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Losing sleep

A new study may reveal a genetic reason for why people with Fragile X syndrome and autism have trouble sleeping.

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11:36am, June 26, 2008
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If you’ve got rhythm, thank a pair of RNA-binding proteins. A new study in mice shows that the way these proteins function is crucial for synchronizing the biological clocks throughout a person’s body.

The study aimed to understand the source of a symptom in people with Fragile X syndrome, the most common inherited form of mental retardation and the most common known cause of autism. The syndrome is caused by a defect in a gene called fragile X mental retardation 1 or FMR1. People with the syndrome often have unusual sleeping patterns.

Parents often report that it takes two to four years for children with Fragile X syndrome to begin sleeping through the night. Typically developing children usually adopt normal sleep patterns by the time they are six to eight months old.

Many neurological disorders are accompanied by sleep difficulties, says Yung-Hui Fu of the University of California, San Francisco, but the reason for those sleeping problems is often unknown.

An international team of scientists led by David Nelson, a human geneticist at Baylor College of Medicine in Houston, Texas, set out to investigate why. The study appears in the July American Journal of Human Genetics and is the first to suggest a mechanism for the sleep disruptions that accompany Fragile X syndrome.

For eight years, Nelson has been studying FMR1 and two related genes, called FXR1 and FXR2. All three of the genes encode proteins that bind to RNA and help regulate the process that builds proteins from RNA templates.

Previous research had shown that fruit flies that lack the Drosophila FMR1 gene have disrupted circadian rhythms when kept in darkness, but can still reset their biological clocks when exposed to light.

So Nelson and his colleagues tested mice that lack FMR1, FXR2 or both genes to see if their biological clocks are also thrown off. When normal mice are kept in complete darkness, they fall into sleeping-waking patterns slightly shorter than 24 hours. Mice lacking either FMR1 or FXR2 have yet shorter circadian rhythms when kept in the dark, but the difference is subtle, Nelson says. The mice have no trouble resetting their circadian clocks when the lights are turned on.

But mice lacking both genes gave the researchers a big shock — the mice have no circadian rhythm at all in either dark or light. The mice sleep and wake at random times.

“There are no known mutations in the mouse that do this,” Nelson says. Even disruptions of the genes that make up the circadian clock’s gears don’t cause such dramatic disruption of biological rhythms.

When one of Nelson’s collaborators examined the main biological clock in the brains of the mice lacking both genes, the researchers discovered that that clock cycles normally. But circadian clocks in the liver don’t follow the rhythm of the master clock in the brain.

Fragile X protein and its cousin are necessary for synchronizing biological clocks found in every cell in the body, the study suggests.

It also suggests yet another layer of regulation that keeps circadian clocks ticking in unison, Fu says. Scientists have documented the control mechanisms that govern when and how much RNA is produced from the clock genes and described modifications that can affect the function of clock proteins. But researchers have generally ignored the step that controls production of clock proteins, known as translational regulation. The new study may prompt more researchers to explore how protein production affects biological rhythms, she says.

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