Feb. 26, 1998 Cincinnati -- A team of scientists from the University of Cincinnati, the Jackson Laboratory in Bar Harbor, Maine and Northern Illinois University have mapped the first gene known to cause age-related hearing loss in mice.
The researchers reported in the current issue of the journal Hearing Research that they used microsatellite DNA markers to map the age-related hearing loss (Ahl) gene to mouse Chromosome 10. Ahl appears be to a single gene, recessive trait.
The researchers worked with the C57BL/6J inbred strain of mice, the most commonly studied strain in age-related hearing loss research. Its abbreviated name is the B6 mouse.
Larry Erway, professor of biological sciences at the University of Cincinnati, said the mapping work involved traditional and time-consuming genetic crosses as well as the newer DNA microsatellite techniques.
"We started the genetic cross in 1991," said Erway. The mice were produced at the Jackson Laboratory and sent here. I reared the animals and aged them to two years of age."
Tissue samples demonstrated that the Ahl gene was on Chromosome 10, but the research team then did an additional three years of work to confirm their results. This part of the research involved back-crossing the wildtype or normal gene from another strain with normal hearing to the mice with hearing loss. This produced a genetically similar, or congenic, strain with normal hearing. The only difference was the replacement of the mutant Ahl gene with the gene for normal hearing. Because the new congenic strain had normal hearing, and the only difference between the two strains was a single stretch of Chromosome 10, that was further evidence of the location of the Ahl gene.
The researchers used two different techniques to document hearing loss in the mice. The first is called ABR for auditory- evoked brainstem response which measures the reception and transmission of nerve signals in the brain. As mice lose their hearing, it requires a louder audio signal to get a response. In addition, James Willott of Northern Illinois University examined the sensory ganglion cells associated with the inner ear or cochlea.
"When he looked at these cells within the cochlea of B6 mice, the cells begin to be lost by four to six months." said Erway. "We started picking up hearing loss by eight months. We carried them to a year and a half, and most of them had very significant hearing losses. They eventually become deaf in old age."
Most important, Willott found that the year-old congenic mice retained cell densities of a young, normally hearing B6 mouse.
Other genes which cause hearing loss have also been mapped. The only genes cloned so far are from the "shaker-1" mutant and Snell's "waltzer." These mice not only lose their hearing, they have a balance disorder which causes them to run in wild circles. Both the shaker and waltzer genes produce an abnormal form of the protein myosin, which causes degeneration of the hair cells in the cochlea and the vestibular canals the part of the inner ear responsible for balance.
Erway said the Ahl cannot be identical to the shaker or waltzer genes, because Ahl only causes hearing loss, not a balance disorder. However, it could be an allele (a different version) of one of two waltzer genes found on Chromosome 10.
One of the most important implications, according to Erway, is the potential identification of genes related to age-related hearing loss in humans. Mice and humans have very similar auditory systems, and there is a human condition (Usher's syndrome) very similar to the condition caused by the mouse "shaker" gene. Since more than half the human population suffers from hearing loss by the age of 80, the long-term goal is to identify the specific causes of age-related hearing loss in humans.
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