Researchers at the Crick, MRC Harwell Institute and UCL Queen Square Institute of Neurology have identified the genetic cause for the most common type of hearing loss in children with Down syndrome.

Sections through the middle ear of 3 week, 4 week, 8 week and 16 week-old wild-type mice (left) and Dp1Tyb mice (right). Fluid and cellular material can be seen in the middle ear cavities in the Dp1Tyb mice. (Tateossian, H. and Southern, A. et al. eLife)

Down syndrome affects around 1 in 800 new births and is caused by an extra third copy of chromosome 21. About half of children with Down syndrome have hearing loss due to otitis media with effusion (OME), which is inflammation and fluid in the middle ear, also known as glue ear.

These children can require regular rounds of surgery, where tubes are inserted into the eardrum to prevent fluid accumulating. They can also experience problems with learning how to speak.

In research published in elife, the research team, led by MRC Harwell Institute, looked at mice that model Down syndrome by having additional copies of key genes which mirror the extra copy of chromosome 21 in humans.

They observed that all mice of a strain called Dp1Tyb with a third copy of a genetic region on mouse chromosome 16 (which mirrors chromosome 21) had fluid in their middle ear and a thickened middle ear lining from as early as three weeks old. These Dp1Tyb mice also needed louder sounds to initiate a response in their brains, suggesting they had hearing loss.

Using gene mapping, the team narrowed down that a gene called Dyrk1a, found on a smaller segment of Dp1Tyb, was responsible for the OME.

When Dp1Tyb mice that have three copies of the Dyrk1a gene were bred to only have two copies of Dyrk1a, many of them no longer presented with symptoms of OME, highlighting that an extra copy of Dyrk1a is necessary for mice to develop this type of hearing loss.

In further investigations into the changes behind the hearing loss, the researchers showed that DYRK1A protein, which the Dyrk1a gene codes for, switched on genes involved in inflammation and fluid leak from the vasculature. An extra copy of the Dyrk1a gene increased the amount of IL-6, an inflammatory marker, and a molecule called VEGF, which causes fluid to leak into the middle ear cavity.

Finally, the team tested saliva samples from children with Down syndrome and OME. These children had a higher expression of DYRK1A compared to their unaffected mothers.

Extra copies of Dyrk1a have already been linked to heart defects in Down Syndrome, as well as other effects like facial changes and cognitive impairment.

Victor Tybulewicz, Principal Group Leader of the Down Syndrome Laboratory and Immune Cell Biology Laboratory at the Crick led the work on the mouse models alongside Elizabeth Fisher, Professor of Neurogenetics at UCL Queen Square Institute of Neurology.

Victor said: 

There aren’t many treatments for long-term complications of Down syndrome which many people experience. As our research shows, several aspects can be pinpointed to an extra copy of just one gene, Dyrk1a. It will now be useful to explore if we can specifically reduce the activity of this gene. If delivered straight to the middle ear cavity, potential treatments could be used to alleviate otitis media, which will help children with language development.

Elizabeth Fisher, Professor of Neurogenetics at Queen Square Institute of Neurology, said: 

This research shows the value of working with mouse models to help us understand – and ultimately offer treatments for – the pathologies that can arise with Down syndrome.

Steve Brown, Director of the Mammalian Genetics Unit at MRC Harwell Institute at the time of the study, and lead senior author, said: 

Our research brings us a step closer to understanding and addressing a condition that impacts the lives of so many children with Down syndrome. The identification of DYRK1A as a driver of OME opens the door for potentially less invasive therapeutic interventions than the currently used tympanostomy tubes. Suppressing the activity of DYRK1A by localised delivery of inhibitors to the middle ear cavity in Down syndrome patients should be explored in further studies.