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3 results on '"Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Molecular Structure::Amino Acid Sequence [Medical Subject Headings]"'

1. The E3 ubiquitin ligase UBR5 interacts with TTC7A and may be associated with very early onset inflammatory bowel disease

Author

Scott B. Snapper, Qi Li, Christoph Klein, Neil Warner, Neel Dhingani, Sasha Jardine, Claudia Gonzaga-Jauregui, Daniel Kotlarz, Aleixo M. Muise, Conghui Guo, Jie Pan, Gabriella Leung, Víctor Manuel Navas-López, [Dhingani,N, Jardine,S, Muise,AM] Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. [Dhingani,N, Guo,C, Pan,J, Li,Q, Warner,N, Leung,G, Muise,AM] SickKids Infammatory Bowel Disease Centre, Research Institute, Hospital for Sick Children, Toronto, ON, Canada. [Kotlarz,D, Klein,C] Department of Pediatrics, Dr. Von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany. [Gonzaga-Jauregui,C] Regeneron Genetics Center, Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. [Snapper,SB] Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA. [Navas-López,VM] Pediatric Gastroenterology and Nutrition Unit, IBIMA, Hospital Regional Universitario de Málaga, Málaga, Spain. [Muise,AM] Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada. [Muise,AM] Department of Pediatrics, Institute of Medical Science, University of Toronto, Toronto, Canada. [Snapper,SB] Division of Gastroenterology, Brigham and Women’s Hospital, Boston, MA, USA., and AMM is funded by a Canada Research Chair (Tier 1) in Pediatric IBD, CIHR Foundation Grant and NIDDK (RC2DK118640) Grant. AMM, SBS, CK, DK are supported by the Leona M. and Harry B. Helmsley Charitable Trust. CK and DK are supported by the Collaborative Research Consortium SFB1054 project A05.

Subjects
0301 basic medicine, Male, Enfermedades inflamatorias del intestino, lcsh:Medicine, Compound heterozygosity, Inflammatory bowel disease, Diseases::Digestive System Diseases::Gastrointestinal Diseases::Intestinal Diseases::Inflammatory Bowel Diseases [Medical Subject Headings], Unión proteica, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, Age of Onset, lcsh:Science, Child, Immunodeficiency, Exome sequencing, Multidisciplinary, biology, Intestinal atresia, Gastroenterology, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Signal Transduction [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins [Medical Subject Headings], Colitis, 3. Good health, Ubiquitin ligase, Ubiquitin-protein ligases, Tetratricopeptide, 030220 oncology & carcinogenesis, Niño, Child, Preschool, Protein Binding, Signal Transduction, Cell biology, Ubiquitin-Protein Ligases, Check Tags::Male [Medical Subject Headings], Inflammatory bowel diseases, Article, Amino acid sequence, 03 medical and health sciences, Ubiquitina-proteína ligasas, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Protein Binding [Medical Subject Headings], medicine, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Ligases::Ubiquitin-Protein Ligase Complexes::Ubiquitin-Protein Ligases [Medical Subject Headings], Protein binding, Humans, Secuencia de aminoácidos, Amino Acid Sequence, Health Care::Health Care Quality, Access, and Evaluation::Quality of Health Care::Epidemiologic Factors::Age Factors::Age of Onset [Medical Subject Headings], Diseases::Digestive System Diseases::Gastrointestinal Diseases::Intestinal Diseases::Colonic Diseases::Colitis [Medical Subject Headings], Sequence Homology, Amino Acid, business.industry, lcsh:R, Proteins, medicine.disease, Inflammatory Bowel Diseases, 030104 developmental biology, Immunology, biology.protein, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Molecular Structure::Amino Acid Sequence [Medical Subject Headings], lcsh:Q, business, Persons::Persons::Age Groups::Child::Child, Preschool [Medical Subject Headings]
Abstract

