Heidelberg], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Fédératif de Biologie (IFB), Institut NeuroMyoGène (INMG), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and CarMeN, laboratoire
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DOLK ,[SDV]Life Sciences [q-bio] ,syndromic ichthyosis ,Mendelian disorders of cornification ,QH426-470 ,whole exome sequencing ,[SDV] Life Sciences [q-bio] ,interest ,or financial relationships that could be construed as a potential conflict of ,Genetics ,Molecular Medicine ,Genetics (clinical) ,Original Research ,congenital disorders of glycosylation - Abstract
Neonatal collodion baby or ichthyosis can pose a diagnostic challenge, and in many cases, only additional organ involvement or the course of the disease will help differentiate between non-syndromic and syndromic forms. Skin abnormalities are described in about 20% of the congenital disorders of glycosylation (CDG). Among those, some rare CDG forms constitute a special group among the syndromic ichthyoses and can initially misdirect the diagnosis towards non-syndromic genodermatosis. DOLK-CDG is such a rare subtype, resulting from a defect in dolichol kinase, in which the congenital skin phenotype (often ichthyosis) is later associated with variable extracutaneous features such as dilatative cardiomyopathy, epilepsy, microcephaly, visual impairment, and hypoglycemia and may lead to a fatal course. We report two neonatal cases of lethal ichthyosis from the same family, with distal digital constrictions and a progressive course leading to multi-organ failure and death. Postmortem trio whole-exome sequencing revealed the compound heterozygous variants NM_014908.3: c.1342G>A, p.(Gly448Arg) and NM_014908.3: c.1558A>G, p.(Thr520Ala) in the DOLK gene in the first affected child, which were confirmed in the affected sibling. Reduced staining with anti-α-Dystroglycan antibody was observed in frozen heart tissue of the second child as an expression of reduced O-mannosylation due to the dolichol kinase deficiency. In addition to the detailed dermatopathological changes, both cases presented hepatic and extrahepatic hemosiderosis on histological examination. Our patients represent an early and fatal form of DOLK-CDG with a striking presentation at birth resembling severe collodion baby. Both cases emphasize the phenotypic variability of glycosylation disorders and the importance to broaden the differential diagnosis of ichthyosis and to actively search for organ involvement in neonates with ichthyosis.
- Published
- 2021
13. Methylglyoxal Induces Endothelial Dysfunction via Stunning-like Phenotype
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M. La Marois, B. v. Nettelbladt, Ingrid Hausser, C. Schwab, Jakob Morgenstern, Stephan Herzig, J. Szendroedi, Peter P. Nawroth, M. Campos, Maria Bartosova, Thomas Fleming, and Antje H. L. Fischer
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Methylglyoxal ,Stunning ,Pharmacology ,medicine.disease ,In vitro ,Pathogenesis ,chemistry.chemical_compound ,chemistry ,Paralysis ,medicine ,medicine.symptom ,Endothelial dysfunction ,Cytotoxicity ,Tissue homeostasis - Abstract
Elevated levels of methylglyoxal (MG) and its associated post-translational modifications have been reported to be associated with progression and development of numerous pathological conditions. Despite such extensive evidence, it still remains unclear what the specific effects of MG are other than that induction of cytotoxicity. Here we evaluated the effects of MG in cardiac endothelial cells in vitro. We found that MG leads to a non-proliferative state and endothelial dysfunction, which is reversible as MG-H1, a major post-translational modification induced by MG, is turned over by lysosomal degradation. MG-induced cellular stunning/paralysis describes a new hallmark for cellular dysfunction which could lead to alterations in tissue homeostasis as well as cell-to-cell interactions, thereby contributing to the pathogenesis of diseases.
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- 2021
14. Loss of Hsp70 leads to increased albuminuria in a STZ-induced diabetic mouse model
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J Szendrödi, Tanja Poth, C Rodemer, Ingrid Hausser, Peter P. Nawroth, A Erhardt, Stephan Herzig, Ruben Bulkescher, Johanna Zemva, and Jürgen G. Okun
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medicine.medical_specialty ,Endocrinology ,business.industry ,Internal medicine ,medicine ,Albuminuria ,Diabetic mouse ,medicine.symptom ,business ,Hsp70 - Published
- 2021
15. Cell tropism and viral clearance during SARS-CoV-2 lung infection
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Constantin, Schwab, Lisa Maria, Domke, Fabian, Rose, Ingrid, Hausser, Peter, Schirmacher, and Thomas, Longerich
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SARS-CoV-2 ,Spike Glycoprotein, Coronavirus ,COVID-19 ,Endothelial Cells ,Humans ,RNA, Viral ,Thrombosis ,Cell Biology ,Lung ,Tropism ,Pathology and Forensic Medicine - Abstract
Pulmonary capillary microthrombosis has been proposed as a major pathogenetic factor driving severe COVID-19. Autopsy studies reported endothelialitis but it is under debate if it is caused by SARS-CoV-2 infection of endothelial cells. In this study, RNA in situ hybridization was used to detect viral RNA and to identify the infected cell types in lung tissue of 40 patients with fatal COVID-19. SARS-CoV-2 Spike protein-coding RNA showed a steadily decreasing signal abundance over a period of three weeks. Besides the original virus strain the variants of concern Alpha (B.1.1.7), Delta (B.1.617.2), and Omicron (B.1.1.529) could also be detected by the assay. Viral RNA was mainly detected in alveolar macrophages and pulmonary epithelial cells, while only single virus-positive endothelial cells were observed even in cases with high viral load suggesting that viral infection of endothelial cells is not a key factor for the development of pulmonary capillary microthrombosis.
- Published
- 2022
16. Mouse models for dominant dystrophic epidermolysis bullosa carrying common human point mutations recapitulate the human disease
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Ingrid Hausser, Ken C Pang, Cristina Has, Susan J. Robertson, George Varigos, Johannes S. Kern, Blake R. C. Smith, Alexander Nyström, Christine Gretzmeier, and Cameron J. Nowell
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Collagen Type VII ,Neuroscience (miscellaneous) ,Medicine (miscellaneous) ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Mouse model ,Mice ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Immunology and Microbiology (miscellaneous) ,medicine ,RB1-214 ,Animals ,Humans ,Point Mutation ,Missense mutation ,Epidermolysis bullosa ,Allele ,Skin ,Basement membrane ,integumentary system ,Point mutation ,medicine.disease ,Phenotype ,Pathophysiology ,Epidermolysis Bullosa Dystrophica ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Blistering ,Medicine ,CRISPR-Cas Systems ,Immunostaining ,Research Article - Abstract
Heterozygous missense mutations in the human COL7A1 gene – coding for collagen VII – lead to the rare, dominantly inherited skin disorder dominant dystrophic epidermolysis bullosa (DDEB), which is characterised by skin fragility, blistering, scarring and nail dystrophy. To better understand the pathophysiology of DDEB and develop more effective treatments, suitable mouse models for DDEB are required but to date none have existed. We identified the two most common COL7A1 mutations in DDEB patients (p.G2034R and p.G2043R) and used CRISPR-Cas9 to introduce the corresponding mutations into mouse Col7a1 (p.G2028R and p.G2037R). Dominant inheritance of either of these two alleles results in a phenotype that closely resembles that seen in DDEB patients. Specifically, mice carrying these alleles show recurrent blistering that is first observed transiently around the mouth and paws in the early neonatal period and then again around the digits from 5-10 weeks of age. Histologically, the mice show micro-blistering and reduced collagen VII immunostaining. Biochemically, collagen VII from these mice displays reduced thermal stability, which we also observed to be the case for DDEB patients carrying the analogous mutations. Unlike previous rodent models of epidermolysis bullosa, which frequently show early lethality and severe disease, these mouse models, which to our knowledge are the first for DDEB, show no reduction in growth and survival, and – together with a relatively mild phenotype – represent a practically and ethically tractable tool for better understanding and treating epidermolysis bullosa. This article has an associated First Person interview with the first author of the paper., Summary: We developed mouse models for the blistering genetic skin disorder dominant dystrophic epidermolysis bullosa (DDEB) by introducing mutations into mouse Col7a1. These models should help to improve the understanding and treatment of DDEB.
