A team of researchers from around the world has solved the mystery of a child with a rare, unknown, genetic illness. The team found a link between the child’s neurological symptoms and a mutation that affects protein folding within cells. Genome sequencing in affected individuals led to the identification of mutations in subunits of the core protein-folding machinery TRiC/CCT.
The findings suggest that mutations in protein folding are involved in brain malformations. Not only did the work provide the parents with a molecular diagnosis, it also identified an entirely new type of genetic disorder which the authors dub “TRiCopathies.”
The results are published in Science, in the paper, “Brain malformations and seizures by impaired chaperonin function of TRiC.”
“Many patients with severe, rare genetic disease remain undiagnosed despite extensive medical evaluation,” said Stephen Pak, PhD, professor of pediatrics at Washington University in St. Louis School of Medicine. “Our study has helped a family better understand their child’s illness, preventing further unnecessary clinical evaluations and tests. The findings also have made it possible to identify 22 additional patients with the same or overlapping neurological symptoms and genetic changes that affect protein folding, paving the way for even more diagnoses and, ultimately, potential treatments.”
The team identified the cause of the clinical findings in a boy from Germany who had an intellectual disability, low muscle tone, and a small brain with abnormal structures. Given mutations in the CCT3 gene, Pak’s team set out to determine if it could be the cause of the patient’s condition.
The affected CCT3 protein is part of the large TRIC/CCT molecular complex whose job is to fold proteins. The chaperonin TRiC is an obligate hetero-oligomer, and the authors noted that they identified “variants in seven of its eight subunits, all of which impair function or assembly through different mechanisms.” Using C. elegans, which encodes a similar gene to CCT3 called cct-3, allowed the researchers to assess whether specific genetic changes found in undiagnosed patients are responsible for their symptoms. They found that C. elegans with the patient’s genetic variant moved more slowly than wt worms.
The outcome of having reduced protein-folding machinery, they found, was that actin proteins were incorrectly folded and abnormally distributed throughout the cells of C. elegans that carried the patient’s variant.
Collaborators performed complementary investigations into cct3 variants in zebrafish—which illuminated the effects of the gene on brain development—and in yeast, which clarified its role in protein folding, respectively.
Researchers mined a freely accessible global database of individuals with intellectual and developmental disabilities to identify other patients. They identified 22 individuals with genetic changes in seven of the eight CCT proteins that form the protein-folding machine.
Transcriptome and proteome analyses of patient-derived fibroblasts demonstrate the various consequences of TRiC impairment. Abnormalities in mobility and actin folding were again seen in C. elegans with variants affecting CCT1 and CCT7 proteins, similar to the observation with dysfunctional CCT3. Together, these patients represent a new type of rare genetic disease involving the protein folding machinery in the development of the central nervous system and define a disease spectrum of “TRiCopathies.”
“Our findings can inform clinicians, the scientific community, and patients and families all around the world that changes to the genetic message that are needed to make the eight-protein complex cause disease,” added Pak. “If next week a patient with brain malformations and neurological symptoms is found to have a variant that affects the protein-folding machine, the patient will receive a diagnosis.”
