switch causes syndromes
at the University of Virginias 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.
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
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.
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
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.
Angelman Syndrome, Wagstaff said, the converse is true. The same
small piece of chromosome 15 is missing from the chromosome inherited
from the mother. Wagstaffs lab was the first to identify
the specific gene in the maternal chromosome region that has an
error in its code.
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.
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.
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.
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.