Very early onset inflammatory bowel disease (VEOIBD) denotes children with onset of IBD before six years of age. A number of monogenic disorders are associated with VEOIBD including tetratricopeptide repeat domain 7A (TTC7A) deficiency. TTC7A-deficiency is characterized by apoptotic colitis in milder cases with severe intestinal atresia and immunodeficiency in cases with complete loss of protein. We used whole exome sequencing in a VEOIBD patient presenting with colitis characterized by colonic apoptosis and no identified known VEOIBD variants, to identify compound heterozygous deleterious variants in the Ubiquitin protein ligase E3 component N-recognin 5 (UBR5) gene. Functional studies demonstrated that UBR5 co-immunoprecipitates with the TTC7A and the UBR5 variants had reduced interaction between UBR5 and TTC7A. Together this implicates UBR5 in regulating TTC7A signaling in VEOIBD patients with apoptotic colitis.

Published
2019

2. Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production

Author

Kristina I. Rother, Wanxia L. Tsai, Qing Zhou, Elaine F. Remmers, Rhina D. Castillo, Yan Huang, Anja Brehm, Raphaela Goldbach-Mansky, Franziska Sotzny, Yin Liu, Robert Wesley, Bernadette Marrero, Peter W. Hildebrand, Helen J. Lachmann, Deborah L. Stone, André Mégarbané, Ebun Omoyinmi, Adriana Almeida de Jesus, Massimo Gadina, Paul A. Brogan, Antonio Torrelo, Adam L Reinhardt, Angel Vera Casano, Dawn Chapelle, G Montealegre, Phil McCoy, Jae Jin Chae, Lela Kardava, Martin Pelletier, Susan Moir, Suvimol Hill, Elke Krüger, Diane E. Brown, Ling Gao, Abraham Zlotogorski, Angelique Biancotto, Jilian Brady, Hanna Kim, Ivona Aksentijevich, Afzal Sheikh, Daniel L. Kastner, Chyi-Chia Richard Lee, Yongqing Chen, [Brehm,A, Sotzny,F, Krüger,E] Charité-Universitätsmedizin Berlin, Institute of Biochemistry, Berlin, Germany. [Liu,Y, Sheikh,A, Marrero,B, Montealegre,G, Almeida de Jesus,A, Kim,H, Chapelle,D, Huang,Y, Chen,Y, Goldbach-Mansky,R] Translational Autoinflammatory Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Bethesda, Maryland, USA. [Sheikh,A, Zhou,Q, Remmers,EF, Chae,JJ, Brady,J, Stone,D, Kastner,DL, Aksentijevich,I] Inflammatory Disease Section, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA. [Omoyinmi,E, Brogan,P] University College London Institute of Child Health and Great Ormond Street Hospital, NHS Foundation Trust, London, United Kingdom. [Biancotto,A, McCoy,P] Center of Human Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA. [Reinhardt,A] Children’s Hospital and Medical Center and University of Nebraska Medical Center, Omaha, Nebraska, USA. [Pelletier,M] Autoimmunity Branch. [Tsai,WL, Gadina,M] Office of Science and Technology, NIAMS. [Kardava,L, Moir,S] Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases. [Hill,S] Clinical Center, NIH, Bethesda, Maryland, USA. [Lachmann,HJ] National Amyloidosis Centre, University College Medical School, London, United Kingdom. [Megarbane,A] Medical Genetics Unit, Saint Joseph University, Beirut, Lebanon. Institut Jerome Lejeune, Paris, France. [Castillo,RD, Brown,D] Children’s Hospital Los Angeles and University of Southern California, Los Angeles, California, USA. [Vera Castillo,A] Hospital Carlos Haya, Malaga, Andalusia, Spain. [Gao,L] College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA. [Lee,CR] Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland, USA. [Torrelo,A] Pediatric Dermatology, Hospital Niño Jesús, Madrid, Spain. [Zlotogorski,A] Hadassah-Hebrew University Medical Center, Jerusalem, Israel. [Wesley,R] Reproductive Biology and Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development. [Rother,KR] Section on Pediatric Diabetes and Metabolism, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA. [Hildebrand,PW] Charité-Universitätsmedizin Berlin, Institute of Medical Physics and Biophysics, Berlin, Germany., and This research was supported by the Intramural Research Program of NIAMS at the NIH, by the Berlin Institute of Health, and by the Deutsche Forschungsgemeinschaft (SFB TR 43 to E. Krüger, SFB740 to E. Krüger and P.W. Hildebrand).

