Gene discovery sheds light on common ear condition in people with Down syndrome

Researchers have identified a key gene that drives susceptibility to ‘glue ear’ in people with Down syndrome, paving the way for future targeted therapies. 

The work, published today as a Reviewed Preprint in eLife and described as a fundamental study by the editors, highlights the role of the gene DYRK1A in increasing susceptibility to otitis media with effusion (OME) – a type of middle ear condition commonly known as glue ear in people with Down syndrome. The editors say that the strength of evidence is compelling, and that the gene represents a promising therapeutic target for addressing hearing loss in patients.   

Down syndrome is a genetic condition caused by the presence of an extra copy of chromosome 21, leading to the overexpression of certain genes. It can result in a range of developmental, cognitive and health challenges. Around 50% of children with Down syndrome have hearing loss due to OME, which can impact skills such as the acquisition of language. OME is characterised by a middle ear inflammation accompanied by the presence of fluid in the ear cavity.

“Treatments such as tympanostomy tubes, also known as grommets, help alleviate OME by balancing pressure around the eardrum and preventing fluid accumulation,” explains co-lead author Hilda Tateossian, Senior Scientist at the Mammalian Genetics Unit, MRC Harwell Institute, Oxfordshire, UK. “However, children with Down syndrome often require multiple rounds of this surgery, increasing the risk of surgery-related complications.” 

“Despite the prevalence of OME in people with Down syndrome, the genetic basis of the condition has remained unclear,” adds co-lead author Amy Southern, a PhD student at the Mammalian Genetics Unit, MRC Harwell Institute. “Our research aimed to identify the genes responsible to guide the development of better treatments for this common and challenging condition.” 

The team began by studying mouse lines with complete and partial duplications of gene regions on chromosomes 10, 16 and 17 – the counterparts to human chromosome 21. Upon investigation, they found that mice with genetic duplications on chromosomes 10 and 17 showed no signs of middle ear infection. However, some of the mice with duplications on chromosome 16 showed the characteristic symptoms of OME, including hearing loss not caused by issues in the inner ear. This suggested that there must be a location on mouse chromosome 16 which drives chronic OME.

The team systematically narrowed down the region of interest to a section of the chromosome containing only 12 candidate genes. Of these, a gene called Dyrk1a is known to play a role in a number of cellular pathways, making it a possible candidate. Therefore, the team investigated the effects of varying Dyrk1a expression in mice. 

They began with two lines of mice with duplications in Dyrk1a: Dp1Tyb – a model with a larger duplication covering multiple genes other than Dyrk1a – and Dp3Tyb – a more focused duplication with fewer genes other than Dyrk1a. Each of these lines developed chronic OME. By crossing these lines with mice with a partial knockout of Dyr1ka (having one copy of the gene instead of two), the team then created “double mutants” with a normal Dyrk1a gene dosage (two copies of the gene). 

Among the offspring of the Dp1Tyb and Dyrk1a knockout cross, about 37% had no signs of OME, while 50% had OME in one ear, and only 13% had it in both ears. These results were a significant improvement compared to mice with three copies of Dyrk1a, which had a much higher incidence of OME. This suggested that reducing Dyrk1a gene dosage significantly alleviates the disease, but does not completely restore normal conditions.

When the team examined the offspring of the Dp3Tyb and Dyrk1a knockout cross, they found that around 77% of these double mutants had no OME, 8% had it in one ear, and only 15% had it in both ears. This outcome was comparable to healthy, non-mutant mice, showing that normalising Dyrk1a dosage fully corrected the OME in this model.

Further investigation revealed how Dyrk1a overexpression triggers OME. The team found that the gene activates inflammatory pathways and increases the production of VEGF, a protein linked to blood vessel leakage and fluid accumulation in the ear. It also affects the immune system’s balance, contributing to the inflammation seen in OME. Interestingly, they discovered that the loss of tiny hair-like structures called cilia in the middle ear, previously thought to be a primary cause, is likely a secondary effect of the inflammation rather than a direct consequence of Dyrk1a overexpression.

“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,” says co-senior author Victor Tybulewicz, Principal Group Leader and Assistant Research Director at the Francis Crick Institute, London, UK. “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.” 

“We have made a panel of mouse models that are extremely powerful for investigating aspects of Down syndrome,” adds co-senior author Elizabeth Fisher, Professor of Neurogenetics, UCL Queen Square Institute of Neurology, London, UK. “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.”

“Our discovery brings us a step closer to understanding and addressing a condition that impacts the lives of so many children with Down syndrome,” says co-senior author Steve Brown, who was Director of the Mammalian Genetics unit, MRC Harwell Institute, at the time of the study. 

“The identification of DYRK1A as a driver of OME opens the door for potentially less invasive therapeutic interventions than the currently used tympanostomy tubes,” concludes Brown. “There are many available DYRK1A inhibitors including Leucettinibs, a new class of DYRK/CLK kinase inhibitors. Therefore, suppressing the activity of DYRK1A by localised delivery of inhibitors such as this to the middle ear cavity in Down syndrome patients should be explored in further studies.” 

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