230 results on '"Markus Schuelke"'
Search Results
52. DMD – ANIMAL MODELS
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O. Petrova, T. Tensorer, A. Morin, Isabelle Richard, A. Stantzou, Luis Garcia, Aurélie Goyenvalle, C. Laplace-Builhé, T. Manoliu, Helge Amthor, Markus Schuelke, and M. Petkova
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Neurology ,Pediatrics, Perinatology and Child Health ,Neurology (clinical) ,Genetics (clinical) - Published
- 2021
53. Inflammation, fibrosis and skeletal muscle regeneration in LGMDR9 are orchestrated by macrophages
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Adela Della Marina, Ulrike Schara-Schmidt, Hans-Hilmar Goebel, Markus Schuelke, Heike Kölbel, Andreas Roos, Corinna Preuße, Werner Stenzel, Lukas Brand, and Arpad von Moers
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Male ,0301 basic medicine ,Muscle tissue ,Pathology ,medicine.medical_specialty ,Histology ,Medizin ,Inflammation ,Biology ,Pathology and Forensic Medicine ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Fibrosis ,alpha dystroglycan ,Physiology (medical) ,Myosin ,LGMDR9 ,medicine ,Humans ,Pentosyltransferases ,Muscle, Skeletal ,Myogenesis ,Regeneration (biology) ,fibrosis ,Skeletal muscle ,medicine.disease ,VEGF ,macrophages ,030104 developmental biology ,medicine.anatomical_structure ,Muscular Dystrophies, Limb-Girdle ,Neurology ,CD206 ,inflammation ,regeneration ,Female ,Neurology (clinical) ,medicine.symptom ,030217 neurology & neurosurgery ,600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit - Abstract
Aims Variable degrees of inflammation, necrosis, regeneration and fibrofatty replacement are part of the pathological spectrum of the dystrophic process in alpha dystroglycanopathy LGMDR9 (FKRP-related, OMIM #607155), one of the most prevailing types of LGMDs worldwide. Inflammatory processes and their complex interplay with vascular, myogenic and mesenchymal cells may have a major impact on disease development. The purpose of our study is to describe the specific immune morphological features in muscle tissue of patients with LGMDR9 in order to enable a better understanding of the phenotype of muscle damage leading to disease progression. Methods We have analysed skeletal muscle biopsies of 17 patients genetically confirmed as having LGMDR9 by histopathological and molecular techniques. Results We identified CD206+ MHC class II+ and STAT6+ immune-repressed macrophages dominating the endomysial infiltrate in areas of myofibre regeneration and fibrosis. Additionally, PDGFRβ+ pericytes were located around MHC class II+ activated capillaries residing in close proximity to areas of fibrosis and regenerating fibres. Expression of VEGF was found on many regenerating neonatal myosin+ fibres myofibres and CD206+ macrophages also co-expressed VEGF. Conclusion Our results show characteristic immune inflammatory features in LGMDR9 and more specifically shed light on the predominant role of macrophages and their function in vascular organization, fibrosis and myogenesis. Understanding disease-specific immune phenomena potentially inform about possibilities for anti-fibrotic and anti-inflammatory therapeutic strategies, which may complement Ribitol replacement and gene therapies for LGMDR9 that may be available in the future.
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- 2021
54. Mutation detection in the non-coding genome
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Markus Schuelke
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Genetics ,Genetics (clinical) - Published
- 2021
55. Live‐imaging of revertant and therapeutically restored dystrophin in the Dmd EGFP‐mdx mouse model for Duchenne muscular dystrophy
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Adrien Morin, Amalia Stantzou, Olga Petrova, Tudor Manoliu, Markus Schuelke, Isabelle Richard, Helge Amthor, Mina V. Petkova, Corinne Laplace-Builhé, Luis Garcia, Franziska Seifert, Susanne Morales-Gonzalez, Jessica Bellec‐Dyevre, Aurélie Goyenvalle, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humboldt-Universität zu Berlin, Institut Gustave Roussy (IGR), Laboratoire International Associé 'Biothérapies Appliquées aux Handicaps Neuromusculaires' (LIA BAHN), Centre Scientifique de Monaco, Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Hôpital Raymond Poincaré [AP-HP], Association Française contre les Myopathies, AFM Deutsche Forschungsgemeinschaft, DFG: 369424301 CDFA‐06‐11 Deutsche Forschungsgemeinschaft, DFG Association Française contre les Myopathies, AFM Deutsche Forschungsgemeinschaft, DFG: 369424301 CDFA‐06‐11 Deutsche Forschungsgemeinschaft, DFG Association Française contre les Myopathies, AFM Association Française contre les Myopathies, AFM, We thank Synthena (Bern, Switzerland) for providing tcDNA and Thomas Bestetti for performing tcDNA injections. This work was supported by the Association Monegasque contre les Myopathies, the Action Benni&Co, the German research foundation (DFG, project number: 369424301), the Université Franco‐Allemande (CDFA‐06‐11) and the Association Française contre les Myopathies. We thank Dr. Jan Schmoranzer from the Charité AMBIO imaging facility for his help and Dr. Feng Zhang for the plasmid pX601‐AAV‐CMV::NLS‐SaCas9‐NLS‐3xHA‐bGHpA, U6::BsaI‐sgRNA. Open access funding enabled and organized by Projekt DEAL., This work was supported by the Association Monégasque contre les Myopathies, the Action Benni&Co, the German research foundation (DFG, project number: 369424301), the Université Franco‐Allemande (CDFA‐06‐11), and the Association Française contre les Myopathies., Université Humboldt de Berlin, CHU Raymond Poincaré, Richard, Isabelle, and Humboldt University Of Berlin
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0301 basic medicine ,musculoskeletal diseases ,Duchenne muscular dystrophy ,mdx mouse ,congenital, hereditary, and neonatal diseases and abnormalities ,tcDNA ,Histology ,[SDV.BIO]Life Sciences [q-bio]/Biotechnology ,[SDV]Life Sciences [q-bio] ,Nonsense mutation ,Biology ,revertant muscle fibre ,Pathology and Forensic Medicine ,03 medical and health sciences ,Exon ,0302 clinical medicine ,In vivo ,Physiology (medical) ,medicine ,CRISPR/Cas9 ,dystrophin-EGFP fusion protein ,ComputingMilieux_MISCELLANEOUS ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,medicine.disease ,musculoskeletal system ,mdx reporter mouse model ,Cell biology ,[SDV] Life Sciences [q-bio] ,030104 developmental biology ,Neurology ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,biology.protein ,Neurology (clinical) ,Dystrophin ,600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit ,030217 neurology & neurosurgery ,Ex vivo ,Intravital microscopy - Abstract
International audience; Background: Dmdmdx, harbouring the c.2983C>T nonsense mutation in Dmd exon 23, is a mouse model for Duchenne muscular dystrophy (DMD), frequently used to test therapies aimed at dystrophin restoration. Current translational research is methodologically hampered by the lack of a reporter mouse model, which would allow direct visualization of dystrophin expression as well as longitudinal in vivo studies. Methods: We generated a DmdEGFP-mdx reporter allele carrying in cis the mdx-23 mutation and a C-terminal EGFP-tag. This mouse model allows direct visualization of spontaneously and therapeutically restored dystrophin-EGFP fusion protein either after natural fibre reversion, or for example, after splice modulation using tricyclo-DNA to skip Dmd exon 23, or after gene editing using AAV-encoded CRISPR/Cas9 for Dmd exon 23 excision. Results: Intravital microscopy in anaesthetized mice allowed live-imaging of sarcolemmal dystrophin-EGFP fusion protein of revertant fibres as well as following therapeutic restoration. Dystrophin-EGFP-fluorescence persisted ex vivo, allowing live-imaging of revertant and therapeutically restored dystrophin in isolated fibres ex vivo. Expression of the shorter dystrophin-EGFP isoforms Dp71 in the brain, Dp260 in the retina, and Dp116 in the peripheral nerve remained unabated by the mdx-23 mutation. Conclusion: Intravital imaging of DmdEGFP-mdx muscle permits novel experimental approaches such as the study of revertant and therapeutically restored dystrophin in vivo and ex vivo.
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- 2020
56. A novel mutation in NEB causing foetal nemaline myopathy with arthrogryposis during early gestation
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Dirk Korinth, Markus Schuelke, Benjamin Englert, Akinori Uruha, Rabih Chaoui, Eun Kyung Suk, Werner Stenzel, Rainer Rossi, Dietmar Schlembach, Carsten Dittmayer, Simone Schmid, Maria Linda Rocha, Katarina Pelin, and Hans H. Goebel
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0301 basic medicine ,Male ,Pathology ,medicine.medical_specialty ,Muscle Proteins ,Prenatal diagnosis ,Context (language use) ,Gestational Age ,Myopathies, Nemaline ,Ultrasonography, Prenatal ,03 medical and health sciences ,0302 clinical medicine ,Nemaline myopathy ,Fetus ,Pregnancy ,Medicine ,Humans ,Lebanon ,Muscle, Skeletal ,Genetics (clinical) ,Arthrogryposis ,Muscle Weakness ,business.industry ,Muscle weakness ,Skeletal muscle ,medicine.disease ,Hypotonia ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,Pediatrics, Perinatology and Child Health ,Mutation ,Female ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Nemaline myopathies are a clinically and genetically heterogeneous group of congenital myopathies, mainly characterized by muscle weakness, hypotonia and respiratory insufficiency. Here, we report a male foetus of consanguineous parents with a severe congenital syndrome characterized by arthrogryposis detected at 13 weeks of gestation. We describe severe complex dysmorphic facial and musculoskeletal features by post mortem fetal examination confirming the prenatal diagnosis. Histomorphological and ultrastructural studies of skeletal muscle reveal mini-rods in myotubes caused by a novel homozygous splice-site mutation in NEB (NM_001164508, chr2:g.152,417,623C>A GRCh37.p11 | c.19,102-1G>T ENST00000397345.3). No rods were seen in the myocardium. We discuss the relevance of this mutation in the context of nemaline myopathies associated with early developmental musculoskeletal disorders.
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- 2020
57. Identification of Taenia solium based on single tapeworm eggs in diagnostic stool samples using RNA sequencing v1
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Henrik Sadlowski, Veronika Schmidt, Jonathan Hiss, Christian G. Schneider, Gideon Zulu, Alex Hachangu, Chummy S. Sikasunge, Kabemba E. Mwape, Andrea S. Winkler, and Markus Schuelke
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parasitic diseases - Abstract
Here we present a detailed protocol for the identification of Taenia solium based on the few Taenia spp. eggs found in diagnostic stool samples. Our approach is based on "mail order" RNA sequencing of single eggs and can be performed in laboratories equipped with basic tools such as a microscope, a Bunsen burner, and access to an international post office for shipping samples to a next-generation sequencing facility. This protocol describes sample collection and transport, isolation of individual Taenia spp. eggs, reliable disruption of individual Taenia eggs, and important considerations for shipping samples to a next-generation sequencing facility. We provide images and videos to help prepare the tools needed for the protocol. Additional information on our rationale for designing the critical steps can help implement the protocol in new environments.
