Researchers at The University of Hong Kong believe they have found the mouse gene whose human counterpart, when damaged, may be responsible for inner ear disorders.
About one in 1,000 infants are born with hearing defects. Of these, half have balance problems caused by abnormal development of the inner ear and in two-thirds of cases the defects are genetic. The road to the gene’s discovery began in 1995 when Principal Investigator Prof Kathryn Cheah’s PhD student, Keith Leung, accidentally produced a mouse mutant with an inner ear defect.
Studying how genes are controlled, Keith injected DNA into mouse eggs producing a transgenic mouse carrying the foreign genes in its chromosome. One of the mice and its offspring were noticed because of abnormal circling behaviour and because they had yellow coats.

Prof Cheah in her laboratory at Hong Kong U.

Tests showed they could not swim like normal mice, and they could not tell which way was up. Because of this, they were nicknamed Yellow Submarine (Ysb) mice. “The behaviour was indicative of a balance problem caused by some kind of defect in the inner ear,” said Prof Cheah. The Ysb mice were also found to be deaf. Chance played a large part in producing the Ysb mouse, added Prof Cheah. “When the DNA was injected, it could have inserted itself in any of the mouse’s 40 chromosomes.

Most of the time, the DNA insertion is harmless and doesn’t disrupt any of the genes,” she said. The next step in the research was to discover where the DNA had inserted itself, and which gene had been affected. Eventually, the abnormality was traced to Chromosome 3.
The identity of the Ysb gene has yet to come out in a publication but Prof Cheah hopes to go public on the discovery before the end of the year. She said: “What happened was a very complicated event; the DNA had caused part of the chromosome to break and to turn around in two directions and basically rearrange. We wanted to find out the molecular change and what gene had been disrupted.” Prof Cheah’s research took a fortunate turn when she was contacted by Karen Steel and Charles Tease of Britain’s Medical Research Council. They had another mouse mutant with a similar inner ear defect, the product of exposure to Xrays.

In the collaboration that followed, the two mice were mated. The resulting double mutant offspring had the same inner ear defect; confirmation that the same gene was involved. Contrary to expectation, however, the defect arose not because the gene had been destroyed but because regulatory DNA had been disrupted. Said Prof Cheah: “Regulatory DNAs are like switches attached to genes which tell them when and where to turn on in the body. In our mice, we had disrupted one of the switches that directed the expression of the gene to the inner ear.
“Most human genes have a counterpart in the mouse and are organised similarly in the corresponding chromosomes. Potentially, this could mean the same gene is damaged in families with a genetic defect that affects the inner ear and hearing.

“In the long term, we may be able to repair the fault by gene or stem therapies,” said Prof Cheah. “The difficult with congenital defects is repairing them in the foetus.

Principal Investigator
Prof Kathryn Cheah: hrmbdkc@hkusua.hku.hk