Gene Explains Heart Abnormalities Associated with Neurofibromatosis

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 development.

“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.”