1. Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production
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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).
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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
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- 2015