Doctors and researchers at Vanderbilt University Medical Center have identified a gene that causes Primary Pulmonary Hypertension (PPH), high blood pressure in the lungs. Without treatment, the disease is considered fatal.
VUMC researchers have determined that the gene involved is Bone Morphogenic Protein Receptor Two (BMPR2). When mutated, the gene causes cells to grow and clog the inside of blood vessels in the lungs, similar to clogged arteries in the heart.
"It's in the Transforming Growth Factor Beta (TGFb) family, which is a large family of different proteins that regulate cell growth and proliferation," said Dr. James E. Loyd, professor of medicine and one of the researchers.
"TGFb is a growth suppressor gene so this gene, BMPR2, normally prevents the cells from growing. When it mutates or is defective, the suppressor is stopped and it allows the cells to grow unregulated and they ultimately block the blood vessels.
"This is the first report of the gene and what it does. Now, for the first time, we know that there is a specific genetic defect of a particular receptor that is highly associated with the disease and must be the root cause of PPH."
Their research is reported in the September issue of Nature Genetics. Loyd was joined in this research by molecular biologist Kirk B. Lane, Ph.D., assistant professor in Medicine, the first to select BMPR2 as a candidate gene after reviewing the hundreds of genes which were known to reside in the region of chromosome 2q linked to PPH. Lane recognized that BMPR2 is a member of the TGFb family.
The first mutation of BMPR2 was demonstrated by DNA fingerprinting in the labs of Dr. John A. Phillips III, David T. Karzon Chair in Pediatrics. Other workers who participated in the PPH studies in Lane's labs were Dr. Radhika Gaddipati and upcoming medical student Emily Loyd, in addition to Melissa Prince in Phillips' lab. Also involved in the research were Dr. John H. Newman, Elsa S. Hanigan Chair in Pulmonary Medicine; and Lisa Wheeler, director of the PPH registry.
The VUMC research was part of an international research consortium of four medical centers, including researchers in England. Loyd says the PPH develops in microscopic blood vessels, literally the size of a hair.
"They are so small that it seems like they couldn't be important," Loyd said. "But when enough of them become blocked off, blood is not able to flow through the lungs normally and the right ventricle tries to pump harder to pump blood through obstructed vessels. That is what causes the higher pressure. Once enough blood vessels are blocked off, blood flow is inadequate. Most of the symptoms of this disease are related to poor blood flow. Either the patient passes out because the brain doesn't get enough blood flow during exercise or it causes shortness of breath."
Seven mutations have been identified so far, co-author Lane said. All the mutations have the same impact, but researchers still have questions about the gene.
"This is a very large gene that has 13 different coding regions and there are mutations that are spaced across the gene," Lane said. "The mutations we see somehow constantly inactivate this receptor and stop it from transmitting information to the cell. All these mutations disrupt this receptor. It is possible that that disallows or in some way causes a dysfunctional complex to form. It still forms, but it doesn't transmit a signal because it has one bad copy. Or it could be that all of these mutations may just completely inactivate the cell.
"We have shown the mutations are in people that we know have this disease. We have looked at the DNA from their parents and shown that they also have the same mutation. We can follow the bloodline back. People who are unaffected in their families don't show this change."
PPH is high blood pressure in the lungs. The disease can happen at any age in either gender, although it does affect twice as many women as men. One in 100,000 to one in a million people are affected by PPH. It is considered a fatal disease without treatment or a transplant.
In 1987, PPH caused enough damage to the lungs of patient Jean Lefkowitz that she became VUMC's first heart-lung transplant recipient. There was no other effective therapy at the time.
Now therapy is available in the form of continuous intravenous medication, Loyd said, but it is a very complicated process, is very expensive and has substantial risk.
PPH has been associated with appetite suppressants both in the United States in the mid-1990s with the use of fenluramine/dexfenfluramine and in Europe in the 1970s with the use of Aminorex/menocil. Identification of the BMPR2 gene should also provide the tools to investigate and better understand the mechanisms that cause pulmonary hypertension in other conditions, including sporadic PPH or PPH occurring in association with appetite suppressant use, Loyd said.
In 1997, in Nature Genetics, Loyd and the research group reported the first identification that a gene caused PPH in families. "It's especially exciting to us because a lot of work about TGFb has been previously done at VUMC. Dr. Harold L. Moses (director of Vanderbilt-Ingram Cancer Center and Benjamin F. Byrd Professor of Oncology) was one of the original discoverers of TGFb.
"Hopefully we will eventually be able to get to the point where we understand how the gene works and what it does and not only whether you are at risk or not, but also at what age you might be at risk."
This research is the culmination of 20 years of study for Loyd.
"I would say this is the single most important discovery in my career. It feels very good," he said.
"We began working on this when I was a Fellow here in 1980. There was a 30-year-old patient who died here. Her cousin, a nurse here also died with PPH and there were six family members who had PPH and died. The patient's mother had two brothers, both of whom had three daughters, and they wanted to know if their daughters could get PPH. That is the reason we began working on it. We were able to follow 14 families and worked on this data and data from additional families since then.
"We have been working on it a very long time and it's very good to know exactly what causes PPH. Our hope is that it will lead us to other findings so we can change the outcome and the treatments for those in the future."
Journal
Nature Genetics