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Discovering the genes that cause hearing loss – why does it matter?

Many hearing researchers are dedicated to finding genes linked to hearing loss. But why is it so important to find these genes? Tracey Pollard, from our Biomedical Research team, explains.

So far, we know of over 100 genes that are linked in some way to hearing loss. This isn’t entirely surprising, as hearing is an incredibly complex process, and the cells and structures in the body involved in it are also therefore complex. Thousands of genes are involved in forming and maintaining the cells of the ear and the hearing brain. It’s possible that many, if not all, of these genes may cause hearing loss if they are mutated. So although the figure currently stands at around 100 genes, the true number may be much higher.

How do researchers find new genes linked to hearing loss?

One way that researchers search for genes linked to hearing loss is to look at families where multiple generations have been affected by hearing loss. They collect DNA samples from family members, both with and without hearing loss, and compare them. Thanks to new DNA sequencing techniques, researchers can look at the DNA sequence of every single gene in a person, and identify every difference in a person’s DNA compared to another person’s. They look for differences which are found in every family member with hearing loss, but which are absent from the DNA of those family members without hearing loss. These are the differences most likely to underlie the hearing loss.

A research group in the US, at the University of Miami, used this strategy recently to identify the mutation causing hearing loss in a large Chinese family. The mutation was in a gene called PDE1C.

What does PDE1C do?

PDE1C produces a protein called phosphodiesterase 1C, which controls the levels of two small molecules called cyclic AMP (cAMP) and cyclic GMP (cGMP) inside cells. These molecules are ‘second messengers’ – when a cell receives a signal from the outside, these molecules carry the information into the cell and bring about a response. They control many processes inside a cell, and how different biological processes within a cell interact with each other – they can be crucial to a cell’s survival.

Phosphodiesterases react with these molecules and deactivate them. This is important for the cell, as it ensures that it only responds to an external signal for as long as it needs to – phosphodiesterases then ‘switch off’ the signal, preventing damage to the cell. Mutations in phosphodiesterase genes (of which there are several) have been linked to a number of health conditions, such as cardiovascular disease and autoimmune disorders.

How might the mutation in PDE1C cause hearing loss?

The researchers investigated the mutation they had found in more detail, trying to work out how it causes hearing loss.

First, they used computer software and the DNA sequence of the gene to build a model of the mutated phosphodiesterase 1C protein. The DNA sequence provides a recipe for the protein – and changing even one letter in that sequence can change one of the amino acids that make up the protein – and that’s exactly what happens here. The changed amino acid is found in the part of the protein which interacts with cAMP and cGMP, and probably interferes with what the protein does.

Next, the team looked at where in the ear the protein is normally found. They found it in the hair cells, the sound-sensing cells in the inner ear. More specifically, they found it in small structures within the hair cells called lysosomes, which are used by cells to break down proteins when they become damaged or are otherwise no longer needed. If phosphodiesterase 1C plays a role in these processes, its changed structure is likely to affect them.

Finally, the researchers produced both the mutated and unmutated phosphodiesterase 1C protein and studied how the changed amino acid affected how well the protein breaks down cAMP and cGMP. They found that the mutated protein was actually better at breaking them down! The effect of the mutation in hair cells may be to reduce levels of cAMP and cGMP too much and too quickly, throwing a number of processes within the cells off-balance, which ultimately leads to hearing loss. Further study will be needed to determine this for certain.

What does this mean?

Every time we identify a gene that is linked to hearing loss, and figure out what role it plays in the hearing system (e.g. is it important in the cells that detect sound, or the ones that pass information from the ear to the brain?), we learn more about how hearing works. This helps us to understand what hearing “looks like” at the cellular and molecular level, and what we’re trying to restore the system to in order to reverse hearing loss. It can also help us to identify ‘targets’ – genes, proteins or the biological processes they’re involved in – so that we can design medicines, or other treatments, to interfere with or reset them, to restore hearing.

In addition, finding new genes that are linked to hearing loss improves our ability to diagnose genetic hearing loss. If a child is born deaf, or if hearing loss runs in someone’s family, it’s likely that there is a genetic component to their hearing loss. Families in this situation may be able to have a DNA test to try to identify the specific cause of their hearing loss. A genetic counsellor can help the family to understand more about their hearing loss – what has caused it, how it may change throughout life, if there will be any related health conditions, and how likely it is that they will pass their hearing loss on to their children. This can be of great benefit to people as they plan for their future.

This is also important for when treatments for hearing loss become available – being able to accurately diagnose the cause of someone’s hearing loss will mean that doctors can ensure they get the most appropriate and effective treatment.

Further information

The research described in this blog post was published online in the journal Human Genetics earlier this month.

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