- Published
- 2021
17. Genetical, clinical, and functional analysis of a large international cohort of patients with autosomal recessive congenital ichthyosis due to mutations in NIPAL4
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Davide Brognoli, Andreas Zimmer, Lisa Heinz, Pierre Vabres, Judith Fischer, Cristina Has, Ingrid Hausser, Slaheddine Marrakchi, Vinzenz Oji, Alrun Hotz, Alan D. Irvine, Ulrike Blume-Peytavi, Geoffroy Hickman, Nadja Ballin, Bakar Bouadjar, Gianluca Tadini, Marina Reitenbach, Henning Hamm, Emmanuelle Bourrat, Diana Mitter, J. Küsel, Stéphanie Leclerc-Mercier, and Svenja Alter
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Adult ,Male ,Biopsy ,Receptors, Cell Surface ,Biology ,Cell Line ,Young Adult ,03 medical and health sciences ,Congenital ichthyosis ,Genetics ,medicine ,Humans ,ddc:610 ,Clinical phenotype ,Gene ,Genetics (clinical) ,Aged ,030304 developmental biology ,Aged, 80 and over ,0303 health sciences ,Splice site mutation ,Heterogeneous group ,Ichthyosis ,030305 genetics & heredity ,High-Throughput Nucleotide Sequencing ,Sequence Analysis, DNA ,Middle Aged ,medicine.disease ,Pedigree ,Large cohort ,Mutation ,Cohort ,Female - Abstract
Autosomal recessive congenital ichthyosis (ARCI) belongs to a heterogeneous group of disorders of keratinization. To date, 10 genes have been identified to be causative for ARCI. NIPAL4 (Nipa‐Like Domain‐Containing 4) is the second most commonly mutated gene in ARCI. In this study, we present a large cohort of 101 families affected with ARCI carrying mutations in NIPAL4. We identified 16 novel mutations and increase the total number of pathogenic mutations in NIPAL4 to 34. Ultrastructural analysis of biopsies from six patients showed morphological abnormalities consistent with an ARCI EM type III. One patient with a homozygous splice site mutation, which leads to a loss of NIPAL4 mRNA, showed additional ultrastructural aberrations together with a more severe clinical phenotype. Our study gives insights into the frequency of mutations, a potential hot spot for mutations, and genotype–phenotype correlations.
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- 2019
18. Neue Therapieansätze für entzündliche und bullöse Formen kongenitaler Ichthyosen: erste klinische Erfahrungen
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Ingrid Hausser, Heiko Traupe, Judith Fischer, Nora Ullrich, Vincent Oji, Dieter Metze, Kira Süßmuth, and Kerstin Steinbrink
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Gynecology ,medicine.medical_specialty ,business.industry ,Medicine ,Dermatology ,business - Published
- 2019
19. Accumulation of acetaldehyde in aldh2.1 zebrafish causes increased retinal angiogenesis and impaired glucose metabolism
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David Philipp Wohlfart, Bowen Lou, Chiara Simone Middel, Jakob Morgenstern, Thomas Fleming, Carsten Sticht, Ingrid Hausser, Rüdiger Hell, Hans-Peter Hammes, Julia Szendrödi, Peter Paul Nawroth, and Jens Kroll
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Glucose metabolism ,Medicine (General) ,R5-920 ,Acetaldehyde (AA) ,QH301-705.5 ,Organic Chemistry ,Clinical Biochemistry ,Microvascular organ complications ,Reactive carbonyl species (RCS) ,Biology (General) ,Biochemistry ,Zebrafish ,Aldehyde dehydrogenase (ALDH) - Abstract
Reactive carbonyl species (RCS) are spontaneously formed in the metabolism and modify and impair the function of DNA, proteins and lipids leading to several organ complications. In zebrafish, knockout of the RCS detoxifying enzymes glyoxalase 1 (Glo 1), aldehyde dehydrogenase 3a1 (Aldh3a1) and aldo-ketoreductase 1a1a (Akr1a1a) showed a signature of elevated RCS which specifically regulated glucose metabolism, hyperglycemia and diabetic organ damage. aldh2.1 was compensatory upregulated in glo1−/− animals and therefore this study aimed to investigate the detoxification ability for RCS by Aldh2.1 in zebrafish independent of ethanol exposure. aldh2.1 knockout zebrafish were generated using CRISPR/Cas9 and subsequently analyzed on a histological, metabolomic and transcriptomic level. aldh2.1−/− zebrafish displayed increased endogenous acetaldehyde (AA) inducing an increased angiogenesis in retinal vasculature. Expression and pharmacological interventional studies identified an imbalance of c-Jun N-terminal kinase (JNK) and p38 MAPK induced by AA, which mediate an activation of angiogenesis. Moreover, increased AA in aldh2.1−/− zebrafish did not induce hyperglycemia, instead AA inhibited the expression of glucokinase (gck) and glucose-6-phosphatase (g6pc), which led to an impaired glucose metabolism. In conclusion, the data have identified AA as the preferred substrate for Aldh2.1's detoxification ability, which subsequently causes microvascular organ damage and impaired glucose metabolism.
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- 2022
20. Author Correction: Mutations in PYCR1 cause cutis laxa with progeroid features
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Bruno Reversade, Nathalie Escande-Beillard, Aikaterini Dimopoulou, Björn Fischer, Serene C. Chng, Yun Li, Mohammad Shboul, Puay-Yoke Tham, Hülya Kayserili, Lihadh Al-Gazali, Monzer Shahwan, Francesco Brancati, Hane Lee, Brian D. O’Connor, Mareen Schmidt-von Kegler, Barry Merriman, Stanley F. Nelson, Amira Masri, Fawaz Alkazaleh, Deanna Guerra, Paola Ferrari, Arti Nanda, Anna Rajab, David Markie, Mary Gray, John Nelson, Arthur Grix, Annemarie Sommer, Ravi Savarirayan, Andreas R. Janecke, Elisabeth Steichen, David Sillence, Ingrid Haußer, Birgit Budde, Gudrun Nürnberg, Peter Nürnberg, Petra Seemann, Désirée Kunkel, Giovanna Zambruno, Bruno Dallapiccola, Markus Schuelke, Stephen Robertson, Hanan Hamamy, Bernd Wollnik, Lionel Van Maldergem, Stefan Mundlos, and Uwe Kornak
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Genetics - Published
- 2022
21. Mutation update for CYP4F22 variants associated with autosomal recessive congenital ichthyosis
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Ingrid Hausser, Svenja Alter, Alrun Hotz, Lisanne Hake, Hagen Ott, Vinzenz Oji, Mouna Korbi, Judith Fischer, Emmanuelle Bourrat, Andreas Zimmer, and J. Küsel
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Male ,0301 basic medicine ,Genotype ,ALOX12B ,Genes, Recessive ,ALOXE3 ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,CYP4F22 ,Cytochrome P-450 Enzyme System ,Congenital ichthyosis ,Genetics ,medicine ,Humans ,Genetic Testing ,ABCA12 ,Alleles ,Genetic Association Studies ,Genetics (clinical) ,Skin ,Genetic testing ,biology ,medicine.diagnostic_test ,Ichthyosis ,Computational Biology ,Lamellar ichthyosis ,medicine.disease ,Pedigree ,Phenotype ,030104 developmental biology ,Mutation ,biology.protein ,Female - Abstract
Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of rare disorders of keratinization characterized by generalized abnormal scaling of the skin. Ten genes are currently known to be associated with ARCI: TGM1, ALOXE3, ALOX12B, NIPAL4 (ICHTHYIN), ABCA12, CYP4F22, PNPLA1, CERS3, SDR9C7, and SULT2B1. Over a period of 22 years, we have studied a large patient cohort from 770 families with a clinical diagnosis of ARCI. Since the first report that mutations in the gene CYP4F22 are causative for ARCI in 2006, we have identified 54 families with pathogenic mutations in CYP4F22 including 23 previously unreported mutations. In this report, we provide an up-to-date overview of all published and novel CYP4F22 mutations and point out possible mutation hot spots. We discuss the molecular and clinical findings, the genotype-phenotype correlations and consequences on genetic testing.
- Published
- 2018
22. QR-313, an Antisense Oligonucleotide, Shows Therapeutic Efficacy for Treatment of Dominant and Recessive Dystrophic Epidermolysis Bullosa: A Preclinical Study
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Verena Wally, Douglas R. Keene, M. Peter Marinkovich, Sara F. Tufa, Eva M. Murauer, Elisabeth M. Haisma, Alexander Nyström, Ulrich Koller, Dimitra Kiritsi, Pauline Nauroy, Marieke Hogervorst, Olivier Bornert, Stefan Hainzl, Gerard Platenburg, Ingrid Hausser, Tita Ritsema, Ioannis Athanasiou, Jim Swildens, and Johannes Bischof
- Subjects
0301 basic medicine ,Keratinocytes ,Collagen Type VII ,Biopsy ,Primary Cell Culture ,Mice, Transgenic ,Dermatology ,Biochemistry ,Cell Line ,03 medical and health sciences ,Exon ,Mice ,0302 clinical medicine ,Fibrosis ,Medicine ,Animals ,Humans ,Molecular Biology ,Gene ,Dermoepidermal junction ,Skin ,Wound Healing ,integumentary system ,business.industry ,Wild type ,Cell Biology ,Exons ,Genetic Therapy ,Fibroblasts ,Oligonucleotides, Antisense ,medicine.disease ,Exon skipping ,Epidermolysis Bullosa Dystrophica ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,business ,Wound healing ,Keratinocyte - Abstract
Dystrophic epidermolysis bullosa (DEB) is a blistering skin disease caused by mutations in the gene COL7A1 encoding collagen VII. DEB can be inherited as recessive DEB (RDEB) or dominant DEB (DDEB) and is associated with a high wound burden. Perpetual cycles of wounding and healing drive fibrosis in DDEB and RDEB, as well as the formation of a tumor-permissive microenvironment. Prolonging wound-free episodes by improving the quality of wound healing would therefore confer substantial benefit for individuals with DEB. The collagenous domain of collagen VII is encoded by 82 in-frame exons, which makes splice-modulation therapies attractive for DEB. Indeed, antisense oligonucleotide–based exon skipping has shown promise for RDEB. However, the suitability of antisense oligonucleotides for treatment of DDEB remains unexplored. Here, we developed QR-313, a clinically applicable, potent antisense oligonucleotide specifically targeting exon 73. We show the feasibility of topical delivery of QR-313 in a carbomer-composed gel for treatment of wounds to restore collagen VII abundance in human RDEB skin. Our data reveal that QR-313 also shows direct benefit for DDEB caused by exon 73 mutations. Thus, the same topically applied therapeutic could be used to improve the wound healing quality in RDEB and DDEB.
