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Why Dervishes Whirl
Sixty years later, scientists pinpoint the mutation behind a schoolboy's spinning, deaf mouse
Edward R. Winstead

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Scientists have identified the gene that, when mutated, causes mice to lose their hearing early in life and spend most of their waking hours spinning in circles. The mutation disrupts the gene that produces espin, a protein that is essential for the structural integrity of hair cells in the inner ear. Without espin, hair cells degenerate, causing "jerker" mice to go deaf, become hyperactive, toss their heads, and circle constantly, a remarkable display of behavior that was reported in the scientific literature nearly 60 years ago.

The first article on jerker mice appeared in the Proceedings of the National Academy of Sciences in 1941. The paper begins: "In June, 1938, a woman who raised mice for her own amusement brought to one of us a dancing adult female mouse which had been given to her by a schoolboy." The mouse, we now know, inherited two copies of a gene with a naturally occurring, or spontaneous, mutation. For decades, the Jackson Laboratory in Maine has maintained a population of jerker mice that presumably are descendants of the schoolboy's mouse.

The mouse geneticist George D. Snell was co-author of the PNAS paper, and he may have been the reason the 'dancing' mouse ended up at the Jackson Laboratory. (A note in the paper thanks an individual for bringing the mouse from London.) Snell, who received the 1980 Nobel Prize in Physiology or Medicine for his work on genetics and immunology, conducted research at the Jackson Labs from 1935 until his retirement in 1973.

James R. Bartles, of Northwestern University Medical School in Chicago, Illinois, led the team that identified the jerker mutation. "I personally find it fascinating that this single point mutation seems to cause all the abnormal behavior," says Bartles. "The net result is that the mouse looks like a whirling dervish. Seeing this in person certainly helps one buy into the notion of gene-behavior relationships."

The mutated espin gene appears to cause hair cells in the inner ear to send false signals to the brain. Bartles suspects that the false signals tell the animal it is falling or circling in one direction, when it really isn't; the actual circling in the opposite direction may be the mouse's attempt to compensate for the false signals.

The actin-bundling protein espin (black) is present in hair cells of mice with one copy of the jerker mutation (left). Mice with two copies of the mutation lack espin (right).

In 1996, Bartles and his colleagues discovered espin proteins in mice and later reported their presence in the testis, kidneys, and intestine. More recently, the researchers detected espin in hair cells, where it "bundles" filaments called actin. Actin is essential for the conversion of sound vibrations into the electrical energy that the brain subsequently recognizes as auditory information. Without the structural support of espin in hair cells, the entire process breaks down.

Bartles does not specialize in deafness research, and the jerker study involved a bit of serendipity. After his group mapped the espin gene to a region of mouse chromosome 4, Bartles read an article on deafness by Karen P. Steel that made him think there might be a connection between espin and jerker mice. The jerker mutation, it turned out, mapped to roughly the same location in the mouse genome as the espin gene.

"Many genes reside in that region and there was no good reason for this particular connection, but we took a chance," says Bartles. "The beauty is that our guess turned out to be right."

At least 60 different genes have been linked to deafness

A human version of the espin gene has been identified, but the current research, which appeared in a recent issue of Cell, is limited to the mouse. "I would not be terribly surprised if a mutation in this gene turned up in humans somewhere in the future," says Karen P. Steel, of the Medical Research Council Institute of Hearing Research in Nottingham, England. A number of single gene mutations that cause inherited deafness in small populations of humans have been identified using information about gene defects in deaf mice.

Steel's team of researchers is using mutagenesis screens to identify mice with balance or hearing problems. After identifying a deafness gene in the mouse, Steel contacts her network of clinical geneticist colleagues to see if they know of cases involving a similar mutation in humans.

"At least 60 different genes are involved in forms of deafness that aren't accompanied by other symptoms," says Steel, who studied jerker mice nearly twenty years ago. "The ear is such a complicated structure that this number is not surprising." If deafness were critical to survival, she notes, then mutations causing deafness would die out; since it isn't, lots of deafness mutations have accumulated in populations around the world.

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Zheng, L. et al. The deaf jerker mouse has a mutation in the gene encoding the espin actin-bundling proteins of hair cell stereocilia and lacks espins. Cell 102, 377-385 (August 4, 2000).
Grüneberg, H., Burnett, J.B. & Snell, G.D. The origin of jerker, a new gene mutation of the house mouse, and linkage studies made with it. Proc Natl Acad Sci USA 27, 562-565 (1941).

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