Study Points to Treatment for Fragile X Syndrome

UNIVERSITY OF UTAH MEDIA RELEASE

Embargoed by the journal Cell for release at 10 a.m. MST Thursday Nov. 29, 2001

Contacts:-- Kendal Broadie, assistant professor of biology -- office (801) 585-9426, lab (801) 585-9425, home (801) 359-1590, [email protected]-- Lee Siegel, science news specialist, University of Utah -- office (801) 581-8993, cell (801) 244-5399, [email protected]

STUDY POINTS TO TREATMENT FOR FRAGILE X SYNDROMEUtah Biologists Pinpoint Defects in Common Form of Mental Retardation

Nov. 29, 2001 -- A new study by Utah and California biologists appears to overturn the long-held belief that fragile X syndrome is too complex to be treated effectively in the foreseeable future. The findings raise hope that existing drugs might be used within a few years to treat the most common inherited form of mental retardation.

The discovery, published in the Nov. 30 issue of the journal Cell, indicates the disease's cause is much simpler than previously believed, resulting from nerve defects caused by the interaction of only two genes.

Biologists Kendal Broadie at the University of Utah and Gerald M. Rubin at the University of California, Berkeley, led the research.

The study involved the fruit fly version of the human fragile X gene. When the fruit fly and human genes are mutated, each fails to produce a protein, resulting in strikingly similar symptoms in both flies and in humans with fragile X syndrome.

The researchers showed how the absence of the fragile X protein in fruit flies causes over-activity of a second gene, resulting in excessive growth of tube-like support structures named "microtubules" at the ends of nerve cells. There, at places called synapses, nerve signals are transmitted from one nerve cell to another.

The excessive growth of microtubules made nerve-signal transmission go haywire in the flies. That suggests an almost identical process makes nerve-signal transmission malfunction in humans to cause fragile X syndrome.

The scientists cured the flies by using genetic manipulation to eliminate the excessive growth of microtubules. Because excessive microtubules can be broken down with medications such as colchicine -- a drug now used to combat certain cancers -- the discovery in fruit flies points directly to the possibility of using colchicine or similar drugs to treat mental retardation and other fragile X symptoms in people.

"Something like colchicine at very low doses -- much lower than you would give to a cancer patient -- might serve to counteract the effects of fragile X disease," said Broadie, chief author of the study and an assistant professor of biology at the University of Utah.

Treatment "could be just a few years away," he said. "It depends entirely on the side effects of drug treatments and the dosage of the drug required to counteract the brain defects."

Treatment with colchicine could cause side effects because microtubules, in normal amounts, are essential to help cells maintain their structure and divide.

But "in fragile X, the mental retardation is so severe [with an IQ averaging 35, or 65 points below normal], you might be willing to put up with some side effects," Broadie said.

The new study was conducted in Broadie's Utah lab and in Rubin's lab at Berkeley. Postdoctoral researchers Yong Zhang at Utah and Adina Bailey at Berkeley conducted much of the work. Other coauthors were University of Utah postdoctoral biologist Heinrich Matthies and graduate students Robert Renden, Mark A. Smith and Sean Speese.

Fragile X syndrome -- which was identified and named in 1991 -- afflicts one of every 2,000 male newborns and one in every 4,000 female newborns in the United States, with an estimated 100,000 affected Americans. Severity of symptoms can vary. It is the most common inherited form of mental retardation. Down syndrome is more common, but is not inherited.

Other symptoms include elongated ears, a prominent chin, unusually flexible fingers and loose joints, visual problems, flat feet, speech and emotional delays, occasional heart valve abnormalities and, in boys, enlarged testicles at puberty. Fragile X patients also often suffer anxiety, attention deficit and hyperactivity, shyness, impaired social skills, hypersensitivity to sensory stimulation, over-reaction to changes and behavior resembling autism, including hand-flapping, avoidance of eye contact, and hand-biting.

While some symptoms can be treated by drugs and speech, occupational and physical therapy, there has been no treatment for the syndrome, which is detected through a blood test.

