Pulmonary hypertension is a chronic, progressive disease characterized by high blood pressure in the blood vessels of the lungs or the pulmonary arteries.
The World Health Organization divides pulmonary hypertension into five groups, based on the potential cause of the disease. For example, the hallmark of group 1 pulmonary hypertension, also known as pulmonary arterial hypertension, or PAH, is narrowed pulmonary arteries. This increases resistance to blood flow, making it more difficult for the heart to pump blood.
Mutations of certain genes can cause or increase the likelihood of someone developing PAH. Because the mutations can be passed on to the next generation, this type of disease is known as familial or heritable pulmonary arterial hypertension, or HPAH. Cases of HPAH are rare, representing less than 4 percent of PAH.
Genes involved in HPAH
Scientists link most HPAH cases to mutations of the BMPR2 gene, whose full scientific name is bone morphogenetic protein receptor type 2 gene. BMPR2 protein is an important regulator of proliferation, growth, and survival of the lungs’ blood vessel cells. It receives and transmits signals to surrounding cells, triggering cell division — or production of new cells — and, when necessary, cell death. This maintains a healthy balance of cells in tissue.
Over 350 mutations of the BMPR2 gene can cause HPAH. These tend to either disrupt the production of the BMPR2 protein or reduce its signaling capability.
While the exact connection between BMPR2 and HPAH is unknown, scientists think a disruption in the cell cycle balance can lead to increased cell growth and reduced cell death in the lungs’ small blood vessels. The result is an increase in cell mass that causes blood vessel walls to thicken, narrowing or blocking the vessels. This makes it more difficult for blood to flow and increases pressure in the pulmonary arteries.
Certain gene mutations can increase the risk of HPAH developing alongside other conditions. For example, scientists have found ACVRL1 mutations in people with a condition known as PAH associated with hereditary hemorrhagic telangiectasia, or HHT. This gene codes for a protein involved in blood vessel development.
Some people can have mutations in a number of genes, increasing their risk of developing HPAH.
Inheritance pattern of HPAH
HPAH is inherited in an autosomal dominant pattern. Everyone has two copies of each gene, one inherited from the mother and one from the father. If a condition is inherited in a dominant pattern, it means one mutated copy of a gene is enough for the condition to develop.
A person with HPAH has a 50 percent risk of passing a mutated BMPR2 copy to their children. A mutated copy does not guarantee that PAH will develop — it only increases the risk.
There is about a 20 percent risk that a person with a mutated copy of BMPR2 will develop PAH. The risk is three times higher in women — 42 percent — than in men, where it is 14 percent. This means the disease can skip generations. A person carrying it may not know they have it and can pass it on to the next generation.
The risk of developing PAH increases if a BMPR2 mutation coincides with mutations of other genes. Some health conditions, such as HIV, and use of illegal drugs can also increase the risk.
Genetic testing can identify whether a mutation is the cause of PAH, or if a mutation with a risk runs in the family. Before deciding on the testing, a person should discuss whether to do it with a genetic counselor to understand the implications of finding a PAH-related mutation.
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