Study lays groundwork for mutation-specific Rett treatments
Different mutations can have different effects on brain cell activity
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Different mutations that cause Rett syndrome can have divergent effects on brain cell activity, a study found.
The findings “hold promise for understanding mutation-specific mechanisms of Rett syndrome, and developing targeted mutation-specific therapeutics,” the researchers wrote.
Through a series of experiments using cell models, the researchers identified biochemical strategies to normalize brain cell activity in people with Rett caused by specific mutations.
“Individual mutations matter,” Mriganka Sur, PhD, neuroscience professor at the Massachusetts Institute of Technology’s Picower Institute and senior author of the study, said in an institute news story. “This is an approach to personalizing treatment, even for a single-gene disorder.”
The study, “Early differential impact of MeCP2 mutations on functional networks in Rett syndrome patient-derived human cortical organoids,” was published in Nature Communications.
Mutations and manifestations
Rett syndrome is a genetic disorder marked by abnormalities in neurological development that manifest in early childhood. Rett is caused mainly by mutations in the MECP2 gene, which encodes the MeCP2 protein.
More than 800 distinct Rett-causing mutations have been described, and there’s growing evidence that specific mutations may lead to distinct clinical outcomes. Studies have suggested that patients with so-called missense mutations, in which a mutated but complete version of the MeCP2 protein is produced, tend to have less severe manifestations than those with so-called truncating mutations, which lead to the production of an incomplete MeCP2 protein.
A team led by scientists at MIT set out to better understand how these different types of Rett-causing mutations influence the development and activity of nerve cells in the brain. To do this, the researchers used cell models in which easily accessible skin or blood cells are collected from patients, then biochemically manipulated to grow into cortical organoids, lab models that aim to recapitulate the makeup of cells in the human brain.
The scientists developed organoids carrying two Rett-causing mutations: a missense mutation called R306C and a truncating mutation called V247X. R306C is one of the most common Rett-causing mutations, accounting for up to 8% of all cases, while V247X is much rarer.
The team found that organoids with each type of mutation showed similar defects. For example, nerve cells in Rett organoids were less well connected with each other than nerve cells in healthy organoids. However, there were notable differences in organoids with the two specific mutations: for instance, organoids with the truncating V247X mutation generally showed more pronounced structural differences, including being larger.
The researchers found that the two mutations don’t necessarily cause the same types of abnormalities. In particular, they noted divergent effects related to small-world propensity (SWP), which is a measure of whether nerve cells are mostly connected to nearby cells or to cells farther away. Organoids with the R306 mutation had abnormally low SWP, but in organoids with the V247X mutation, SWP was slightly higher than normal.
Analyses of brain activity in a small group of children with Rett showed abnormalities consistent with those observed in the lab models, the researchers noted. These findings indicate “that MeCP2 dysfunction exerts both mutation-specific and convergent effects in the [disease development] of Rett syndrome, underscoring the need for mutation-specific therapeutic strategies,” the researchers wrote.
In further tests, they analyzed gene expression (activity) profiles in organoid cells, looking for individual genes that were more or less active in cells with each mutation. Their data indicated that the R306C mutation led to increased activity of HDAC2, a protein that normally works with the MeCP2 protein to help regulate gene activity. Meanwhile, the V247X mutation led to reduced production of a brain signaling molecule called GABA and defects in astrocytes, star-shaped cells that support neurons.
This led the researchers to test whether targeting HDAC2 or GABA might have beneficial effects. They found that treatment with an HDAC2 inhibitor called CAY10683 normalized SWP in organoids with the R306C mutation. Meanwhile, treatment with baclofen (a muscle relaxant  normalized SWP in organoids with the V247X mutation.
The data show that “specific gene expression changes may underlie neuronal activity levels and functional architecture in different [Rett-causing] mutations, and selective application of molecules that counter these changes may be plausible mechanisms for restoration of function,” the researchers wrote.
