The research team, funded by the National Institute of Child Health and Human Development (NICHD), published its results in the October 1999 Nature Genetics.
"Rett syndrome affects girls," said Huda Zoghbi, M.D., the study's senior author. "At about 6 to 18 months of age, otherwise normal children gradually stop responding to and interacting with their parents." Eventually, the girls lose the ability to speak, walk, and purposefully use their hands. Children with Rett syndrome develop repetitive hand motions, such as hand wringing or hand "washing." They may also develop breathing abnormalities and experience sudden, unexpected heart attacks.
"Rett syndrome has long frustrated researchers and clinicians because of its unusual pattern of inheritance," said NICHD Director Duane Alexander, M.D. "The discovery of Dr. Zoghbi and her coworkers is a definite turning point, which we hope will soon lead to better diagnosis, and, ultimately, treatment, for this disorder."
Rett syndrome affects roughly 1 in every 10,000 females, Dr. Zoghbi said. Except for a few rare families in which more than one child is affected, the disorder occurs spontaneously.
Dr. Zoghbi and her coworkers located the gene for Rett syndrome on a region of the X chromosome, one of the two sex-determining chromosomes found in human cells.
Briefly, females receive an X chromosome from each parent; males receive an X chromosome from their mothers and a Y chromosome from their fathers. Because each cell needs only one functioning X chromosome, roughly half the X chromosomes in genetically normal females are permanently switched off. The X chromosomes are shut down in an apparently random pattern. In about half the cells in a female body, the X chromosome inherited from the father is switched off, in the other half, the X chromosome from the mother is switched off.
Like other females, girls and women with Rett syndrome have two X chromosomes. For this reason, they have some normally functioning copies of the gene, and so their symptoms do not develop until about 6 to 18 months of age.
Specifically, the genetic abnormality responsible for Rett syndrome interferes with the operation of one of the many biochemical switches that regulate how genes are expressed. The researchers found that the disorder results from the mutation of the gene that makes methyl cytosine binding protein 2 (MECP2). MECP2 is the lynchpin in one of the elaborate networks of proteins needed to switch off a group of genes. In the absence of this genetic switch, certain genes fail to shut down, and excessive amounts of otherwise beneficial proteins are made. The cells that have an active X chromosome confer some protection against excessive amounts of the proteins, and so infants with Rett syndrome do not develop any ill effects for a time. The molecular events leading to their decline in the second year of life can be explained by the over expression of certain genes that govern the development of the nervous system. (An accompanying article in the same issue of Nature Genetics discusses possible ways in which this over expression could lead to severe damage to the brain and nervous system.)
The discovery also sheds light on why only females are affected by the syndrome: because they have only one X chromosome, males with Rett syndrome possess only the mutant version of MECP2. Presumably, because they do not have a "backup" copy of the gene, males with Rett syndrome die before birth.
Dr. Zoghbi explained that MECP2 functions on the molecular level by binding to methylated cytosine molecules in the DNA. (Cytosine is one of the fundamental molecules that make up DNA and sometimes binds to molecules known as methyl groups.) After MECP2 binds to methylated cytosine, it links with other molecules in an elaborate network that silences a set of genes.
Dr. Zoghbi said that she and her coworkers intend to pursue a strategy to find other genetic switches that, in the absence of properly functioning MECP2, can serve to switch off the necessary genes.
Noting the potential of the discovery, NICHD Director Dr. Alexander said that the Institute would immediately seek grant applications to conduct studies of how to manipulate the gene to slow, reverse, or even prevent, the progression of the disease. Basic information on Rett Syndrome is also available on the website of the National Institute of Neurological Disorders and Stroke at www.ninds.nih.gov/patients/Disorder/rett/rett.htm/.
The NICHD is one of the Institutes comprising the National Institutes of Health, the Federal government's premier biomedical research agency. NICHD supports and conducts research on the reproductive, neurobiological, developmental, and behavioral processes that determine and maintain the health of children, adults, families, and populations. The NICHD website, www.nichd.nih.gov, contains additional information about the Institute and its mission.