Brain malformations and seizures by impaired chaperonin function of TRiC

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, Julia Suh, Dong Sun, Knopp, Cordula, Lausberg, Eva, Krause, Jeremias, Zhang, Xiaomeng, Trapane, Pamela, Carroll, Riley, McClatchey, Martin, Fry, Andrew E. ORCID: https://orcid.org/0000-0001-9778-6924, Wang, Lisa, Giesselmann, Sebastian, Hoang, Hieu, Baldridge, Dustin, Silverman, Gary A., Radio, Francesca Clementina, Bertini, Enrico, Ciolfi, Andrea, Blood, Katherine A, de Sainte Agathe, Jean-Madeleine, Charles, Perrine, Bergant, Gaber, Čuturilo, 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, Lochmüller, 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, Jörg B., Wagner, Norbert, Wiesmann, Martin, Weis, Joachim, Eggermann, Thomas, Begemann, Matthias, Roos, Andreas, Häusler, Martin, Schedl, Tim, Tartaglia, Marco, Bremer, Juliane, Pak, Stephen C., Frydman, Judith, Elbracht, Miriam and Kurth, Ingo 2024. Brain malformations and seizures by impaired chaperonin function of TRiC. Science 386 (6721) , pp. 516-525. 10.1126/science.adp8721

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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.”

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	American Association for the Advancement of Science
ISSN:	0036-8075
Date of First Compliant Deposit:	22 November 2024
Date of Acceptance:	22 August 2024
Last Modified:	22 Nov 2024 15:42
URI:	https://orca.cardiff.ac.uk/id/eprint/173814

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