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- 2020
58. Defining the ATPome reveals cross-optimization of metabolic pathways
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Martin Kampmann, Markus Schuelke, Johanna ten Hoeve, Bryce A. Mendelsohn, Jean L. Nakamura, Mai K. Nguyen, Maxwell A. Darch, Thomas G. Graeber, Emin Maltepe, Derek Cousineau, Ken Nakamura, Hiroki J. Nakaoka, and Neal K. Bennett
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0301 basic medicine ,General Physics and Astronomy ,02 engineering and technology ,Mitochondrion ,Pentose Phosphate Pathway ,Cell growth ,Adenosine Triphosphate ,Hexokinase ,2.1 Biological and endogenous factors ,Glycolysis ,Aetiology ,lcsh:Science ,chemistry.chemical_classification ,Multidisciplinary ,Chemistry ,Functional genomics ,021001 nanoscience & nanotechnology ,Cell biology ,Mitochondria ,Metabolic pathways ,Gene Knockdown Techniques ,Female ,0210 nano-technology ,Metabolic Networks and Pathways ,1.1 Normal biological development and functioning ,Science ,Pentose phosphate pathway ,Carbohydrate metabolism ,General Biochemistry, Genetics and Molecular Biology ,Article ,Cell Line ,03 medical and health sciences ,Affordable and Clean Energy ,Underpinning research ,Humans ,Metabolomics ,Point Mutation ,Nutrition ,CRISPR interference ,General Chemistry ,Metabolism ,Fibroblasts ,Metabolic pathway ,030104 developmental biology ,Enzyme ,Glucose ,Gene Expression Regulation ,lcsh:Q ,CRISPR-Cas Systems ,Energy Metabolism ,K562 Cells - Abstract
Disrupted energy metabolism drives cell dysfunction and disease, but approaches to increase or preserve ATP are lacking. To generate a comprehensive metabolic map of genes and pathways that regulate cellular ATP—the ATPome—we conducted a genome-wide CRISPR interference/activation screen integrated with an ATP biosensor. We show that ATP level is modulated by distinct mechanisms that promote energy production or inhibit consumption. In our system HK2 is the greatest ATP consumer, indicating energy failure may not be a general deficiency in producing ATP, but rather failure to recoup the ATP cost of glycolysis and diversion of glucose metabolites to the pentose phosphate pathway. We identify systems-level reciprocal inhibition between the HIF1 pathway and mitochondria; glycolysis-promoting enzymes inhibit respiration even when there is no glycolytic ATP production, and vice versa. Consequently, suppressing alternative metabolism modes paradoxically increases energy levels under substrate restriction. This work reveals mechanisms of metabolic control, and identifies therapeutic targets to correct energy failure., Energy metabolism and ATP levels are controlled by an interlocking network of pathways. Here, the authors apply a genome-wide CRISPR screen to define genes that increase or decrease ATP levels to define the “ATPome”, a map of pathways that contribute to cellular ATP regulation.
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- 2020
59. Extracellular matrix remodelling is associated with muscle force increase in overloaded mouse plantaris muscle
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Charles Gallen, Amalia Stantzou, Arnaud Ferry, Antoine Grassin, Helge Amthor, Karima Relizani, Susanne Morales-Gonzalez, Markus Schuelke, Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Genetics, Institute for Biology, Free University Berlin, Free University of Berlin (FU), Centre de Recherche en Myologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ANR-10-BLAN-1108,Androgluco,Etude des mécanismes physiopathologiques des récepteurs des androgènes et des glucocorticoïdes dans les muscles striés et identification de nouvelles cibles thérapeutiques pour la prévention et le traitement de l'atrophie musculaire(2010), and Centre de recherche en Myologie – U974 SU-INSERM
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0301 basic medicine ,[SDV]Life Sciences [q-bio] ,Myostatin ,Muscle hypertrophy ,Extracellular matrix ,Mice ,0302 clinical medicine ,Muscular dystrophy ,Halofuginone ,biology ,Chemistry ,Extracellular Matrix ,medicine.anatomical_structure ,Neurology ,muscle force ,myostatin ,Female ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,medicine.symptom ,600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit ,medicine.drug ,TGF-β ,muscular dystrophy ,medicine.medical_specialty ,Histology ,overload ,Inflammation ,Pathology and Forensic Medicine ,03 medical and health sciences ,halofuginone ,TGF-�� ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Muscle, Skeletal ,fibrosis ,array-based transcriptome analysis ,Skeletal muscle ,Muscular Dystrophy, Animal ,medicine.disease ,Mice, Inbred C57BL ,TGF-b ,030104 developmental biology ,Endocrinology ,biology.protein ,Neurology (clinical) ,Plantaris muscle ,030217 neurology & neurosurgery - Abstract
International audience; Extracellular matrix remodelling is associated with muscle force increase in overloaded mouse plantaris muscle Aims: Transforming growth factor-b (TGF-b) signalling is thought to contribute to the remodelling of extracellular matrix (ECM) of skeletal muscle and to functional decline in patients with muscular dystrophies. We wanted to determine the role of TGF-b-induced ECM remodelling in dystrophic muscle. Methods: We experimentally induced the pathological hallmarks of severe muscular dystrophy by mechanically overloading the plantaris muscle in mice. Furthermore, we determined the role of TGF-b signalling on dystrophic tissue modulation and on muscle function by (i) overloading myostatin knockout (Mstn À/À) mice and (ii) by additional pharmacological TGF-b inhibition via halofuginone. Results: Transcriptome analysis of overloaded muscles revealed upregulation predominantly of genes associated with ECM, inflammation and metalloproteinase activity. Histology revealed in wild-type mice signs of severe muscular dystrophy including myofibres with large variation in size and internalized myonuclei, as well as increased ECM deposition. At the same time, muscle weight had increased by 208% and muscle force by 234%. Myostatin deficiency blunted the effect of overload on muscle mass (59% increase) and force (76% increase), while having no effect on ECM deposition. Concomitant treatment with halofuginone blunted overload-induced muscle hypertro-phy and muscle force increase, while reducing ECM depo-sition and increasing myofibre size. Conclusions: ECM remodelling is associated with an increase in muscle mass and force in overload-modelled dystrophic muscle. Lack of myostatin is not advantageous and inhibition of ECM deposition by halofuginone is disadvantageous for muscle plasticity in response to stimuli that induce dystrophic muscle.
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- 2020
60. Presence of anti-neuronal antibodies in children with neurological disorders beyond encephalitis
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Christian Meisel, Markus Reindl, Marc Nikolaus, Angela M. Kaindl, Markus Schuelke, Harald Prüss, Jakob Kreye, and Ellen Knierim
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Male ,Adolescent ,Clinical Neurology ,Immunofluorescence ,Autoimmune Diseases ,03 medical and health sciences ,0302 clinical medicine ,Cerebrospinal fluid ,Antigen ,immunology [Autoimmune Diseases] ,Central Nervous System Diseases ,030225 pediatrics ,medicine ,Animals ,Humans ,ddc:610 ,Pediatrics, Perinatology, and Child Health ,Child ,immunology [Central Nervous System Diseases] ,Autoantibodies ,Retrospective Studies ,Autoimmune encephalitis ,biology ,medicine.diagnostic_test ,business.industry ,Autoantibody ,Infant, Newborn ,Infant ,General Medicine ,medicine.disease ,cerebrospinal fluid [Autoantibodies] ,cerebrospinal fluid [Autoimmune Diseases] ,cerebrospinal fluid [Biomarkers] ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Immunology ,cerebrospinal fluid [Central Nervous System Diseases] ,Etiology ,biology.protein ,Female ,Neurology (clinical) ,Antibody ,business ,030217 neurology & neurosurgery ,Encephalitis ,Biomarkers - Abstract
Background Anti-neuronal autoantibodies have been reported as the cause of several neurologic disorders other than encephalitis. Unfortunately, data are mostly based on serum analysis. Predictions about pathogenicity are thus limited. To determine the presence of so far unidentified autoantibody-derived neuroreactivity we analyzed cerebrospinal fluid (CSF) of children with neurological disorders other than encephalitis. Patients and methods We did a retrospective analysis of CSF from 254 children with various neurologic diseases other than encephalitis and searched for reactivity against neuronal surface antigens by immunofluorescence on unfixed murine brain sections (tissue-based assay, TBA) and by commercial cell-based assays (CBA). A semi-quantitative fluorescence score classified our results and we described the clinical course of all positive patients with strong neuroreactivity. Results Strong anti-neuronal IgG immunoreactivity of unknown antigen specificity was detected in CSF samples of 10 pediatric patients (4%, n = 10/254) with unsolved neurological disorders. CSF inflammatory markers were elevated. Most patients did not or only partly recover. Five screening-positive patients presented with a combination of headache and visual impairment due to optic nerve atrophy. Our data suggest to consider inflammatory, autoantibody-related etiologies, especially in cases without definite diagnoses. Conclusions We present an overview of CSF neuroreactivity in children with neurological disorders other than encephalitis, indicating the presence of unidentified anti-neuronal autoantibodies. As TBA enables screening for unknown autoantibodies, we suggest this method as a second step if commercial CBAs do not yield a result. Further studies are necessary to characterize such antibodies, evaluate pathogenicity, and answer the question whether positive CSF neuroreactivity should prompt an immunotherapeutic approach.
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- 2020
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61. Allan-Herndon-Dudley-Syndrome: Considerations about the Brain Phenotype with Implications for Treatment Strategies
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Markus Schuelke, Heiko Krude, Matthias H. Tschöp, Timo D. Müller, and Heike Biebermann
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0301 basic medicine ,Monocarboxylic Acid Transporters ,Cerebellum ,Ataxia ,Endocrinology, Diabetes and Metabolism ,Pyramidal Tracts ,030209 endocrinology & metabolism ,Basal Ganglia ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Basal ganglia ,Internal Medicine ,medicine ,Humans ,Athetosis ,Dystonia ,Allan–Herndon–Dudley syndrome ,business.industry ,Thyroid ,Chorea ,General Medicine ,medicine.disease ,Muscular Atrophy ,030104 developmental biology ,medicine.anatomical_structure ,Mental Retardation, X-Linked ,Muscle Hypotonia ,Triiodothyronine ,medicine.symptom ,business ,Neuroscience - Abstract
Despite its first description more than 75 years ago, effective treatment for “Allan-Herndon-Dudley-Syndrome (AHDS)”, an X-linked thyroid hormone transporter defect, is unavailable. Mutations in the SLC16A2 gene have been discovered to be causative for AHDS in 2004, but a comprehensive understanding of the function of the encoded protein, monocarboxylate transporter 8 (MCT8), is incomplete. Patients with AHDS suffer from neurodevelopmental delay, as well as extrapyramidal (dystonia, chorea, athetosis), pyramidal (spasticity), and cerebellar symptoms (ataxia). This suggests an affection of the pyramidal tracts, basal ganglia, and cerebellum, most likely already during fetal brain development. The function of other brain areas relevant for mood, behavior, and vigilance seems to be intact. An optimal treatment strategy should thus aim to deliver T3 to these relevant structures at the correct time points during development. A potential therapeutic strategy meeting these needs might be the delivery of T3 via a “Trojan horse mechanism” by which T3 is delivered into target cells by a thyroid hormone transporter independent T3 internalization.
- Published
- 2020
62. Homozygous mutation in murine retrovirus integration site 1 gene associated with a non-syndromic form of isolated familial achalasia
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Nicole Reisch, Angela Huebner, Markus Schuelke, Dana Landgraf, Jens Schlossmann, Katrin Koehler, and Dorra Hmida
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0301 basic medicine ,Gene isoform ,Adult ,Tunisia ,Adolescent ,Physiology ,Nonsense mutation ,Achalasia ,Biology ,medicine.disease_cause ,03 medical and health sciences ,symbols.namesake ,Mice ,0302 clinical medicine ,Retrovirus ,Chlorocebus aethiops ,medicine ,Animals ,Humans ,Gene ,Whole genome sequencing ,Sanger sequencing ,Mutation ,Whole Genome Sequencing ,Endocrine and Autonomic Systems ,Homozygote ,Gastroenterology ,Membrane Proteins ,medicine.disease ,biology.organism_classification ,Phosphoproteins ,Molecular biology ,Pedigree ,Esophageal Achalasia ,030104 developmental biology ,Retroviridae ,COS Cells ,symbols ,Female ,030217 neurology & neurosurgery - Abstract
Background Achalasia is a condition characterized by impaired function of esophageal motility and incomplete relaxation of the lower esophagus sphincter, causing dysphagia and regurgitation. Rare cases of early-onset achalasia appear often in combination with further symptoms in a syndromic form as an inherited disease. Methods Whole genome sequencing was used to investigate the genetic basis of isolated achalasia in a family of Tunisian origin. We analyzed the function of the affected protein with immunofluorescence and affinity chromatography study. Key Results A homozygous nonsense mutation was detected in murine retrovirus integration site 1 (MRVI1) gene (Human Genome Organisation Gene Nomenclature Committee (HGNC) approved gene symbol:IRAG1) encoding the inositol 1,4,5-trisphosphate receptor 1 (IP(3)R1)-associated cyclic guanosine monophosphate (cGMP) kinase substrate (IRAG). Sanger sequencing confirmed co-segregation of the mutation with the disease. Sequencing of the entireMRVI1gene in 35 additional patients with a syndromic form of achalasia did not uncover further cases withMRVI1mutations. Immunofluorescence analysis of transfected COS7 cells revealed GFP-IRAG with the truncating mutation p.Arg112* (transcript variant 1) or p.Arg121* (transcript variant 2) to be mislocalized in the cytoplasm and the nucleus. Co-transfection with cGMP-dependent protein kinase 1 isoform beta (cGK1 beta) depicted a partial mislocalization of cGK1 beta due to mislocalized truncated IRAG. Isolation of protein complexes revealed that the truncation of this protein causes the loss of the interaction domain of IRAG with cGK1 beta. Conclusions & Inferences In individuals with an early onset of achalasia without further accompanying symptoms,MRVI1mutations should be considered as the disease-causing defect.
