Genetic switch causes syndromes

By Catherine Wolz

Researchers at the University of Virginia’s Health System are getting closer to finding out what causes two disabling childhood diseases, by identifying a naturally occurring on-off switching process that may control activation of genes that are missing pieces, according to results published online this month in the American Journal of Human Genetics.

The deficiencies — mirror images of each other — cause Prader-Willi Syndrome, the most common genetic cause of obesity, and Angelman Syndrome, which has different symptoms, including severe mental retardation.

“Most gene mutations have the same effect regardless of whether they are inherited from the mother or the father,” said Dr. Joseph Wagstaff, the lead researcher and associate professor of two departments, pediatrics, and biochemistry and molecular genetics. “However, in these two disorders, genes on the maternal and paternal copies of chromosomes function differently. So the same genetic change has very different effects, depending on whether you inherit it from your mother or your father.”

For some genes, only the paternal copy is active; if this copy is missing, Prader-Willi Syndrome results. For other genes, only the maternal copy is active, and loss of this copy causes Angelman Syndrome.

In Prader-Willi Syndrome, a piece of DNA missing from the copy of chromosome 15 that a child inherits from his or her father results in very low muscle tone at birth, later food obsession and obesity, reduced sexual development and mild to moderate developmental delays. This is estimated to occur in between one in every 12,000 to 15,000 people, according to the Prader-Willi Syndrome Association.

In Angelman Syndrome, Wagstaff said, the converse is true. The same small piece of chromosome 15 is missing from the chromosome inherited from the mother. Wagstaff’s lab was the first to identify the specific gene in the maternal chromosome region that has an error in its code.

Children with Angelman Syndrome have different symptoms, including severe mental retardation, seizures, no speech but almost constant laughter, unusual walking patterns and sleeplessness. The disease is estimated to affect about the same number of children as Prader-Willi Syndrome, one in 12,000 to 15,000.

“Two small pieces of DNA, which we call imprinting centers for Prader-Willi or Angelman syndromes, control how the genes around them are turned on or turned off,” he said. Understanding this process, Wagstaff believes, may lead to therapies to activate the genes.

Wagstaff and U.Va. researcher Zhenghan Xin conducted the study in collaboration with C. David Allis, Harry Flood Byrd Professor of Biochemistry and Molecular Genetics at U.Va., who has pioneered the field of histone modification and gene control.

Most cases of Prader-Willi and Angelman syndromes are not diagnosed prenatally, Wagstaff said, because chromosome changes are too miniscule to detect through standard tests. However, if the diseases are accurately diagnosed by pediatric specialists, some symptoms — such as the seizures and sleep disturbances that occur in Angelman Syndrome — can be effectively treated, he said.