Subjects
Phenomena and Processes::Genetic Phenomena::Phenotype [Medical Subject Headings], Lipodystrophy, Transcription, Genetic, PSMA3, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Células cultivadas, Subunidades de proteínas, 0302 clinical medicine, Clinical investigation, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Theoretical::Models, Molecular [Medical Subject Headings], Medicine, Chemicals and Drugs::Biological Factors::Intercellular Signaling Peptides and Proteins::Interferons::Interferon Type I [Medical Subject Headings], Interferón de tipo I, Chaperonas moleculares, Cells, Cultured, Alineación de secuencias, General Medicine, Pedigree, Enfermedades autoinflamatorias hereditarias, Deleción de secuencias, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease::Syndrome [Medical Subject Headings], Interferon Type I, RNA Interference, Phenomena and Processes::Genetic Phenomena::Genotype [Medical Subject Headings], Erratum, Fenotipo, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Molecular Chaperones [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation [Medical Subject Headings], Genotype, Molecular Sequence Data, Síndrome, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Protein Subunits [Medical Subject Headings], 03 medical and health sciences, Mutación de sentido erróneo, Diseases::Congenital, Hereditary, and Neonatal Diseases and Abnormalities::Genetic Diseases, Inborn::Hereditary Autoinflammatory Diseases [Medical Subject Headings], Humans, Secuencia de aminoácidos, Amino Acid Sequence, Loss function, Hereditary Autoinflammatory Diseases, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation::Sequence Deletion [Medical Subject Headings], Fibroblasts, Conformación de proteínas, Transcripción genética, Protein Subunits, Regulación de la expresión génica, 030104 developmental biology, Information Science::Information Science::Information Services::Documentation::Molecular Sequence Data [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Epigenesis, Genetic::Gene Silencing::RNA Interference [Medical Subject Headings], Proteasome, Complejo de endopeptidasas de los proteasomas, Anatomy::Cells::Cells, Cultured [Medical Subject Headings], Immunology, Mutation, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Molecular Structure::Amino Acid Sequence [Medical Subject Headings], Genotipo, Molecular Chaperones, 0301 basic medicine, Models, Molecular, Protein Conformation, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Pedigree [Medical Subject Headings], Modelos moleculares, Chemicals and Drugs::Macromolecular Substances::Multiprotein Complexes::Multienzyme Complexes::Proteasome Endopeptidase Complex [Medical Subject Headings], Missense mutation, Homología de secuencias de aminoácidos, RNA, Small Interfering, Anatomy::Cells::Connective Tissue Cells::Fibroblasts::Myofibroblasts [Medical Subject Headings], Sequence Deletion, Genetics, Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::RNA::RNA, Untranslated::RNA, Small Untranslated::RNA, Small Interfering [Medical Subject Headings], Type I IFN production, Syndrome, Interferencia por ARN, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation::Mutation, Missense [Medical Subject Headings], Phenotype, Research Article, Datos de Secuencia Molecular, Proteasome Endopeptidase Complex, Protein subunit, Mutation, Missense, Biology, Linaje, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression::Transcription, Genetic [Medical Subject Headings], Mutación, Sequence Homology, Amino Acid, business.industry, PSMB8, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Molecular Structure::Molecular Conformation::Protein Conformation [Medical Subject Headings], PSMB9, PSMB4, Molecular biology, Fibroblastos, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Sequence Alignment [Medical Subject Headings], Gene Expression Regulation, Proteasome assembly, Proteasome maturation protein, business, Sequence Alignment, Phenomena and Processes::Genetic Phenomena::Sequence Homology::Sequence Homology, Amino Acid [Medical Subject Headings], 030215 immunology
Abstract

Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't;Erratium en J Clin Invest. 2016 Feb 1;126(2):795. doi: 10.1172/JCI86020: https://www.jci.org/articles/view/86020 Autosomal recessive mutations in proteasome subunit β 8 (PSMB8), which encodes the inducible proteasome subunit β5i, cause the immune-dysregulatory disease chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), which is classified as a proteasome-associated autoinflammatory syndrome (PRAAS). Here, we identified 8 mutations in 4 proteasome genes, PSMA3 (encodes α7), PSMB4 (encodes β7), PSMB9 (encodes β1i), and proteasome maturation protein (POMP), that have not been previously associated with disease and 1 mutation in PSMB8 that has not been previously reported. One patient was compound heterozygous for PSMB4 mutations, 6 patients from 4 families were heterozygous for a missense mutation in 1 inducible proteasome subunit and a mutation in a constitutive proteasome subunit, and 1 patient was heterozygous for a POMP mutation, thus establishing a digenic and autosomal dominant inheritance pattern of PRAAS. Function evaluation revealed that these mutations variably affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity. Moreover, defects in proteasome formation and function were recapitulated by siRNA-mediated knockdown of the respective subunits in primary fibroblasts from healthy individuals. Patient-isolated hematopoietic and nonhematopoietic cells exhibited a strong IFN gene-expression signature, irrespective of genotype. Additionally, chemical proteasome inhibition or progressive depletion of proteasome subunit gene transcription with siRNA induced transcription of type I IFN genes in healthy control cells. Our results provide further insight into CANDLE genetics and link global proteasome dysfunction to increased type I IFN production. Yes

Published
2015

3. Analysis of Genes Encoding Penicillin-Binding Proteins in Clinical Isolates of Acinetobacter baumannii

Author

María-Cruz Rodríguez, Jordi Vila, Felipe Fernández-Cuenca, Álvaro Pascual, Juan A. Ayala, Paula Espinal, Luis Martínez-Martínez, Rodrigo Cayô, Alain A. Ocampo-Sosa, Instituto de Salud Carlos III, Red Española de Investigación en Patología Infecciosa, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Brasil), Ministerio de Economía y Competitividad (España), [Cayô,R, Rodríguez,MC, Ocampo-Sosa,AA, Martínez-Martínez,L] Service of Microbiology, University Hospital Marqués de Valdecilla—IFIMAV [Espinal,P, Vila,J] Service of Microbiology, Hospital Clinic, School of Medicine, University of Barcelona, Barcelona. [Fernández-Cuenca,F, Pascual,A] Service of Microbiology, University Hospital Virgen Macarena, Seville. [Ayala,JA] Centro de Biología Molecular Severo Ochoa—CSIC-UAM, Campus de Cantoblanco, Madrid, Spain. [Rodríguez,MC, Martínez-Martínez,L] Department of Molecular Biology, School of Medicine, University of Cantabria, Santander., and This work was partially supported by the Instituto de Salud Carlos III, Spanish Network for Research in Infectious Diseases (REIPI, RD06/0008), and FIS (PI080209). We are grateful to the Coordenacao de Aperfeicoamento de Pessoal de Nível Superior (CAPES), which gave a PDEE grant to R.C. (protocol 4149/08-4). We acknowledge the funding of MICINN (BFU2009-09200) to J.A.A. L. Dijkshoorn is thanked for providing A. baumannii strains RUH-134 and RUH-875.

