What Have We Learned About PAH from Genetics?

from Winter 2010 Pathlight

Ten years ago we knew very little about the underlying causes of pulmonary arterial hypertension (PAH). We knew that certain conditions were associated with PAH, such as congenital heart disease or connective tissue disease, but in the absence of these associated conditions, the cause of idiopathic PAH remained a mystery.

It had been known for many years that severe PAH could occur in families. The NIH registry in the 1980s established that approximately 10 percent of patients with PAH have at least one other affected family member. Study of family pedigrees of patients with PAH established that males and females could both be affected and that the disease could skip generations.

This latter finding was very important. It means that a family member can carry the disease gene without actually developing PAH and the disease could then manifest in their children or grandchildren. If a parent carries the disease gene then the chances of passing the gene on to each child would be 50:50. Because the disease gene does not inevitably cause PAH, the risk of a child developing PAH if he or she inherits the disease gene is usually less than 50 percent. And if a child inherits a normal copy of the gene their risk of developing PAH is the same as the rest of the population, in other words, about a million to one.

So what is this disease gene?

In 2000, two groups of researchers independently identified mutations in a particular gene in families with PAH. A mutation is a mistake in the DNA genetic code. Since the genetic code is used to make a whole range of proteins in the body, if a mutation occurs, the protein may not work properly. In familial PAH, mutations were identified in the gene responsible for making a protein called the bone morphogenetic protein type 2 receptor, or BMPR2 for short.

At least 70 percent of families with PAH have these mutations. This important receptor is usually found on the surface of cells, which make up the tissues and organs of the body. Like other receptors it transmits signals from the outside to the inside of cells to instruct them to divide or die, or change from one type of cell to another. As its name suggests, BMPR2 belongs to a family of receptors that were originally identified as playing a role in the formation of bone and cartilage. However, we now know that BMPR2 and related receptors have a much wider role in embryonic development and formation of many organs, including the heart and lungs. The sort of mutations found in BMPR2 in families with PAH lead to reduced function of the protein.

Without the power of genetic studies such as these it would have taken years and years, or a lucky accident, to discover that BMPR2 was involved in PAH. Here, suddenly, we were presented with the most important part of the puzzle to understanding the underlying cause of familial PAH. Indeed, having identified mutations in BMPR2 in the rare familial form of PAH, studies have now shown that abnormal BMPR2 function is also a feature of other forms of PAH, for example in idiopathic PAH.

What can we still hope to learn from genetics?

It is now nearly 10 years since the discovery of mutations in the BMPR2 gene in familial PAH. We have made much progress in understanding what happens when the BMPR2 gene is mutated. There are still many questions to answer. For example, why does a mutation in such an important gene cause a disease confined to the blood vessels of the lung? And what additional triggers are required to cause PAH in an individual carrying the mutant BMPR2? Ultimately, knowing the answers to these questions may allow us to prevent or treat the disease.

Should I consider being tested?

When should patients or relatives consider being tested for the BMPR2 mutation? In general if you have a family history of PAH, that is if there are at least two members of your family with PAH, it is highly likely that a BMPR2 mutation is the cause. At present we do not have any specific way of preventing the disease in someone carrying the disease gene so knowing you have the mutation will not alter the chances of developing it. At the same time, if you don’t have PAH and you are found not to have a mutation, this may be reassuring. If you are found to have a BMPR2 mutation, this may have consequences for life insurance and, of course, for your children. Whether or not to get tested and what to do with this information is a complex area that varies with individual circumstances. Your pulmonary hypertension physician may be able to give further advice on this and would likely recommend speaking with a clinical geneticist to discuss the implications of genetic testing.

By Nick Morrell, MD
Professor of Cardiopulmonary Medicine
University of Cambridge, United Kingdom