Genetic basis of facial changes in Down syndrome


Researchers at UCL, the Francis Crick Institute and King’s College London have shed light on the genetics underlying changes in the structure and shape of the face and head in a mouse model of Down syndrome.

They found that having a third copy of the gene Dyrk1a and at least three other genes was responsible for changes in development that result in ’craniofacial dysmorphology’, which shows up as shortened back-to-front length and widened diameter of the head.

Down syndrome affects one in 800 live births and is known as a ’gene dosage disorder’ - meaning that it involves changes in the number of copies of genes. People with Down syndrome have three copies of chromosome 21 instead of two. Having three copies of certain genes on this chromosome causes aspects typical of Down syndrome, but it’s not yet known which genes are responsible.

Using genetic engineering, teams led by Professor Elizabeth Fisher (UCL Queen Square Institute of Neurology) and Professor Victor Tybulewicz (the Francis Crick Institute), created mouse strains with duplications of three regions on mouse chromosome 16, which mimics having a third chromosome 21. The mice show lots of traits associated with Down syndrome, including changes in the shape of the face and skull.

Previous research has linked Dyrk1a to aspects of Down syndrome, so the researchers wanted to test how three copies of this gene impacted craniofacial dysmorphology.

Now, working with Professor Jeremy Green’s group (King’s College London), they showed that mice with an extra copy of Dykr1a had a reduced number of cells in the bones at the front of the skull and in the face. Also, cartilaginous joints at the base of the skull called synchondroses were abnormally fused together. These effects were partly reversed when the third copy of Dyrk1a was removed - showing that three copies of Dyrk1a are necessary to cause these changes in the skull.

The researchers believe that this is because having a third copy of Dyrk1a hinders the growth of neural crest cells that are needed to form the bones at the front of the skull.

In addition to Dyrk1a, the research showed that three other genes also contribute to the changes in the skull, but more research is needed to confirm their identity.

Professor Elizabeth Fisher (UCL Queen Square Institute of Neurology) said: "This is an important step towards understanding a fundamental aspect of Down syndrome that arises during development, and it will shed light on other characteristics of the disorder. It is also a good example of a group of collaborators with different expertise, working together to understand human biology, using model systems."

Professor Victor Tybulewicz, Group Leader of the Down Syndrome Laboratory at the Crick, said: "There’s currently limited treatments for the aspects of Down syndrome which have a negative impact on people’s health, like congenital heart conditions and cognitive impairment, so it’s essential we work out which genes are important.

"Understanding the genetics involved in the development of the head and face gives us clues to other aspects of Down syndrome like heart conditions. Because Dyrk1a is so key for craniofacial dysmorphology, it’s highly likely that it’s involved in other changes in Down syndrome too."

Researchers at King’s College London used shape-measuring tools to map the changing skull shape of the mice. These showed changes in skull shape that were remarkably similar to those seen in people with Down syndrome.

Professor Jeremy Green (Developmental Biology at King’s College London) said: "With the help of great collaborators at the University of Calgary in Canada and a medical imaging software group here at King’s, we were able to apply both quite traditional and some very novel methods for comparing complex anatomical shapes. These were sensitive enough to pick up difference even at foetal stages. This helped us pin down not only the locations of genes that cause Down syndrome but also get clues as to how those genes cause the differences that they do."

This research forms part of an ongoing project to understand the genetics of Down syndrome. The researchers will next aim to identify the genes involved in heart defects and in cognitive impairment, bringing us a step closer to understanding how to develop targeted treatments for aspects of Down syndrome which impact health.

  • University College London, Gower Street, London, WC1E 6BT (0) 20 7679 2000