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- 2020
63. 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
64. Autophagic vacuolar myopathy is a common feature of CLN3 disease
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Werner Stenzel, Christian Hagel, Alfried Kohlschütter, Randi Koll, Josefine Radke, Esther Gill, Hans H. Goebel, Angela Schulz, Lars Wiese, and Markus Schuelke
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Degenerative Disorder ,medicine.disease_cause ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Medicine ,Research Articles ,Sanger sequencing ,Mutation ,business.industry ,Genetic heterogeneity ,General Neuroscience ,Skeletal muscle ,Histology ,030104 developmental biology ,medicine.anatomical_structure ,CLN3 ,symbols ,Immunohistochemistry ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Research Article - Abstract
Objective The neuronal ceroid lipofuscinoses (NCL) are genetic degenerative disorders of brain and retina. NCL with juvenile onset (JNCL) is genetically heterogeneous but most frequently caused by mutations of CLN3. Classical juvenile CLN3 includes a rare protracted form, which has previously been linked to autophagic vacuolar myopathy (AVM). Our study investigates the association of AVM with classic, non‐protracted CLN3. Methods Evaluation of skeletal muscle biopsies from three, non‐related patients with classic, non‐protracted and one patient with protracted CLN3 disease by histology, immunohistochemistry, electron microscopy, and Sanger sequencing of the coding region of the CLN3 gene. Results We identified a novel heterozygous CLN3 mutation (c.1056+34C>A) in one of our patients with classic, non‐protracted CLN3 disease. The skeletal muscle of all CLN3 patients was homogeneously affected by an AVM characterized by autophagic vacuoles with sarcolemmal features and characteristic lysosomal pathology. Interpretation Our observations show that AVM is not an exceptional phenomenon restricted to protracted CLN3 but rather a common feature in CLN3 myopathology. Therefore, CLN3 myopathology should be included in the diagnostic spectrum of autophagic vacuolar myopathies.
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- 2018
65. A young woman with multiple acyl-CoA dehydrogenase deficiency (MADD)
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Markus Schuelke, D Pehl, Werner Stenzel, Hans-Hilmar Goebel, and Ulf C. Schneider
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Weakness ,business.industry ,Physiology ,Muscle weakness ,Inflammation ,General Medicine ,Mitochondrion ,medicine.disease ,Neurology ,Intensive care ,medicine ,Vomiting ,Neurology (clinical) ,medicine.symptom ,Multiple Acyl-CoA Dehydrogenase Deficiency ,business ,Myositis - Abstract
A 31-year-old female hairdresser whose parents were first degree cousins complained of episodic attacks of headache, vomiting, and dizziness for the past eight years after an uneventful childhood and adolescence. Four years ago, she developed progressive weakness, muscle pain and difficulties walking and lifting her arms that she could not work in her profession anymore. She lost hair, weight and became amenorrhoic. Finally, her muscle weakness required intensive care. Early on her CK was mildly elevated to 237 U/l (normal < 167), but later to 900 and 1800. By MRI, skeletal muscles showed minimal contrast enhancement.The clinically suspected diagnosis of myositis prompted repeated muscle biopsies, which disclosed non-specific myopathic changes, scattered necrotic muscle fibers without inflammation, protein aggregation, or vacuolation by light microscopy, but abnormally structured mitochondria with inclusions by electron microscopy, and treatment with steroids without any clinical improvement.A panel of 1131 mitochondrial genes revealed a homozygous mutation in the ETFDH gene.LEARNING OBJECTIVESThis presentation will enable the learner to: 1.Discuss MADD as a mitochondrial and lipid storage disease2.Recognize the myopathology of MADD
- Published
- 2021
66. Motor Function in Pediatric ALL Survivors after Chemotherapy-Only
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A.-M. Goebel, Markus Schuelke, S. Rückriegel, Hernáiz Driever, Deborah A Sival, L. Pfuhlmann, E. Koustenis, and R. Brandsma
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Chemotherapy ,Pediatrics ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Pediatrics, Perinatology and Child Health ,medicine ,Neurology (clinical) ,General Medicine ,business ,Motor function - Published
- 2017
67. Myopathology in the times of modern genetics
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Nancy Christine Øien, Markus Schuelke, and Anders Oldfors
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0301 basic medicine ,Disease gene ,Genetics ,Whole genome sequencing ,Histology ,Ethical issues ,Disease classification ,Neuromuscular Diseases ,Biology ,DNA sequencing ,Pathology and Forensic Medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Genetic Techniques ,Neurology ,Physiology (medical) ,Neurology (clinical) ,030217 neurology & neurosurgery ,Exome sequencing - Abstract
The advent of Next Generation Sequencing (NGS) technologies has accelerated the rate of novel disease gene discovery. Analysis of the large datasets generated by whole exome sequencing, whole genome sequencing, and other NGS approaches poses a challenge to physicians and pathologists searching for disease causing variants amongst the 50,000—3 million polymorphisms typically seen in these datasets. This review describes strategies that successfully combine classical neuropathological investigation (e.g. histology, immunostaining, and electron microscopy) with modern NGS technologies to pinpoint the underlying genetic cause of a disease. We describe filtering techniques and free online bioinformatic tools that can help physicians and researchers establish a molecular diagnosis from NGS data. The ethical issues raised by NGS data are outlined. We provide specific examples that illustrate how traditional and contemporary approaches integrate to solve a difficult diagnosis or to correct initially wrong assumptions based on data generated from one method alone. This article is protected by copyright. All rights reserved.
- Published
- 2017
68. Klüver–Bucy syndrome associated with a recessive variant in HGSNAT in two siblings with Mucopolysaccharidosis type IIIC (Sanfilippo C)
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Markus Schuelke, Zoltan Lukacs, Thomas F. Wienker, Esther Gill, Ellen Knierim, Luciana Musante, Hans-Hilger Ropers, Christoph Hübner, and Hao Hu
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Male ,0301 basic medicine ,medicine.medical_specialty ,Short Report ,Genes, Recessive ,Biology ,Klüver–Bucy syndrome ,Mucopolysaccharidosis III ,03 medical and health sciences ,0302 clinical medicine ,Acetyltransferases ,Genetic linkage ,Molecular genetics ,Genetics ,Lysosomal storage disease ,medicine ,Humans ,Exome ,Child ,Genetics (clinical) ,Mucopolysaccharidosis Type IIIC ,Siblings ,Homozygote ,Cytogenetics ,medicine.disease ,Phenotype ,030104 developmental biology ,Kluver-Bucy Syndrome ,Medical genetics ,Female ,030217 neurology & neurosurgery - Abstract
Kluver-Bucy syndrome (KBS) comprises a set of neurobehavioral symptoms with psychic blindness, hypersexuality, disinhibition, hyperorality, and hypermetamorphosis that were originally observed after bilateral lobectomy in Rhesus monkeys. We investigated two siblings with KBS from a consanguineous family by whole-exome sequencing and autozygosity mapping. We detected a homozygous variant in the heparan-alpha-glucosaminidase-N-acetyltransferase gene (HGSNAT; c.518G>A, p.(G173D), NCBI ClinVar RCV000239404.1), which segregated with the phenotype. Disease-causing variants in this gene are known to be associated with autosomal recessive Mucopolysaccharidosis type IIIC (MPSIIIC, Sanfilippo C). This lysosomal storage disease is due to deficiency of the acetyl-CoA:alpha-glucosaminidase-N-acetyltransferase, which was shown to be reduced in patient fibroblasts. Our report extends the phenotype associated with MPSIIIC. Besides MPSIIIA and MPSIIIB, due to variants in SGSH and NAGLU, this is the third subtype of Sanfilippo disease to be associated with KBS. MPSIII should be included in the differential diagnosis of young patients with KBS.
