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