Gene That Causes Common Form of Retardation Found : Science: Discovery offers for the first time the ability to conduct prenatal screening for fragile X syndrome.
U.S. and Dutch researchers have discovered the defective gene that causes fragile X syndrome, the most common form of inherited mental retardation.
The report of the discovery, which will be published Friday in the journal Cell, is exciting to researchers because it offers for the first time the ability to perform prenatal screening for the disorder, and may eventually lead to the discovery of new ways to treat it. The syndrome affects one in every 1,250 males and one in every 2,000 females.
Perhaps even more important, this is the first time scientists have discovered a gene thought to play a direct role in intelligence. Moreover, the protein for which it serves as a blueprint “is completely unlike any protein ever seen before” and may provide valuable insight into the functioning of the brain, according to geneticist Stephen T. Warren of Emory University in Atlanta.
Biologist Charles D. Laird of the University of Washington Health Sciences Center called the work an important step in understanding the disease: “We desperately need to know everything we can. We need to know all the molecular details.”
The identification of the gene caps two years of intense research in which molecular biologists have homed in on the precise location of the gene, which lies on the X chromosome, one of the two sex chromosomes in humans.
That portion of the X chromosome is particularly susceptible to damage during reproduction, and the presence of the syndrome is often indicated by an abnormal appearance of the X chromosome. The damage produces symptoms ranging from subtle learning disabilities to behavior problems such as hyperactivity, violent outbursts and hand biting to severe mental retardation. Males with the disorder are usually infertile; there is no effective therapy for the syndrome.
Fragile X syndrome is a most peculiar genetic disorder. In all other genetic disorders linked to the X chromosome, all males with the defective gene develop the disease and females rarely, if ever, do.
In fragile X, about 20% of males with the genetic defect never develop symptoms of the disorder, even though their X chromosome is visibly damaged. About one-third of the females who carry the genetic defect develop them, although with lesser severity than males. About half of the females who carry the defective gene, including many who are otherwise normal, have subtle learning disabilities, such as problems in learning arithmetic.
Warren and his colleagues at Emory, Baylor College of Medicine in Houston and two institutions in the Netherlands were able to identify the gene, which they called FMR-1, and clone it--make multiple copies for further research.
Although they have not completely determined the structure of the gene, what they have learned enables them to predict part of the structure of the protein for which it is the blueprint. The gene and the protein have so far proved to be very unusual.
The key feature of the FMR-1 gene, Warren said, is a long fragment in which a sequence of three nucleic acids--the building blocks of genes--is repeated 27 times. Such a repetition has never been observed in a gene before, although it is common in the segments of chromosomes interspersed between genes.
Molecular biologists know that such repeated sequences outside genes are very unstable. When they are copied by cellular machinery during reproduction, mistakes are frequently made, most often by increasing the number of times the sequence is repeated.
The presence of such a repetitive sequence within a gene would thus explain its fragility: mistakes would often be made in copying it during the production of eggs or sperm. In fact, the researchers have shown that in fragile X patients they have examined, this sequence may be repeated as many as 2,000 times.
The affected protein is also unusual, both in its healthy and defective forms, Warren said. A search of the structures of known proteins revealed none other with similar structures, he said.
Researchers are particularly anxious to learn the function of this protein in healthy people. Because defects in the protein produce retardation, he added, “it is clearly involved in cognitive functions” or thought processes.
The possibility that the normal protein is involved in brain function is bolstered by the finding that it is produced not only in the brain of humans, but also in the brain of every other type of animal researchers have looked at, Warren noted. Because it is universally present, it must be important, he suggested.
Once the researchers have finished determining the structure of the protein, he concluded, they will look to see where the protein is normally found in brain cells and what it does there. That discovery should throw light on how the brain works. It may also allow them to devise drugs that could mimic the protein’s function and thereby alleviate the symptoms of the disorder.
