果冻影院

They found that having a third copy of the gene聽Dyrk1a聽and at least three other genes was responsible for changes in development that result in 鈥榗raniofacial dysmorphology鈥�, 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 鈥榞ene dosage disorder鈥� 鈥� 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鈥檚 not yet known which genes are responsible.

Using genetic engineering, teams led by Professor Elizabeth Fisher (Professor of Neurogenetics,聽Department of Neuromuscular Diseases,果冻影院 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聽Dyrk1a聽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鈥檚 group (King鈥檚 College London), they showed that mice with an extra copy of聽Dykr1a聽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聽顿测谤办1补听was removed 鈥� showing that three copies of聽顿测谤办1补听are necessary to cause these changes in the skull.

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

In addition to聽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 (果冻影院 Queen Square Institute of Neurology) said: 鈥淭his 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.鈥�

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

鈥淯nderstanding the genetics involved in the development of the head and face gives us clues to other aspects of Down syndrome like heart conditions. Because聽顿测谤办1补听is so key for craniofacial dysmorphology, it鈥檚 highly likely that it鈥檚 involved in other changes in Down syndrome too.鈥�

Researchers at King鈥檚 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鈥檚 College London) said: 鈥淲ith the help of great collaborators at the University of Calgary in Canada and a medical imaging software group here at King鈥檚, 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.鈥�

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.

Links

• Redhead et al. .听Development聽(2023) 150 (8): dev201077.

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