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- 2016
69. CoQ deficiency causes disruption of mitochondrial sulfide oxidation, a new pathomechanism associated with this syndrome
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Germaine Escames, Holger Prokisch, Darío Acuña-Castroviejo, Juan Duarte, Felix Distelmaier, Marta Luna-Sánchez, Julio Chaves-Serrano, Eliana Barriocanal-Casado, Ángela Santos-Fandila, Tatjana M. Hildebrandt, Miguel Romero, Agustín Hidalgo-Gutiérrez, Luis C. López, Markus Schuelke, and Ramy K. A. Sayed
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0301 basic medicine ,Mitochondrial Diseases ,Dewey Decimal Classification::500 | Naturwissenschaften::570 | Biowissenschaften, Biologie ,Ubiquinone ,Mitochondrion ,600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit ,chemistry.chemical_compound ,Mice ,Quinone Reductases ,Dewey Decimal Classification::500 | Naturwissenschaften::580 | Pflanzen (Botanik) ,glutathione ,Research Articles ,Cells, Cultured ,Muscle Weakness ,food and beverages ,blood pressure ,SQR ,Mitochondria ,mitochondrial disease ,ddc:580 ,Mitochondrial respiratory chain ,Biochemistry ,Molecular Medicine ,Oxidation-Reduction ,Research Article ,Mitochondrial disease ,Sulfides ,03 medical and health sciences ,ddc:570 ,Sulfite oxidase ,medicine ,Animals ,Humans ,ddc:610 ,Cerebrum ,COX ,Metabolism ,Fibroblasts ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,chemistry ,Coenzyme Q – cytochrome c reductase ,Ataxia ,Genetics, Gene Therapy & Genetic Disease ,Dewey Decimal Classification::600 | Technik::610 | Medizin, Gesundheit ,Thiosulfate sulfurtransferase - Abstract
Coenzyme Q (CoQ) is a key component of the mitochondrial respiratory chain, but it also has several other functions in the cellular metabolism. One of them is to function as an electron carrier in the reaction catalyzed by sulfide:quinone oxidoreductase (SQR), which catalyzes the first reaction in the hydrogen sulfide oxidation pathway. Therefore, SQR may be affected by CoQ deficiency. Using human skin fibroblasts and two mouse models with primary CoQ deficiency, we demonstrate that severe CoQ deficiency causes a reduction in SQR levels and activity, which leads to an alteration of mitochondrial sulfide metabolism. In cerebrum of Coq9R239X mice, the deficit in SQR induces an increase in thiosulfate sulfurtransferase and sulfite oxidase, as well as modifications in the levels of thiols. As a result, biosynthetic pathways of glutamate, serotonin, and catecholamines were altered in the cerebrum, and the blood pressure was reduced. Therefore, this study reveals the reduction in SQR activity as one of the pathomechanisms associated with CoQ deficiency syndrome. Ministerio de Economía y Competitividad ERDF/SAF2013-47761-R ERDF/SAF2014-55523-R ERDF/RD12/0042/0011 ERDF/SAF2015-65786-R Junta de Andalucía NIH/P01HD080642
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- 2016
70. A novel homozygous nonsense mutation of VPS13B associated with previously unreported features of Cohen syndrome
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M. P. Schittkowski, Angela Huebner, Katrin Koehler, Anna K. Hell, Knut Brockmann, and Markus Schuelke
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0301 basic medicine ,Adult ,Male ,Microcephaly ,VPS13B gene ,Cohen syndrome ,prepubertal alacrima ,prepubertal anhidrosis ,Developmental Disabilities ,Nonsense mutation ,Vesicular Transport Proteins ,030105 genetics & heredity ,Alacrima ,Short stature ,Fingers ,03 medical and health sciences ,Young Adult ,Intellectual Disability ,Genetics ,medicine ,Myopia ,Humans ,Abnormalities, Multiple ,Genetic Predisposition to Disease ,Obesity ,Anhidrosis ,Child ,Genetics (clinical) ,Muscular hypotonia ,Whole Genome Sequencing ,business.industry ,Homozygote ,Retinal Degeneration ,Brain ,medicine.disease ,3. Good health ,VPS13B ,030104 developmental biology ,Codon, Nonsense ,Child, Preschool ,Muscle Hypotonia ,Female ,medicine.symptom ,business - Abstract
Cohen syndrome (CS) is a rare autosomal recessive disorder associated with mutations in the vacuolar protein sorting 13 homolog B (VPS13B; formerly COH1) gene. The core clinical phenotype comprises a characteristic facial gestalt, marked developmental delay, and myopia. Additional, nonobligatory features include obesity, microcephaly, short stature, muscular hypotonia, scoliosis, narrow hands and feet, progressive retinopathy, as well as neutropenia. Here we report a novel homozygous nonsense mutation in the VPS13B gene and previously undescribed clinical features in a 19-year-old woman with developmental delay, intellectual disability, and a particular facial appearance. The patient showed several features consistent with CS. In addition, the parents observed congenital alacrima and anhidrosis persisting until onset of puberty. The diagnosis was not established based on the clinical phenotype. We performed whole-genome sequencing and identified a novel homozygous nonsense mutation c.62T>G (NM_152564.4), p.(Leu21*) in the VPS13B gene. Our findings extended the previously reported phenotype of CS. We conclude that transient, prepubertal alacrima and anhidrosis are part of the phenotypic spectrum of CS associated with a novel homozygous nonsense mutation in the VPS13B gene. peerReviewed
- Published
- 2019
71. SURF1 mutations causative of Leigh syndrome impair human neurogenesis
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Christopher Secker, Sebastian Diecke, Nikolaus Rajewsky, Barbara Mlody, U.H. Ciptasari, Josef Priller, T. Hahn, Werner Stenzel, Erich E. Wanker, Michael Gotthardt, Gizem Inak, R. Juettner, Markus Schuelke, Pawel Lisowski, R. Kuehn, Annika Zink, P. Glazar, Alessandro Prigione, and Agnieszka Rybak-Wolf
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Neurogenesis ,Organoid ,Cancer research ,medicine ,CRISPR ,SURF1 ,Neurological disorder ,Biology ,Induced pluripotent stem cell ,medicine.disease ,Gene ,Neural stem cell - Abstract
Mutations in the mitochondrial complex IV assembly factor SURF1 represent a major cause of Leigh syndrome (LS), a rare fatal neurological disorder. SURF1-deficient animals have failed to recapitulate the neuronal pathology of human LS, hindering our understanding of the disease mechanisms. We generated induced pluripotent stem cells from LS patients carrying homozygous SURF1 mutations (SURF1 iPS) and performed biallelic correction via CRISPR/Cas9. In contrast to corrected cells, SURF1 iPS showed impaired neuronal differentiation. Aberrant bioenergetics in SURF1 iPS occurred already in neural progenitor cells (NPCs), disrupting their neurogenic potency. Cerebral organoids from SURF1 iPS were smaller and recapitulated the neurogenesis defects. Our data imply that SURF1 mutations cause a failure in the development of maturing neurons. Using NPC function as an interventional target, we identified SURF1 gene augmentation as a potential strategy for restoring neurogenesis in LS patients carrying SURF1 mutations.
- Published
- 2019
72. Hybrid genome assembly and annotation of Danionella translucida, a transparent fish with the smallest known vertebrate brain
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Mykola Kadobianskyi, Lisanne Schulze, Benjamin Judkewitz, and Markus Schuelke
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0303 health sciences ,ved/biology ,ved/biology.organism_classification_rank.species ,Vertebrate ,Hybrid genome assembly ,Computational biology ,Biology ,biology.organism_classification ,Genome ,Danionella translucida ,Transcriptome ,03 medical and health sciences ,Annotation ,0302 clinical medicine ,biology.animal ,Model organism ,Zebrafish ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Studying the activity of distributed neuronal circuits at a cellular resolution in vertebrates is very challenging due to the size and optical turbidity of their brains. We recently presented Danionella translucida, a close relative of zebrafish, as a model organism suited for studying large-scale neural network interactions in adult individuals. Danionella remains transparent throughout its life, has the smallest known vertebrate brain and possesses a rich repertoire of complex behaviours. Here we sequenced, assembled and annotated the Danionella translucida genome employing a hybrid Illumina/Nanopore read library as well as RNA-seq of embryonic, larval and adult mRNA. We achieved high assembly continuity using low-coverage long-read data and annotated a large fraction of the transcriptome. This dataset will pave the way for molecular research and targeted genetic manipulation of the smallest known vertebrate brain.
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- 2019
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73. Phenotero: Annotate as you write
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Jana Marie Schwarz, Dominik Seelow, Daniela Hombach, Sebastian Koehler, Markus Schuelke, and Ellen Knierim
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0301 basic medicine ,Knowledge representation and reasoning ,Databases, Factual ,Computer science ,Genetics, Medical ,Word processing ,education ,Target audience ,030105 genetics & heredity ,Ontology (information science) ,Web Browser ,computer.software_genre ,Workflow ,World Wide Web ,03 medical and health sciences ,User-Computer Interface ,Software ,Controlled vocabulary ,Human Phenotype Ontology ,Databases, Genetic ,Genetics ,Humans ,Medical diagnosis ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,business.industry ,030305 genetics & heredity ,Workload ,3. Good health ,030104 developmental biology ,Phenotype ,Ontology ,business ,computer ,Data integration - Abstract
Controlled vocabularies and ontologies have become a valuable resource for knowledge representation, data integration, and downstream analyses in the biomedical domain. In precision medicine, especially in clinical genetics, the Human Phenotype Ontology (HPO) as well as disease ontologies like the Orphanet Rare Disease Ontology (ORDO) or Medical Subject Headings (MeSH) are often used for deep phenotyping of patients and coding of clinical diagnoses. However, the process of assigning ontology classes (annotating) to patient descriptions is often disconnected from the process of writing patient reports or manuscripts in word processing software such as Microsoft Word or LibreOffice. This additional workload and the requirement to install dedicated software may discourage usage of ontologies for parts of the target audience.To improve this situation, we present Phenotero, a freely available and simple solution to annotate patient phenotypes and diseases at the time of writing clinical reports or manuscripts. We adopt Zotero, a well-established, actively developed citation management software to generate a tool which allows to reference classes from ontologies within clinical reports or manuscripts at the time of writing. We expect this approach to decrease the additional workload to a minimum while ensuring high quality associations with ontology classes. Standardised collection of phenotypic information at the time of describing the patient allows for streamlining of clinic workflow, efficient data entry, and will subsequently promote clinical and molecular diagnosis, remove ambiguousness from manuscripts, and allow sharing of anonymised patient phenotype data with ultimate goal of a better understanding of the disease. Thus, we hope that our integrated approach will further promote the usage of ontologies and controlled vocabularies in the clinical setting and in the biomedical domain.
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- 2019
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74. Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination
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Stephanie Efthymiou, Vincenzo Salpietro, Nancy Malintan, Mallory Poncelet, Yamna Kriouile, Sara Fortuna, Rita De Zorzi, Katelyn Payne, Lindsay B Henderson, Andrea Cortese, Sateesh Maddirevula, Nadia Alhashmi, Sarah Wiethoff, Mina Ryten, Juan A Botia, Vincenzo Provitera, Markus Schuelke, Jana Vandrovcova, Stanislav Groppa, Blagovesta Marinova Karashova, Wolfgang Nachbauer, Sylvia Boesch, Larissa Ar
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- 2019
- Full Text
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75. Muscle weakness, cardiomyopathy, and l-2-hydroxyglutaric aciduria associated with a novel recessive SLC25A4 mutation
- Author
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Susanne Morales-Gonzalez, Gajja S. Salomons, Esther Gill, Anja von Renesse, Markus Schuelke, Werner Stenzel, Clinical chemistry, Amsterdam Reproduction & Development (AR&D), AGEM - Endocrinology, metabolism and nutrition, AGEM - Inborn errors of metabolism, and Amsterdam Neuroscience - Cellular & Molecular Mechanisms
- Subjects
0301 basic medicine ,medicine.medical_specialty ,business.industry ,Mitochondrial disease ,External ophthalmoplegia ,Hypertrophic cardiomyopathy ,Cardiomyopathy ,Muscle weakness ,030105 genetics & heredity ,medicine.disease ,eye diseases ,Article ,03 medical and health sciences ,030104 developmental biology ,Endocrinology ,Mitochondrial myopathy ,Lactic acidosis ,Internal medicine ,medicine ,medicine.symptom ,Myopathy ,business - Abstract
Background: Mutations in SLC25A4 (syn. ANT1, Adenine nucleotide translocase, type 1) are known to cause either autosomal dominant progressive external ophthalmoplegia (adPEO) or recessive mitochondrial myopathy, hypertrophic cardiomyopathy, and lactic acidosis. Methods and Results: Whole exome sequencing in a young man with myopathy, subsarcolemmal mitochondrial aggregations, cardiomyopathy, lactic acidosis, and L-2-hydroxyglutaric aciduria (L-2-HGA) revealed a new homozygous mutation in SLC25A4[c.653A>C, NM_001151], leading to the replacement of a highly conserved glutamine by proline [p.(Q218P); NP_001142] that most likely affects the folding of the ANT1 protein. No pathogenic mutation was found in L2HGDH, which is associated with “classic” L-2-HGA. Furthermore, L-2-HGDH enzymatic activity in the patient fibroblasts was normal. Long-range PCR and Southern blot confirmed absence of mtDNA-deletions in blood and muscle. Conclusion: The disturbed ADP/ATP transport across the inner mitochondrial membrane may lead to an accumulation of different TCA-cycle intermediates such as 2-ketoglutarate (2-KG) in our patient. As L-2-HG is generated from 2-KG we hypothesize that the L-2-HG increase is a secondary effect of 2-KG accumulation. Hence, our report expands the spectrum of laboratory findings in ANT1-related diseases and hints towards a connection with organic acidurias.
