University of Virginia Health System

U.VA. RESEARCHERS TRACE TWO CHILDHOOD DISEASES TO SPECIFIC GENETIC ON-OFF SWITCH

Researchers at the University of Virginia Health System are getting closer to finding out what causes two disabling childhood diseases. They identified a naturally occurring on-off switching process that may control activation of genes causing Prader-Willi and Angelman syndromes, according to results published on-line today in the American Journal of Human Genetics.

Most gene mutations have the same effect regardless of whether they are inherited from the mother or the father, said Dr. Joseph Wagstaff, the study's principal investigator and associate professor, Departments of 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.

The deficiencies that cause each disease are mirror images of each other, Wagstaff said. In Prader-Willi Syndrome, a tiny piece of DNA is missing from the copy of chromosome 15 that a child has inherited from her father. This results in very low muscle tone at birth, later food obsession and obesity, reduced sexual development and mild to moderate developmental delays.

Prader-Willi Syndrome is estimated to occur in between one in every 12,000 to 15,000 people and is the most common genetic cause of obesity, according to the Prader-Willi Syndrome Association.

In Angelman Syndrome, Wagstaff said, the converse is true. Most people with this disease are missing the same small piece of chromosome 15 that is missing in Prader-Willi Syndrome -- but in Angelman Syndrome, it is missing from the chromosome inherited from the mother. Five to 10 percent have inherited the chromosome region from each parent -- however, on the maternal one a specific gene, UBE3A, which Wagstaff's lab was the first to identify in a previous study, has an error in its genetic 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.

Wagstaff said that, in normal individuals, the piece of chromosome 15 inherited from the mother functions differently from the piece inherited from the father, even though the two copies have the same DNA sequence. For some genes in the region, 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.

When the chemical group methyl is attached to proteins called histones, it plays a role in those genes' activation or nonactivation, according to the results of Wagstaff's newly published study.

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. Our study indicates that the Prader-Willi imprinting center becomes associated with histone attached to a methyl group. We believe that this histone methylation takes place in a specific place on maternal chromosome 15 in the ovary of the mother, and serves to identify the maternal chromosome as different from the paternal chromosome.

U.Va. researchers Wagstaff and 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.

Wagstaff believes that understanding how histone methylation of the Prader-Willi imprinting center occurs may lead to therapies designed to activate genes on chromosomes where they are usually switched off.

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.

October 4, 2001