New Hope for Noonan Syndrome Heart Defects

Noonan syndrome with multiple lentigines (NSML) is a rare genetic disorder that causes short stature, distinctive facial features, and clusters of dark skin spots called lentigines. But its most serious impact is a dangerous thickening of the heart muscle, the onset of which is not well understood.

Now, researchers at Yale School of Medicine (YSM) have discovered how certain genetic mutations can lead to this severe heart condition, additionally identifying a leukemia drug that shows promise as a therapeutic.

Their findings are published in Proceedings of the National Academy of Sciences.

"Newborns with Noonan syndrome that have severe heart failure often die within the first six months of life. No treatment exists, which is why finding one is so important," says Sravan Perla, Ph.D., associate research scientist in the Department of Pharmacology at YSM and lead author of the study. "It is very difficult and time-consuming to develop a new drug, so we thought it's best if we could repurpose a drug that already exists."

The molecules underlying heart thickening

NSML is caused by mutations in a gene that codes for an enzyme called SHP2, which plays a critical role in cell signaling. Previous research has found that in NSML, SHP2 variants are less active than typical forms of the enzyme. But Yale researchers discovered this wasn't what was behind the heart-thickening condition known as hypertrophic cardiomyopathy.

"We revealed that the key lies not in SHP2's enzymatic action, but in its ability to act as a scaffolding platform due to these specific mutations," says senior author Anton Bennett, Ph.D., Dorys McConnell Duberg Professor of Pharmacology, professor of comparative medicine, and director of the Yale Center for Molecular and Systems Metabolism at YSM.

The researchers found that when mutated in NSML, SHP2 binds to another protein and recruits another enzyme called c-Src, a tyrosine kinase. Together, this molecular trio sets off a chain reaction that abnormally boosts two transcription factors—proteins that turn a gene on or off—that are critical for normal heart development.

These transcription factors were elevated in NSML mouse models, the research team found. And when they rose too high, they dramatically reduced levels of BMP10, a growth-regulating protein essential for healthy heart muscle structure.

Leukemia drug offers new hope

With these findings in hand, the team used a drug known to inhibit c-Src activity, which they had found in earlier studies could reverse hypertrophic cardiomyopathy. They tested whether the drug—a leukemia treatment called dasatinib—could restore the balance of BMP10 molecules driving hypertrophic cardiomyopathy in Noonan syndrome.

The researchers found that very low doses of dasatinib returned BMP10 levels in NSML mice to normal levels. By inhibiting c-Src, dasatinib prevented the transcription factors from becoming overly active, essentially counteracting the effect of the mutated gene implicated in NSML.

The drug, therefore, offers a potential path for treating heart thickening in patients with NSML, the researchers say.

"We were able to connect the dots from gene expression all the way to protein structure and cardiac function," says Perla. "That gives us confidence that targeting this pathway could actually work in patients."

In future clinical trials, the work could lead the way towards the development of a lifesaving therapy for NSML patients.