Genetic Cause of Leaky Brain Vessels in Rett Found

MIT researchers discover two common Rett syndrome mutations compromise blood vessel integrity through overexpression of a microRNA.

Mar. 14, 2026 at 6:20am

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MIT researchers have discovered that two common genetic mutations that cause Rett syndrome each set off a molecular chain of events that compromises the structural integrity of developing brain blood vessels, making them leaky. The study traces the problem to overexpression of a particular microRNA (miRNA-126-3p), and shows that tamping down the miRNA's levels helps to rescue the vascular defect.

Why it matters

Rett syndrome is a severe developmental disorder affecting both the brain and body, and problems with the brain's blood vessels are suspected of contributing to the disease's profound neurological pathology. Understanding the genetic mechanisms behind these vascular defects could lead to new treatment approaches.

The details

The researchers developed advanced human tissue cultures to model vessel development, with and without the MeCP2 mutations that cause Rett syndrome. They found that vessels harboring either the R306C or R168X mutations showed reduced expression of the protein ZO-1, which is critical for ensuring tight seals between endothelial cells. This led to increased leakiness in the Rett mutation cultures compared to controls. Further analysis revealed the overexpression of miRNA-126-3p as the culprit, and treating the Rett cultures with an inhibitor of this miRNA helped restore vascular integrity.

  • The study was recently published in Molecular Psychiatry.

The players

Tatsuya Osaki

The lead author of the study and a researcher who built the advanced human tissue cultures used in the research.

Mriganka Sur

The senior author of the study and the Newton Professor of Neuroscience in the Picower Institute and MIT's Department of Brain and Cognitive Sciences.

Roger D. Kamm

A co-author of the study and a professor of mechanical engineering and biological engineering at MIT.

miRisten

A drug that inhibits miR-126 and is undergoing clinical testing for leukemia, which the researchers plan to administer to mice modeling Rett syndrome.

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What they’re saying

“A role for microRNAs in Rett syndrome has been shown, but now demonstrating that miRNA-126-3p is actually downstream of MeCP2 and directly implicated in the endothelial cell dysfunction is an important piece of the Rett syndrome puzzle.”

— Mriganka Sur, Newton Professor of Neuroscience in the Picower Institute and MIT's Department of Brain and Cognitive Sciences

“That's why we hypothesized that we should have some mediator between the MeCP2 mutation and ZO-1 downregulation and the BBB permeability increase. We focused on the microRNAs.”

— Tatsuya Osaki, Lead author

What’s next

The researchers are planning on administering the miR-126 inhibitor drug miRisten to mice modeling Rett syndrome to see if it helps improve the vascular defects.

The takeaway

This study provides important insights into the genetic mechanisms underlying the vascular problems associated with Rett syndrome, which could lead to new treatment approaches targeting the overexpression of miRNA-126-3p to help restore blood-brain barrier integrity.