- Published
- 2019
23. Integra®-Dermal Regeneration Template and Split-Thickness Skin Grafting: A Therapy Approach to Correct Aplasia Cutis Congenita and Epidermolysis Bullosa in Carmi Syndrome
- Author
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Heinz Kutzner, Julian Trah, Konrad Reinshagen, Christina Has, Ingrid Hausser, and Ingo Königs
- Subjects
0301 basic medicine ,medicine.medical_specialty ,integumentary system ,business.industry ,Regeneration (biology) ,medicine.medical_treatment ,Pyloric Atresia ,Dermatology ,medicine.disease ,Aplasia cutis congenita ,030207 dermatology & venereal diseases ,03 medical and health sciences ,Plastic surgery ,030104 developmental biology ,0302 clinical medicine ,CARMI SYNDROME ,Medicine ,Skin grafting ,Epidermolysis bullosa ,medicine.symptom ,business ,Junctional epidermolysis bullosa (veterinary medicine) - Abstract
The association of junctional epidermolysis bullosa with pyloric atresia (JEB-PA) and aplasia cutis congenita (ACC) was described by El Shafie et al. (J Pediatr Surg 14(4):446–449, 1979) and Carmi et al. (Am J Med Genet 11:319–328, 1982). Most patients die in the first weeks of life, and no curative treatment options are available so far. We describe a patient with JEB-PA and ACC (OMIM # 226730) who was treated for extensive areas of ACC by Integra®-Dermal Regeneration Template and split-thickness skin grafting (STSG). Clinically, the dermal template changed into well-vascularized neodermis, and after STSG, full take of the transplants was detected. No infections of the huge ACC areas were seen. Further studies must validate this treatment option in severe and acute cases of JEB-PA with ACC. Based on clinical findings, we postulate that placement of Integra®-Dermal Regeneration Template with STSG could be a new treatment option for patients having JEB-PA with ACC to prevent severe infection, compartment-syndrome-like conditions, and deformities. Based on literature findings, we assume that Integra®-Dermal Regeneration Template with STSG could even be able to prevent new blistering and thereby be a treatment option in cases of ACC and JEB.
- Published
- 2018
24. Large Deletions Targeting the Triple-Helical Domain of Collagen VII Lead to Mild Acral Dominant Dystrophic Epidermolysis Bullosa
- Author
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Ingrid Hausser, Nadja Chmel, Jürgen Kohlhase, Cristina Has, Wiktor Borozkin, Olivier Bornert, Alexander Nyström, and G. Grüninger
- Subjects
Male ,0301 basic medicine ,Collagen Type VII ,Dermatology ,Biochemistry ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Skin fragility ,Anchoring fibrils ,medicine ,Humans ,Amino Acid Sequence ,Molecular Biology ,Dominant dystrophic epidermolysis bullosa ,Sequence Deletion ,Basement membrane ,business.industry ,DNA ,Cell Biology ,medicine.disease ,Virology ,Molecular biology ,Epidermolysis Bullosa Dystrophica ,Pedigree ,Dystrophic epidermolysis bullosa ,030104 developmental biology ,medicine.anatomical_structure ,Female ,Epidermolysis bullosa ,business - Published
- 2018
25. Sixteen novel mutations in PNPLA1 in patients with autosomal recessive congenital ichthyosis reveal the importance of an extended patatin domain in PNPLA1 that is essential for proper human skin barrier function
- Author
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Benedikt Weber, Alrun Hotz, Karola Stieler, Philipp Demmer, Gwang-Jin Kim, V. Kunde, Stéphanie Leclerc-Mercier, Cristina Has, N. Schlipf, Anders Vahlquist, Ingrid Hausser, Vinzenz Oji, J. Küsel, Judith Fischer, Andreas Zimmer, Franz P.W. Radner, and Emmanuelle Bourrat
- Subjects
Adult ,Male ,0301 basic medicine ,Adolescent ,DNA Mutational Analysis ,Genes, Recessive ,Dermatology ,Biology ,Bioinformatics ,Diagnosis, Differential ,Young Adult ,030207 dermatology & venereal diseases ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Skin Physiological Phenomena ,Congenital ichthyosis ,medicine ,Humans ,Child ,Gene ,Aged ,Aged, 80 and over ,Sanger sequencing ,Genetics ,Ichthyosis ,Genetic heterogeneity ,Infant ,Lipase ,Middle Aged ,medicine.disease ,Phenotype ,Pedigree ,Microscopy, Electron ,030104 developmental biology ,Child, Preschool ,Mutation ,symbols ,Mutation testing ,Mendelian inheritance ,Female ,Ichthyosis, Lamellar - Abstract
Background Autosomal recessive congenital ichthyosis (ARCI) is a genetically heterogeneous group of rare Mendelian skin disorders characterized by cornification and differentiation defects of keratinocytes. Mutations in nine genes including PNPLA1 are known to cause non-syndromic forms of ARCI. To date, only ten distinct pathogenic mutations in PNPLA1 have been reported. Objectives To identify new causative PNPLA1 mutations, we screened genetically unresolved cases including our ARCI collection comprising more than 700 families. Here, we report on 16 novel mutations present in patients from 17 families. Methods The screening for mutations was performed either by direct Sanger sequencing or in combination with a multi gene panel, followed by sequence and mutation analysis. Results While all previously reported mutations and most of our novel mutations are located within the core patatin domain, here we report on five novel PNPLA1 mutations, which are downstream of this domain. Thus, as recently described for PNPLA2, we hypothesize that a region larger than core domain is required for full enzymatic activity of PNPLA1 in human skin barrier formation. Conclusions We estimate the frequency of PNPLA1 mutations amongst ARCI patients to around 3%. Most of our patients were born as collodion babies and showed a relatively mild ichthyosis phenotype. In four unrelated patients we observed a cyclic scaling course, which seems to be a potential phenotype variation in a small percentage of patients with PNPLA1 mutations. The variability of the clinical manifestations as well as the lack of typical clinical features are specific for patients with PNPLA1 mutations, and emphasize the importance of DNA sequencing for differential diagnosis of ARCIs. This article is protected by copyright. All rights reserved.
- Published
- 2017
26. Increased Prevalence of Filaggrin Deficiency in 51 Patients with Recessive X-Linked Ichthyosis Presenting for Dermatological Examination
- Author
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Stephan Weidinger, Ingrid Hausser, Natalia Straub, F. Valentin, Heiko Traupe, Elke Rodriguez, Hansjörg Baurecht, Kira Süßmuth, Vinzenz Oji, Stefan W. Schneider, Alberto Sánchez-Guijo, T. Tarinski, Dieter Metze, Susanne Amler, and Robert Gruber
- Subjects
Adult ,0301 basic medicine ,Keratohyalin ,medicine.medical_specialty ,Ichthyosis, X-Linked ,Adolescent ,Population ,Dermatology ,Filaggrin Proteins ,medicine.disease_cause ,Biochemistry ,Young Adult ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Intermediate Filament Proteins ,Prevalence ,medicine ,Humans ,Prospective Studies ,Child ,education ,Molecular Biology ,Aged ,education.field_of_study ,Mutation ,X-linked ichthyosis ,Ichthyosis ,business.industry ,Cell Biology ,Middle Aged ,medicine.disease ,Phenotype ,030104 developmental biology ,Child, Preschool ,Immunology ,business ,Filaggrin ,Ichthyosis vulgaris - Abstract
X-linked ichthyosis (XLI) is a keratinization disorder caused by deficient activity of steroidsulfatase. In contrast, ichthyosis vulgaris is due to semidominant mutations of the filaggrin gene ( FLG ). In view of phenotypic variations of these ichthyoses we speculated that XLI may be influenced by additional FLG mutations in a significant number of patients. We characterized a group of 51 patients with XLI and systematically analyzed them for additional FLG mutations (R501X, 2282del4, R2447X, S3247X). The study was complemented by morphological analyses. Full FLG sequencing for rare mutations was performed in special cases. Interestingly, prevalence of FLG mutations was significantly increased compared to a population-based control cohort of 1,377 individuals (17.6% vs. 8.4%, p=0.038). Palmoplantar hyperlinearity was significantly associated with the FLG mutation status. Ichthyosis severity score seemed to be increased in XLI with FLG mutations, but the difference was not significant (p=0.124). To our surprise, percentages of atopic manifestations were highly prevalent in both subgroups, 40% and 33% in XLI without and with filaggrin deficiency, respectively. Of note, reduction of filaggrin staining or keratohyalin could not be explained by FLG mutations in all patients. However, we conclude that FLG mutations represent a significant genetic modifier of XLI. [196 words]
- Published
- 2018
27. TGFBR2‑dependent alterations of microRNA profiles in extracellular vesicles and parental colorectal cancer cells
- Author
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Ingrid Hausser, Jürgen Kopitz, Veronika Mussack, Michael W. Pfaffl, Dominik Buschmann, Johannes Gebert, and Fabia Fricke
- Subjects
0301 basic medicine ,Cancer Research ,Biology ,Extracellular Vesicles ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,microRNA ,Gene expression ,medicine ,Humans ,Regulation of gene expression ,Oncogene ,Receptor, Transforming Growth Factor-beta Type II ,Microsatellite instability ,Cell cycle ,HCT116 Cells ,medicine.disease ,digestive system diseases ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030104 developmental biology ,Oncology ,Tumor progression ,Doxycycline ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Microsatellite Instability ,Colorectal Neoplasms - Abstract
In colorectal cancer (CRC) with microsatellite instability (MSI), >90% of cases are affected by inactivating frameshift mutations of transforming growth factor β receptor type 2 (TGFBR2). TGFBR2 deficiency is considered to drive MSI tumor progression by abrogating downstream TGF‑β signaling. This pathway can alter the expression of coding and non‑coding RNAs, including microRNAs (miRNAs), which are also present in extracellular vesicles (EVs) as post‑transcriptional modulators of gene expression. In our previous study, it was shown that TGFBR2 deficiency alters the protein composition and function of EVs in MSI tumors. To investigate whether mutant TGFBR2 may also affect the miRNA cargo of EVs, the present study characterized miRNAs in EVs and their parental MSI tumor cells that differed only in TGFBR2 expression status. The HCT116‑TGFBR2 MSI cell line model enables the doxycycline (dox)‑inducible reconstituted expression of TGFBR2 in an isogenic background (‑dox, TGFBR2 deficient; +dox, TGFBR2 proficient). Small RNA sequencing of cellular and EV miRNAs showed that the majority of the miRNAs (263/471; 56%) were shared between MSI tumor cells and their EVs. Exploratory data analysis revealed the TGBFR2‑dependent cluster separation of miRNA profiles in EVs and MSI tumor cells. This segregation appeared to result from two subsets of miRNAs, the expression of which were regulated in a TGFBR2‑dependent manner (EVs: n=10; MSI cells: n=15). In the EV subset, 7/10 miRNAs were downregulated and 3/10 were upregulated by TGFBR2 deficiency. In the cellular subset, 13/15 miRNAs were downregulated and 2/15 miRNAs were upregulated in the TGFBR2‑deficient cells. The present study emphasizes the general overlap of miRNA profiles in MSI tumor cells and their EVs, but also highlights the impact of a single tumor driver mutation on the expression of individual miRNAs, as exemplified by the downregulation of miR‑381‑3p in TGFBR2‑deficient MSI tumor cells and their secreted EVs.
