New insights into progressive hearing loss

In parallel studies in human and mouse, two groups of researchers have come to the same conclusion: that a new kind of gene is associated with progressive hearing loss. The new gene - called a microRNA - is a tiny fragment of RNA that affects the production of hundreds of other molecules within sensory hair cells of the inner ear.

The research provides important new genetic understanding of a condition that is common in humans but remains poorly understood.

One team, led by researchers from the Hospital Ramón y Cajal, Madrid, Spain, followed families who showed hearing loss. The second team, led by researchers from the Wellcome Trust Sanger Institute, Cambridge, UK, examined a new line of mice, called diminuendo, that showed progressive hearing loss from an early age. The two groups shared their emerging data.

"We were able quite quickly to show that if the mice carried one copy of the gene variant they suffered progressive hearing loss, if they carried two variants they were profoundly deaf," explains Professor Karen Steel, principal investigator of the programme at the Wellcome Trust Sanger Institute. "The important questions were could we determine what the variant is and how does it exert its effect on hearing?"

In their studies of families with progressive hearing loss, the Spanish team had proposed that the gene responsible lay on human chromosome 7. Both teams set about sequencing every gene in the equivalent genomic regions in human and mouse identified as implicated in hearing loss; the sequencing showed that most of the genes in the region could not be responsible for hearing loss.

However, they each found that a mutation in a microRNA gene called miR-96 was associated with the hearing loss.

"We know of a number of genes involved in deafness in humans and mice but, to our great surprise, this was one of a new class of genes called microRNAs," explains Professor Miguel Angel Moreno-Pelayo, senior author on the human study, from Hospital Ramón y Cajal and Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain.

MicroRNAs are tiny snippets of genetic information that, it is increasingly clear, can have dramatic consequences. Only five years ago, their role in human biology and disease was unknown. Today, it is becoming clear that these little molecules can control the activity of many genes. MicroRNAs can bind to the messengers involved in protein production in cells, disrupting this process.

"No one has seen a disease-causing mutation in the mature sequence of a microRNA," says Dr Moreno-Pelayo. "This is the first microRNA gene associated with hearing impairment and, remarkably, it is the first to be associated with an inherited disorder."

In the mouse, the precise role of the mutation can be examined. Mutation of the miR-96 gene seemed to disrupt development of intricate sensory hair cells in the mutant mice. Mice with two copies of the mutant gene had malformed hair cells from birth and the cells degenerated from an early age. In mice with one copy of the mutant gene, the effects were less severe, but became worse with age.