Many people with Down syndrome have a congenital heart defect. The cause is the additional copy of chromosome 21. However, which of the 230 genes on chromosome 21 is responsible for this was previously unclear. Researchers have now identified one of the genes responsible. To do this, they examined the heart tissue of human embryos with and without trisomy 21 as well as a mouse model of Down syndrome. The results also point to a possible treatment approach: If the Down syndrome mice were given a drug that suppresses the activity of the gene in the embryonic stage, their heart defects were less severe.
About one in 800 newborns has a third copy of chromosome 21. This so-called trisomy 21 leads to a variety of symptoms that are summarized under the term Down syndrome. These include cognitive impairments, changed facial features and physical deformities. Around every second person with Down syndrome is born with a heart defect. Often the chambers of the heart are not completely separated from each other, which leads to reduced physical performance and a lower life expectancy. Those affected often have to undergo a risky operation in infancy and be monitored throughout their lives.
Studies on embryonic hearts
In order to develop alternative treatment options, it is crucial to find the causes of the heart problems. A team led by Eva Lana-Elola from the Francis Crick Institute in London has now looked into this. “This clinically significant cardiac pathology is the result of a third copy of one or more of the approximately 230 genes on chromosome 21,” explain the researchers. “However, it was unclear which genes underlie cardiac pathology. That’s why the disease mechanisms are largely unknown.”
To answer this question, the team first examined ten hearts from human embryos that had been aborted in the 13th or 14th week of pregnancy and made available to scientists. Five of these came from embryos with trisomy 21, five from embryos with a normal number of chromosomes. During the analysis, the researchers discovered several genes on chromosome 21 that were read significantly more strongly in the Down syndrome hearts.
Tracking down disease mechanisms
But which of these genes are actually the cause of heart defects? The researchers investigated this with the help of mice, in which they created an additional copy of the regions of the genome that correspond to human chromosome 21, thus causing Down syndrome. In fact, the hearts of the mouse embryos genetically modified in this way showed the same pathological processes as in human embryos with Down syndrome - a first insight into possible disease mechanisms. These included reduced cell division, weakened energy metabolism and increased immune reactions.
In the next step, Lana-Elola and her team used mice in which only some of the relevant genes were present in triplicate. In each case, they recorded the effect of the tripled genes and whether this led to heart defects. In this way, they narrowed down the genes in question until they finally found one without which heart defects do not occur if it is tripled. This is a gene called Dyrk1a, which, among other things, is responsible for cell division in the developing heart and also influences the function of the mitochondria, the cell's power plants.
Drug prevents heart defects in mice
“The extra copy of Dyrk1a was responsible for most of the changes observed in the developing mouse hearts with Down syndrome,” the team writes. According to the results, the tripling of Dyrk1a is necessary for a heart defect to develop, but is not enough on its own. At least one other gene must also be involved. The team would like to identify this in future studies.
However, Dyrk1a already offers a potential starting point for therapies. To test possible treatment options, the researchers administered a drug to Down syndrome mice at an early embryonic stage that suppresses the excessive function of Dyrk1a. And indeed: “Our research shows that inhibiting DYRK1A can partially reverse the changes in mouse hearts,” reports Lana-Elola’s colleague Victor Tybulewicz.
Not yet ready for use by humans
However, treatment in this form is not suitable for humans because the heart forms during the first eight weeks of pregnancy - well before potential Down syndrome would usually be recognized. In this case, the treatment would come too late. “The hope is that a DYRK1A inhibitor could also have an effect on the heart later in pregnancy or ideally even after birth,” says Tybulewicz. “These are possibilities we are currently exploring.”
Source: Eva Lana-Elola (Francis Crick Institute, London) et al., Science Translational Medicine, doi: 10.1126/scitranslmed.add6883