- Published
- 2019
28. Clinically Relevant Correction of Recessive Dystrophic Epidermolysis Bullosa by Dual sgRNA CRISPR/Cas9-Mediated Gene Editing
- Author
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Raul M. Torres, María José Escámez, Carlos León, E. Chacón-Solano, Marcela Del Rio, Lucía Marinas, Marta García, Silvia Modamio-Høybjør, Jose Bonafont, Ángeles Mencía, Sandra Rodriguez, Marta Carretero, Fernando Larcher, Ingrid Hausser, Rodolfo Murillas, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, DEBRA Austria, and European Commission
- Subjects
Keratinocytes ,Collagen Type VII ,Medicina ,Population ,Biology ,Gene mutation ,Frameshift mutation ,Mice ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Genome editing ,epidermal stem cells ,Drug Discovery ,Genetics ,medicine ,Animals ,Humans ,CRISPR ,epidermolysis bullosa ,Frameshift Mutation ,education ,Molecular Biology ,Gene ,CRISPR/Cas9 ,030304 developmental biology ,Gene Editing ,Pharmacology ,0303 health sciences ,education.field_of_study ,High-Throughput Nucleotide Sequencing ,Exons ,medicine.disease ,gene therapy ,Epidermolysis Bullosa Dystrophica ,Disease Models, Animal ,030220 oncology & carcinogenesis ,Molecular Medicine ,Original Article ,Epidermolysis bullosa ,CRISPR-Cas Systems ,RNA, Guide, Kinetoplastida - Abstract
Gene editing constitutes a novel approach for precisely correcting disease-causing gene mutations. Frameshift mutations in COL7A1 causing recessive dystrophic epidermolysis bullosa are amenable to open reading frame restoration by non-homologous end joining repair-based approaches. Efficient targeted deletion of faulty COL7A1 exons in polyclonal patient keratinocytes would enable the translation of this therapeutic strategy to the clinic. In this study, using a dual single-guide RNA (sgRNA)-guided Cas9 nuclease delivered as a ribonucleoprotein complex through electroporation, we have achieved very efficient targeted deletion of COL7A1 exon 80 in recessive dystrophic epidermolysis bullosa (RDEB) patient keratinocytes carrying a highly prevalent frameshift mutation. This ex vivo non-viral approach rendered a large proportion of corrected cells producing a functional collagen VII variant. The effective targeting of the epidermal stem cell population enabled long-term regeneration of a properly adhesive skin upon grafting onto immunodeficient mice. A safety assessment by next-generation sequencing (NGS) analysis of potential off-target sites did not reveal any unintended nuclease activity. Our strategy could potentially be extended to a large number of COL7A1 mutation-bearing exons within the long collagenous domain of this gene, opening the way to precision medicine for RDEB., Highly efficient and safe approaches for precise correction of pathogenic mutations are required to realize the full potential of gene-editing protocols for clinical practice. Here we describe a single-step NHEJ-based CRISPR/Cas9 strategy of COL7A1 mutation-bearing exon deletion with unprecedented efficacy for ex vivo correction of recessive dystrophic epidermolysis bullosa.
- Published
- 2019
29. SOPH syndrome in three affected individuals showing similarities with progeroid cutis laxa conditions in early infancy
- Author
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Nilay Güneş, Stefan Mundlos, Stephan Henning, Clemens Kamrath, Katrin Hoffmann, Bjoern Fischer-Zirnsak, Beyhan Tüysüz, Ingrid Hausser, Uwe Kornak, Denise Horn, Christian Thiel, Rainer Koenig, Namrata Saha, Stefanie Beck-Woedl, Franz Alisch, and Tobias B. Haack
- Subjects
0301 basic medicine ,Male ,Pathology ,medicine.medical_specialty ,030105 genetics & heredity ,Short stature ,Cutis Laxa ,Hypogammaglobulinemia ,Diagnosis, Differential ,03 medical and health sciences ,Young Adult ,Atrophy ,Progeria ,Agammaglobulinemia ,Optic Nerve Diseases ,Exome Sequencing ,Genetics ,medicine ,Humans ,Genetics (clinical) ,Exome sequencing ,Growth Disorders ,Skin ,business.industry ,Infant ,Syndrome ,medicine.disease ,Early infancy ,Elastic Tissue ,Neoplasm Proteins ,030104 developmental biology ,Liver ,Translucent skin ,Differential diagnosis ,medicine.symptom ,business ,Pelger-Huet Anomaly ,Cutis laxa - Abstract
Individuals affected with autosomal recessive cutis laxa type 2B and 3 usually show translucent skin with visible veins and abnormal elastic fibers, intrauterine and/or postnatal growth restriction and a typical triangular facial gestalt. Here we describe three unrelated individuals in whom such a cutis laxa syndrome was suspected, especially after electron microscopy revealed immature and less dense dermal elastic fibers in one of them. However, one of these children also displayed optic atrophy and two hypogammaglobulinemia. All had elevated liver enzymes and acute liver failure during febrile episodes leading to early demise in two of them. The only surviving patient had been treated with immunoglobulins. Through exome sequencing we identified mutations in NBAS, coding for a protein involved in Golgi-to-ER transport. NBAS deficiency causes several rare conditions ranging from isolated recurrent acute liver failure to a multisystem disorder mainly characterized by short stature, optic nerve atrophy and Pelger-Huet anomaly (SOPH). Since we subsequently verified Pelger-Huet anomaly in two of the patients the diagnosis SOPH syndrome was unequivocally proven. Our data show that SOPH syndrome can be regarded as a differential diagnosis for the progeroid forms of cutis laxa in early infancy and that possibly treatment of the hypogammaglobulinemia can be of high relevance for the prognosis.
- Published
- 2018
30. Vitamin D Status in Distinct Types of Ichthyosis: Importance of Genetic Type and Severity of Scaling
- Author
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Jerzy-Roch Nofer, Mi-Ran Kim, Kira Süßmuth, Vinzenz Oji, Ingrid Hausser, F. Valentin, Katja Martina Eckl, Judith Fischer, Alberto Sánchez-Guijo, Hans Christian Hennies, Heiko Traupe, Stefan A. Wudy, Laura Kerschke, Selbsthilfe Ichthyose, University of Münster, and German Research Foundation
- Subjects
medicine.medical_specialty ,Congenital ichthyosiform erythroderma ,Dermatology ,Gastroenterology ,vitamin D deficiency ,Internal medicine ,medicine ,Vitamin D and neurology ,Humans ,Netherton syndrome ,Vitamin D ,Parathyroid hormone ,Vitamin D deficiency ,business.industry ,Ichthyosis ,General Medicine ,Harlequin Ichthyosis ,Lamellar ichthyosis ,Vitamin D Deficiency ,medicine.disease ,Parathyroid Hormone ,RL1-803 ,business ,Ichthyosis, Lamellar ,Ichthyosis vulgaris - Abstract
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., This study was supported by the Selbsthilfe Ichthyose e.V., the Medical Faculty of the University of Münster (OJI120817 & OJ111409) and of the German Research Foundation (DFG OJ 53/3-1). It is part of the medical thesis of Mi-Ran Kim. The work was supported by the Selbsthilfe Ichthyose e.V., the Medical Faculty of the University of Muenster (OJI120817 & OJ111409) and by the German Research Foundation (DFG OJ 53/3-1). Furthermore, we cooperated with members of the European Reference Network (ERN, subgroup ERN-skin). The cohort of this paper was also part of a project funded by the programme “Innovative Medizinische Forschung” (IMF); project number: SÜ212007.