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- 2019
76. A novelTRAPPC11mutation in two Turkish families associated with cerebral atrophy, global retardation, scoliosis, achalasia and alacrima
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Susann Kutzner, Eda Utine, Felix Reschke, Filiz Hazan, Angela Huebner, Michael Sacher, Ramona Jühlen, Katrin Koehler, Dana Landgraf, Miroslav P. Milev, Markus Schuelke, Keshika Prematilake, and Gulden Diniz
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0301 basic medicine ,Genetics ,Mutation ,medicine.medical_specialty ,Triple-A syndrome ,Biology ,medicine.disease ,medicine.disease_cause ,Alacrima ,Molecular biology ,Exon skipping ,3. Good health ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Genetic linkage ,Molecular genetics ,medicine ,Muscular dystrophy ,medicine.symptom ,Myopathy ,030217 neurology & neurosurgery ,Genetics (clinical) - Abstract
Background Triple A syndrome (MIM #231550) is associated with mutations in the AAAS gene. However, about 30% of patients with triple A syndrome symptoms but an unresolved diagnosis do not harbour mutations in AAAS . Objective Search for novel genetic defects in families with a triple A-like phenotype in whom AAAS mutations are not detected. Methods Genome-wide linkage analysis, whole-exome sequencing and functional analyses were used to discover and verify a novel genetic defect in two families with achalasia, alacrima, myopathy and further symptoms. Effect and pathogenicity of the mutation were verified by cell biological studies. Results We identified a homozygous splice mutation in TRAPPC11 (c.1893+3A>G, [NM_021942.5], g.4:184,607,904A>G [hg19]) in four patients from two unrelated families leading to incomplete exon skipping and reduction in full-length mRNA levels. TRAPPC11 encodes for trafficking protein particle complex subunit 11 (TRAPPC11), a protein of the transport protein particle (TRAPP) complex. Western blot analysis revealed a dramatic decrease in full-length TRAPPC11 protein levels and hypoglycosylation of LAMP1. Trafficking experiments in patient fibroblasts revealed a delayed arrival of marker proteins in the Golgi and a delay in their release from the Golgi to the plasma membrane. Mutations in TRAPPC11 have previously been described to cause limb-girdle muscular dystrophy type 2S (MIM #615356). Indeed, muscle histology of our patients also revealed mild dystrophic changes. Immunohistochemically, β-sarcoglycan was absent from focal patches. Conclusions The identified novel TRAPPC11 mutation represents an expansion of the myopathy phenotype described before and is characterised particularly by achalasia, alacrima, neurological and muscular phenotypes.
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- 2016
77. Kyphoscoliosis peptidase (KY) mutation causes a novel congenital myopathy with core targetoid defects
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Werner Stenzel, Ayelet Halevy, Rachel Straussberg, John Rendu, Esther Gill, Gudrun Schottmann, Franziska Seifert, Peter F.M. van der Ven, Kaiyal Qassem, Markus Schuelke, and Menachem Sadeh
- Subjects
0301 basic medicine ,Family health ,medicine.medical_specialty ,Pathology ,Biology ,medicine.disease ,Rigid spine ,Congenital myopathy ,Pathology and Forensic Medicine ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,030104 developmental biology ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Mutation (genetic algorithm) ,medicine ,Myofibrillar myopathy ,Neurology (clinical) ,medicine.symptom ,Kyphoscoliosis peptidase ,Myopathy ,030217 neurology & neurosurgery - Published
- 2016
78. A movement disorder with dystonia and ataxia caused by a mutation in theHIBCHgene
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Ronald J.A. Wanders, Natalie Weinhold, Esther Gill, Gudrun Schottmann, Sacha Ferdinandusse, Akosua Sarpong, Markus Schuelke, Carmen Lorenz, Alessandro Prigione, and Lisa Teschner
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0301 basic medicine ,Dystonia ,Sanger sequencing ,Genetics ,Mutation ,Ataxia ,Disease ,Biology ,medicine.disease ,medicine.disease_cause ,Phenotype ,03 medical and health sciences ,symbols.namesake ,030104 developmental biology ,0302 clinical medicine ,Neurology ,Basal ganglia ,medicine ,symbols ,Neurology (clinical) ,medicine.symptom ,Exome ,030217 neurology & neurosurgery - Abstract
BACKGROUND: Recessive mutations in the 3-hydroxyisobutyryl-CoA hydrolase gene (HIBCH) are associated with a rare neurodegenerative disease that affects the basal ganglia. Most patients die during infancy or early childhood. Here we describe 5 adolescent and adult patients from 2 unrelated families, who presented with a movement disorder and MRI features suggestive of Leigh syndrome. METHODS: Clinical and metabolic assessment was followed by autozygosity mapping and whole exome and Sanger sequencing. HIBCH enzyme activity and the bioenergetic profile were determined in patient fibroblasts. RESULTS: The movement disorder was dominated by ataxia in one family and by dystonia in the other. All affected family members carried the identical homozygous c.913A>G (p.T305A) HIBCH mutation. Enzyme activity was reduced, and a valine challenge reduced the oxygen consumption rate. CONCLUSIONS: We report the first adult patients with HIBCH deficiency and a disease course much milder than previously reported, thereby expanding the HIBCH-associated phenotypic spectrum.
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- 2016
79. BRAT1mutations are associated with infantile epileptic encephalopathy, mitochondrial dysfunction, and survival into childhood
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Markus Schuelke, Tomasz Zemojtel, Werner Stenzel, Denise Horn, Björn Fischer-Zirnsak, Bernhard Weschke, and Ellen Knierim
- Subjects
0301 basic medicine ,Sanger sequencing ,Genetics ,Mutation ,business.industry ,BRAT1 ,Heterozygote advantage ,Postnatal microcephaly ,Bioinformatics ,Compound heterozygosity ,medicine.disease ,medicine.disease_cause ,Frameshift mutation ,03 medical and health sciences ,symbols.namesake ,Epilepsy ,030104 developmental biology ,0302 clinical medicine ,symbols ,Medicine ,business ,030217 neurology & neurosurgery ,Genetics (clinical) - Abstract
We describe two siblings who were affected with early onset focal seizures, severe progressive postnatal microcephaly, muscular hypertonia, feeding problems and bouts of apnea, only minimal psychomotor development, as well as death in infancy and childhood. We identified compound heterozygous mutations in BRAT1 exons 5 (c.638_639insA) and 8 (c.1134+1G>A) in one affected child via next-generation sequencing of the disease-associated genome followed by phenotype-driven bioinformatic analysis. Sanger sequencing confirmed the presence of these mutations in both patients and a heterozygote status of the parents. Whereas the frameshift mutation (c.638_639insA) has been described in one family, the splice-site mutation (c.1134+1G>A) is novel. In contrast to all cases published so far, one of our patients showed a considerably milder clinical course with survival into childhood. Investigation of a skeletal muscle biopsy showed a severely reduced COX enzyme histochemical staining, indicating mitochondrial dysfunction. Our data expand the clinical and mutational spectrum of the BRAT1-associated phenotype. © 2016 Wiley Periodicals, Inc.
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- 2016
80. Author response for 'Phenotero: Annotate as you write'
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Markus Schuelke, Daniela Hombach, Ellen Knierim, Jana Marie Schwarz, Dominik Seelow, and Sebastian Köhler
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- 2018
81. P 328. Novel Homozygous Variants Confirm SPTBN4-Related Congenital Myopathy and Expand the Clinical Phenotype
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Laurie G. Smith, Esther Gill, Markus Buelow, Ellen Knierim, David Süßmut, Markus Schuelke, and Jutta Köhler
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Pathology ,medicine.medical_specialty ,business.industry ,medicine ,business ,medicine.disease ,Clinical phenotype ,Congenital myopathy - Published
- 2018
82. Cytoplasmic body myopathy revisited
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Hans H. Goebel, Michael Schwarz, Markus Schuelke, and Werner Stenzel
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Cytoplasmic body ,business.industry ,medicine.disease ,Congenital myopathy ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Neurology ,Skeletal pathology ,Muscular Diseases ,Pediatrics, Perinatology and Child Health ,Mutation (genetic algorithm) ,Mutation ,medicine ,Humans ,Neurology (clinical) ,medicine.symptom ,Myopathy ,business ,Muscle, Skeletal ,030217 neurology & neurosurgery ,Genetics (clinical) - Published
- 2018
83. Mutant Plasticity Related Gene 1 (PRG1) acts as a potential modifier in SCN1A related epilepsy
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Andrew Escayg, Alexey Ponomarenko, Dietmar Schmitz, Robert Nitsch, Ellen Knierim, Ulrich Stephani, Markus Schuelke, Michael Kintscher, Korotkova T, Prateep Beed, Jan Baumgart, Panzer A, Johannes Vogt, Holger Lerche, and Thorsten Trimbuch
- Subjects
Epilepsy ,Mutation ,Glutamatergic ,Mutant ,Wild type ,medicine ,Hippocampal formation ,Biology ,medicine.disease ,medicine.disease_cause ,Phenotype ,Molecular biology ,Exome sequencing - Abstract
Plasticity related gene 1 encodes a cerebral neuron-specific synaptic transmembrane protein that modulates hippocampal excitatory transmission on glutamatergic neurons. In mice, homozygous Prg1-deficiency results in juvenile epilepsy. Screening a cohort of 18 patients with infantile spasms (West syndrome), we identified one patient with a heterozygous mutation in the highly conserved third extracellular phosphatase domain (p.T299S). The functional relevance of this mutation was verified by in-utero electroporation of a mutant Prg1 construct into neurons of Prg1-knockout embryos, and the subsequent inability of hippocampal neurons to rescue the knockout phenotype on the single cell level. Whole exome sequencing revealed the index patient to additionally harbor a novel heterozygous SCN1A variant (p.N541S) that was inherited from her healthy mother. Only the affected child carried both heterozygous PRG1 and SCN1A mutations. The aggravating effect of Prg1-haploinsufficiency on the epileptic phenotype was verified using the kainate-model of epilepsy. Double heterozygous Prg1-/+|Scn1awt/p.R1648Hmice exhibited higher seizure susceptibility than either wildtype, Prg1-/+, or Scn1awt/p.R1648H littermates. Our study provides evidence that PRG1-mutations have a potential modifying influence on SCN1A-related epilepsy in humans.
- Published
- 2018
84. P.286Restoration of dystrophin at critical sites of expression following exon skipping
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Luis Garcia, Markus Schuelke, Aurélie Goyenvalle, Helge Amthor, C. Laplace-Builhé, A. Morin, M. Petkova, A. Stantzou, V. Rouffiac, and Isabelle Richard
- Subjects
Neurology ,biology ,Expression (architecture) ,Pediatrics, Perinatology and Child Health ,biology.protein ,Neurology (clinical) ,Dystrophin ,Molecular biology ,Genetics (clinical) ,Exon skipping - Published
- 2019
85. Transparent Danionella translucida as a genetically tractable vertebrate brain model
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Thomas Chaigne, Leonard Maler, Nahid Hakiy, Jörg Henninger, Markus Schuelke, Mykola Kadobianskyi, Benjamin Judkewitz, Lisanne Schulze, Ana I. Faustino, Shahad Albadri, and Filippo Del Bene
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0301 basic medicine ,Nerve net ,Model organsisms ,ved/biology.organism_classification_rank.species ,500 Naturwissenschaften und Mathematik::570 Biowissenschaften ,Biologie::571 Physiologie und verwandte Themen ,Cyprinidae ,Sensory system ,Biochemistry ,Danionella translucida ,03 medical and health sciences ,0302 clinical medicine ,Genome editing ,biology.animal ,Biological neural network ,medicine ,Image Processing, Computer-Assisted ,Animals ,Nervous System Physiological Phenomena ,Model organism ,Molecular Biology ,Gene Editing ,Neurons ,biology ,Behavior, Animal ,ved/biology ,Gene Transfer Techniques ,Vertebrate ,Brain ,Cell Biology ,biology.organism_classification ,030104 developmental biology ,Order (biology) ,medicine.anatomical_structure ,Models, Animal ,Nerve Net ,Neuroscience ,600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit ,030217 neurology & neurosurgery ,Biotechnology - Abstract
Understanding how distributed neuronal circuits integrate sensory information and generate behavior is a central goal of neuroscience. However, it has been difficult to study neuronal networks at single-cell resolution across the entire adult brain in vertebrates because of their size and opacity. We address this challenge here by introducing the fish Danionella translucida to neuroscience as a potential model organism. This teleost remains small and transparent even in adulthood, when neural circuits and behavior have matured. Despite having the smallest known adult vertebrate brain, D. translucida displays a rich set of complex behaviors, including courtship, shoaling, schooling, and acoustic communication. In order to carry out optical measurements and perturbations of neural activity with genetically encoded tools, we established CRISPR-Cas9 genome editing and Tol2 transgenesis techniques. These features make D. translucida a promising model organism for the study of adult vertebrate brain function at single-cell resolution.
