Brain malformations and seizures by impaired chaperonin function of TRiC.

Document Type

Article

Publication Date

11-2024

Identifier

DOI: 10.1126/science.adp8721

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."

Journal Title

Science

Volume

386

Issue

6721

First Page

516

Last Page

525

MeSH Keywords

Humans; Chaperonin Containing TCP-1; Brain; Seizures; Protein Folding; Intellectual Disability; Fibroblasts; Protein Subunits; Male; Proteome; Transcriptome; Female

Keywords

Chaperonin Containing TCP-1; Brain; Seizures; Protein Folding; Intellectual Disability; Fibroblasts; Protein Subunits; Proteome; Transcriptome

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