Feature: Genetics of deafness
“Hearing impairment affects so many people,” points out Karen Steel. “About 1 in 800 children are born with a hearing impairment; this rises to about 1 in 500 in 12–14 year-olds and about 60 per cent in the over-70s. It’s very socially isolating, and has huge effects on people’s economic potential.”
Although hearing aids and cochlear implants help many people, Dr Steel argues that more needs to be done. “I think hearing impairment has often been ignored,” she says. “Perhaps this is because it’s difficult for people to understand what it’s like to be deaf – it’s easy to shut your eyes and know what it is to be blind. We should take the possibility of improved treatments a lot more seriously.”
The ear itself is a masterpiece of engineering, converting the vibrations of sound waves into electrical signals that are sent to the brain. But studying this masterpiece is a tricky task, for its components are both tiny and incredibly delicate. Dr Steel’s approach is to use mouse genetics to investigate the molecules involved in normal hearing and deafness.
Hearing genes
The mouse has proved a very useful model for the study of human hearing. Not only are mouse and human ears almost identical structurally, but their genetics appear very similar too. Mutations in more than 100 genes can lead to deafness, but there are probably hundreds more waiting to be discovered. “In the past, when I was working at the MRC, people would send me deaf mice from all over the world,” says Dr Steel. “They would phone me up and say ‘I’ve got this mouse that appears to be deaf; can you look at it?’ For some, we knew the genes already, but others had mutations in genes we didn’t suspect would be involved in deafness.”
Having found a mutated gene, Dr Steel’s team examines the ear to see which structures are affected first. This needs to be done early in development, as the inner ear is a very complex and integrated system; if a single molecule is affected, there can be a knock-on effect on the whole inner ear – triggering degeneration of sensory hair cells, the cells that convert sound vibrations to nerve impulses.
Not surprisingly, therefore, most mutations affect the inner ear (and indeed inner-ear defects are likely to explain most human deafness), but mutations have been found affecting almost every other part of the auditory system – from the shape of the ear lobe, to the middle ear and, in a single case, the auditory neurons in the brain.
“Once we’ve found a gene in the mouse, we then link up with our collaborators who study human genetic deafness,” says Dr Steel. “They have fridges full of DNA samples from families with hearing impairment that haven’t been diagnosed yet; we can run through those samples to see whether the families have a mutation in the equivalent human gene. In most cases, this is a much quicker way of finding deafness genes than trying to puzzle it out directly in humans.”
Having moved to the Sanger, Dr Steel will be screening genetically modified mice to see if any have hearing defects. “The advantage here is that the way the mutagenesis is carried out, we know the gene before we start. This will speed up our research considerably. And we’ll be able to design new mutants specifically for our research.”
Thinking ahead
Finding new genes may have an even wider import: more subtle variations in these genes may influence people’s susceptibility to environmentally induced hearing loss. Many things can affect hearing – loud noises, drugs, infections – and, Dr Steel argues, it would be surprising if the same genes didn’t affect sensitivity to these agents. “We’re beginning to find variations in genes that make you more susceptible to environmental noise,” she says. “And people with a certain mutation in their mitochondrial genome lose their hearing if they take the antibiotic kanamycin.”
Dr Steel also has her eye on longer-term goals. “We need to find the molecules involved, and there is a lot that is yet to be discovered, but the results could be of help to many. People with progressive hearing impairment are likely to be the first to benefit, as it would seem easier to stop or reverse a degenerative process than to reverse the whole process of development that takes place in the first few months in the uterus.”
Identifying the key molecules would also open up new possibilities for drug treatments. “There are a number of approaches one could imagine,” says Dr Steel.
“The drugs could perhaps trigger a process of regeneration of sensory hair cells [normally, once the hair cells are dead, they are gone for ever], or stop hair cells dying if they’ve been damaged by noise. There are lots of other examples one can think of. It might take 15–20 years for such treatments to be developed. But you need to have imagination to have something to aim for.”
