After decades of mystery, researchers have identified the gene responsible for birth defects in the hearts of children with Down syndrome, and proven that fixing it prevents this problem in mice.
The study was conducted by scientists from the Gladstone Institutes in the United States, and its results were published in Nature magazine on October 22, and the Eurick Alert website wrote about it.
About half of children born with Down syndrome have congenital heart defects, often serious malformations that require surgery in the first months of life.
Decades later, scientists knew that an extra copy of chromosome 21 — the genetic cause of Down syndrome — was responsible, but they were unable to pinpoint the genes that caused the heart problems.
Researchers used stem cell science and artificial intelligence to discover that a gene called HMGN1 disrupts the mechanism of DNA assembly and regulation, and can affect hundreds of other molecules involved in healthy heart development.
When the team removed the extra copy of HMGN1 from mice with Down syndrome, the animals no longer developed heart defects.
“This new knowledge may pave the way for a treatment that helps prevent heart defects in people with Down syndrome and associated heart defects, which would be a huge win for patients and their families,” says Deepak Srivastava, MD, a pediatric cardiologist at UCSF and head of the Gladstone Center.
Mosaic Down syndrome
Down syndrome is the most common chromosomal disorder, affecting one in every 700 children. It is also known as trisomy 21, and results from the presence of three copies of chromosome 21 instead of two.
This extra chromosome increases the risk of many health problems, the most common of which are heart problems.
People with Down syndrome are 40 to 50 times more likely to develop congenital heart defects – usually a hole in the wall of the heart’s chambers – than the general population.
The researchers worked with cells from people with mosaic Down syndrome, a rare condition in which some of the body’s cells contain three copies of chromosome 21, while other cells contain the usual two copies.
Individuals with mosaic Down syndrome do not exhibit features of Down syndrome, but they are at high risk of having children with the condition.
Scientists took cell samples from individuals with mosaic makeup and turned them into heart cells in the laboratory.
“The moment of discovery came when we found a noticeable difference in heart cells that contain three copies of chromosome 21, compared to those that contain two copies,” Srivastava said. “This made us wonder about the gene on the chromosome that causes this radical transformation in the cells.”
Gene activation
Using CRISPR, which can precisely nudge genes into slightly higher activity, the researchers boosted the levels of each of the candidate genes on chromosome 21.
The researchers turned on the genes, one by one, in healthy cells containing two normal copies of the chromosome, wondering whether any of them would be able to mimic the problem seen in trisomy cells.
The researchers used an artificial intelligence algorithm to model the differences between healthy heart cells and those with Down syndrome.
Once scientists identified the HMGN1 gene, they moved on to validate the prediction from animal studies.
The team showed – in a model of mice with Down syndrome – that reducing the number of copies of HMGN1 to two copies restored normal heart development.
Scientists believe that although high levels of HMGN1 are necessary for heart defects, other genes are likely to be involved as well, including a gene called DYRK1.
The team is now testing whether the combination of these two genes is enough to cause heart defects in mice, and these new results may one day open the door to treatments that reduce the activity of the genes responsible for this, perhaps through a treatment given to the mother.