Genetic cause for main type of hearing loss in children with Down syndrome identified microbiologystudy

The genetic cause for the most common type of hearing loss in children with Down syndrome has been identified in mice by researchers at UCL, the Francis Crick Institute and MRC Harwell Institute.

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 new 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.

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

Professor Fisher said, “We have made a panel of mouse models that are extremely powerful for investigating aspects of Down syndrome. Here, this research shows the value of working with these mice to help us understand—and ultimately offer treatments for—the pathologies that can arise with Down syndrome.”

In the new study, the researchers observed that all Dp1Tyb mice—a genetically modified mouse model with an extra copy of a genetic region on mouse chromosome 16 (which mirrors human chromosome 21)—had fluid in their middle ear and a thickened middle ear lining 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, which originally have three copies of the Dyrk1a gene, were bred to have only two copies, many no longer exhibited symptoms of OME. This indicates that an extra copy of the Dyrk1a gene is necessary for the development of this type of hearing loss in mice.

In further investigations into the causes of hearing loss, the researchers found that the DYRK1A protein, produced by the Dyrk1a gene, activated genes involved in inflammation and fluid leak from the vasculature (the network of blood vessels in the body).

They also showed that 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.

Dr. Tybulewicz 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.”

Professor 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 localized delivery of inhibitors to the middle ear cavity in Down syndrome patients should be explored in further studies.”