Researchers Identify Rare Mutations That Could Lead to Pulmonary Hypertension

British researchers have identified rare mutations of four genes that could lead to pulmonary arterial hypertension.

The team said scientists might be able to develop PAH treatments around the mutations of the genes GDF2, ATP13A3, AQP1, and SOX17.

Their study, “Identification of rare sequence variation underlying heritable pulmonary arterial hypertension,” was published in the journal Nature Communications.

Pulmonary arterial hypertension is caused by the narrowing of blood vessels in the lungs, which prevents normal blood flow. Scientists have identified several mutations that contribute to PAH. Mutations in a gene called BMPR2 account for more than 80 percent of inherited PAH cases and 20 percent of non-inherited ones.

Scientists have also discovered that some PAH patients have mutations of genes that function alongside BMPR2 — such as ACVRL1 — in the BMP signaling pathway.

Researchers wondered if they could find rare mutations that underlie the disease.

Their search involved using whole-genome sequencing on 1,038 PAH patients and 6,385 controls.

They found a significantly higher rate of mutations in three genes — ATP13A3, AQP1 and SOX17 — in PAH patients than in controls.

The gene ATP13A3 generates ATP13A3 protein in lung endothelial cells. A reduction in the protein’s levels leads to an increase in the cells’ death — a known trigger of PAH.

Researchers also discovered a link between mutations in the gene GDF2 and PAH. GDF2 is part of the BMP signaling pathway. This suggested that a deficiency in GDF2, BMPR2, or ACVRL1 signaling plays a key role in the mechanisms that lead to PAH.

Previous studies identified mutations that account for about 20 percent of PAH cases. Adding the mutations discovered in the recent study means that scientists can now account for about 23 1/2 percent of cases.

“This research takes us several steps closer to improved diagnosis and treatment as well as providing a comprehensive data set for future researchers.” Laura Southgate, PhD, a genetics lecturer at St George’s University of London who was a co-author of the study, said in a press release.