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X marks the spot. A karyotype of an individual with fragile x syndrome.

Leonard Lessin/Peter Arnold Inc.

Mammoth Study Finds New Genes for Mental Retardation

An intense scouring of the X chromosome has turned up nine new genes tied to X-linked mental retardation, a group of conditions marked by severe cognitive impairment. The study also surprisingly indicates that more than 1% of the estimated 800 genes on the X chromosome have no function in the body. "[The work] sets the stage for the next frontier in human and medical genetics," says Han Brunner, an expert in congenital conditions at the University of Nijmegen in the Netherlands who was not involved in the research.

Mental retardation afflicts 2% to 3% of the general population, and researchers have linked a small proportion of these cases to a faulty X chromosome. In addition to cognitive problems, patients with X-linked mental retardation (XLMR)--which includes fragile x syndrome (ScienceNOW, 24 May 2007)--may also suffer from epilepsy, macrocephaly (an enlarged head), and reproductive defects. XLMR is far more common in boys, as they only inherit one X chromosome and thus don't have the backup copy that girls do.

Traditional genetic methods, such as looking at family trees and sequencing individual genes, have linked defects in 80 genes on the X chromosome to XLMR, but the discovery rate has slowed, suggesting that those techniques have reached their limit. So, in the current study, 18 research teams from the United States, the United Kingdom, Australia, France, and Germany turned to a new computer program called AutoCSA, which ramps up the amount of DNA that can be sequenced at one time. The researchers sequenced 720 out of about 800 genes on the X chromosome, comparing 208 individuals with XLMR with unaffected family members. In all, the effort took 6 years and would have been "unthinkable" using traditional methods, says Patrick Tarpey, a molecular geneticist at the Sanger Institute in Cambridge, U.K., who was part of the collaboration.

Reporting online this week in Nature Genetics, the team says it uncovered nine genes, each of which, when nonfunctional, causes XLMR. "Many of the genes we found were not obvious candidates for the disease," notes Tarpey. Most had not previously been linked to learning or brain functions but instead controlled basic body biochemistry. The gene UPF3B, for example, helps cells rid themselves of abnormal proteins.

The researchers also found that perhaps as many as 19 genes on the X chromosome have no obvious role at all. All of these genes were mutated to the point of nonfunctionality in many of the seemingly healthy family members used as controls. That's a "remarkable" number, says Christopher Walsh, a Harvard University brain development disorders specialist, who was not affiliated with the study.

Tarpey says that the methodology used to identify the new XLMR genes could be applied to other diseases. And although he cautions that scientists are still "far from a cure" for XLMR, he says the newly identified genes may help stem its incidence. Couples could use prenatal testing to look for problematic genes on the X chromosome, for example. Still, all 89 genes now linked to XLMR account for just 25% of cases in the study, notes Helen Firth, a learning disabilities genetics expert at Addenbrooke's hospital in Cambridge, U.K. So screening for those genes alone won't prevent all cases of XLMR.