- Published
- 2017
86. De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction
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Denise Horn, Penelope E. Bonnen, Anna Floriane Hennig, Marten Jäger, Fernando Scaglia, Bernd Wollnik, Stefan Mundlos, Christian Netzer, Markus Schuelke, Uwe Kornak, Beatrix Fauler, Luitgard Graul-Neumann, Namrata Saha, Holger Thiele, Peter Krawitz, Lara Segebrecht, Jochen Hecht, Nadja Ehmke, Thorsten Mielke, Gökhan Yigit, Rainer Koenig, Carlos A. Bacino, Friederike Hennig, Nicolai Adolphs, Janine Altmüller, Pilar L. Magoulas, Lukasz Smorag, Vera M. Kalscheuer, Peter Nürnberg, Ulrike Krüger, Björn Fischer-Zirnsak, and Esra Kılıç
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0301 basic medicine ,Hypertrichosis ,Mitochondrion ,Microphthalmia ,Antiporters ,Cutis Laxa ,Craniofacial Abnormalities ,0302 clinical medicine ,Adenosine Triphosphate ,Progeria ,Exome ,Inner mitochondrial membrane ,Child ,Ductus Arteriosus, Patent ,Genetics (clinical) ,Growth Disorders ,Membrane Potential, Mitochondrial ,Fetal Growth Retardation ,3. Good health ,Mitochondria ,Premature aging ,Child, Preschool ,Female ,Gorlin-chaudhry-moss syndrome ,medicine.medical_specialty ,Mitochondrial DNA ,Adolescent ,Biology ,DNA, Mitochondrial ,Mitochondrial Proteins ,03 medical and health sciences ,Craniosynostoses ,Craniosynostosis ,Internal medicine ,Report ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,Cutis laxa ,SLC25A24 ,Calcium-Binding Proteins ,Infant ,Hydrogen Peroxide ,Fibroblasts ,medicine.disease ,Oxidative Stress ,030104 developmental biology ,Endocrinology ,Oxidative stress ,Mitochondrial swelling ,Mutation ,Lipoatrophy ,030217 neurology & neurosurgery - Abstract
Gorlin-Chaudhry-Moss syndrome (GCMS) is a dysmorphic syndrome characterized by coronal craniosynostosis and severe midface hypoplasia, body and facial hypertrichosis, microphthalmia, short stature, and short distal phalanges. Variable lipoatrophy and cutis laxa are the basis for a progeroid appearance. Using exome and genome sequencing, we identified the recurrent de novo mutations c.650G>A (p.Arg217His) and c.649C>T (p.Arg217Cys) in SLC25A24 in five unrelated girls diagnosed with GCMS. Two of the girls had pronounced neonatal progeroid features and were initially diagnosed with Wiedemann-Rautenstrauch syndrome. SLC25A24 encodes a mitochondrial inner membrane ATP-Mg/Pi carrier. In fibroblasts from affected individuals, the mutated SLC25A24 showed normal stability. In contrast to control cells, the probands' cells showed mitochondrial swelling, which was exacerbated upon treatment with hydrogen peroxide (H2O2). The same effect was observed after overexpression of the mutant cDNA. Under normal culture conditions, the mitochondrial membrane potential of the probands' fibroblasts was intact, whereas ATP content in the mitochondrial matrix was lower than that in control cells. However, upon H2O2 exposure, the membrane potential was significantly elevated in cells harboring the mutated SLC25A24. No reduction of mitochondrial DNA copy number was observed. These findings demonstrate that mitochondrial dysfunction with increased sensitivity to oxidative stress is due to the SLC25A24 mutations. Our results suggest that the SLC25A24 mutations induce a gain of pathological function and link mitochondrial ATP-Mg/Pi transport to the development of skeletal and connective tissue. N.E. is a participant in the Berlin Institute of Health Charité Clinician Scientist Program, funded by the Charité - Universitätsmedizin Berlin and the Berlin Institute of Health. S.M. was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) and the Max Planck Foundation, B.W. was supported by grants from the DFG SFB1002 project D02, and B.F.-Z. was supported by a grant from the DFG (FI 2240/1-1). U.K. received funding from FP7-EU grant agreement no. 602300 (SYBIL) and the DFG Research Unit FOR 2165 (249509554). Research reported in this publication was supported by National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number R01NS08372 to P.E.B.
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- 2017
87. Nemaline body myopathy caused by a novel mutation in troponin T1 (TNNT1 )
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Markus Schuelke, Talia Dor, Mohannad Daana, Avraham Shaag, Yakov Fellig, Sharon Eylon, Orly Elpeleg, Ulla Najwa Abdulhaq, and Simon Edvardson
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Physiology ,medicine.disease_cause ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Nemaline myopathy ,Physiology (medical) ,medicine ,Myopathy ,Exome sequencing ,Genetics ,Mutation ,Muscle biopsy ,medicine.diagnostic_test ,biology ,Troponin T ,business.industry ,medicine.disease ,Troponin ,Congenital myopathy ,030104 developmental biology ,biology.protein ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Introduction: Nemaline myopathy is a rare disorder characterized by skeletal muscle weakness of varying severity and onset, with the presence of nemaline rods on muscle biopsy. Congenital nemaline body myopathy due to mutations in TNNT1 has hitherto only been described as a result of a single founder mutation in patients of Amish origin and in 2 other individuals with different recessive mutations. Methods: Autozygosity mapping and whole exome sequencing were applied after we identified 9 Palestinian patients from 7 unrelated families who have nemaline myopathy. Results: All patients were homozygous for a novel complex rearrangement of the TNNT1 gene (c.574_577delinsTAGTGCTGT | NM_003283) leading to C-terminal truncation of the protein (p.L203* | NP_003274.3). Their clinical course was remarkable for early respiratory failure and striking stiffness of the cervical spine. Conclusions: This report exemplifies the utility of combining autozygosity mapping and whole exome sequencing and expands the phenotype associated with TNNT1 mutations. Muscle Nerve, 2015
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- 2015
88. RecessiveDEAF1mutation associates with autism, intellectual disability, basal ganglia dysfunction and epilepsy
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Esther Gill, Anna Rajab, Ellen Knierim, Susanne Morales Gonzalez, Markus Schuelke, Angelika Zwirner, and Franziska Seifert
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Male ,Candidate gene ,Adolescent ,Oman ,Genes, Recessive ,Biology ,Consanguinity ,Epilepsy ,Autosomal recessive trait ,Basal Ganglia Diseases ,Intellectual Disability ,Intellectual disability ,Genetics ,medicine ,Humans ,Autistic Disorder ,Genetics (clinical) ,Exome sequencing ,Dyskinesias ,Chromosome Mapping ,Nuclear Proteins ,Sequence Analysis, DNA ,medicine.disease ,Exon skipping ,Pedigree ,DNA-Binding Proteins ,Mutation ,Mutation (genetic algorithm) ,Autism ,RNA Splice Sites ,Transcription Factors - Abstract
Background Various genetic defects cause autism associated with intellectual disability and epilepsy. Here, we set out to identify the genetic defect in a consanguineous Omani family with three affected children in whom mutations in known candidate genes had been excluded beforehand. Methods For mutation screening, we combined autozygosity mapping and whole exome sequencing. Segregation of potential disease variants with the phenotype was verified by Sanger sequencing. A splice-site mutation was confirmed and quantified by qPCR. Results We found an autosomal recessive splice acceptor mutation in DEAF1 (c.997+4A>C, p.G292Pfs*) in all affected individuals, which led to exon skipping, and reduced the normal full-length mRNA copy number in the patients to 5% of the wild-type level. Besides intellectual disability and autism, two of three affected siblings suffered from severe epilepsy. All patients exhibited dyskinesia of the limbs coinciding with symmetric T 2 hyperintensities of the basal ganglia on cranial MRI. Conclusions A recent report has shown dominant DEAF1 mutations to occur de novo in patients with intellectual disability. Here, we demonstrate that a DEAF1 -associated disorder can also be inherited as an autosomal recessive trait with heterozygous individuals being entirely healthy. Our findings expand the clinical and genetic spectrum of DEAF1 mutations to comprise epilepsy and extrapyramidal symptoms.
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- 2015
89. TRMT5 Mutations Cause a Defect in Post-transcriptional Modification of Mitochondrial tRNA Associated with Multiple Respiratory-Chain Deficiencies
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Nadine Romain, Thomas Meitinger, Claudia Donnini, Patrick F. Chinnery, Christopher A. Powell, Tim M. Strom, Ileana Ferrero, Richard J. Rodenburg, Markus Schuelke, Gudrun Schottmann, Joanna Rorbach, Helen Griffin, Laura S. Kremer, Robert W. Taylor, Angela Pyle, Holger Prokisch, Michal Minczuk, Robert Kopajtich, Charlotte L. Alston, Tobias B. Haack, Cristina Dallabona, Ralf A. Husain, Ronald G. Haller, and Aaron R. D’Souza
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Models, Molecular ,Mitochondrial Diseases ,Molecular Sequence Data ,Respiratory chain ,Biology ,Compound heterozygosity ,Polymerase Chain Reaction ,Human mitochondrial genetics ,RNA, Transfer ,Report ,Genetics ,medicine ,Humans ,Genetics(clinical) ,Exome ,Amino Acid Sequence ,RNA Processing, Post-Transcriptional ,Frameshift Mutation ,Base Pairing ,Gene ,Genetics (clinical) ,tRNA Methyltransferases ,Base Sequence ,TRNA Methyltransferase ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,Sequence Analysis, DNA ,medicine.disease ,Phenotype ,Pedigree ,Post-transcriptional modification ,Lactic acidosis - Abstract
Contains fulltext : 154074.pdf (Publisher’s version ) (Open Access) Deficiencies in respiratory-chain complexes lead to a variety of clinical phenotypes resulting from inadequate energy production by the mitochondrial oxidative phosphorylation system. Defective expression of mtDNA-encoded genes, caused by mutations in either the mitochondrial or nuclear genome, represents a rapidly growing group of human disorders. By whole-exome sequencing, we identified two unrelated individuals carrying compound heterozygous variants in TRMT5 (tRNA methyltransferase 5). TRMT5 encodes a mitochondrial protein with strong homology to members of the class I-like methyltransferase superfamily. Both affected individuals presented with lactic acidosis and evidence of multiple mitochondrial respiratory-chain-complex deficiencies in skeletal muscle, although the clinical presentation of the two affected subjects was remarkably different; one presented in childhood with failure to thrive and hypertrophic cardiomyopathy, and the other was an adult with a life-long history of exercise intolerance. Mutations in TRMT5 were associated with the hypomodification of a guanosine residue at position 37 (G37) of mitochondrial tRNA; this hypomodification was particularly prominent in skeletal muscle. Deficiency of the G37 modification was also detected in human cells subjected to TRMT5 RNAi. The pathogenicity of the detected variants was further confirmed in a heterologous yeast model and by the rescue of the molecular phenotype after re-expression of wild-type TRMT5 cDNA in cells derived from the affected individuals. Our study highlights the importance of post-transcriptional modification of mitochondrial tRNAs for faithful mitochondrial function.
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- 2015
90. Two patients with MIRAGE syndrome lacking haematological features: role of somatic second-site reversion SAMD9 mutations
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Angela Huebner, Katrin Koehler, Tsutomu Ogata, Hirohito Shima, Klaus Mohnike, Yumiko Nomura, Akira Satoh, Markus Schuelke, Ramona Jühlen, Kazuhiko Sugimoto, Satoshi Narumi, and Maki Fukami
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0301 basic medicine ,Adrenal disorder ,Biology ,medicine.disease_cause ,Germline ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,X Chromosome Inactivation ,Genetics ,medicine ,Missense mutation ,Humans ,Allele ,Skewed X-inactivation ,Genetics (clinical) ,Sanger sequencing ,Mutation ,Intracellular Signaling Peptides and Proteins ,Infant ,Proteins ,medicine.disease ,Molecular biology ,030104 developmental biology ,030220 oncology & carcinogenesis ,Child, Preschool ,Myelodysplastic Syndromes ,symbols ,Congenital disorder ,Adrenal Insufficiency - Abstract
BackgroundMyelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes and enteropathy (MIRAGE) syndrome is a recently described congenital disorder caused by heterozygous SAMD9 mutations. The phenotypic spectrum of the syndrome remains to be elucidated.Methods and resultsWe describe two unrelated patients who showed manifestations compatible with MIRAGE syndrome, with the exception of haematological features. Leucocyte genomic DNA samples were analysed with next-generation sequencing and Sanger sequencing, revealing the patients to have two de novoSAMD9 mutations on the same allele (patient 1 p.[Gln695*; Ala722Glu] and patient 2 p.[Gln39*; Asp769Gly]). In patient 1, p.Gln695* was absent in genomic DNA extracted from hair follicles, implying that the non-sense mutation was acquired somatically. In patient 2, with the 46,XX karyotype, skewed X chromosome inactivation pattern was found in leucocyte DNA, suggesting monoclonality of cells in the haematopoietic system. In vitro expression experiments confirmed the growth-restricting capacity of the two missense mutant SAMD9 proteins that is a characteristic of MIRAGE-associated SAMD9 mutations.ConclusionsAcquisition of a somatic nonsense SAMD9 mutation in the cells of the haematopoietic system might revert the cellular growth repression caused by the germline SAMD9 mutations (ie, second-site reversion mutations). Unexpected lack of haematological features in the two patients would be explained by the reversion mutations.
