Scientists Identify Gene for Common Cause of Mental Retardation.

STANFORD, Calif.--(BW HealthWire)--Sept. 30, 1999--

Culminating a 14-year search, researchers at Stanford University and Baylor College of Medicine in Houston announced they have located the gene for Rett's syndrome, one of the most common causes of mental retardation among girls.

The gene, which is located on the X chromosome, produces part of a switch that shuts off production of as yet unidentified proteins, said Uta Francke, MD, professor of genetics at Stanford University School of Medicine and a Howard Hughes Medical Institute investigator. Francke and her colleagues now suspect that overproduction of some proteins might cause the nervous system deterioration that characterizes the disease. Discovery of the gene will enable scientists to unravel the steps in the disease process and could eventually lead to drugs to mitigate the damage.

Rett's syndrome affects one in every 10,000 to 15,000 girls and follows a tragic and irreversible course. The child grows and develops normally for the first six to 18 months of life, then begins to gradually deteriorate mentally and physically. As the damage to the nervous systems worsens, she loses the ability to speak, begins to have difficulty walking or crawling, and is shaken by seizures. One of the most striking symptoms is loss of conscious control of the hands, which shows up as continual, compulsive hand-wringing. Though rarely fatal, Rett's syndrome nevertheless leaves its victims permanently impaired.

Finding the genetic culprit has been particularly challenging because most cases of Rett's syndrome are sporadic instead of inherited, Francke said. That is, most patients do not have an affected parent. With this paper, the scientists confirmed that these cases result from mutations, or genetic errors, that arise in one of the parent's reproductive cells and are transmitted to the children.

For several years, Francke's group at Stanford raced with a team from Baylor College of Medicine to locate the gene. But about five years ago, the two groups decided to collaborate on the laborious work of first identifying the region of the X chromosome that contains the Rett's gene, then winnowing the gene from among 200 possible candidates. Pinpointing the gene required searching for mutations in the DNA from people with the disease.

As Francke and five other scientists report in the October issue of Nature Genetics, the gene instructs cells throughout the body to make a protein known as methyl-CpG-binding protein 2 -- MeCP2 for short. MeCP2 is a regulatory protein that controls the activity of several other genes, its target genes. Inside cells, the head of the protein attaches directly to the control region of the DNA of a target gene. The protein's tail fastens to a large complex of proteins that compact the target gene and keep it silent. Rhett's syndrome is the first disease shown to result from defects in a protein that silences other genes, Francke said.

Diagnosing the disorder before the child is four or five years old is often very difficult, Francke said. One of the first payoffs from this discovery will be a genetic test to improve the accuracy of early diagnosis. If combined with an effective therapy, the test might allow doctors to ameliorate or forestall the drastic consequences of the disease.

Because of differences in the sex chromosomes, girls can survive with Rett's syndrome, while affected males die before or shortly after birth, Francke explained. Females have two X chromosomes, but only one is active in any particular cell. That means that only about half of the cells in a girl's nervous system will actually be using the defective gene. But males have a single X chromosome, so all of their cells are obliged to use the faulty version of the gene, a situation that presumably results in fatal defects.

The other Stanford coauthor on the paper is Mimi Wan, MD, PhD, a postdoctoral fellow in Francke's lab. The remainder of the team is from Baylor College of Medicine in Houston: Huda Y. Zoghbi, MD, HHMI investigator and professor of pediatrics and molecular and human genetics; Ignatia B. Van den Veyver, MD, assistant professor of obstetrics and gynecology; Ruthie E. Amir, MD, postdoctoral fellow; and Charles Q. Tran, research technician.

Funding for the work came from the Howard Hughes Medical Institute, the National Institutes of Health, the International Rett Syndrome Association, the Society for Gynecologic Investigation and the L.M. Chandler Research Fund.