Researchers have found that possessing a third copy of the Dyrk1a gene and at least three other genes was responsible for the structural changes of the face and skull in Down syndrome. Down syndrome affects 1 in every 800 live births and is known as a "gene dosage disorder," meaning it involves changes in the number of gene copies. It is known that individuals with Down syndrome have three copies of chromosome 21 instead of the usual two. However, it is not clear exactly which duplicated genes within this chromosome are responsible for the various aspects of the syndrome.
Using genetic engineering, teams led by Viktor Tybulevich from the Francis Crick Institute and Elizabeth Fisher from King's College London developed strains of mice with triplicated regions on mouse chromosome 16, which mimics the presence of an additional chromosome 21. The mice exhibit many traits associated with Down syndrome, including changes in facial and skull shape. Previous research linked a gene called Dyrk1a to Down syndrome, so the researchers wanted to test its impact on craniofacial malformation.
The team demonstrated that mice with an extra copy of Dyrk1a had fewer bone cells in the front of the skull and in the face. Additionally, cartilaginous joints called synchondroses located at the base of the skull were abnormally fused together. These effects were partially reversed when the third copy of Dyrk1a was removed, indicating that three copies of Dyrk1a are necessary to induce these changes in the skull.
Researchers believe that the presence of a third copy of Dyrk1a hinders the growth of neural crest cells needed for bone formation at the front of the skull. Besides Dyrk1a, the research showed that three other genes also contribute to changes in the skull, but further study is needed to confirm their identities.
Viktor Tybulevich, head of the Down Syndrome Center at Crick, explained that "there are currently limited treatments for aspects of Down syndrome that negatively affect health, such as congenital heart diseases and cognitive impairments, so it is vital to identify important genes. Understanding the genes associated with head and face development provides clues to other aspects of Down syndrome like heart diseases. Since Dyrk1a is key to craniofacial dysmorphology, it is very likely that it is involved in other changes related to Down syndrome as well."
Researchers at King's College London utilized shape measurement tools to map the changing skull shape of the mice, and these changes in skull shape were notably similar to those observed in individuals with Down syndrome. This research is part of an ongoing project to understand the genetic origins of Down syndrome. The researchers aim to subsequently identify genes associated with heart defects and cognitive impairment, thus bringing them closer to developing targeted treatments for aspects of Down syndrome that affect health.
