NEW YORK – A team from the Francis Crick Institute, University College London, and other centers in the UK and France has demonstrated that additional copies of the DYRK1A gene contribute to the congenital heart defects described in individuals with Down syndrome, or trisomy 21, by altering the expression of mitochondrial respiration and cell proliferation genes in developing cardiac muscle cells.
"Increased dosage of DYRK1A protein resulted in impairment of mitochondrial function and congenital heart disease pathology in mice with [Down syndrome]," Francis Crick Institute researcher Victor Tybulewicz and Elizabeth Fisher, a neuromuscular diseases researcher at the UCL Institute of Neurology, and their colleagues wrote in Science Translational Medicine on Wednesday, "suggesting that DYRK1A may be a useful therapeutic target for treating this common human condition."
Using RNA sequencing in heart tissues from human fetuses with Down syndrome and embryonic tissues from the mouse model of the condition known as Dp1Tyb, the researchers searched for gene dosage contributors to Down syndrome-related heart defects, starting with hundreds of genes found on chromosome 21.
After whittling the set down to more than three-dozen duplicated genes, the team turned to gene mapping and additional mouse model testing to systematically assess the consequences of duplicating such genes.
"The use of highly refined and tailored mouse models that we created to answer specific genetic and biological questions led to this finding that is directly [relevant] to human congenital heart defects and Down syndrome," Fisher explained in an email.
The team's findings highlighted the apparent heart defect found in mouse models carrying three copies of DYRK1A, which coincided with lower-than-usual expression levels of genes involved in cell proliferation and mitochondrial respiration.
Because developing cardiomyocytes also showed altered mitochondrial activity, a feature linked to other Down syndrome patient tissues in the past, the authors hypothesized that congenital heart defects found in individuals with Down syndrome "[arise] in part from increased DYRK1A activity in cardiomyocytes leading to reduced proliferation and mitochondrial dysfunction."
On the other hand, cell proliferation, mitochondrial respiration, and related heart changes were restored in Dp1Tyb mouse embryos with two copies of the DYRK1A gene, rather than three. Similarly, such defects were dialed down in developing mouse embryos when pregnant mice were treated with the DYRK1 inhibitor leucettinib-21, Tybulewicz explained in an email, noting that "if we treat pregnant mice with a DYRK1A inhibitor, we can partially reverse the transcriptomic changes in the embryonic hearts that are caused by an extra copy of DYRK1A."
He predicted that "it's going to be very difficult if not impossible to treat pregnant human mothers with this drug to try and reverse heart defects," since the heart forms at a stage of gestation when most mothers do not know they are carrying a fetus with Down syndrome.
Even so, Tybulewicz suggested that it might be possible to combat Down syndrome-associated congenital heart defects using a DYRK1A inhibitor after birth — a possibility they plan to explore using their mouse model.
The team is also interested in exploring the other phenotypic effects of DYRK1A inhibition, since enhanced dosage of the gene has been linked to other features of Down syndrome, Tybulewicz explained, noting that the France-based pharmaceutical company called Perha Pharmaceuticals is reportedly planning an early-stage trial of its DYRK1A inhibitor as a potential cognitive impairment treatment.
More broadly, authors of the current study suggested that "our systematic genetic mapping approach for dosage-sensitive genes can be used to identify causative genes and mechanisms responsible for the many other phenotypes of [Down syndrome]."