- Published
- 2021
31. Collagen VII Half-Life at the Dermal-Epidermal Junction Zone: Implications for Mechanisms and Therapy of Genodermatoses
- Author
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Tobias Kühl, Ingrid Hausser, Leena Bruckner-Tuderman, Alexander Nyström, Markus Mezger, Lin T. Guey, and Rupert Handgretinger
- Subjects
Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Collagen Type VII ,Blotting, Western ,Cell ,Cell- and Tissue-Based Therapy ,Dermatology ,Mesenchymal Stem Cell Transplantation ,Biochemistry ,Mice ,Random Allocation ,03 medical and health sciences ,Dermis ,medicine ,Animals ,Humans ,Molecular Biology ,Cells, Cultured ,Dermoepidermal junction ,Mice, Knockout ,integumentary system ,Epidermis (botany) ,Chemistry ,Mesenchymal stem cell ,Epidermolysis bullosa dystrophica ,Skin Diseases, Genetic ,Genetic Therapy ,Cell Biology ,Fibroblasts ,medicine.disease ,Epidermolysis Bullosa Dystrophica ,Cell biology ,Blot ,Disease Models, Animal ,Dystrophic epidermolysis bullosa ,030104 developmental biology ,medicine.anatomical_structure ,Epidermis ,Half-Life - Abstract
The tissue half-life of proteins largely determines treatment frequency of non-gene-editing-based therapies targeting the cause of genodermatoses. Surprisingly, such knowledge is missing for a vast number of proteins involved in pathologies. The dermal-epidermal junction zone is believed to be a rather static structure, but to our knowledge no detailed analysis of the stability of proteins within this zone has been performed. Here, we addressed the in vivo half-life of collagen type VII using genetic ablation of its expression and therapeutic introduction of exogenous collagen VII in a preclinical model. A similar in vivo stability of collagen VII was observed in the skin, tongue, and esophagus, with a half-life of about 1 month. Collagen VII expressed by intradermally injected mesenchymal stromal cells also exhibited a similar half-life. Our study provides key information needed for the development of protein replacement or cell-based therapies for dystrophic epidermolysis bullosa caused by genetic deficiency of collagen VII. Moreover, by showing what we define as an intermediate half-life of collagen VII, our study challenges the view of the dermal-epidermal junction zone as a static structure with very slow turnover.
- Published
- 2016
32. Spiny keratoderma of the palms and soles - once seen, never forgotten
- Author
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Jessica C. Hassel, Maria Rita Gaiser, and Ingrid Hausser
- Subjects
030207 dermatology & venereal diseases ,03 medical and health sciences ,medicine.medical_specialty ,0302 clinical medicine ,030220 oncology & carcinogenesis ,medicine ,Dermatology ,Biology ,Keratoderma ,medicine.disease ,Palm - Published
- 2017
33. ECM1 Prevents Activation of Transforming Growth Factor β, Hepatic Stellate Cells, and Fibrogenesis in Mice
- Author
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Wen Chen, Weiguo Fan, Ingrid Hausser, Cui Liu, Xinhao Zhao, Yajing He, Min Cong, Tianhui Liu, Lijian Hui, Hong You, Li Li, Steven Dooley, Yan Wang, Thomas Longerich, Xinyan Zhao, Zhiyang Ling, Chunyan Yi, Bing Sun, Seddik Hammad, Yaguang Zhang, Liyan Ma, Jidong Jia, Yadong Fu, Qiaoshi Lian, Ping Wang, Chenghua Yan, Zhihong Liu, Hufeng Xu, Li Nan, Jinlin Hou, Jianfeng Chen, and Dangsheng Li
- Subjects
0301 basic medicine ,Male ,Cirrhosis ,ATP Binding Cassette Transporter, Subfamily B ,Hepatitis, Viral, Human ,In situ hybridization ,Chronic liver disease ,Liver Cirrhosis, Experimental ,03 medical and health sciences ,Extracellular matrix protein 1 ,0302 clinical medicine ,Fibrosis ,Liver Cirrhosis, Alcoholic ,Transforming Growth Factor beta ,medicine ,Hepatic Stellate Cells ,Animals ,Humans ,education ,Carbon Tetrachloride ,Mice, Knockout ,education.field_of_study ,Extracellular Matrix Proteins ,Mice, Inbred BALB C ,Hepatology ,Chemistry ,Hepatitis, Alcoholic ,Kupffer cell ,Gastroenterology ,medicine.disease ,Molecular biology ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Liver ,Hepatocyte ,Hepatic stellate cell ,030211 gastroenterology & hepatology ,Chemical and Drug Induced Liver Injury ,Signal Transduction - Abstract
Background & Aims Activation of TGFB (transforming growth factor β) promotes liver fibrosis by activating hepatic stellate cells (HSCs), but the mechanisms of TGFB activation are not clear. We investigated the role of ECM1 (extracellular matrix protein 1), which interacts with extracellular and structural proteins, in TGFB activation in mouse livers. Methods We performed studies with C57BL/6J mice (controls), ECM1-knockout (ECM1-KO) mice, and mice with hepatocyte-specific knockout of EMC1 (ECM1Δhep). ECM1 or soluble TGFBR2 (TGFB receptor 2) were expressed in livers of mice after injection of an adeno-associated virus vector. Liver fibrosis was induced by carbon tetrachloride (CCl4) administration. Livers were collected from mice and analyzed by histology, immunohistochemistry, in situ hybridization, and immunofluorescence analyses. Hepatocytes and HSCs were isolated from livers of mice and incubated with ECM1; production of cytokines and activation of reporter genes were quantified. Liver tissues from patients with viral or alcohol-induced hepatitis (with different stages of fibrosis) and individuals with healthy livers were analyzed by immunohistochemistry and in situ hybridization. Results ECM1-KO mice spontaneously developed liver fibrosis and died by 2 months of age without significant hepatocyte damage or inflammation. In liver tissues of mice, we found that ECM1 stabilized extracellular matrix–deposited TGFB in its inactive form by interacting with αv integrins to prevent activation of HSCs. In liver tissues from patients and in mice with CCl4-induced liver fibrosis, we found an inverse correlation between level of ECM1 and severity of fibrosis. CCl4-induced liver fibrosis was accelerated in ECM1Δhep mice compared with control mice. Hepatocytes produced the highest levels of ECM1 in livers of mice. Ectopic expression of ECM1 or soluble TGFBR2 in liver prevented fibrogenesis in ECM1-KO mice and prolonged their survival. Ectopic expression of ECM1 in liver also reduced the severity of CCl4-induced fibrosis in mice. Conclusions ECM1, produced by hepatocytes, inhibits activation of TGFB and its activation of HSCs to prevent fibrogenesis in mouse liver. Strategies to increase levels of ECM1 in liver might be developed for treatment of fibrosis.
- Published
- 2018
34. Constitutional absence of epithelial integrin α3 impacts the composition of the cellular microenvironment of ILNEB keratinocytes
- Author
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Joern Dengjel, Ingrid Hausser, Kerstin Thriene, Melanie Boerries, Cristina Has, Claus-Werner Franzke, Hauke Busch, and Yinghong He
- Subjects
0301 basic medicine ,Keratinocytes ,Proteomics ,Nephrotic Syndrome ,Integrin alpha3 ,Integrin ,Cell Culture Techniques ,Basement Membrane ,Cell Line ,Extracellular matrix ,03 medical and health sciences ,Protein Interaction Mapping ,Extracellular ,medicine ,Cell Adhesion ,Humans ,Cell adhesion ,Molecular Biology ,Basement membrane ,biology ,Chemistry ,Cell biology ,Extracellular Matrix ,Fibronectins ,Fibronectin ,030104 developmental biology ,medicine.anatomical_structure ,Cellular Microenvironment ,Gene Expression Regulation ,Culture Media, Conditioned ,biology.protein ,Wound healing ,Keratinocyte ,Epidermolysis Bullosa ,Lung Diseases, Interstitial - Abstract
Integrin α3β1, a major epidermal adhesion receptor is critical for organization of the basement membrane during development and wound healing. Integrin α3 deficiency leads to interstitial lung disease, nephrotic syndrome and epidermolysis bullosa (ILNEB), an autosomal recessive multiorgan disease characterized by basement membrane abnormalities in skin, lung and kidney. The pathogenetic chains from ITGA3 mutation to tissue abnormalities are still unclear. Although integrin α3 was reported to regulate multiple extracellular proteins, the composition of the extracellular compartment of integrin α3-negative keratinocytes has not been resolved so far. In a comprehensive approach, quantitative proteomics of deposited extracellular matrix, conditioned cultured media as well as of the intracellular compartment of keratinocytes isolated from an ILNEB patient and from normal skin were performed. By mass spectrometry-based proteomics, 167 proteins corresponding to the GO terms “extracellular” and “cell adhesion”, or included in the “human matrisome” were identified in the deposited extracellular matrix, and 217 in the conditioned media of normal human keratinocytes. In the absence of integrin α3, 33% and 26% respectively were dysregulated. Dysregulated proteins were functionally related to integrin α3 or were known interaction partners. The results show that in the absence of integrin α3 ILNEB keratinocytes produce a fibronectin-rich microenvironment and make use of fibronectin-binding integrin subunits αv and α5. The most important results were validated in monolayer and organotypic coculture models. Finally, the in vivo relevance of the most dysregulated components was demonstrated by immunostainings of skin, kidney and lung samples of three ILNEB patients.
