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Sound science – Exploring the genetics of hearing loss

14 Apr, 2009

Sensory hair bundle of a guinea pig inner hair cellProgressive hearing loss is a common and debilitating problem in humans, yet relatively little is known about the hundreds of genes thought to be involved. Chrissie Giles spoke to Professor Karen Steel, whose work with mice is shedding light on the complex process of hearing.

Headbanger, oblivion, catweasel: not Scandinavian death metal bands, or the latest celebrity fragrances, but mutant mouse strains that share defects in the sensory hair cells found in their ears. These defects frequently affect the balance and/or hearing of the mice, and research into them can bring new insights into human hearing.

Now, we can add to the list of mutant strains ‘diminuendo’. This mouse carries a mutation that causes hearing problems, and is the latest mutant to have been identified by Professor Karen Steel at the Wellcome Trust Sanger Institute. Professor Steel has been investigating the genetics of deafness for some 30 years. Her ultimate aim is to help develop therapies to prevent or minimise the effects of progressive hearing loss, a debilitating and distressing condition that affects around 60 per cent of people over 70.


Unlike all of the other genes implicated in deafness so far, the gene mutated in the ‘diminuendo’ mouse does not code for a protein, but for a microRNA – a short length of RNA that affects the expression of other genes. A study by a Spanish group, published alongside Professor Steel’s paper, has found the same gene is involved in some people with a family history of deafness.

As such, the researchers are the first to have identified a disease-causing mutation in the mature sequence of a microRNA. What’s more, the microRNA gene in question is the first ever to be associated with hearing impairment and with an inherited disorder.

The ‘diminuendo’ mouse is one of many mutants studied by Professor Steel’s team derived from large-scale mutagenesis programmes. “A chemical was used to introduce single base changes into the DNA sequence of sperm precursor cells,” says Professor Steel. Most of these random mutations don’t make a difference to the organism, but if they occur in coding or controlling regions of DNA, they can have an effect. Researchers then examine the mouse offspring to select those with a desired characteristic, such as deafness or balance defects, and then identify the gene that contains the mutation.

Professor Steel’s research also involves mice in which mutations have been made in targeted genes. She has been involved in setting up the large-scale Mouse Genetics Programme at the Sanger Institute, aimed at investigating the function of each gene in the genome.

Dr Bill Skarnes at the Sanger Institute is leading a key part of an international effort to “knock-out” (block the action of) all genes in the mouse genome, one by one, by manipulating mouse embryonic stem cells to produce mutations in a particular gene. The Mouse Genetics Programme then screens the resulting mice for various diseases and characteristics – from liver function to fertility, and including hearing and balance problems.

But why use animal models of hearing at all? Mice are particularly useful because their auditory system is very similar to that of humans, just a bit smaller, and having an animal model allows researchers to explore the impact of a mutation on the function of the ear.

“Having a mouse model allows us to examine the development of the deafness, and the molecular and cellular processes involved, giving us insight into the early stages of the progressive loss of hearing, something that is not possible in humans,” says Professor Steel. “Furthermore, we can alter the genes of a mouse to introduce the equivalent mutations found in humans, meaning that researchers can look at precisely how a mutation affects the development of the ear’s anatomy and function.”

Hair trigger

The ear’s sensory receptors, hair cells, are central to hearing. Found in part of the inner ear called the cochlea, the hair cells detect the tiny vibrations of sound and convert them into electrical signals that trigger activity in auditory nerves. Without hair cells there is no hearing, and mammalian hair cells are not replaced during life.

Does this mean that degeneration of hair cells is a major cause of deafness, or just something that happens alongside hearing loss? “I’ve never found a mouse mutant where hair-cell degeneration is the direct cause of deafness,” says Professor Steel. “There’s always some pre-existing problem with the hair cells.”

The ‘diminuendo’ findings published recently reinforce the idea that abnormal hair cells can be associated with hearing impairment. Professor Steel and colleagues showed that the mutation caused mice to be born with malformed hair bundles – the regular arrays of hair-like projections from the top of the hair cells that are essential for detecting vibrations, like grasses bending in the wind. “If the mice carried one copy of the gene variant they suffered progressive hearing loss, if they carried two they were profoundly deaf,” says Professor Steel.

Scanning electron micrographs of inner ear from five-day-old mice. Top: wildtype mouse; bottom: mouse carrying two copies of the mutated miR-96 gene.

Scanning electron micrographs of inner ear from five-day-old mice. Top: wildtype mouse; bottom: mouse carrying two copies of the mutated miR-96 gene.

The team mapped the ‘diminuendo’ mutation to chromosome 6, and found it was in a gene encoding a microRNA, called miR-96. These short pieces of RNA, around 22 nucleotides in length, are thought to bind to specific sequences in mRNA (messenger RNA) from protein-coding genes and degrade the message. This, in turn, reduces the amount of the corresponding protein produced.

The ‘diminuendo’ mutation was seen to alter the expression of hundreds of different mRNAs – just under 100 significantly. Of these, the researchers identified five genes that they think could individually be responsible for hearing impairment in the mice. They are now following these genes to discover if they are indeed causing the damage to the hair cells and if this damage can be halted by modulating their activity.

Little by little, the work of Professor Steel and colleagues is increasing our understanding of the genetic basis of one of our most vital and complex senses, hearing. And with the recent publications on the ‘diminuendo’ mouse and similar mutations in humans, the researchers have identified the first ever microRNA involved in an inherited disorder or human disease, begging the question of just how many other human conditions and diseases are affected by these tiny pieces of RNA.

Further information

  • Researchers link microRNA gene to hearing loss (news: 14 April 2009)
  • Mencía A et al. Mutations in the seed region of human miR-96 are responsible for non-syndromic progressive hearing loss. Nat Genet 12 April 2009 [Epub ahead of print].
  • Lewis M et al. An ENU-induced mutation of miR-96 associated with progressive hearing loss in mice. Nat Genet 12 April 2009 [Epub ahead of print].

Of mice and men

‘Dancing mice’ have fascinated people for centuries. These mutant mice are similar to some of those studied by Professor Steel, except that they come from the wild, and are affected by spontaneously occurring mutations in genes linked to balance and/or hearing. The ‘dancing’ refers to the animals’ strange movement (often including head-bobbing and circling) and was reflected in the names given to these mice many years ago by breeders – including ‘dancer’, ‘pirouette’ and ‘waltzer’.

Fascination with these and other mutant mice blossomed in the 18th and 19th centuries with the ‘mouse fancy’, where people bred mice for their interesting appearance and characteristics. Many of the hundreds of mutant mouse strains being studied by scientists today originated from those bred as part of the mouse fancy.

Image credits: Dr David Furness, Wellcome Images (top image) and Liz Quint
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