Brain malformations and seizures by impaired chaperonin function of TRiC

• 成果类型: Article
• 署名作者: Kraft, Florian; Rodriguez-Aliaga, Piere; Yuan, Weimin; Franken, Lena; Zajt, Kamil; Hasan, Dimah; Lee, Ting-Ting; Flex, Elisabetta; Hentschel, Andreas; Innes, A. Micheil; Zheng, Bixia; Suh, Dong Sun Julia; Knopp, Cordula; Lausberg, Eva; Krause, Jeremias; Zhang, Xiaomeng; Trapane, Pamela; Carroll, Riley; Mcclatchey, Martin; Fry, Andrew E.; Wang, Lisa; Giesselmann, Sebastian; Hoang, Hieu; Baldridge, Dustin; Silverman, Gary A.; Radio, Francesca Clementina; Bertini, Enrico; Ciolfi, Andrea; Blood, Katherine A.; Agathe, Jean-Madeleine de Sainte; Charles, Perrine; Bergant, Gaber; Cuturilo, Goran; Peterlin, Borut; Diderich, Karin; Streff, Haley; Robak, Laurie; Oegema, Renske; van Binsbergen, Ellen; Herriges, John; Saunders, Carol J.; Maier, Andrea; Wolking, Stefan; Weber, Yvonne; Lochmuller, Hanns; Meyer, Stefanie; Aleman, Alberto; Polavarapu, Kiran; Nicolas, Gael; Goldenberg, Alice; Guyant, Lucie; Pope, Kathleen; Hehmeyer, Katherine N.; Monaghan, Kristin G.; Quade, Annegret; Smol, Thomas; Caumes, Roseline; Duerinckx, Sarah; Depondt, Chantal; Van Paesschen, Wim; Rieubland, Claudine; Poloni, Claudia; Guipponi, Michel; Arcioni, Severine; Meuwissen, Marije; Jansen, Anna C.; Rosenblum, Jessica; Haack, Tobias B.; Bertrand, Miriam; Gerstner, Lea; Magg, Janine; Riess, Olaf; Schulz, Joerg B.; Wagner, Norbert; Wiesmann, Martin; Weis, Joachim; Eggermann, Thomas; Begemann, Matthias; Roos, Andreas; Haeusler, Martin; Schedl, Tim; Tartaglia, Marco; Bremer, Juliane; Pak, Stephen C.; Frydman, Judith; Elbracht, Miriam; Kurth, Ingo
• 署名单位: RWTH Aachen University; Stanford University; Washington University (WUSTL); RWTH Aachen University; RWTH Aachen University Hospital; RWTH Aachen University; RWTH Aachen University Hospital; Dortmund University of Technology; Leibniz Association; Leibniz Institut fur Analytische Wissenschaften (ISAS); University of Calgary; University of Calgary; Nanjing Medical University; State University System of Florida; University of Florida; Cardiff University; Cardiff University; IRCCS Bambino Gesu; IRCCS Bambino Gesu; University of British Columbia; Assistance Publique Hopitaux Paris (APHP); Hopital Universitaire Pitie-Salpetriere - APHP; Sorbonne Universite; Sorbonne Universite; University Medical Centre Ljubljana; University of Belgrade; University of Belgrade; Erasmus University Rotterdam; Erasmus MC; Baylor College of Medicine; Utrecht University; Utrecht University Medical Center; Children's Mercy Hospital; University of Missouri System; University of Missouri Kansas City; RWTH Aachen University; RWTH Aachen University Hospital; RWTH Aachen University; RWTH Aachen University Hospital; RWTH Aachen University; University of Ottawa; Ottawa Hospital Research Institute; Children's Hospital of Eastern Ontario; University of Ottawa; National Institute of Mental Health & Neurosciences - India; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite de Rouen Normandie; Universite de Rouen Normandie; CHU de Rouen; State University System of Florida; University of South Florida; RWTH Aachen University; RWTH Aachen University Hospital; Universite de Lille; CHU Lille; Universite Libre de Bruxelles; Universite Libre de Bruxelles; KU Leuven; KU Leuven; University Hospital Leuven; University of Geneva; University of Geneva; University of Antwerp; University of Antwerp; Eberhard Karls University of Tubingen; Eberhard Karls University of Tubingen; TUBINGEN UNIVERSITY CHILDRENS HOSPITAL; RWTH Aachen University; RWTH Aachen University Hospital; University of Duisburg Essen; Heinrich Heine University Dusseldorf; Heinrich Heine University Dusseldorf Hospital; Washington University (WUSTL)
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8721
• DOI: 10.1126/science.adp8721
• 发表日期: 2024-11-01
• 页码: 516-525
• 关键词: caenorhabditis-elegans chaperonin; de-novo mutations; eukaryotic chaperonin; cortical development; neuronal migration; tubulin; subunit; genes; interactome; zebrafish

摘要

Malformations of the brain are common and vary in severity, from negligible to potentially fatal. Their causes have not been fully elucidated. Here, we report pathogenic variants in the core protein-folding machinery TRiC/CCT in individuals with brain malformations, intellectual disability, and seizures. The chaperonin TRiC is an obligate hetero-oligomer, and we identify variants in seven of its eight subunits, all of which impair function or assembly through different mechanisms. Transcriptome and proteome analyses of patient-derived fibroblasts demonstrate the various consequences of TRiC impairment. The results reveal an unexpected and potentially widespread role for protein folding in the development of the central nervous system and define a disease spectrum of TRiCopathies.