- Published
- 2018
35. Restrictive Dermopathy: Four Case Reports and Structural Skin Changes
- Author
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Adelheid Elbe-Bürger, Felix Lasitzschka, Knut Schäkel, Mona Bidier, Ingrid Hausser, Mareen Salz, and Jochen Meyburg
- Subjects
Male ,medicine.medical_specialty ,Fatal outcome ,Contracture ,Biopsy ,MEDLINE ,Gestational Age ,Dermatology ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Fatal Outcome ,medicine ,lcsh:Dermatology ,Humans ,Skin pathology ,Skin ,medicine.diagnostic_test ,business.industry ,Infant, Newborn ,Gestational age ,General Medicine ,lcsh:RL1-803 ,medicine.disease ,Elastic Tissue ,Skin Abnormalities ,Restrictive dermopathy ,business ,Respiratory Insufficiency ,Infant, Premature - Published
- 2018
36. Integra
- Author
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Julian, Trah, Christina, Has, Ingrid, Hausser, Heinz, Kutzner, Konrad, Reinshagen, and Ingo, Königs
- Subjects
Skin graft ,integumentary system ,Brief Report ,Integra®-Dermal Regeneration Template ,Aplasia cutis congenita ,Carmi syndrome ,Epidermolysis bullosa - Abstract
The association of junctional epidermolysis bullosa with pyloric atresia (JEB-PA) and aplasia cutis congenita (ACC) was described by El Shafie et al. (J Pediatr Surg 14(4):446–449, 1979) and Carmi et al. (Am J Med Genet 11:319–328, 1982). Most patients die in the first weeks of life, and no curative treatment options are available so far. We describe a patient with JEB-PA and ACC (OMIM # 226730) who was treated for extensive areas of ACC by Integra®-Dermal Regeneration Template and split-thickness skin grafting (STSG). Clinically, the dermal template changed into well-vascularized neodermis, and after STSG, full take of the transplants was detected. No infections of the huge ACC areas were seen. Further studies must validate this treatment option in severe and acute cases of JEB-PA with ACC. Based on clinical findings, we postulate that placement of Integra®-Dermal Regeneration Template with STSG could be a new treatment option for patients having JEB-PA with ACC to prevent severe infection, compartment-syndrome-like conditions, and deformities. Based on literature findings, we assume that Integra®-Dermal Regeneration Template with STSG could even be able to prevent new blistering and thereby be a treatment option in cases of ACC and JEB.
- Published
- 2018
37. Diagnosis of Ehlers–Danlos syndrome: data deficiency still does not allow establishment of a complete history of the disease and its pathomechanisms
- Author
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Ingrid Hausser
- Subjects
Microscopy, Electron ,medicine.medical_specialty ,Ehlers–Danlos syndrome ,business.industry ,medicine ,Humans ,Ehlers-Danlos Syndrome ,Dermatology ,Disease ,medicine.disease ,business - Published
- 2019
38. 2. Morphologische Grundlagen erblicher Bindegewebserkrankungen
- Author
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Andreas Luttkus and Ingrid Haußer
- Subjects
Biology - Published
- 2017
39. High Local Concentrations of Intradermal MSCs Restore Skin Integrity and Facilitate Wound Healing in Dystrophic Epidermolysis Bullosa
- Author
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Alexander Nyström, Markus Mezger, Tobias Kühl, Leena Bruckner-Tuderman, Ingrid Hausser, and Rupert Handgretinger
- Subjects
Pathology ,medicine.medical_specialty ,Stromal cell ,Collagen Type VII ,Injections, Intradermal ,Anti-Inflammatory Agents ,Inflammation ,Mice ,Fibrosis ,Anchoring fibrils ,Drug Discovery ,medicine ,Genetics ,Animals ,Humans ,Regeneration ,Molecular Biology ,Skin ,Pharmacology ,Wound Healing ,integumentary system ,business.industry ,Regeneration (biology) ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Anatomy ,Fibroblasts ,medicine.disease ,Epidermolysis Bullosa Dystrophica ,Disease Models, Animal ,Systemic administration ,Commentary ,Molecular Medicine ,medicine.symptom ,Epidermis ,Wound healing ,business - Abstract
Dystrophic epidermolysis bullosa (DEB) is an incurable skin fragility disorder caused by mutations in the COL7A1 gene, coding for the anchoring fibril protein collagen VII (C7). Life-long mechanosensitivity of skin and mucosal surfaces is associated with large body surface erosions, chronic wounds, and secondary fibrosis that severely impede functionality. Here, we present the first systematic long-term evaluation of the therapeutic potential of a mesenchymal stromal cell (MSC)-based therapy for DEB. Intradermal administration of MSCs in a DEB mouse model resulted in production and deposition of C7 at the dermal-epidermal junction, the physiological site of function. The effect was dose-dependent with MSCs being up to 10-fold more potent than dermal fibroblasts. MSCs promoted regeneration of DEB wounds via normalization of dermal and epidermal healing and improved skin integrity through de novo formation of functional immature anchoring fibrils. Additional benefits were gained by MSCs' anti-inflammatory effects, which led to decreased immune cell infiltration into injured DEB skin. In our setting, the clinical benefit of MSC injections lasted for more than 3 months. We conclude that MSCs are viable options for localized DEB therapy. Importantly, however, the cell number needed to achieve therapeutic efficacy excludes the use of systemic administration.
- Published
- 2015
- Full Text
- View/download PDF
40. Two novel mutations in the LOR gene in three families with loricrin keratoderma
- Author
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Judith Fischer, Ingrid Hausser, Alrun Hotz, M. Haftek, Emmanuelle Bourrat, and M.V. da Silva
- Subjects
Genetics ,LORICRIN KERATODERMA ,medicine ,Heterozygote advantage ,Dermatology ,Biology ,Keratoderma ,medicine.disease ,Gene - Published
- 2015
41. Molecular Consequences of the SERPINH1/HSP47 Mutation in the Dachshund Natural Model of Osteogenesis Imperfecta
- Author
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Jyoti Rai, David R. Eyre, Marianne Rohrbach, Ingrid Hausser, Tosso Leeb, Frank Seeliger, Uschi Lindert, MaryAnn Weis, Cecilia Giunta, University of Zurich, and Giunta, Cecilia
- Subjects
1303 Biochemistry ,genetic structures ,Biochemistry ,1307 Cell Biology ,Extracellular matrix ,chemistry.chemical_compound ,0302 clinical medicine ,Endoplasmic Reticulum Chaperone BiP ,Cells, Cultured ,Heat shock protein 47 ,0303 health sciences ,Pyridinoline ,biology ,Protein Stability ,Molecular Bases of Disease ,Anatomy ,Osteogenesis Imperfecta ,Endoplasmic Reticulum Stress ,medicine.anatomical_structure ,Osteogenesis imperfecta ,030220 oncology & carcinogenesis ,embryonic structures ,Type I collagen ,musculoskeletal diseases ,animal structures ,Connective tissue ,610 Medicine & health ,Bone and Bones ,Collagen Type I ,03 medical and health sciences ,Dogs ,1312 Molecular Biology ,medicine ,Animals ,Point Mutation ,Molecular Biology ,HSP47 Heat-Shock Proteins ,030304 developmental biology ,Cell Biology ,Fibroblasts ,medicine.disease ,Molecular biology ,Procollagen peptidase ,Collagen, type I, alpha 1 ,stomatognathic diseases ,Disease Models, Animal ,chemistry ,10036 Medical Clinic ,biology.protein ,Protein Processing, Post-Translational - Abstract
Osteogenesis imperfecta (OI) is a heritable connective tissue disease characterized by bone fragility and increased risk of fractures. Up to now, mutations in at least 18 genes have been associated with dominant and recessive forms of OI that affect the production or post-translational processing of procollagen or alter bone homeostasis. Among those, SERPINH1 encoding heat shock protein 47 (HSP47), a chaperone exclusive for collagen folding in the ER, was identified to cause a severe form of OI in dachshunds (L326P) as well as in humans (one single case with a L78P mutation). To elucidate the disease mechanism underlying OI in the dog model, we applied a range of biochemical assays to mutant and control skin fibroblasts as well as on bone samples. These experiments revealed that type I collagen synthesized by mutant cells had decreased electrophoretic mobility. Procollagen was retained intracellularly with concomitant dilation of ER cisternae and activation of the ER stress response markers GRP78 and phospho-eIF2α, thus suggesting a defect in procollagen processing. In line with the migration shift detected on SDS-PAGE of cell culture collagen, extracts of bone collagen from the OI dog showed a similar mobility shift, and on tandem mass spectrometry, the chains were post-translationally overmodified. The bone collagen had a higher content of pyridinoline than control dog bone. We conclude that the SERPINH1 mutation in this naturally occurring model of OI impairs how HSP47 acts as a chaperone in the ER. This results in abnormal post-translational modification and cross-linking of the bone collagen.
