Pulmonary hypertension (PH) is a rare, chronic, progressive disease characterized by high blood pressure in the blood vessels of the lungs, known as the pulmonary arteries.
The World Health Organization classifies PH into five groups, based on the disease’s potential cause. For example, the hallmark of group 1, also known as pulmonary arterial hypertension (PAH), is narrowed pulmonary arteries. Such narrowing increases resistance to blood flow, making it more difficult for the heart to pump blood.
Mutations in 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 PAH, or HPAH. This subtype of PAH is rare, representing less than 4% of PAH cases.
Genes involved in HPAH
Scientists link most HPAH cases to mutations in the BMPR2 gene, which encodes a protein called bone morphogenetic protein receptor type 2. BMPR2 protein is an important regulator of the proliferation, growth, and survival of the lungs’ blood vessel cells. It receives and transmits signals to cells, triggering cell division — or production of new cells — and, when necessary, cell death. This maintains a healthy balance of cells in tissue.
More than 350 mutations in the BMPR2 gene can cause HPAH. These tend to either lower the amount of the BMPR2 protein in cells 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, thus narrowing or blocking the vessels. This makes it more difficult for blood to flow and increases pressure in the pulmonary arteries.
Mutations in several other genes have also been associated with HPAH, although they are less common. Some that appear in families are in the genes BMPR1B, CAV1, KCNK3, SMAD9, and TBX4.
Certain gene mutations can increase a person’s 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. This gene codes for a protein involved in blood vessel development.
Altogether, scientists have identified the genes involved in around 75% of HPAH cases.
Some people have multiple mutations in genes associated with HPAH, which seems to lead to a more severe disease course. A key gene in such cases is BMPR2.
Inheritance pattern of HPAH
HPAH is inherited in an autosomal dominant pattern. Everyone has two copies of most genes, one inherited from each biological parent. If a disease 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% risk of passing a mutated BMPR2 copy to his or her children. However, a mutated copy does not guarantee that PAH will develop — it only increases the risk. That suggests that other factors, genetic or environmental, modify this risk.
People who inherit a mutated copy of BMPR2 have a 20% risk of developing PAH. The risk is three times higher for women — 42% — than for men (14%). This means the disease can skip generations. A person may not be aware that he or she has a mutated gene and can pass it on to the next generation.
Genetic testing can identify whether a person has a PAH-linked mutation, or if one such mutation runs in the family. Before deciding on the testing, a person should consult with a genetic counselor to discuss whether to have it done. This also can help individuals understand the implications of finding a PAH-related mutation.
Last updated: June 24, 2021
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