Brehm, AnjaLiu, YinSheikh, AfzalMarrero, BernadetteOmoyinmi, EbunZhou, QingMontealegre, GinaBiancotto, AngeliqueReinhardt, AdamAlmeida de Jesus, AdrianaPelletier, MartinTsai, Wanxia LRemmers, Elaine FKardava, LelaHill, SuvimolKim, HannaLachmann, Helen JMegarbane, AndreChae, Jae JinBrady, JilianCastillo, Rhina DBrown, DianeVera Casano, AngelGao, LingChapelle, DawnHuang, YanStone, DeborahChen, YongqingSotzny, FranziskaLee, Chyi-Chia RichardKastner, Daniel LTorrelo, AntonioZlotogorski, AbrahamMoir, SusanGadina, MassimoMcCoy, PhilWesley, RobertRother, KristinaHildebrand, Peter WBrogan, PaulKrüger, ElkeAksentijevich, IvonaGoldbach-Mansky, Raphaela2016-06-132016-06-132015-11-02Brehm A, Liu Y, Sheikh A, Marrero B, Omoyinmi E, Zhou Q, et al. Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production. J. Clin. Invest. 2015; 125(11):4196-2110021-9738http://hdl.handle.net/10668/2213Journal 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/86020Autosomal 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.enCélulas cultivadasFibroblastosRegulación de la expresión génicaGenotipoEnfermedades autoinflamatorias hereditariasSecuencia de aminoácidosInterferón de tipo IModelos molecularesChaperonas molecularesDatos de Secuencia MolecularMutaciónMutación de sentido erróneoLinajeFenotipoComplejo de endopeptidasas de los proteasomasConformación de proteínasSubunidades de proteínasInterferencia por ARNAlineación de secuenciasDeleción de secuenciasHomología de secuencias de aminoácidosSíndromeTranscripción genéticaMedical Subject Headings::Anatomy::Cells::Cells, CulturedMedical Subject Headings::Anatomy::Cells::Connective Tissue Cells::Fibroblasts::MyofibroblastsMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression RegulationMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::GenotypeMedical Subject Headings::Diseases::Congenital, Hereditary, and Neonatal Diseases and Abnormalities::Genetic Diseases, Inborn::Hereditary Autoinflammatory DiseasesMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Chemicals and Drugs::Biological Factors::Intercellular Signaling Peptides and Proteins::Interferons::Interferon Type IMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Theoretical::Models, MolecularMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Molecular ChaperonesMedical Subject Headings::Information Science::Information Science::Information Services::Documentation::Molecular Sequence DataMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Variation::MutationMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation::Mutation, MissenseMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::PedigreeMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::PhenotypeMedical Subject Headings::Chemicals and Drugs::Macromolecular Substances::Multiprotein Complexes::Multienzyme Complexes::Proteasome Endopeptidase ComplexMedical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Molecular Structure::Molecular Conformation::Protein ConformationMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Protein SubunitsMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Epigenesis, Genetic::Gene Silencing::RNA InterferenceMedical Subject Headings::Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::RNA::RNA, Untranslated::RNA, Small Untranslated::RNA, Small InterferingMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Sequence AlignmentMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation::Sequence DeletionMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Sequence Homology::Sequence Homology, Amino AcidMedical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease::SyndromeMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression::Transcription, GeneticMedical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Molecular Structure::Amino Acid Sequenceresearch article26524591open access10.1172/JCI812601558-8238PMC4639987