The genetic mutation that causes fragile X syndrome occurs in the X chromosome. Every female has two X chromosomes. Every male has one X chromosome and one Y chromosome. Fragile X syndrome is so named because the long arm of the X-shaped X chromosome looks like it may break off. This is due to extra genetic material -- a stuttering-like repeat of a sequence of nucleic acids within the chromosome's long arm.

Boys with the mutant fragile X chromosome always have symptoms -- ranging from mild to severe retardation -- because they have only one X chromosome. Girls have two X chromosomes, so the normal X chromosome often compensates when the other one is mutated. Thus, about one-third of fragile X girls suffer mental retardation, another 20 percent have less severe learning problems, and other have no symptoms.

One in 260 women carries the fragile X chromosome and has a 50-50 chance of passing the defect to her children, male or female. About one in 800 men carries the defect, but can pass it only to daughters, not to sons.

DETAILS OF THE STUDY:

Scientists already knew a human gene named FMR1 carries the code that makes human cells produce a protein named FMRP. In people with fragile X syndrome, the FMR1 gene is mutant, resulting in either reduced amounts or an absence of the FMRP protein.

In the new study, Broadie and colleagues showed a gene named dfxr is the fruit fly equivalent of the human fragile X gene FMR1. Then they "knocked out" or disabled the dfxr gene in fruit flies, resulting in abnormalities in the synapses where nerve signals are transmitted. Because of the abnormalities, the fruit flies suffered impaired vision as well as uncoordinated movements that made them fly poorly.

Broadie noted that people with fragile X syndrome also have visual problems and trouble coordinating complex behaviors such as movement and learning.

In a series of experiments, Broadie and the other researchers showed exactly why the nerve transmission abnormalities and resulting problems developed in flies. They found that when the fruit fly fragile X gene dfxr was disabled, there was a resulting increase in activity of another gene that produces a protein named "futsch." The overproduction of futsch led to excessive growth of microtubules at the synapses, impairing the structure of the synapses and their ability to transmit nerve signals.

To confirm the finding, Broadie and colleagues created "double knock-out" fruit flies in which both the dfxr gene and the futsch gene were disabled. While the disabled dfxr gene led to abnormalities in the flies, disabling the futsch gene prevented excessive growth of microtubules and reversed the abnormalities. The double-knockout flies showed perfectly normal behavior -- and normal synapse structure and nerve-signal transmission.

The equivalent of the fruit fly futsch gene in humans in named MAP1B, which helps form microtubules in people. So Broadie and colleagues concluded that in people, a crippled FMR1 gene causes over-activity of the MAP1B gene and protein, resulting in excessive growth of microtubules, nerve synapse abnormalities and symptoms of fragile X syndrome -- just as a crippled dfxr gene in fruit flies led to futsch over-activity, excessive microtubule growth, nerve signal abnormalities and fly symptoms analogous to fragile X syndrome.

Broadie said the human FMR1 and fruit fly dfxr genes each regulate formation of hundreds of proteins. The new study's big surprise is that dfxr's influence on only one protein -- futsch -- causes the fruit fly equivalent of fragile X syndrome. That implies the disease also has a similar simple cause in humans: the interaction of the FMR1 and MAP1B genes.

The new study is the second major fragile X paper published recently in Cell. The Nov. 16 issue carried an Emory University/Rockefeller University study showing the human fragile X protein, FMRP, normally interacts with a variety of proteins in human brain cells.

Broadie said that even though his study was in fruit flies, it goes well beyond the other study by showing the specific interaction between the dfxr gene and futsch protein in fruit flies, thus implying human fragile X results solely from FMR1's interaction with MAP1B.

Kendal Broadie's web site is at:http://synapse.biology.utah.edu

The FRAXA Research Foundation web site is at:http://www.fraxa.org

University of Utah Public Relations201 S Presidents Circle, Room 308Salt Lake City, Utah 84112-9017801) 581-6773 fax: 585-3350

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