دورية أكاديمية
PSMC3 proteasome subunit variants are associated with neurodevelopmental delay and type I interferon production.
العنوان: | PSMC3 proteasome subunit variants are associated with neurodevelopmental delay and type I interferon production. |
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المؤلفون: | Ebstein F; Institut für Medizinische Biochemie und Molekularbiologie (IMBM), Universitätsmedizin Greifswald, Ferdinand-Sauerbruch-Straße, 17475 Greifswald, Germany., Küry S; Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000 Nantes, France.; Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France., Most V; Institut für Medizinische Physik und Biophysik, Universität Leipzig, Medizinische Fakultät, Härtelstr. 16-18, 04107 Leipzig, Germany., Rosenfelt C; Department of Pediatrics, University of Alberta, Edmonton, AB CT6G 1C9, Canada., Scott-Boyer MP; Research Center of Quebec CHU-Université Laval, Québec, QC PQ G1E6W2, Canada., van Woerden GM; Department of Neuroscience, Erasmus University Medical Center, 3015 CN, Rotterdam, Netherlands.; ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus University Medical Center, 3015 CN, Rotterdam, Netherlands.; Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN, Rotterdam, Netherlands., Besnard T; Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000 Nantes, France.; Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France., Papendorf JJ; Institut für Medizinische Biochemie und Molekularbiologie (IMBM), Universitätsmedizin Greifswald, Ferdinand-Sauerbruch-Straße, 17475 Greifswald, Germany., Studencka-Turski M; Institut für Medizinische Biochemie und Molekularbiologie (IMBM), Universitätsmedizin Greifswald, Ferdinand-Sauerbruch-Straße, 17475 Greifswald, Germany., Wang T; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.; Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.; Neuroscience Research Institute, Peking University; Key Laboratory for Neuroscience, Ministry of Education of China & National Health Commission of China, Beijing 100191, China., Hsieh TC; Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53127 Bonn, Germany., Golnik R; Klinik für Pädiatrie I, Universitätsklinikum Halle (Saale), 06120 Halle (Saale), Germany., Baldridge D; Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63130-4899, USA., Forster C; GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA., de Konink C; Department of Neuroscience, Erasmus University Medical Center, 3015 CN, Rotterdam, Netherlands.; ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus University Medical Center, 3015 CN, Rotterdam, Netherlands., Teurlings SMW; Department of Neuroscience, Erasmus University Medical Center, 3015 CN, Rotterdam, Netherlands.; ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus University Medical Center, 3015 CN, Rotterdam, Netherlands., Vignard V; Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000 Nantes, France.; Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France., van Jaarsveld RH; Department of Genetics, University Medical Center Utrecht, 3508 AB, Utrecht, Netherlands., Ades L; Department of Clinical Genetics, Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia.; Disciplines of Genomic Medicine & Child and Adolescent Health, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2145, Australia., Cogné B; Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000 Nantes, France.; Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France., Mignot C; APHP, Hôpital Pitié-Salpêtrière, Département de Génétique, Centre de Reference Déficience Intellectuelle de Causes Rares, GRC UPMC Déficience Intellectuelle et Autisme, 75013 Paris, France.; Sorbonne Universités, Institut du Cerveau et de la Moelle épinière, ICM, Inserm U1127, CNRS UMR 7225, 75013, Paris, France., Deb W; Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000 Nantes, France.; Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France., Jongmans MCJ; Department of Genetics, University Medical Center Utrecht, 3508 AB, Utrecht, Netherlands.; Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, Netherlands., Cole FS; Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63130-4899, USA., van den Boogaard MH; Department of Genetics, University Medical Center Utrecht, 3508 AB, Utrecht, Netherlands., Wambach JA; Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63130-4899, USA., Wegner DJ; Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63130-4899, USA., Yang S; GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA., Hannig V; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Brault JA; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Zadeh N; Genetics Center and Division of Medical Genetics, Children's Hospital of Orange County, Orange, CA 92868, USA., Bennetts B; Disciplines of Genomic Medicine & Child and Adolescent Health, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2145, Australia.; Sydney Genome Diagnostics, Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, NSW, 2145, Australia., Keren B; Département de Génétique, Centre de Référence des Déficiences Intellectuelles de Causes Rares, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 75013 Paris, France., Gélineau AC; Département de Génétique, Centre de Référence des Déficiences Intellectuelles de Causes Rares, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 75013 Paris, France., Powis Z; Department of Clinical Research, Ambry Genetics, Aliso Viejo, CA 92656, USA., Towne M; Department of Clinical Research, Ambry Genetics, Aliso Viejo, CA 92656, USA., Bachman K; Genomic Medicine Institute, Geisinger, Danville, PA 17822, USA., Seeley A; Genomic Medicine Institute, Geisinger, Danville, PA 17822, USA., Beck AE; Department of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98195-6320, USA., Morrison J; Division of Genetics, Arnold Palmer Hospital for Children, Orlando Health, Orlando, FL 32806, USA., Westman R; Division of Genetics, St. Luke's Clinic, Boise, ID 83712, USA., Averill K; Department of Pediatrics, Division of Pediatric Neurology, UT Health Science Center at San Antonio, San Antonio, TX 78229, USA., Brunet T; Institute of Human Genetics, Technical University of Munich, School of Medicine, 81675 Munich, Germany.; Institute of Neurogenomics (ING), Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany., Haasters J; Klinikum der Universität München, Integriertes Sozialpädiatrisches Zentrum, 80337 Munich, Germany., Carter MT; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.; Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada., Osmond M; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada., Wheeler PG; Division of Genetics, Arnold Palmer Hospital for Children, Orlando Health, Orlando, FL 32806, USA., Forzano F; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.; Clinical Genetics Department, Guy's and St Thomas' NHS Foundation Trust, London SE1 9RT, UK., Mohammed S; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.; Clinical Genetics Department, Guy's and St Thomas' NHS Foundation Trust, London SE1 9RT, UK., Trakadis Y; Division of Medical Genetics, McGill University Health Centre, Montreal, QC H4A 3J1, Canada., Accogli A; Division of Medical Genetics, McGill University Health Centre, Montreal, QC H4A 3J1, Canada., Harrison R; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.; Department of Clinical Genetics, Nottingham University Hospitals NHS Trust, City Hospital Campus, the Gables, Gate 3, Hucknall Road, Nottingham NG5 1PB, UK., Guo Y; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; Center for Data Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA 19146, USA., Hakonarson H; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA., Rondeau S; Service de Médecine Génomique des Maladies Rares, Hôpital Universitaire Necker-Enfants Malades, 75743 Paris, France., Baujat G; Service de Médecine Génomique des Maladies Rares, Hôpital Universitaire Necker-Enfants Malades, 75743 Paris, France., Barcia G; Service de Médecine Génomique des Maladies Rares, Hôpital Universitaire Necker-Enfants Malades, 75743 Paris, France., Feichtinger RG; University Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), 5020 Salzburg, Austria., Mayr JA; University Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), 5020 Salzburg, Austria., Preisel M; University Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), 5020 Salzburg, Austria., Laumonnier F; UMR 1253, iBrain, Université de Tours, Inserm, 37032 Tours, France.; Service de Génétique, Centre Hospitalier Régional Universitaire, 37032 Tours, France., Kallinich T; Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.; Deutsches Rheumaforschungszentrum, an institute of the Leibniz Association, Berlin and Berlin Institute of Health, 10117 Berlin, Germany., Knaus A; Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53127 Bonn, Germany., Isidor B; Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000 Nantes, France.; Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France., Krawitz P; Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53127 Bonn, Germany., Völker U; Universitätsmedizin Greifswald, Interfakultäres Institut für Genetik und Funktionelle Genomforschung, Abteilung für Funktionelle Genomforschung, 17487 Greifswald, Germany., Hammer E; Universitätsmedizin Greifswald, Interfakultäres Institut für Genetik und Funktionelle Genomforschung, Abteilung für Funktionelle Genomforschung, 17487 Greifswald, Germany., Droit A; Research Center of Quebec CHU-Université Laval, Québec, QC PQ G1E6W2, Canada., Eichler EE; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA., Elgersma Y; ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus University Medical Center, 3015 CN, Rotterdam, Netherlands.; Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN, Rotterdam, Netherlands., Hildebrand PW; Institut für Medizinische Physik und Biophysik, Universität Leipzig, Medizinische Fakultät, Härtelstr. 16-18, 04107 Leipzig, Germany.; Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Berlin, Germany.; Berlin Institute of Health, 10178 Berlin, Germany., Bolduc F; Department of Pediatrics, University of Alberta, Edmonton, AB CT6G 1C9, Canada.; Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada.; Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2H7, Canada., Krüger E; Institut für Medizinische Biochemie und Molekularbiologie (IMBM), Universitätsmedizin Greifswald, Ferdinand-Sauerbruch-Straße, 17475 Greifswald, Germany., Bézieau S; Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000 Nantes, France.; Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France. |
المصدر: | Science translational medicine [Sci Transl Med] 2023 May 31; Vol. 15 (698), pp. eabo3189. Date of Electronic Publication: 2023 May 31. |
نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101505086 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1946-6242 (Electronic) Linking ISSN: 19466234 NLM ISO Abbreviation: Sci Transl Med Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: Washington, DC : American Association for the Advancement of Science |
مواضيع طبية MeSH: | Interferon Type I* , Proteasome Endopeptidase Complex*/metabolism, Animals ; Humans ; Mice ; Adenosine Triphosphatases/genetics ; Drosophila melanogaster ; Gene Expression ; Proteomics |
مستخلص: | A critical step in preserving protein homeostasis is the recognition, binding, unfolding, and translocation of protein substrates by six AAA-ATPase proteasome subunits (ATPase-associated with various cellular activities) termed PSMC1-6, which are required for degradation of proteins by 26 S proteasomes. Here, we identified 15 de novo missense variants in the PSMC3 gene encoding the AAA-ATPase proteasome subunit PSMC3/Rpt5 in 23 unrelated heterozygous patients with an autosomal dominant form of neurodevelopmental delay and intellectual disability. Expression of PSMC3 variants in mouse neuronal cultures led to altered dendrite development, and deletion of the PSMC3 fly ortholog Rpt5 impaired reversal learning capabilities in fruit flies. Structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune programs. The proteostatic perturbations in T cells from patients with PSMC3 variants correlated with a dysregulation in type I interferon (IFN) signaling in these T cells, which could be blocked by inhibition of the intracellular stress sensor protein kinase R (PKR). These results suggest that proteotoxic stress activated PKR in patient-derived T cells, resulting in a type I IFN response. The potential relationship among proteosome dysfunction, type I IFN production, and neurodevelopment suggests new directions in our understanding of pathogenesis in some neurodevelopmental disorders. |
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معلومات مُعتمدة: | United Kingdom WT_ Wellcome Trust; R01 MH101221 United States MH NIMH NIH HHS |
المشرفين على المادة: | EC 3.6.1.- (Adenosine Triphosphatases) 0 (Interferon Type I) EC 3.4.25.1 (Proteasome Endopeptidase Complex) EC 3.6.4.- (PSMC3 protein, human) EC 3.6.4.- (Psmc3 protein, mouse) EC 3.4.- (Prosbeta6 protein, Drosophila) |
تواريخ الأحداث: | Date Created: 20230531 Date Completed: 20240122 Latest Revision: 20240122 |
رمز التحديث: | 20240123 |
مُعرف محوري في PubMed: | PMC10506367 |
DOI: | 10.1126/scitranslmed.abo3189 |
PMID: | 37256937 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1946-6242 |
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DOI: | 10.1126/scitranslmed.abo3189 |