Rett syndrome

A search to explain a baffling form of mental retardation exclusive to girls has led scientists to an unusual mechanism of genetic disease. The gene that goes awry is one that helps orchestrate the activity of many, if not all, of a person's genes.

The disease, called Rett syndrome, is the most common cause of severe retardation in women. It begins affecting girls when they are 12 to 18 months old, eroding speech and hand skills just as the children are learning them. Physicians diagnose thousands of cases each year, but the disease almost never recurs within a family. Epidemiologists, therefore, have doubted that Rett syndrome could be genetic. In a report in the October NATURE GENETICS, however, scientists pinpoint a gene as the cause.

Commenting on the find, neurologist Alan K. Percy of the University of Alabama at Birmingham says, "It's absolutely fantastic. It opens whole new avenues."

The implicated gene figures in a biological process that scientists have studied avidly but never before associated with a disease. Known as gene silencing, the process does just what its name implies. It so tightly bundles the DNA within chromosomes that gene-reading enzymes can't get to it.

Gene silencing helps orchestrate development by preventing the bundled genes from chiming in at the wrong time. Scientists propose that defects in the gene now linked to Rett disrupt this process. They would have expected such a disruption to prove fatal, and the new study suggests that indeed is the case--but just for male fetuses.

The gene, called MECP2, resides on the X chromosome. Boys have just one X, so in a male embryo, a faulty MECP2 gene would cause the genes under its control to go unsilenced in every cell.

According to Huda Y. Zoghbi of the Howard Hughes Medical Institute at Baylor College of Medicine in Houston, male embryos probably die in the womb. That would explain, she says, why boys are missing from the epidemiologists' rolls. Zoghbi codirected the recent study with Uta Francke of Stanford University.

Girls with Rett syndrome have a defective MECP2 gene on one of their two X chromosomes and a sound gene on the other. Because every cell in a girl's body consults only one X, and picks which one at random, half her cells are ruled by the healthy silencing gene and half by the faulty copy.

Scientists are still puzzling over how girls with Rett survive at all. Defects in MECP2 must not unleash genes to the extent biologists had expected, say Huntington E Willard of Case Western Reserve University in Cleveland and Brian D. Hendrich of the University of Edinburgh in a commentary accompanying the report. One possibility is that only a few MECP2-regulated genes are freed to shout out. Another is that many genes are not silenced but are only whispering instead of blaring out of turn.

A treatment for Rett is not likely to emerge until researchers learn more, Zoghbi says. Meanwhile, says Francke, parents will benefit from the ability to screen girls for MECP2 defects. It now takes 4 to 5 years to diagnose Rett. During that time, parents don't know whether other children that they conceive will be at high risk for the condition. A diagnosis of Rett rules against this possibility because 99.5 percent of cases arise spontaneously, says Francke.

The link between Rett and gene regulation suggests a pattern. In a study reported in August, scientists at U.S. and French laboratories showed a connection between Coffin-Lowry syndrome, another form of mental retardation, and chromosome changes related to silencing.

Because nerve cells must make myriad interconnections during development, scientists regard the brain as particularly vulnerable to disruptions as an organism grows. Francke predicts that future research will link other neurological disorders to defective gene silencing.

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