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| Vol. 21, No. 19 |
| October 15, 1999 |
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Baylor Researchers Uncover Genetic Cause of Rett Syndrome by KRISTINA VAN ARSDEL Texas Medical Center News
When functioning properly, the gene known as MECP2 (pronounced meck-p-two), encodes a protein that signals other genes to "turn off" at certain times. Dr. Huda Y. Zoghbi, the Howard Hughes Medical Institute (HHMI) investigator at Baylor who led the team in its discovery, likens the role of MECP2 to that of a symphony conductor signaling instruments. If the conductor falls asleep, there is chaos. Likewise, if the MECP2 gene fails to do its job in silencing other genes, those genes may get expressed at the wrong times. This is suspected to be the case with Rett syndrome, one of the most common causes of mental retardation in females. The team, which included Baylor researchers and HHMI investigator Dr. Uta Francke of Stanford University School of Medicine, discuss their findings in the October issue of Nature Genetics. The discovery is the first instance in which a human disease has been linked to mutations in this type of gene. "Girls with Rett appear to develop normally during the first few months," said Dr. Zoghbi at a press conference to announce these findings. "Then between 6 and 18 months of age, they hit a developmental wall." It is during this period of developmental regression that girls with Rett syndrome lose acquired speech and hand skills, develop seizures, repetitive hand-wringing or hand-washing movements, irregular breathing and motor-control problems. Girls with Rett syndrome can live into adulthood, but most never regain their speech or hand movement. A defective MECP2 gene is lethal for males because they lack a back-up copy of the X chromosome. Females have two X chromosomes (males have an X and a Y), and therefore, can survive with one defective MECP2 gene and one normal MECP2 on the other chromosome. Because the X chromosomes are activated randomly, some cells may contain the mutated version of the gene while others have a normal copy. The percentage of cells containing the mutated version determines the severity of the disease. "The fact that it [Rett syndrome] is seen only in girls provided a first clue as to which chromosome carried the gene," said Dr. Zoghbi. Rett syndrome occurs sporadically 99 percent of the time, making it challenging to find families where more than one member has the disorder. Information from two families in which half-sisters developed Rett syndrome aided Dr. Zoghbi in her initial research. "Because the girls had different fathers, we suspected that the disease gene was being transmitted from their mother," Dr. Zoghbi said.
Research conducted with other families narrowed the list to 1,000 possible genes. Dr. Zoghbi's group then relied on a family in Brazil in which several girls had Rett to decrease that group to 200 possible genetic suspects responsible for the disorder's cause. "Having this gene in hand will allow us to confirm diagnoses earlier and determine the full clinical spectrum of this disorder," said Dr. 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. "We're excited about the fact that this discovery gives hope for our patients and a tool for understanding brain development. This, in turn, may provide insight into other diseases and ultimately help us unravel the most complex system in the human body." It is thought that other diseases with childhood onset after the period of normal development, such as autism, may be caused by similar defects in this pathway. The team plans to create an animal model to study possible treatments. Currently, the treatment for Rett syndrome consists of therapy and medication to alleviate the symptoms. Dr. Zoghbi's quest for the genetic cause of Rett syndrome began 16 years ago when she saw her first patient with Rett syndrome, Ashley Fry. Kathy Hunter, president of the International Rett Syndrome Association and mother of a daughter with Rett syndrome, praised the team for their efforts. "I am the happiest person in this room," she said at the press conference. "It is the fulfillment of my life's dream to be in a room like this." The research was funded by the National Institute for Child Health and Human Development and the International Rett Syndrome Association.
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