Subjects
Acinetobacter baumannii, Penicillin binding proteins, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], polycyclic compounds, Pharmacology (medical), Insertion sequence, Peptide sequence, Geographicals::Geographic Locations::Europe::Spain [Medical Subject Headings], Genetics, biology, Phenomena and Processes::Microbiological Phenomena::Bacterial Physiological Phenomena::Drug Resistance, Bacterial::beta-Lactam Resistance [Medical Subject Headings], Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Penicillin-Binding Proteins [Medical Subject Headings], Anti-Bacterial Agents, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Microbiological Techniques::Microbial Sensitivity Tests [Medical Subject Headings], Infectious Diseases, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation::Point Mutation [Medical Subject Headings], Chemicals and Drugs::Organic Chemicals::Amides::Lactams::beta-Lactams::Carbapenems [Medical Subject Headings], Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Anti-Bacterial Agents [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Sequence Analysis::Sequence Analysis, DNA [Medical Subject Headings], Acinetobacter Infections, Silent mutation, Sequence analysis, Molecular Sequence Data, Health Care::Health Care Facilities, Manpower, and Services::Health Facilities::Academic Medical Centers::Hospitals, Teaching [Medical Subject Headings], Análisis de Secuencia de ADN, Microbial Sensitivity Tests, beta-Lactam Resistance, Microbiology, Secuencia de Aminoácidos, Organisms::Bacteria::Gram-Negative Bacteria::Gram-Negative Aerobic Bacteria::Gram-Negative Aerobic Rods and Cocci::Moraxellaceae::Acinetobacter::Acinetobacter baumannii [Medical Subject Headings], Diseases::Bacterial Infections and Mycoses::Bacterial Infections::Gram-Negative Bacterial Infections::Moraxellaceae Infections::Acinetobacter Infections [Medical Subject Headings], Mechanisms of Resistance, Consensus sequence, Humans, Penicillin-Binding Proteins, Point Mutation, Amino Acid Sequence, Hospitals, Teaching, Gene, Pharmacology, Proteínas de Unión a las Penicilinas, Hospitales Escuela, Sequence Analysis, DNA, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, Information Science::Information Science::Information Services::Documentation::Molecular Sequence Data [Medical Subject Headings], Carbapenems, Spain, Resistencia beta-Lactámica, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Molecular Structure::Amino Acid Sequence [Medical Subject Headings], Pruebas de Sensibilidad Microbiana
Abstract

et al., There is limited information on the role of penicillin-binding proteins (PBPs) in the resistance of Acinetobacter baumannii to β-lactams. This study presents an analysis of the allelic variations of PBP genes in A. baumannii isolates. Twenty-six A. baumannii clinical isolates (susceptible or resistant to carbapenems) from three teaching hospitals in Spain were included. The antimicrobial susceptibility profile, clonal pattern, and genomic species identification were also evaluated. Based on the six complete genomes of A. baumannii, the PBP genes were identified, and primers were designed for each gene. The nucleotide sequences of the genes identified that encode PBPs and the corresponding amino acid sequences were compared with those of ATCC 17978. Seven PBP genes and one monofunctional transglycosylase (MGT) gene were identified in the six genomes, encoding (i) four high-molecular-mass proteins (two of class A, PBP1a [ponA] and PBP1b [mrcB], and two of class B, PBP2 [pbpA or mrdA] and PBP3 [ftsI]), (ii) three low-molecular-mass proteins (two of type 5, PBP5/6 [dacC] and PBP6b [dacD], and one of type 7 (PBP7/8 [pbpG]), and (iii) a monofunctional enzyme (MtgA [mtgA]). Hot spot mutation regions were observed, although most of the allelic changes found translated into silent mutations. The amino acid consensus sequences corresponding to the PBP genes in the genomes and the clinical isolates were highly conserved. The changes found in amino acid sequences were associated with concrete clonal patterns but were not directly related to susceptibility or resistance to β-lactams. An insertion sequence disrupting the gene encoding PBP6b was identified in an endemic carbapenem-resistant clone in one of the participant hospitals., This work was partially supported by the Instituto de Salud Carlos III, Spanish Network for Research in Infectious Diseases (REIPI, RD06/0008), and FIS (PI080209). We are grateful to the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), which gave a PDEE grant to R.C. (protocol 4149/08-4). We acknowledge the funding of MICINN (BFU2009-09200) to J.A.A.

Published
2011

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