About half of all babies born with Down syndrome have heart defects that may require high-risk surgery or ongoing monitoring depending on the severity of the condition. Now, scientists from the Francis Crick Institute and University College London have linked Dyrk1a, a gene on human chromosome 21, to heart defects in these individuals that could open a door to new therapeutic possibilities. Their findings are reported in Science Translational Medicine in a paper titled, “Increased dosage of DYRK1A leads to congenital heart defects in a mouse model of Down syndrome.” 

This isn’t the first time that Dyrk1a has been linked to Down syndrome. Other studies have tied it to cognitive impairment and craniofacial dysmorphology observed in people with Down syndrome, but its link to heart defects is a novel finding. By looking at heart data from embryonic mouse models, the researchers found that Dyrk1a caused heart defects when present in three copies in mice. 

Dyrk1a codes for an enzyme called DYRK1A. The study showed that an extra copy of Dyrk1a turned down the activity of genes required for cell division in the developing heart and the function of the mitochondria. These changes were correlated with a failure to correctly separate the chambers of the heart.

Furthermore, when the researchers tested a DYRK1A inhibitor on pregnant mice with pups that model Down syndrome hearts defects as their hearts were forming, they observed that the genetic changes were partially reversed and the heart defects in the pups were less severe.  

The findings do suggest a potential therapeutic approach targeting this gene could work in humans. “However, in humans the heart forms in the first 8 weeks of pregnancy, likely before a baby could be screened for Down syndrome, so this would be too early for treatment,” noted Victor Tybulewicz, PhD, group leader of the Immune Cell Biology Laboratory & Down Syndrome Laboratory at the Crick and senior author on the paper. “The hope is that a DYRK1A inhibitor could have an effect on the heart later in pregnancy, or even better after birth. These are possibilities we are currently investigating.”

They are also investigating the possible involvement of other genes in heart defect development. While Dyrk1a is an important part of the equation, the researchers suspect it isn’t the only player. This was also reflected in the study data. The evidence shows that Dyrk1a is required in three copies to cause heart defects in mice, it was not sufficient alone. Furthermore, the inhibitor they used only partially reversed the changes in the mouse pups’ hearts. This suggests that another unknown gene must also be involved in the origin of heart defects in Down syndrome. And the team is currently searching for it.

Alongside those studies, the researchers are working with Perha Pharmaceuticals to test the DYRK1A inhibitor for treating cognitive disorders associated with both Down syndrome and Alzheimer’s disease. But they are also exploring other potential therapeutic avenues beyond Dyrk1a.

Rifdat Aoidi, PhD, a postdoctoral project research scientist at the Crick and co-first author, added, “We don’t yet know why the changes in cell division and mitochondria mean the heart can’t correctly form chambers. Dysfunction in the mitochondria has also been linked to cognitive impairment in Down syndrome, so boosting mitochondrial function could be another promising avenue for therapy.”

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