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A study of a disorder that limits eye movement demonstrates, for the first time, that a human disorder can result from errors in axon guidance--or the ability of growing nerve fibers to navigate to the right location. This has been a popular hypothesis in neuroscience, but had never actually been shown.
The researchers, led by neurologist Elizabeth Engle, MD, a Howard Hughes Medical Institute Investigator in the Children's Hospital Boston Neurobiology Program, identified a gene mutated in Duane syndrome, a disorder affecting 1 in 1,000 people that restricts the movement of the eyes. Their findings, published online July 24 by the journal Science, confirm and expand on Engle's longstanding hypothesis that many congenital complex eye movement disorders arise from improper development of the nerves that control movement of the eyeball. Researchers once thought the disorders resulted from muscle defects. Instead, the mutation leaves the nerves unable to respond to growth signals and reach the necessary eye muscles.
"Vision requires rapid, precise, and coordinated eye movements," Engle said, "and we continue to find that congenital eye movement disorders are a very sensitive indicator for errors in the development of motor circuitry."
People with Duane syndrome, the most common congenital complex eye movement disorder, are unable to move their eye(s) in a particular direction: "People born with this condition cannot move one or both eyes outward toward their ear," said Engle, who also holds an appointment at Harvard Medical School. "When they try to look out, the eye doesn't move. When they look in, the eyeball retracts and gets pulled back into the socket."
The team studied an inherited form of Duane syndrome identified in large families. In earlier linkage analysis studies, researchers identified a region, or locus, on chromosome 2 that held a genetic mutation unique to the affected family members. "Our project benefited from collaborations with the researchers who had previously genetically mapped the disorder and with clinicians worldwide who identified additional families with Duane syndrome," said Engle. "Additionally, neurodevelopmental biologists, including Professor Sarah Guthrie at King's College in London, modeled the genetic defect in chick embryos."
Engle's team zeroed in on the Duane syndrome gene by studying DNA extracted from blood or saliva samples provided by multiple members of different families, and that mapped to the locus identified in the genetic linkage studies. By screening genes in the linked region, Engle's group identified a unique mutation in the gene CHN1 in each of seven families. CHN1 encodes a RacGAP signaling molecule, a2-chimaerin. In mice, the mutation led to a loss of a2-chimaerin function, impairing normal upper motor neuron axon guidance.
In contrast, Engle and her colleagues found that the Duane syndrome mutations led to over-activity of a2-chimaerin in humans, but also resulted in a lower motor neuron defect. When Engle and her colleagues recreated the mutation in developing chick embryos, they saw that the developing nerve stalls out and doesn't make it to its target muscle. Engle hypothesizes that the increased activity of the a2-chimaerin protein blocks the ability of the nerve to respond to growth signals that normally target the nerve to the muscle.
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