PA) -While type 1 Neurofibromatosis (NF1) is primarily
known to cause tumors of the nervous system, scientists
were puzzled as to why patients with NF1 are also prone
to cardiovascular problems such as hypertension and
congenital heart disease. Researchers from the University
of Pennsylvania School of Medicine have solved this
particular part of the puzzle by showing how the Nf1
gene - which is mutated in those suffering from Neurofibromatosis
- is also essential in endothelial cells, the cells
that make up blood vessels.
Type 1 Neurofibromatosis affects many children, occurring
in one in every 4,000 births. The researchers believe
their findings may result in new therapeutics for NF1,
as well as provide validation of an animal model for
the disease. Their findings will appear online today
in advance of publication in the January issue of the
journal Nature Genetics.
"We've known NF1 as primarily a problem among cells
of the developing neural crest - the part of the embryo
that forms the peripheral nervous system," said
Jonathan A. Epstein, MD, associate professor
in the Cardiovascular Division of Penn's Department
of Medicine. "NF1, however, is associated with
cardiovascular problems, which our findings could explain
by linking the loss of the Nf1 gene to abnormal
function of endothelial cells."
In both endothelial and neural crest cells, the Nf1
gene encodes neurofibromin, a protein that suppresses
the ras oncogene, thereby suppressing tumors. In endothelial
cells, the authors showed that the ras oncogene also
over-activates a protein, called NFATc1, which is related
to heart valve development. Using tissue-specific gene
activation, the researchers found that deactivating
the Nf1 gene in the neural crest causes tumors,
but not cardiac problems. Conversely, Nf1 function
in the neural crest is not required for normal heart
"Our work shows that the Nf1 gene blocks
the ras oncogene for different purposes in the
different cell types," said Epstein. "In endothelial
cells, we see a possibility to mitigate some of the
harm done by the loss of Nf1 by blocking the
excessive amounts of NFATc1 protein."
The endothelial cell connection also explains why some
of the previous attempts to create a mouse model for
NF1 - thought to be a crucial step in understanding
and treating Neurofibromatosis - have failed. In mice
bred to lack the Nf1 gene, the neurofibromin
deficiency had a much stronger effect on cardiac cells
than it does in humans, causing cardiac abnormalities
so severe that they did not survive to birth. Epstein
and his colleagues managed to work around this problem
by breeding mice that mimic the loss of Nf1 in
the neural crest cells only. These mice survived to
birth and had tumors.
"The more we learn about the mechanisms behind
type 1 Neurofibromatosis, the better our options for
treating the disease," said Epstein. "Creating
animal models of the human disease will allow us to
test therapies more quickly, and understanding how the
gene works provides opportunities for therapies that
will need to be tested."
Support for this research was provided by grants from
the WW Smith Foundation, the American Heart Association,
and the National Institutes of Health.
# # #
Editor's Note: Subscribers to Nature Genetics
may find the full-text of the article online at www.nature.com/ng/
-- in the Advance Online Publication section, entitled
"The Type 1 Neurofibromatosis (Nf1) Gene Product
Has an Essential Role in Endothelial Cells"
Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise.
The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year.
The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.