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- 2017
91. BMP signaling regulates satellite cell-dependent postnatal muscle growth
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Thomas Braun, Etienne Mouisel, Céline Colnot, Amalia Stantzou, Faouzi Zarrouki, Sandra Swist, Fabien Le Grand, Cyriaque Beley, Frédéric Relaix, Ioanna Polydorou, Helge Amthor, Luis Garcia, Sonia Alonso-Martin, Carmen Birchmeier, Markus Schuelke, Anaïs Julien, Elija Schirwis, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Thérapie des maladies du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Instituto de Ciências Mathemàticas e de Computação [São Carlos] (ICMC-USP), Universidade de São Paulo = University of São Paulo (USP), Max Delbrueck Center for Molecular Medicine, Helmholtz-Gemeinschaft = Helmholtz Association, Groupe Myologie, Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-16-CE14-0002,BMP-MYOSTEM,Régulation des cellules souches du muscle squelettique adulte par la signalisation des ' Bone morphogenetic proteins '(2016), ANR-13-BSV1-0011,Bone-Muscle-Repair,Interactions os-muscle au cours de la régénération musculosquelettique(2013), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, 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 National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universidade de São Paulo (USP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), IMRB - Institut Mondor de Recherche Biomédicale, Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Inst Malad Metabol & Cardiovasc, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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0301 basic medicine ,medicine.medical_specialty ,Satellite Cells, Skeletal Muscle ,[SDV]Life Sciences [q-bio] ,Blotting, Western ,Muscle Fibers, Skeletal ,Biology ,Bone morphogenetic protein ,Real-Time Polymerase Chain Reaction ,03 medical and health sciences ,Mice ,Internal medicine ,medicine ,Myocyte ,Animals ,Progenitor cell ,Muscle, Skeletal ,Molecular Biology ,Cells, Cultured ,ComputingMilieux_MISCELLANEOUS ,Cell Proliferation ,Cell growth ,Skeletal muscle ,Stem Cells and Regeneration ,Immunohistochemistry ,Mice, Mutant Strains ,BMPR2 ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Bone Morphogenetic Proteins ,Female ,Signal transduction ,Stem cell ,Developmental Biology ,Signal Transduction - Abstract
Postnatal growth of skeletal muscle largely depends on the expansion and differentiation of resident stem cells, the so-called satellite cells. Here, we demonstrate that postnatal satellite cells express components of the bone morphogenetic protein (BMP) signaling machinery. Overexpression of noggin in postnatal mice (to antagonize BMP ligands), satellite cell-specific knockout of Alk3 (the gene encoding the BMP transmembrane receptor) or overexpression of inhibitory SMAD6 decreased satellite cell proliferation and accretion during myofiber growth, and ultimately retarded muscle growth. Moreover, reduced BMP signaling diminished the adult satellite cell pool. Abrogation of BMP signaling in satellite cell-derived primary myoblasts strongly diminished cell proliferation and upregulated the expression of cell cycle inhibitors p21 and p57. In conclusion, these results show that BMP signaling defines postnatal muscle development by regulating satellite cell-dependent myofiber growth and the generation of the adult muscle stem cell pool.
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- 2017
92. Morvan syndrome associated with CASPR2 and LGI1 antibodies in a child
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Markus Schuelke, Ellen Knierim, Harald Prüss, Marc Nikolaus, and Sabine Jackowski-Dohrmann
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0301 basic medicine ,Male ,medicine.medical_specialty ,Adolescent ,immunology [Nerve Tissue Proteins] ,Nerve Tissue Proteins ,LGI1 protein, human ,Gastroenterology ,immunology [Autoimmune Diseases of the Nervous System] ,CNTNAP2 protein, human ,Fasciculation ,Diagnosis, Differential ,03 medical and health sciences ,0302 clinical medicine ,Autoimmune Diseases of the Nervous System ,Internal medicine ,immunology [Autoantibodies] ,medicine ,Humans ,ddc:610 ,Autoantibodies ,business.industry ,diagnosis [Autoimmune Diseases of the Nervous System] ,Intracellular Signaling Peptides and Proteins ,Muscle weakness ,Respiratory infection ,Membrane Proteins ,Proteins ,therapy [Autoimmune Diseases of the Nervous System] ,Radioimmunoassay ,medicine.disease ,immunology [Proteins] ,030104 developmental biology ,Peripheral neuropathy ,Blood chemistry ,immunology [Membrane Proteins] ,Neurology (clinical) ,medicine.symptom ,Hyponatremia ,business ,030217 neurology & neurosurgery ,Muscle cramp - Abstract
A 16-year-old boy presented with a 3-week history of back pain, insomnia, profuse sweating, and constipation following a respiratory infection. Physical examination revealed tachycardia, arterial hypertension, muscle weakness, and postural tremor. After hospital admission, he showed almost complete insomnia and massive hyperhidrosis, forcing him to change clothes every 15 minutes and drink up to 12 L/d. He deteriorated, with confusion, hallucination, and additional motor symptoms like fasciculations, areflexia, and muscle cramps/stiffness of both legs that prevented walking. His modified Rankin Scale (mRS) score was 4. Initial blood chemistry only revealed mild hyponatremia. Repeated neuroimaging and extended screening for infectious and neoplastic disease were unremarkable. Electroneurography revealed demyelinating peripheral neuropathy and EMG showed rare spontaneous discharges without the full picture of peripheral nerve hyperexcitability. Serum catecholamine levels were elevated and CSF analysis revealed high protein levels with normal cell count and without oligoclonal bands. Antineuronal antibody screening in serum detected antibodies against the voltage-gated potassium channel (VGKC) complex by radioimmunoassay (RIA, 283 pmol/L) and high titers (1:10,000) against contactin-associated protein 2 (CASPR2) by a commercial cell-based assay (CBA; indirect immunofluorescence on BIOCHIP-Mosaic, Euroimmun, Lubeck, Germany). As the CNS was strongly affected, we analyzed CSF reactivity with a tissue-based assay (TBA). CSF incubation on murine brain sections and subsequent visualization with fluorescent-labeled antihuman immunoglobulin G antibodies revealed a strong signal in the neuropil, mainly of hippocampus and cerebellum (figure, A–D). The CBA confirmed a low CSF anti-CASPR2 antibody titer (1:10) without intrathecal synthesis (table e-1, [links.lww.com/WNL/A71][1], for full diagnostic results). [1]: http://links.lww.com/WNL/A71
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- 2017
93. Caveolin 1 Promotes Renal Water and Salt Reabsorption
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Carsten Dittmayer, Sebastian Bachmann, Markus Schuelke, Andreas Patzak, Yan Willière, Aljona Borschewski, Kerim Mutig, Tatiana Nikitina, and Anna L. Daigeler
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0301 basic medicine ,Male ,medicine.medical_specialty ,Nitric Oxide Synthase Type III ,Caveolin 1 ,lcsh:Medicine ,030204 cardiovascular system & hematology ,Kidney ,Nitric Oxide ,Sodium-Calcium Exchanger ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Renal Artery ,Enos ,Caveolae ,Internal medicine ,medicine ,Animals ,Humans ,Distal convoluted tubule ,lcsh:Science ,Cells, Cultured ,Multidisciplinary ,biology ,Reabsorption ,Chemistry ,lcsh:R ,Sodium ,Kidney metabolism ,Renal Reabsorption ,biology.organism_classification ,Connecting tubule ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,lcsh:Q ,Endothelium, Vascular - Abstract
Caveolin-1 (Cav1) is essential for the formation of caveolae. Little is known about their functional role in the kidney. We tested the hypothesis that caveolae modulate renal salt and water reabsorption. Wild-type (WT) and Cav1-deficient (Cav1−/−) mice were studied. Cav1 expression and caveolae formation were present in vascular cells, late distal convoluted tubule and principal connecting tubule and collecting duct cells of WT but not Cav1−/− kidneys. Urinary sodium excretion was increased by 94% and urine flow by 126% in Cav1−/− mice (p
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- 2017
94. A homozygous PIGO mutation associated with severe infantile epileptic encephalopathy and corpus callosum hypoplasia, but normal alkaline phosphatase levels
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Luci Zalman, Yonatan Sapir, Ilana Chervinsky, Ronen Spiegel, Yoav Zehavi, Anja von Renesse, Markus Schuelke, Etty Daniel-Spiegel, and Rachel Straussberg
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Biology ,Gene mutation ,Biochemistry ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,medicine ,Missense mutation ,Humans ,Global developmental delay ,Hypertelorism ,Exome sequencing ,Low-set ears ,Ultrasonography ,Homozygote ,Dystrophy ,Brain ,Infant ,Membrane Proteins ,Alkaline Phosphatase ,030104 developmental biology ,Child, Preschool ,Mutation ,Alkaline phosphatase ,Female ,Neurology (clinical) ,medicine.symptom ,Agenesis of Corpus Callosum ,Spasms, Infantile - Abstract
We describe two sisters from a consanguineous Arab family with global developmental delay, dystrophy, axial hypotonia, epileptic encephalopathy dominated by intractable complex partial seizures that were resistant to various anti-epileptic treatments. Dysmorphic features comprised low set ears, hypertelorism, upslanting palpebral fissures, a broad nasal bridge, and blue sclera with elongated eyelashes. Brain MRI in both children showed a corpus callosum hypoplasia that was evident already in utero and evolving cortical atrophy. Autozygosity mapping in combination with Whole Exome Sequencing revealed a homozygous missense mutation in the PIGO gene [c.765G > A, NM_032634.3] that affected a highly conserved methionine in the alkaline phosphatase-like core domain of the protein [p.(Met255Ile), NP_116023.2]. PIGO encodes the GPI-ethanolamine phosphate transferase 3, which is crucial for the final synthetic step of the glycosylphosphatidylinositol-anchor that attaches many enzymes to their cell surfaces, such as the alkaline phosphatase and granulocyte surface markers. Interestingly, measurement of serum alkaline phosphatase activities in both children was normal or only slightly elevated. Quantification of granulocyte surface antigens CD16/24/59 yielded reduced levels only for CD59. Phenotype analysis of our and other published patients with PIGO mutations reveals a more severe affectation and predominantly neurological presentation in individuals carrying a mutation in the alkaline phosphatase-like core domain thereby hinting towards a genotype-phenotype relation for PIGO gene mutations.
