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Discovery links BMPR2 gene to primary pulmonary hypertension
By Julie Buckles

Two groups of scientists have simultaneously identified genetic mutations associated with primary pulmonary hypertension, or PPH, a rare but devastating lung disease. The two groups—one an international collaboration and one from Columbia University—discovered mutations in the BMPR2 gene, revealing the first known cause of PPH.

Chest radiograph showing cardiac silhouette due to PPH.

Known for its role in bone development, BMPR2 was not an obvious candidate for a lung-related condition, says William Nichols, of the Division of Human Genetics at Children's Hospital Medical Center in Cincinnati and a member of The International PPH Consortium. "This is the first evidence that a mutation in this gene is related to lung development and disease," says Nichols.

The researchers believe the BMPR2 mutations somehow prevent pulmonary cells from responding to injury, resulting in a proliferation of lesions. The lesions begin to block the lung's blood vessels, forcing the right side of the heart to pump harder. This raises blood pressure in the pulmonary artery—causing faintness, fatigue, and eventually heart failure or sudden death.

The international group began their search for the mutated gene responsible for the familial form of PPH, which accounts for six percent of cases, five years ago. Studying six large families drawn from the PPH Patient Registry, they mapped the gene to chromosome 2. By 1999 the two groups, analyzing the DNA from families worldwide, narrowed the search further. "We then started looking at specific genes and what they do," says James Knowles, of the College of Physicians and Surgeons at Columbia University in New York.

The International Consortium sequenced three genes, and the Columbia group sequenced two, before pinpointing mutations in the BMPR2 gene. "This discovery is very important for the people who have PPH," says Knowles. "It could lead to robust diagnosis at the molecular level to determine who is, and who isn't, a carrier. So people could, if they choose, learn if they are a carrier." Once they know, says Knowles, steps can be taken to reduce the likelihood of triggering the disease. Only 30 to 40 percent of people who carry the defective gene actually develop the disease.

Photomicrograph of lung biopsy from an individual with PPH.

Although both studies suggest that only one gene is involved in PPH, neither group identified the defects in BMPR2 as the sole cause. Scientists do not yet understand why some people with the mutations get the disease and others don't; why women get it twice as much as men; and why it doesn't exhibit itself until an average age of 36. But they have a few theories. For one, certain arterial vascular injuries could trigger PPH, Knowles says. There also appears to be a connection between the onset of PPH and environmental factors such as oral contraceptives and appetite suppressants.

In addition, the majority of people who get the disease do not have a known family history of PPH. Referred to as "sporadics," they account for most cases of PPH. There is no difference in the symptoms or outcome between these two types. Researchers are now looking at whether patients with sporadic PPH are truly sporadics and if so, whether they have the same mutations, Nichols says. "We have evidence that a significant percentage of sporadics carry BMPR2 mutations, which can be passed to their children. Most of those that carry mutations actually inherited it from a parent, which means that their siblings are also at risk for inheriting the defect and developing the disease."

Primary pulmonary hypertension occurs most commonly in women in their childbearing years. An estimated one to two persons per million are diagnosed with PPH each year—about 300 cases in the United States. It is tough to diagnose and nearly impossible to cure. The most common treatments include lung transplantation and drug therapy. With or without treatment, life expectancy is limited.

The reports are now available online and will appear in the September issue of Nature Genetics and The American Journal of Human Genetics.

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The International PPH Consortium et al. Heterozygous germline mutations in BMPR2, encoding a TGF-b receptor, cause familial primary pulmonary hypertension. Nat Gen 26 (September 2000).
Deng, Z. et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 67 (September 2000).

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