- Published
- 2015
- Full Text
- View/download PDF
42. Loss of desmoglein 1 associated with palmoplantar keratoderma, dermatitis and multiple allergies
- Author
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Thilo Jakob, Dimitra Kiritsi, Yinghong He, Cristina Has, Leena Bruckner-Tuderman, and Ingrid Hausser
- Subjects
medicine.medical_specialty ,Malabsorption ,Adolescent ,Nonsense mutation ,Dermatitis ,Dermatology ,medicine.disease_cause ,Exon ,Keratoderma, Palmoplantar ,Hypersensitivity ,medicine ,Humans ,Wasting ,Mutation ,Wasting Syndrome ,business.industry ,Desmoglein 1 ,Homozygote ,medicine.disease ,Palmoplantar keratoderma ,Codon, Nonsense ,Hypotrichosis ,Female ,medicine.symptom ,business - Abstract
Summary Monoallelic desmoglein 1 mutations have been known for many years to cause striate palmoplantar keratoderma, but only recently, biallelic loss-of-function mutations were associated with a new disorder, designated as SAM syndrome (comprising severe dermatitis, multiple allergies and metabolic wasting) in two consanguineous families. We report on a new case from a third independent family with the homozygous nonsense mutation, c.2659C>T, p.R887* in exon 15 of DSG1 (desmoglein 1 gene). This mutation led to mRNA decay and loss of expression of desmoglein 1. The clinical phenotype consisted of severe palmoplantar keratoderma, dermatitis and multiple allergies. In contrast to the previous cases, malabsorption, hypoalbuminaemia, developmental delay, hypotrichosis or severe recurrent infections were not observed.
- Published
- 2014
43. S1 guidelines for the diagnosis and treatment of ichthyoses - update
- Author
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Regina Fölster-Holst, Judith Fischer, Kathrin A. Giehl, Dirk Breitkreutz, Illiana Tantcheva-Poór, Marie-Luise Preil, Kirstin Kiekbusch, Ingrid Hausser, Geske Wehr, Steffen Emmert, Barbara Kleinow, Irina Zaraeva, Ana Maria Perusquia-Ortiz, Heiko Traupe, Stefan Weidinger, Vinzenz Oji, Hagen Ott, Karola Stieler, Anja Diem, Karin Aufenvenne, Peter Höger, Henning Hamm, and Hans Christian Hennies
- Subjects
Balneotherapy ,Adult ,Male ,Pathology ,medicine.medical_specialty ,Adolescent ,Genetic counseling ,medicine.medical_treatment ,RL ,Alternative medicine ,Context (language use) ,Dermatology ,Diagnosis, Differential ,030207 dermatology & venereal diseases ,03 medical and health sciences ,QH301 ,Young Adult ,0302 clinical medicine ,Pregnancy ,Germany ,medicine ,Humans ,Genetic Predisposition to Disease ,Intensive care medicine ,Child ,QH426 ,Ichthyosis ,business.industry ,Consensus conference ,Infant, Newborn ,Infant ,medicine.disease ,Prognosis ,Psychosocial support ,Patient support ,030220 oncology & carcinogenesis ,Child, Preschool ,Female ,Guideline Adherence ,business - Abstract
Ichthyoses are a group of rare genetic skin disorders that pose numerous clinical\ud challenges, in particular with respect to the correct diagnosis and appropriate management.\ud The present update of the German ichthyosis guidelines addresses recent\ud diagnostic advances that have resulted in the Sorèze consensus classification. In this\ud context, we provide an updated diagnostic algorithm, taking into account clinical features\ud as well as the molecular genetic basis of these disorders. Moreover, we highlight\ud current therapeutic approaches such as psychosocial support, balneotherapy, mechanical\ud scale removal, topical therapy, and systemic retinoid therapy. General aspects\ud such as the indication for physical therapy, ergotherapy, or genetic counseling are\ud also discussed. The present update was consented by an interdisciplinary consensus\ud conference that included dermatologists, pediatricians, human geneticists, and natural\ud scientists as well as representatives of the German patient support organization\ud Selbsthilfe Ichthyose e. V.
- Published
- 2017
44. S1-Leitlinie zur Diagnostik und Therapie der Ichthyosen - Aktualisierung
- Author
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Kirstin Kiekbusch, Geske Wehr, Dirk Breitkreutz, Ingrid Hausser, Marie Luise Preil, Judith Fischer, Stefan Weidinger, Henning Hamm, Irina Zaraeva, Hans Christian Hennies, Karola Stieler, Steffen Emmert, Karin Aufenvenne, Kathrin A. Giehl, Regina Fölster-Holst, Peter Höger, Hagen Ott, Ana Maria Perusquia-Ortiz, Illiana Tantcheva-Poór, Heiko Traupe, Vinzenz Oji, Anja Diem, and Barbara Kleinow
- Subjects
Gynecology ,030207 dermatology & venereal diseases ,03 medical and health sciences ,medicine.medical_specialty ,0302 clinical medicine ,business.industry ,030220 oncology & carcinogenesis ,Medicine ,Dermatology ,business - Published
- 2017
45. Spiny Keratoderma der Hand- und Fußflächen - einmal gesehen, nie wieder vergessen
- Author
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Jessica C. Hassel, Maria Rita Gaiser, and Ingrid Hausser
- Subjects
media_common.quotation_subject ,Dermatology ,Art ,Theology ,media_common - Published
- 2017
46. Familial aortic disease and a large duplication in chromosome 16p13.1
- Author
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Philipp, Erhart, Tobias, Brandt, Beate K, Straub, Ingrid, Hausser, Sabine, Hentze, Dittmar, Böckler, and Caspar, Grond-Ginsbach
- Subjects
Adult ,Male ,Aortic Diseases ,Clinical Reports ,whole exome sequencing ,Gene Duplication ,Databases, Genetic ,Exome Sequencing ,Humans ,familial thoracic aortic aneurysm and dissection ,Exome ,Family ,Genetic Predisposition to Disease ,Aorta ,Aged ,Clinical Report ,Aortic Aneurysm, Thoracic ,Middle Aged ,Pedigree ,Aortic Dissection ,Phenotype ,Chromosome Structures ,Mutation ,cardiovascular system ,Female ,cosegregation ,duplication 16p13.1 ,Chromosomes, Human, Pair 16 - Abstract
Background and purpose A recurrent duplication of chromosome 16p13.1 was associated with aortic dissection as well as with cervical artery dissection. We explore the segregation of this duplication in a family with familial aortic disease. Methods Whole exome sequencing (WES) analysis was performed in a patient with a family history of aortic diseases and ischemic stroke due to an aortic dissection extending into both carotid arteries. Results The index patient, his affected father, and an affected sister of his father carried a large duplication of region 16p13.1, which was also verified by quantitative PCR. The duplication was also found in clinically asymptomatic sister of the index patient. WES did not detect pathogenic variants in a predefined panel of 11 genes associated with aortic disease, but identified rare deleterious variants in 14 genes that cosegregated with the aortic phenotype. Conclusions The cosegregation of duplication 16p13.1 with the aortic phenotype in this family suggested a causal relationship between the duplication and aortic disease. Variants in known candidate genes were excluded as disease‐causing in this family, but cosegregating variants in other genes might modify the contribution of duplication 16p13.1 on aortic disease.
- Published
- 2017
47. Recurrence of cervical artery dissection: An underestimated risk
- Author
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Ingrid Hausser, Caspar Grond-Ginsbach, Werner Hacke, Peter A. Ringleb, Manja Kloss, and Tobias Brandt
- Subjects
Adult ,Male ,medicine.medical_specialty ,Time Factors ,Cervical Artery ,Connective tissue ,Carotid Artery, Internal, Dissection ,030204 cardiovascular system & hematology ,Statistics, Nonparametric ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Sex Factors ,Recurrence ,Risk Factors ,medicine ,Humans ,In patient ,Stroke ,Vertebral Artery Dissection ,medicine.diagnostic_test ,business.industry ,Age Factors ,Magnetic resonance imaging ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,Current analysis ,Surgery ,Dissection ,medicine.anatomical_structure ,Cervical Vertebrae ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Cohort study - Abstract
ObjectiveTo explore the recurrence of cervical artery dissection (CeAD).MethodsA single-center consecutive series of 282 CeAD patients was prospectively recruited during first admission from 1995 to 2012. Patients with a follow-up of at least 1 year (n = 238) were eligible for the current analysis. All patients with clinical symptoms or signs of recurrent CeAD on ultrasound were examined by MRI. Dermal connective tissue morphology was studied in 108 (45.4%) patients.ResultsMedian follow-up was 52 months (range 12–204 months). In all, 221 (92.8%) patients presented with monophasic CeAD, including 188 (79.0%) patients with a single CeAD event, 11 (4.6%) with simultaneous dissections in multiple cervical arteries, and 22 (9.2%) with subsequent events within a single phase of 4 weeks. Seventeen patients (7.1%) had late (>1 month after the initial event) recurrent CeAD events, including 5 (2.1%) with multiple recurrences. Patients with late recurrences were younger (37.5 ± 6.9 years) than those without (43.8 ± 9.9; p = 0.011). Ischemic stroke occurred in 164 (68.9%) patients at first diagnosis, but only 4 of 46 (8.7%) subsequent events caused stroke (p < 0.0001), while 19 (41.3%) were asymptomatic. Connective tissue abnormalities were found in 54 (56.3%) patients with monophasic and 8 (66.7%) with late recurrent dissections (p = 0.494).ConclusionTwenty-two (9.2%) patients had new CeAD events within 1 month and 17 (7.1%) later recurrences. The risk for new events was significantly higher (about 60-fold) during the acute phase than during later follow-up. Connective tissue abnormalities were not more frequent in patients with late recurrent events than in those with monophasic CeAD.
