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Baylor researchers
discover defective gene that causes HOUSTON-The cause of Rett syndrome, one of the most common forms of mental retardation in females, has been traced to a defective gene on the X chromosome. The gene, called MECP2 ("meck-p-two"), plays a significant role in "silencing", or turning off, other genes. Rett syndrome is the first human disease found to be caused by mutations in this type of gene. A research team led by Dr. Huda Y. Zoghbi, a Howard Hughes Medical Institute (HHMI) Investigator at Baylor College of Medicine in Houston, reports this discovery in the October issue of the scientific journal Nature Genetics. They collaborated with Dr. Uta Francke, an HHMI invest Investigator at Stanford University School of Medicine. "Finding the genetic cause of Rett syndrome has been the most challenging problem I've worked on", said Zoghbi, who made the first confirmed diagnosis of Rett syndrome in the United States in 1983 at Texas Children's Hospital with Dr. Alan Percy. "Usually we can map the location of a disease gene by studying the way the genetic defect is inherited in families," she said. "But Rett syndrome occurs sporadically more than 99% of the time, so we had very few families to study where more than one member is affected with this neurological disorder." When Zoghbi began the search for the Rett syndrome gene 16 years ago, information from two families in which half sisters developed Rett syndrome helped her zero-in on the X chromosome. "Because the girls had different fathers, we suspected that the disease gene was being transmitted from their mother," Zoghbi said. She began hunting for the disease gene on the long arm of the X chromosome, which contains 2,000 to 3,000 genes. Finding more families with Rett syndrome enabled the researchers to narrow their focus to 1,000 candidate genes. A family in Brazil in which several girls had Rett helped researchers confine the hunt to 200 genes. The Zoghbi group analyzed more than a dozen before finding the culprit, MECP2. The discovery that the Rett syndrome gene is on the X chromosome is interesting, Zoghbi said. Most other forms of X-linked mental retardation, such as Fragile X syndrome, affect males. Unlike females, who have two X chromosomes, males have an X and a Y chromosome. Because males lack a "backup" copy of the X chromosome that can compensate for a defective one, mutations in MECP2 are lethal to the male fetus. That's why Rett syndrome is found in females only. "This gene is essential for life, not just for brain development," said Zoghbi. a professor of pediatrics, molecular and human genetics, neurology and neuroscience at Baylor and a pediatrician at Texas Children's Hospital and Ben Taub General Hospital. Girls with a mutated MECP2 on one X chromosome are able to survive if they have a normal MECP2 gene active in some cells and the defective copy active in other cells. The defective MECP2 leads to development of Rett syndrome, and the severity of the disorder depends on the percentage of defective MECP2 genes that are active. Researchers have known that MECP2 is critical for the regulation of many genes. Certain genes need to be activated at critical times during development and inactivated at others. MECP2 is supposed to help turn off the expression of a number of genes. But in Rett patients, genes remain active at inappropriate times, they could affect the function of nerve cells and alter normal development. Zoghbi is hopeful that knowing the genetic cause of Rett syndrome might make it possible to treat or prevent the disorder. "Because brain development continues long after birth, and symptoms of Rett syndrome do not develop for several months, there appears to be a window of opportunity during infancy in which we might be able to intervene to prevent further damage," Zoghbi said. "Now that we know the problem gene, we can explore the possibility of developing treatments that could be given in early infancy before symptoms appear." The National Institute for Child Health and Human Development and the International Rett syndrome Association funded Zoghbi's research. the Blue Bird Circle Rett Center of Baylor College of Medicine directed by Dr. Daniel G. Glaze, provided a number of patients for the study. Baylor researchers who co-authored the Nature Genetics paper with Zoghbi are Dr. Ruthie Amir, Dr. Ignatia Van den Veyver and Charles Tran. Registration in the Baylor College of Medicine Media Center provides access to Zoghbi's photo and more information about Rett syndrome. Rett Syndrome Rett syndrome is a neurodevelopmental disorder affecting one in 10,000 females. The disorder is named for Dr. Andreas Rett, the Austrian physician who identified the syndrome in 1966. Symptoms Girls with Rett syndrome appear to develop normally until six to 18 months of age. They then enter a period of regression, losing acquired speech and hand skills, and develop seizures, repetitive hand-wringing or hand -washing movements, irregular breathing and motor control problems. The girls can live to adulthood, but most never regain the ability to use their hands or speak. Cause A defect in the MECP2 gene on the X chromosome, as discovered by Dr. Huda Y. Zoghbi and colleagues of the Howard Hughes Medical Institute at Houston's Baylor College of Medicine. Current Treatment Physical, occupational and
speech therapy to improve motor skills, medication to control seizures,
and special diets to maintain adequate weight and meet nutritional needs.
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