scientists Identify Key Protein Linked to Heart Defects in Down Syndrome
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A groundbreaking new study published in Nature sheds light on the genetic mechanisms behind the elevated risk of congenital heart defects (CHDs) in individuals with Down syndrome. Researchers have pinpointed a nuclear binding protein, HMGN1, as a critical contributor to these life-threatening conditions, offering a potential pathway for future therapies.
Roughly half of individuals with Down syndrome (DS) are born with CHDs. While the link between the two conditions is well-established, the underlying biological reasons have remained elusive.
“What our paper did was address a major unresolved question: Yes, three copies of chromosome 21 causes DS, but why? what are the genes on chromosome 21 that are bad if you have them in three copies? How in the world do you try to find those genes?” explained a senior researcher involved in the study.
The trisomy 21 and CHD Connection
Trisomy 21, the genetic condition causing Down syndrome, involves the presence of a third copy of chromosome 21. This genetic anomaly is responsible for the majority of CHD cases linked to chromosomal abnormalities, accounting for approximately 15% of all CHDs. Children with Down syndrome face a 1,000-fold increased risk of developing atrioventricular canal (AVC) defects, which disrupt the normal flow of blood through the heart.
The AVC, crucial for proper heart valve advancement, contains specialized cells vital for maintaining efficient blood transfer.However, the precise mechanisms by which trisomy 21 impacts these cells remained unknown – until now. Approximately 40,000 children, or 1 percent of all births in the U.S., are born with CHDs annually, with causes ranging from maternal health factors to environmental exposures.
HMGN1: A Key Player in Heart Defect Development
The research team, led by Sanjeev S. Ranade, PhD, assistant professor at Sanford Burnham Prebys, focused on High Mobility Group Nucleosome Binding Protein 1 (HMGN1).This protein plays a fundamental role in organizing DNA within the cell nucleus, regulating gene expression, and facilitating DNA repair.
Using a cutting-edge technique called CRISPR activation (CRISPRa), the scientists were able to simulate the genetic environment of Down syndrome in normal cells. “We did this for 66 chromosome 21 genes and then showed that an epigenetic gene – HMGN1 – was a bad guy if you had three copies,” the researcher stated.
Their experiments, conducted on human pluripotent stem cells and mouse models of Down syndrome, revealed that an excess of HMGN1 causes developing AVC cardiomyocytes to enter an abnormal state. Remarkably, when researchers used CRISPR technology to remove one copy of the HMGN1 gene in cells with trisomy 21, normal gene expression was restored. In mouse models, reducing HMGN1 levels led to a notable reduction in valvuloseptal defects – holes in the heart.
A Roadmap for Future Therapies
The findings offer a promising new avenue for developing targeted therapies for CHDs associated with Down syndrome. The researchers believe their approach can be applied to identify the genetic drivers behind other health challenges faced by individuals with Down syndrome, such as intellectual disability and bone formation issues.
“We’re hoping that our approach in this paper lays out a roadmap for finding genes driving other kinds of defects,” said Ranade. “Ultimately, once we find the players that drive disease, we believe we can use that details to find drugs that could help people with Down syndrome.”
The study, published in Nature on February 20, 2025, represents a significant step forward in understanding the complex genetic interplay between Down syndrome and congenital heart defects, offering hope for improved treatments and outcomes for affected individuals.
Source: Ranade, S. S., et al. (2025).Myocardial reprogramming by HMGN1 underlies heart defects in trisomy 21. Nature. doi.org/10.1038/s41586-025-09593-9.
