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[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., 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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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 |