- Published
- 2017
48. Database-augmented Mass Spectrometry Analysis of Exosomes Identifies Claudin 3 as a Putative Prostate Cancer Biomarker
- Author
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Jost von Hardenberg, Michael Boutros, Thomas Stefan Worst, Maurice Stephan Michel, Philipp Erben, Peter Bugert, Martina Schnölzer, Ingrid Hausser, and Julia Christina Gross
- Subjects
0301 basic medicine ,Male ,Databases, Factual ,Prostatic Hyperplasia ,urologic and male genital diseases ,Proteomics ,computer.software_genre ,Exosomes ,Biochemistry ,Exosome ,Mass Spectrometry ,Analytical Chemistry ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Biomarkers, Tumor ,Claudin-3 ,Humans ,Claudin ,Molecular Biology ,Aged ,Database ,business.industry ,Research ,CLDN3 ,Cancer ,Prostatic Neoplasms ,Middle Aged ,medicine.disease ,3. Good health ,Prostate-specific antigen ,030104 developmental biology ,030220 oncology & carcinogenesis ,Biomarker (medicine) ,Neoplasm Grading ,business ,computer - Abstract
In prostate cancer and other malignancies sensitive and robust biomarkers are lacking or have relevant limitations. Prostate specific antigen (PSA), the only biomarker widely used in prostate cancer, is suffering from low specificity. Exosomes offer new perspectives in the discovery of blood-based biomarkers. Here we present a proof-of principle study for a proteomics-based identification pipeline, implementing existing data sources, to exemplarily identify exosome-based biomarker candidates in prostate cancer. Exosomes from malignant PC3 and benign PNT1A cells and from FBS-containing medium were isolated using sequential ultracentrifugation. Exosome and control samples were analyzed on an LTQ-Orbitrap XL mass spectrometer. Proteomic data is available via ProteomeXchange with identifier PXD003651. We developed a scoring scheme to rank 64 proteins exclusively found in PC3 exosomes, integrating data from four public databases and published mass spectrometry data sets. Among the top candidates, we focused on the tight junction protein claudin 3. Retests under serum-free conditions using immunoblotting and immunogold labeling confirmed the presence of claudin 3 on PC3 exosomes. Claudin 3 levels were determined in the blood plasma of patients with localized (n = 58; 42 with Gleason score 6–7, 16 with Gleason score ≥8) and metastatic prostate cancer (n = 11) compared with patients with benign prostatic hyperplasia (n = 15) and healthy individuals (n = 15) using ELISA, without prior laborious exosome isolation. ANOVA showed different CLDN3 plasma levels in these groups (p = 0.004). CLDN3 levels were higher in patients with Gleason ≥8 tumors compared with patients with benign prostatic hyperplasia (p = 0.012) and Gleason 6–7 tumors (p = 0.029). In patients with localized tumors CLDN3 levels predicted a Gleason score ≥ 8 (AUC = 0.705; p = 0.016) and did not correlate with serum PSA. By using the described workflow claudin 3 was identified and validated as a potential blood-based biomarker in prostate cancer. Furthermore this workflow could serve as a template to be used in other cancer entities.
- Published
- 2017
49. Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-Recessive Cutis Laxa
- Author
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Wouter Steyaert, Erik-Jan Kamsteeg, Peter K.C. Leung, Delfien Syx, G. Christoph Korenke, Paul Coucke, Payman Jamali, Sunnie Wong, Uwe Kornak, Peter Freisinger, Brian H.Y. Chung, Gülen Eda Utine, Miski Mohamed, Dirk Lefeber, Tim M. Strom, Sofie Symoens, Ulrich Brandt, Leo G.J. Nijtmans, Bert Callewaert, Thatjana Gardeitchik, Daisy Dalloyaux, Brecht Guillemyn, Sanne van Kraaij, Christopher C.Y. Mak, Riet De Rycke, Björn Fischer-Zirnsak, Tobias B. Haack, Anne De Paepe, Eva Morava, Fransiska Malfait, Thomas Meitinger, Ariana Kariminejad, Tim Van Damme, Ron A. Wevers, Alexander Hoischen, Yasemin Alanay, Monique van Scherpenzeel, Sergio Guerrero-Castillo, Ingrid Hausser, Christian Thiel, Siavash Ghaderi-Sohi, Acibadem University Dspace, and Çocuk Sağlığı ve Hastalıkları
- Subjects
Male ,0301 basic medicine ,Glycosylation ,Protein Conformation ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Golgi Apparatus ,030105 genetics & heredity ,Cutis Laxa ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,chemistry.chemical_compound ,Tandem Mass Spectrometry ,Arcl2 ,Atp6v1a ,Atp6v1e1 ,Autosomal Recessive ,Cdg ,Cellular Trafficking ,Congenital Disorder Of Glycosylation ,V-atpase ,Child ,Genetics (clinical) ,Genetics ,Genetics & Heredity ,Extracellular matrix assembly ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,Brefeldin A ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,Pedigree ,Cell biology ,Protein Transport ,Biochemistry ,symbols ,Female ,Vacuolar Proton-Translocating ATPases ,Adolescent ,Endosome ,Mutation, Missense ,Biology ,Abnormal protein glycosylation ,03 medical and health sciences ,symbols.namesake ,medicine ,Humans ,V-ATPase ,Amino Acid Sequence ,Alleles ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Infant, Newborn ,Correction ,Infant ,Fibroblasts ,Golgi apparatus ,medicine.disease ,Human genetics ,030104 developmental biology ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,Gene Expression Regulation ,chemistry ,Case-Control Studies ,Congenital disorder of glycosylation ,Genome-Wide Association Study ,Cutis laxa - Abstract
Contains fulltext : 169752.pdf (Publisher’s version ) (Closed access) Defects of the V-type proton (H+) ATPase (V-ATPase) impair acidification and intracellular trafficking of membrane-enclosed compartments, including secretory granules, endosomes, and lysosomes. Whole-exome sequencing in five families affected by mild to severe cutis laxa, dysmorphic facial features, and cardiopulmonary involvement identified biallelic missense mutations in ATP6V1E1 and ATP6V1A, which encode the E1 and A subunits, respectively, of the V1 domain of the heteromultimeric V-ATPase complex. Structural modeling indicated that all substitutions affect critical residues and inter- or intrasubunit interactions. Furthermore, complexome profiling, a method combining blue-native gel electrophoresis and liquid chromatography tandem mass spectrometry, showed that they disturb either the assembly or the stability of the V-ATPase complex. Protein glycosylation was variably affected. Abnormal vesicular trafficking was evidenced by delayed retrograde transport after brefeldin A treatment and abnormal swelling and fragmentation of the Golgi apparatus. In addition to showing reduced and fragmented elastic fibers, the histopathological hallmark of cutis laxa, transmission electron microscopy of the dermis also showed pronounced changes in the structure and organization of the collagen fibers. Our findings expand the clinical and molecular spectrum of metabolic cutis laxa syndromes and further link defective extracellular matrix assembly to faulty protein processing and cellular trafficking caused by genetic defects in the V-ATPase complex.
- Published
- 2017
50. Monoallelic Large Intragenic KRT5 Deletions Account for Genetically Unsolved Cases of Epidermolysis Bullosa Simplex
- Author
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Jürgen Kohlhase, Ingrid Hausser, Hauke Schumann, Juna Leppert, Yinghong He, Cristina Has, and Britta Hartmann
- Subjects
0301 basic medicine ,Male ,DNA Mutational Analysis ,Dermatology ,Biology ,Biochemistry ,030207 dermatology & venereal diseases ,03 medical and health sciences ,Epidermolysis bullosa simplex ,0302 clinical medicine ,Keratin ,medicine ,Humans ,Intermediate filament ,Molecular Biology ,Alleles ,Sequence Deletion ,Genetics ,chemistry.chemical_classification ,Cell Biology ,DNA ,medicine.disease ,030104 developmental biology ,chemistry ,Epidermolysis Bullosa Simplex ,Keratin-5 ,Female ,Epidermolysis bullosa - Published
- 2016
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