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- 2017
95. Dynamics of myosin degradation in intensive care unit-acquired weakness during severe critical illness
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Jida Hamati, Janine Woehlecke, Joachim Spranger, Martin Krebs, Steffen Weber-Carstens, Claudia Spies, Anja Luther-Schroeder, Siegfried Labeit, Theresa Radtke, Doerte Lodka, Claudia Langhans, Christian Kleber, Jens Fielitz, Simone Spuler, Markus Schuelke, K. Haas, and Tobias Wollersheim
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Adult ,Male ,Weakness ,medicine.medical_specialty ,Critical Care ,Critical Illness ,macromolecular substances ,Myosins ,Critical Care and Intensive Care Medicine ,law.invention ,law ,Anesthesiology ,Myosin ,medicine ,Humans ,Prospective Studies ,Myopathy ,Intensive care medicine ,Wasting ,Intensive care unit acquired weakness ,Aged ,Muscle Weakness ,business.industry ,Middle Aged ,Intensive care unit ,Muscle atrophy ,Physical therapy ,Female ,medicine.symptom ,business - Abstract
Intensive care unit (ICU)-acquired muscle wasting is a devastating complication leading to persistent weakness and functional disability. The mechanisms of this myopathy are unclear, but a disturbed balance of myosin heavy chain (MyHC) is implicated.To investigate pathways of myosin turnover in severe critically ill patients at high risk of ICU-acquired weakness.Prospective, mechanistic, observational study.Interdisciplinary ICUs of a university hospital.Twenty-nine patients with Sequential Organ Failure Assessment (SOFA) scores of at least 8 on three consecutive days within the first 5 days in ICU underwent two consecutive open skeletal muscle biopsies from the vastus lateralis at median days 5 and 15. Control biopsy specimens were from healthy subjects undergoing hip-replacement surgery.None.Time-dependent changes in myofiber architecture, MyHC synthesis, and degradation were determined and correlated with clinical data.ICU-acquired muscle wasting was characterized by early, disrupted myofiber ultrastructure followed by atrophy of slow- and fast-twitch myofibers at later time points. A rapid decrease in MyHC mRNA and protein expression occurred by day 5 and persisted at day 15 (P0.05). Expression of the atrophy genes MuRF-1 and Atrogin1 was increased at day 5 (P0.05). Early MuRF-1 protein content was closely associated with late myofiber atrophy and the severity of weakness.Decreased synthesis and increased degradation of MyHCs contribute to ICU-acquired muscle wasting. The rates and time frames suggest that pathogenesis of muscle failure is initiated very early during critical illness. The persisting reduction of MyHC suggests that sustained treatment is required.
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- 2014
96. Identifying Dynamic Membrane Structures with Atomic-Force Microscopy and Confocal Imaging
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Tobias Timmel, Simone Spuler, Markus Schuelke, and MDC Library
- Subjects
Fluorescence-lifetime imaging microscopy ,Confocal Microscopy ,Cantilever ,Materials science ,570 Life Sciences ,Nanotechnology ,Caveolae ,Microscopy, Atomic Force ,law.invention ,610 Medical Sciences, Medicine ,Biological specificity ,Confocal microscopy ,law ,Fluorescence Imaging ,Image Processing, Computer-Assisted ,Fluorescence microscope ,Clathrin-Coated Pits ,Humans ,Instrumentation ,Nanoscopic scale ,Microscopy, Confocal ,Cell Membrane ,Fibroblasts ,Fluorescence ,Atomic Force Microscopy ,Membrane ,Microscopy, Fluorescence ,Function and Dysfunction of the Nervous System ,Image Alignment - Abstract
Combining the biological specificity of fluorescence microscopy with topographical features revealed by atomic force microscopy (AFM) provides new insights into cell biology. However, the lack of systematic alignment capabilities especially in scanning-tip AFM has limited the combined application approach as AFM drift leads to increasing image mismatch over time. We present an alignment correction method using the cantilever tip as a reference landmark. Since the precise tip position is known in both the fluorescence and AFM images, exact re-alignment becomes possible. We used beads to demonstrate the validity of the method in a complex artificial sample. We then extended this method to biological samples to depict membrane structures in fixed and living human fibroblasts. We were able to map nanoscale membrane structures, such as clathrin-coated pits, to their respective fluorescent spots. Reliable alignment between fluorescence signals and topographic structures opens possibilities to assess key biological processes at the cell surface such as endocytosis and exocytosis.
- Published
- 2014
97. Potassium channel KIR4.1-specific antibodies in children with acquired demyelinating CNS disease
- Author
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Verena Grummel, Markus Schuelke, Rajneesh Srivastava, S. Leiz, Kevin Rostasy, Sudhakar Reddy Kalluri, Bernhard Hemmer, Stuart Hosie, Mareike Schimmel, Ulrich Seidel, and V. Kraus
- Subjects
Male ,Multiple Sclerosis ,Adolescent ,Enzyme-Linked Immunosorbent Assay ,Immunofluorescence ,Nerve Fibers, Myelinated ,Autoimmune Diseases ,White matter ,Myelin ,Demyelinating disease ,medicine ,Humans ,Potassium Channels, Inwardly Rectifying ,Child ,Autoantibodies ,Autoimmune disease ,biology ,medicine.diagnostic_test ,business.industry ,Multiple sclerosis ,Autoantibody ,Brain ,Infant ,medicine.disease ,medicine.anatomical_structure ,Case-Control Studies ,Child, Preschool ,Immunoglobulin G ,Immunology ,biology.protein ,Female ,Myelin-Oligodendrocyte Glycoprotein ,Neurology (clinical) ,Antibody ,business ,Neuroglia ,Demyelinating Diseases - Abstract
A serum antibody against the inward rectifying potassium channel KIR4.1 (KIR4.1-IgG) was recently discovered, which is found in almost half of adult patients with multiple sclerosis. We investigated the prevalence of KIR4.1-IgG in children with acquired demyelinating disease (ADD) of the CNS. We also compared antibody responses to KIR4.1 and myelin oligodendrocyte glycoproteins (MOGs), another potential autoantigen in childhood ADDs.We measured KIR4.1-IgG by ELISA in children with ADD (n = 47), other neurologic disease (n = 22), and autoimmune disease (n = 22), and in healthy controls (HCs) (n = 18). One hundred six samples were also measured by capture ELISA. Binding of KIR4.1-IgG human subcortical white matter was analyzed by immunofluorescence. Anti-MOG antibodies were measured using a cell-based assay.KIR4.1-IgG titers were significantly higher in children with ADD compared with all control groups by ELISA and capture ELISA (p0.0001, p0.0001). Overall, 27 of 47 patients with ADD (57.45%) but none of the 62 with other neurologic disease or autoimmune disease or the HCs (0%) were KIR4.1-IgG antibody positive by ELISA. Sera containing KIR4.1-IgG stained glial cells in brain tissue sections. No correlation among KIR4.1-IgG, age, or MOG-IgG was observed in the ADD group.Serum antibodies to KIR4.1 are found in the majority of children with ADD but not in children with other diseases or in HCs. These findings suggest that KIR4.1 is an important target of autoantibodies in childhood ADD.
- Published
- 2014
98. MORC2 mutation causes severe spinal muscular atrophy-phenotype, cerebellar atrophy, and diaphragmatic paralysis
- Author
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Franziska Seifert, Christiane Wagner, Gudrun Schottmann, Markus Schuelke, and Werner Stenzel
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Pontocerebellar hypoplasia ,Diaphragmatic paralysis ,medicine.disease_cause ,Muscular Atrophy, Spinal ,03 medical and health sciences ,0302 clinical medicine ,Atrophy ,medicine ,Humans ,Exome ,Mutation ,business.industry ,Spinal muscular atrophy ,medicine.disease ,Phenotype ,Respiratory Paralysis ,030104 developmental biology ,Cerebellar atrophy ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
Sir, With great interest, we read the article by Sevilla et al. (2016) delineating mutations in MORC 2 as a novel genetic cause for axonal Charcot-Marie-Tooth (CMT) disease type 2Z (OMIM #616688) with dominant inheritance. The authors detected MORC2 mutations in nine patients from three unrelated families and showed MORC2 to be expressed in both axons and Schwann cells of the peripheral nerve (Sevilla et al. , 2016). MORC2 belongs to the group of highly conserved MORC proteins, which all share CW-zinc finger and GHL (Gyrase B-Hsp90-MutL)-ATPase domains (Li et al. , 2013). MORC2 is predominantly expressed in the nucleus and is supposed to be relevant for chromatin remodelling, DNA-repair, transcriptional regulation, and lipid metabolism (Shao et al. , 2010; Li et al. , 2012). Following publications describing seven mutations underline the importance of this gene as a novel cause for CMT (Albulym et al. , 2016; Hyun et al. , 2016; Lassuthova et al. , 2016; Zhao et al. , 2016). Following this publication, we re-examined whole exome and whole genome sequencing data of a cohort of 32 patients from 23 families with genetically unsolved neuropathies for mutations in MORC2 and identified a novel de novo c.1085C>G (p.T362R) MORC2 mutation. The 5-year-old girl did not show a CMT phenotype but suffered from severe spinal muscular atrophy (SMA)-like disease with neuropathy, cerebellar atrophy, and diaphragmatic paralysis. This observation broadens the phenotypical spectrum of MORC2 -related disorders towards SMA, spinal muscular atrophy with respiratory distress type 1 (SMARD1), and pontocerebellar hypoplasia. The study was approved by the institutional review board of the Charite (EA1/222/08). Parents provided written informed consent for all aspects of the study according to the Declaration of Helsinki. The now …
- Published
- 2016
99. I.6Arthrogryposis multiplex congenita; new genes & old acquaintances
- Author
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Markus Schuelke
- Subjects
Genetics ,Neurology ,Pediatrics, Perinatology and Child Health ,Multiplex ,Neurology (clinical) ,Biology ,Gene ,Genetics (clinical) - Published
- 2019
100. KIF1Cmutations in two families with hereditary spastic paraparesis and cerebellar dysfunction
- Author
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Ali Benomar, Giovanni Stevanin, Alexis Brice, Marion Gaussen, Alexandra Durr, Simon Edvardson, Markus Schuelke, Talya Dor, Ahmed Bouhouche, Naima Bouslam, Yuval Cinnamon, Avraham Shaag, Laure Raymond, and Vincent Meyer
- Subjects
Male ,Adolescent ,Genetic Linkage ,Hereditary spastic paraplegia ,DNA Mutational Analysis ,Molecular Sequence Data ,Nonsense mutation ,Kinesins ,Biology ,Polymorphism, Single Nucleotide ,Consanguinity ,Young Adult ,Cerebellar Diseases ,Genetic linkage ,Genetics ,medicine ,Spastic ,Humans ,Missense mutation ,Amino Acid Sequence ,Spasticity ,Child ,Genetic Association Studies ,Genetics (clinical) ,KIF1A ,Base Sequence ,Infant ,medicine.disease ,Pedigree ,Chromosome 17 (human) ,HEK293 Cells ,Child, Preschool ,Paraparesis, Spastic ,Female ,medicine.symptom - Abstract
Background Hereditary spastic paraparesis (HSP) (syn. Hereditary spastic paraplegia, SPG) are a group of genetic disorders characterised by spasticity of the lower limbs due to pyramidal tract dysfunction. Nearly 60 disease loci have been identified, which include mutations in two genes ( KIF5A and KIF1A ) that encode motor proteins of the kinesin superfamily. Here we report a novel genetic defect in KIF1C of patients with spastic paraparesis and cerebellar dysfunction in two consanguineous families of Palestinian and Moroccan ancestry. Methods and results We performed autozygosity mapping in a Palestinian and classic linkage analysis in a Moroccan family and found a locus on chromosome 17 that had previously been associated with spastic ataxia type 2 (SPAX2, OMIM %611302). Whole-exome sequencing revealed two homozygous mutations in KIF1C that were absent among controls: a nonsense mutation (c.2191C>T, p.Arg731*) that segregated with the disease phenotype in the Palestinian kindred resulted in the entire absence of KIF1C protein from the patient's fibroblasts, and a missense variant (c.505C>T, p.Arg169Trp) affecting a conserved amino acid of the motor domain that was found in the Moroccan kindred. Conclusions Kinesin genes encode a family of cargo/motor proteins and are known to cause HSP if mutated. Here we identified nonsense and missense mutations in a further member of this protein family. The KIF1C mutation is associated with a HSP subtype (SPAX2/SAX2) that combines spastic paraplegia and weakness with cerebellar dysfunction.
- Published
- 2013
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