Brain malformations and seizures by impaired chaperonin function of TRiC

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."

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Journal
Science
Published
2024-10-31
DOI
https://doi.org/10.1126/science.adp8721
Citations
22
Primary Topic
Heat shock proteins research
Type
article
Field-Weighted Citation Impact
5.14

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article

Brain malformations and seizures by impaired chaperonin function of TRiC

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Science
Heat shock proteins research
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article

Brain malformations and seizures by impaired chaperonin function of TRiC

Jeremias Krause, Laurie Robak, Kristin G. Monaghan, Eva Lausberg, Haley Streff, Alberto Alemán, Kamil K. Zajt, Tobias B. Haack, Sebastian Gießelmann, Alice Goldenberg, Anna Jansen, Ingo Kurth, Thomas Eggermann, Martin Wiesmann, Martin A. McClatchey, Martin Häusler, Michel Guipponi, Stefanie Meyer, Joachim Weis, Ryall Carroll, Florian Kraft, Andrew E. Fry, Lucien Franken, Matthias Begemann, Miriam Elbracht, Jörg B. Schulz, Lea Gerstner, Goran Čuturilo, Karin E. M. Diderich, Judith Frydman, Jessica Rosenblum, Andreas Hentschel, Lisa Wang, Claudia Poloni, Tim Schedl, Gary A. Silverman, Marco Tartaglia, Stephen C. Pak, Juliane Bremer, Chantal Depondt, Sarah Duerinckx, Ellen van Binsbergen, A. Micheil Innes, Andreas Roos, Kiran Polavarapu, Stefan Wolking, Roseline Caumes, Wim Van Paesschen, Enrico Bertini, Cordula Knopp, Francesca Clementina Radio, Bixia Zheng, Piere Rodriguez-Aliaga, Andrea Ciolfi, Hanns Lochmüller, Miriam Bertrand, Olaf Rieß, Renske Oegema, Pamela Trapane, Jean‐Madeleine de Sainte Agathe, Dustin Baldridge, Annegret Quade, Claudine Rieubland, Gaber Bergant, Hieu D. Hoang, Katherine A Blood, Ting-Ting Lee, Thomas Smol, Carol Saunders, Yvonne Weber, John Herriges, Dimah Hasan, Séverine Arcioni, Perrine Charles, Andrea Maier, Gaël Nicolas, Marije E. C. Meuwissen, Janine Magg, Kathleen Pope, Elisabetta Flex, Xiaomeng Zhang, Norbert Wagner, Dong Sun Julia Suh, Weimin Yuan, Borut Peterlin, Lucie Guyant, Katherine N. Hehmeyer
article en
22 citations

Abstract

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."

ScienceVol. 386(6721)
Université Libre de Bruxelles (BE), Children's Mercy Hospital (US), University of British Columbia (CA), Inserm (FR), Baylor College of Medicine (US), Washington University in St. Louis (US), Université de Lille (FR), University of South Florida (US), Istituto Superiore di Sanità (IT), Children's Hospital of Eastern Ontario (CA), University Hospital of Wales (GB), Ljubljana University Medical Centre (SI), Erasmus MC (NL), Alberta Children's Hospital (CA), University Medical Center Utrecht (NL), Centre Hospitalier Universitaire de Lille (FR), Jacksonville University (US), Sorbonne Université (FR), Düsseldorf University Hospital (DE), Lille’s Cardiology Hospital (FR), Assistance Publique – Hôpitaux de Paris (FR), Antwerp University Hospital (BE), Normandie Université (FR), University Hospital of Geneva (CH), Nemours Children's Health System (US), VIB-KU Leuven Center for Microbiology (BE), Universitätsklinikum Aachen (DE), Leibniz Institute for Analytical Sciences - ISAS (DE), Pitié-Salpêtrière Hospital (FR), Bambino Gesù Children's Hospital (IT), University Children's Hospital Tübingen (DE), Centre de Recherche Saint-Antoine (FR), Second Affiliated Hospital of Nanjing Medical University (CN), University Children's Hospital, Belgrade (RS), Mercy Research (US), University Hospitals Geneva Medical Center (US), Nemours Children's Clinic (US), Hôpital du Valais (CH), Heinrich Heine University Düsseldorf (DE), University of Duisburg-Essen (DE), Université de Rouen Normandie (FR), Geneva College (US), National Institute of Mental Health and Neurosciences (IN), University of Missouri–Kansas City (US), Cardiff University (GB), University of Tübingen (DE), RWTH Aachen University (DE), Florida College (US), Stanford University (US), KU Leuven (BE)
Hereditary Disease Foundation, Children's Discovery Institute, Wellcome Trust, Oxford Nanopore Technologies, Children's Hospital Foundation, Government of Canada, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, European Commission, Deutsche Forschungsgemeinschaft, Canada Research Chairs, Ministero della Salute, Medical Research Council Canada, RWTH Aachen University, Canada First Research Excellence Fund, Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen, National Institutes of Health, Canadian Institutes of Health Research, Medical Research Council, National Institute of Child Health and Human Development, Office of Research Infrastructure Programs, National Institutes of Health
Good health and well-being
Openalex Percentile: Top 4%
Heat shock proteins research
5.14
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